%0 Conference Proceedings %B ACC %D 1992 %T Respondent Burden in Studies of the Elderly: Experience from the Cardiovascular Health Study (CHS) %A Manolio, TA %A Hermanson, B %A Hill, J %A Meyer, M %A Cruise, G %A Anton-Culver, H %K Health %K respondent burden %X ACC Workshop entitled "Inclusion of Elderly Individuals in Clinical Trials" September 15-16, 1992 %B ACC %I Marion Merrell Dow Inc %P 135-152 %8 1993-01-01 %G eng %0 Journal Article %J J Am Geriatr Soc %D 1993 %T Serum fructosamine as a screening test for diabetes in the elderly: a pilot study. %A Cefalu, W T %A Ettinger, W H %A Bell-Farrow, A D %A Rushing, J T %K Aged %K Diabetes Mellitus %K Female %K Fructosamine %K Glucose Tolerance Test %K Hexosamines %K Humans %K Insulin %K Male %K Pilot Projects %K Predictive Value of Tests %K Sensitivity and Specificity %X

OBJECTIVE: To determine the value of serum glycated protein, measured as serum fructosamine, as a screening test for diabetes in the elderly.

DESIGN: Cross-sectional pilot study.

SETTING: Ambulatory research clinic in university setting.

PATIENTS: One hundred fifty-seven consecutive community-dwelling participants in the Cardiovascular Health Study, average age 71.8 + 5 (mean +/- SD, range 65-88 years).

MEASUREMENTS: Serum fructosamine levels (first and second generation assay) were obtained. All subjects who did not have a diagnosis of diabetes were given a 75-g glucose tolerance test (GTT).

RESULTS: Twenty-six subjects (17%) (10 previously diagnosed, 16 undiagnosed and asymptomatic) had diabetes mellitus, and 38 subjects (24%) had impaired glucose tolerance by history or by the GTT (WHO criteria). Only the 16 asymptomatic diabetics were included in the analysis for the pilot study. There was a significant difference in the fasting fructosamine level between non-diabetics and asymptomatic diabetics for the first generation (2.06 +/- .21 vs 2.53 +/- .49 mMol/L, P < 0.0015) and second generation assay (221 +/- 27 vs 269 +/- 48 mMol/L, P < 0.0012). Receiver operator curves were constructed to evaluate the test characteristics of serum fructosamine. Using a point of > or = 2.3 mMol/L for the first-generation assay, the sensitivity to detect asymptomatic diabetes was 75%, specificity 83%, and positive predictive value 35%. To detect both diabetes and impaired glucose tolerance using a cutpoint of > or = 2.3 mMol/L, the sensitivity was 24%, specificity 95%, and positive predictive value 68%. Employing a cut point of 250 muMol/L for the second generation assay, the sensitivity to detect diabetes was 81%, specificity 87%, and positive predictive value 43%. However, to detect diabetes and glucose intolerance using the second generation assay, the sensitivity was 39% and specificity was 86%.

CONCLUSION: This study demonstrated that a single measurement of either first or second generation fructosamine showed promise as a screening test for diabetes, but not impaired glucose tolerance, in older people.

%B J Am Geriatr Soc %V 41 %P 1090-4 %8 1993 Oct %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/8409155?dopt=Abstract %0 Journal Article %J Clin Chem %D 1995 %T Laboratory methods and quality assurance in the Cardiovascular Health Study. %A Cushman, M %A Cornell, E S %A Howard, P R %A Bovill, E G %A Tracy, R P %K Aged %K Blood Glucose %K Blood Specimen Collection %K Cardiovascular Diseases %K Chemistry, Clinical %K Factor VII %K Factor VIII %K Fibrinogen %K Humans %K Insulin %K Quality Control %K Regression Analysis %K Triglycerides %X

The Cardiovascular Health Study is an observational cohort study of risk factors for cardiovascular disease in 5201 participants, ages > or = 65 years. We report the methods and quality-assurance results for blood procurement, processing, shipping, storage, and sample analysis used during the first examination period (May 1989-June 1990). The most frequent difficulty in phlebotomy and processing was the requirement of more than one venipuncture (in 2.6% of the participants). The CVs for control materials ranged from 0.93% for glucose to 10.7% for insulin; most were < 4%. In addition to standard quality-assurance methods, we applied two other methods: technical error calculation for replicates, and weighted linear regression to assess time trend in results of control materials. After outliers were excluded, technical error values ranged from 1.7 for uric acid to 18.8 for insulin. Factor VII and factor VIII had slight trends over the 12-month analysis period. Results of quality-assurance analyses used to resolve problems were successful, thereby improving the second laboratory examination.

%B Clin Chem %V 41 %P 264-70 %8 1995 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/7874780?dopt=Abstract %0 Journal Article %J Ann Epidemiol %D 1995 %T Surveillance and ascertainment of cardiovascular events. The Cardiovascular Health Study. %A Ives, D G %A Fitzpatrick, A L %A Bild, D E %A Psaty, B M %A Kuller, L H %A Crowley, P M %A Cruise, R G %A Theroux, S %K Aged %K Cerebrovascular Disorders %K Coronary Disease %K Epidemiologic Methods %K Female %K Hospitalization %K Humans %K Incidence %K Longitudinal Studies %K Male %K Population Surveillance %K Quality Control %K United States %X

While previous prospective multicenter studies have conducted cardiovascular disease surveillance, few have detailed the techniques relating to the ascertainment of and data collection for events. The Cardiovascular Health Study (CHS) is a population-based study of coronary heart disease and stroke in older adults. This article summarizes the CHS events protocol and describes the methods of surveillance and ascertainment of hospitalized and nonhospitalized events, the use of medical records and other support documents, organizational issues at the field center level, and the classification of events through an adjudication process. We present data on incidence and mortality, the classification of adjudicated events, and the agreement between classification by the Events Subcommittee and the medical records diagnostic codes. The CHS techniques are a successful model for complete ascertainment, investigation, and documentation of events in an older cohort.

%B Ann Epidemiol %V 5 %P 278-85 %8 1995 Jul %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/8520709?dopt=Abstract %0 Journal Article %J Am J Epidemiol %D 1996 %T Association of fibrinogen and coagulation factors VII and VIII with cardiovascular risk factors in the elderly: the Cardiovascular Health Study. Cardiovascular Health Study Investigators. %A Cushman, M %A Yanez, D %A Psaty, B M %A Fried, L P %A Heiss, G %A Lee, M %A Polak, J F %A Savage, P J %A Tracy, R P %K Age Distribution %K Aged %K Aged, 80 and over %K Analysis of Variance %K Cardiovascular Diseases %K Cohort Studies %K Factor VII %K Factor VIII %K Female %K Fibrinogen %K Humans %K Linear Models %K Logistic Models %K Male %K Prevalence %K Risk Factors %K Sex Distribution %K United States %X

The cross-sectional correlates of three hemostatic factors--fibrinogen, factor VII, and factor VIII--were examined in the Cardiovascular Health Study, a population-based cohort study of 5,201 subjects over age 65 years. Subjects were recruited in 1989-1990 in Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Pittsburgh, Pennsylvania. In multivariate linear regression models, cardiac risk factors significantly associated with fibrinogen were current smoking, race, lipids, and white blood count. In women, alcohol use, obesity, physical activity, and insulin level were also significant, while in men hypertension was correlated. The significant correlates of factor VII were lipids and white blood count in men and estrogen use, alcohol use, race, lipids, insulin level, white blood count, and obesity in women. The independent correlates of factor VIII were insulin, glucose, and race in both sexes; low density lipoprotein cholesterol, white blood count, and diuretic use in men; and alcohol use in women. In multivariate models, factors known to be modifiable risk factors for cardiovascular disease accounted for more of the population variance of these hemostatic factors in women than in men, especially for factor VII. The hemostatic factors may mediate some effects of risk factors on disease, and this should be considered in longitudinal studies.

%B Am J Epidemiol %V 143 %P 665-76 %8 1996 Apr 01 %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/8651228?dopt=Abstract %0 Journal Article %J Arterioscler Thromb Vasc Biol %D 1996 %T Correlates of thrombin markers in an elderly cohort free of clinical cardiovascular disease. %A Cushman, M %A Psaty, B M %A Macy, E %A Bovill, E G %A Cornell, E S %A Kuller, L H %A Tracy, R P %K Aged %K Biomarkers %K Cardiovascular Diseases %K Cohort Studies %K Female %K Hemostasis %K Humans %K Male %K Risk Factors %K Thrombin %X

Studies suggest that thrombosis is important in the progression of atherosclerotic lesions. The biochemical markers prothrombin fragment 1-2 and fibrinopeptide A reflect in vivo thrombin generation and activity, respectively. As such, they are markers that might be associated with cardiovascular risk. From the Cardiovascular Health Study, a cohort study of 5201 persons over 65 years of age, 399 persons free of clinical cardiovascular disease (CVD) at the baseline examination were selected for study of specialized markers of hemostasis. We report the cross-sectional relationships of the thrombin markers to CVD risk factors and measures of subclinical CVD. The range of fragment 1-2 2 was 0.12 to 0.85 nmol/L. The range of fibrinopeptide A was 0.9 to 44.1 micrograms/L. High levels of fragment 1-2 and fibrinopeptide A were associated with age, with levels higher in women than men. Fragment 1-2 was associated with smoking; high levels of triglyceride, creatinine, and C-reactive protein; and low levels of glucose. Fibrinopeptide A was associated with high C-reactive protein and apolipoprotein(a) and lower ankle-brachial index. There were no significant associations of the thrombin markers with race, fibrinogen, alcohol consumption, diabetes, or most measures of subclinical CVD. Study findings support a hypothesis that there are physiological interrelationships between cardiac risk factors, hemostasis, inflammation, and progression of atherosclerosis.

%B Arterioscler Thromb Vasc Biol %V 16 %P 1163-9 %8 1996 Sep %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/8792770?dopt=Abstract %0 Journal Article %J J Am Diet Assoc %D 1996 %T Picture-sort method for administering a food frequency questionnaire to older adults. %A Kumanyika, S %A Tell, G S %A Fried, L %A Martel, J K %A Chinchilli, V M %K Aged %K Aged, 80 and over %K Audiovisual Aids %K Data Interpretation, Statistical %K Diet Records %K Eating %K Female %K Humans %K Interviews as Topic %K Male %K Mental Recall %K Surveys and Questionnaires %X

OBJECTIVE: To assess the validity of a picture-sort approach to administering the National Cancer Institute food frequency questionnaire to older adults.

DESIGN: A picture-sort interview was conducted in each respondent's home. After the picture sort, a 24-hour recall interview was administered on the same occasion. Five additional in-home recall interviews were subsequently conducted at approximately 1-month intervals.

SUBJECTS/SETTING: Forty-seven female and 49 male volunteers aged 66 to 100 years were recruited from among Cardiovascular Health Study participants from Maryland and North Carolina.

MAIN OUTCOME MEASURES: Estimates from the picture sort and the recall for intakes of macronutrients, cholesterol, fiber, and selected vitamins and minerals exclusive of supplements.

STATISTICAL ANALYSES: Comparison of means estimated by the two methods and correlation analyses were used. Correlations were adjusted under varied assumptions about the nature of the information contained in the six 24-hour recalls relative to respondents' usual intakes.

RESULTS: After correction for attenuation, Pearson correlation coefficients for macronutrients ranged from .41 for protein to .74 for saturated fat and cholesterol. For vitamins and minerals, correlations ranged from .26 for beta carotene to .62 for calcium.

APPLICATIONS: Picture-sort estimates of mean nutrient intakes were comparable with estimates based on 24-hour recalls, and correlations with reference data were similar to those reported in the literature for conventionally administered food frequency questionnaires. This dietary assessment method may, therefore, offer a way to simplify or structure responses to improve ease of administration and increase respondents' liking for the interview without loss of data quality.

%B J Am Diet Assoc %V 96 %P 137-44 %8 1996 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/8557939?dopt=Abstract %R 10.1016/S0002-8223(96)00042-9 %0 Journal Article %J Am J Clin Nutr %D 1997 %T Dietary assessment using a picture-sort approach. %A Kumanyika, S K %A Tell, G S %A Shemanski, L %A Martel, J %A Chinchilli, V M %K Aged %K Audiovisual Aids %K Diet %K Female %K Food %K Humans %K Male %K Nutrition Assessment %K Surveys and Questionnaires %X

Food-frequency questionnaires are usually administered as a list of foods to be checked off by the respondent or interviewer. Techniques in which participants sort into categories cards on which names or pictures of foods are printed can also be used to assess food intake. Food-frequency scores were obtained from a five-category picture sort administered to 4643 men and women aged > or = 65 y in the Cardiovascular Health Study (CHS). This one-step (qualitative) assessment yielded significant associations in expected directions between frequency scores and sex, age, race or ethnicity, body mass index, and use of a special diet. In the two-step (semiquantitative) version of this instrument, an interviewer documented specific frequencies and portion-size information for the foods in each sorting category. A substudy of the two-step version with 96 CHS participants indicated relative validity similar to that of conventionally administered food-frequency questionnaires. The one-step version may be broadly applicable to situations in which general food-pattern data can be informative and cost and time limitations are great. When it is feasible, the two-step picture sort may offer certain methodologic advantages because respondents have a chance to change their responses and the format may simplify the cognitive-response task. Sorting or picture-sort procedures deserve systematic attention in research on dietary assessment methods.

%B Am J Clin Nutr %V 65 %P 1123S-1129S %8 1997 Apr %G eng %N 4 Suppl %1 http://www.ncbi.nlm.nih.gov/pubmed/9094908?dopt=Abstract %0 Journal Article %J Circulation %D 1997 %T Incidence of and risk factors for atrial fibrillation in older adults. %A Psaty, B M %A Manolio, T A %A Kuller, L H %A Kronmal, R A %A Cushman, M %A Fried, L P %A White, R %A Furberg, C D %A Rautaharju, P M %K Adult %K Aged %K Atrial Fibrillation %K Blood Glucose %K Blood Pressure %K Cerebrovascular Disorders %K Cohort Studies %K Coronary Disease %K Electrocardiography %K Female %K Follow-Up Studies %K Hospital Records %K Humans %K Incidence %K Male %K Prospective Studies %K Risk Factors %K United States %X

BACKGROUND: This study aimed to describe the incidence of atrial fibrillation (AF) among older adults during 3 years of follow-up.

METHODS AND RESULTS: In this cohort study, 5201 adults > or = 65 years old were examined annually on four occasions between June 1989 and May 1993. At baseline, participants answered questionnaires and underwent a detailed examination that included carotid ultrasound, pulmonary function tests, ECG, and echocardiography. Subjects with a pacemaker or AF at baseline (n=357) were excluded. New cases of AF were identified from three sources: (1) annual self-reports, (2) annual ECGs, and (3) hospital discharge diagnoses. Cox proportional-hazards models were used to assess baseline risk factors as predictors of incident AF. Among 4844 participants, 304 developed a first episode of AF during an average follow-up of 3.28 years, for an incidence of 19.2 per 1000 person-years. The onset was strongly associated with age, male sex, and the presence of clinical cardiovascular disease. For men 65 to 74 and 75 to 84 years old, the incidences were 17.6 and 42.7, respectively, and for women, 10.1 and 21.6 events per 1000 person-years. In stepwise models, the use of diuretics, a history of valvular heart disease, coronary disease, advancing age, higher levels of systolic blood pressure, height, glucose, and left atrial size were all associated with an increased risk of AF. The use of beta-blockers and high levels of alcohol use, cholesterol, and forced expiratory volume in 1 second were associated with a reduced risk of AF.

CONCLUSIONS: The incidence of AF in older adults may be higher than estimated by previous population studies. Left atrial size appears to be an important risk factor, and the control of blood pressure and glucose may be important in preventing the development of AF.

%B Circulation %V 96 %P 2455-61 %8 1997 Oct 07 %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/9337224?dopt=Abstract %0 Journal Article %J Stroke %D 1997 %T Knowledge of risk among patients at increased risk for stroke. %A Samsa, G P %A Cohen, S J %A Goldstein, L B %A Bonito, A J %A Duncan, P W %A Enarson, C %A DeFriese, G H %A Horner, R D %A Matchar, D B %K Adult %K Aged %K Aged, 80 and over %K Awareness %K Cerebrovascular Disorders %K Female %K Humans %K Knowledge %K Male %K Middle Aged %K Multivariate Analysis %K Risk Factors %X

BACKGROUND AND PURPOSE: Patients who recognize their increased risk for stroke are more likely to engage in (and comply with) stroke prevention practices than those who do not. We describe perceived risk of stroke among a nationally diverse sample of patients at increased risk for stroke and determine whether patients' knowledge of their stroke risk varied according to patients' demographic and clinical characteristics.

METHODS: Respondents were recruited from the Academic Medical Center Consortium (n = 621, five academic medical centers, inpatients of varying age); the Cardiovascular Health Study (n = 321, population-based sample of persons aged 65+ years); and United HealthCare (n = 319, five health plans, inpatients and outpatients typically younger than 65 years). The primary outcome was awareness of being at risk for stroke.

RESULTS: Only 41% of respondents were aware of their increased risk for stroke (including less than one half of patients with previous minor stroke). Approximately 74% of patients who recalled being told of their increased stroke risk by a physician acknowledged this risk in comparison with 28% of patients who did not recall being informed by a physician. Younger patients, depressed patients, those in poor current health, and those with a history of TIA were most likely to be aware of their stroke risk.

CONCLUSIONS: Over one half of patients at increased risk of stroke are unaware of their risk. Healthcare providers play a crucial role in communicating information about risk, and successful communication encourages adoption of stroke prevention practices. Educational messages should be targeted toward patients least likely to be aware of their risk.

%B Stroke %V 28 %P 916-21 %8 1997 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/9158625?dopt=Abstract %0 Journal Article %J Arterioscler Thromb Vasc Biol %D 1997 %T Lifetime smoking exposure affects the association of C-reactive protein with cardiovascular disease risk factors and subclinical disease in healthy elderly subjects. %A Tracy, R P %A Psaty, B M %A Macy, E %A Bovill, E G %A Cushman, M %A Cornell, E S %A Kuller, L H %K Aged %K Body Mass Index %K C-Reactive Protein %K Cardiovascular Diseases %K Female %K Humans %K Male %K Multivariate Analysis %K Risk Factors %K Smoking %X

Blood levels of C-reactive protein (CRP), a marker of inflammation, are related to cardiovascular disease risk. To determine cross-sectional correlates in the elderly, we measured CRP in 400 men and women older than 65 years and free of clinical cardiovascular disease at baseline as part of the Cardiovascular Health Study. Only 2% of the values were greater than 10 mg/L, the cut-point usually used to identify inflammation. CRP levels appeared tightly regulated, since there were strong bivariate correlations between CRP and the following: inflammation-sensitive proteins such as fibrinogen (r = .52); measures of fibrinolysis such as plasmin-antiplasmin complex (r = .23); pack-years of smoking (r = .30); and body mass index (r = .24; all P values < or = .001). The association with pack-years was independent of the length of time since cessation of smoking. CRP levels were also associated with coagulation factors VIIc, IXc, and Xc; HDL cholesterol (negative) and triglyceride; diabetes status; diuretic use; ECG abnormalities; and level of exercise. Because of effect modification, two multiple linear regression prediction models were developed for CRP, one each for never smokers and ever smokers. An a priori physiologic model was used to guide these analyses, which disallowed the use of other inflammation-sensitive variables such as fibrinogen. In never smokers, the independent predictors were body mass index (+), diabetes status (+), plasmin-antiplasmin complex (+), and the presence of ECG abnormalities (+); this model predicted 15% of the CRP population variance. In ever smokers, the predictors were body mass index (+), plasmin-antiplasmin complex (+), pack-years of smoking (+), HDL cholesterol (-), and ankle-arm blood pressure index (-); this model predicted 42% of the population variance. We conclude that levels of CRP in the healthy elderly are tightly regulated and reflect lifetime exposure to smoking as well as level of obesity, ongoing level of fibrinolysis, diabetes status, and level of subclinical atherothrombotic disease. Moreover, exposure to smoking affects the relation of CRP to these other factors.

%B Arterioscler Thromb Vasc Biol %V 17 %P 2167-76 %8 1997 Oct %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/9351386?dopt=Abstract %0 Journal Article %J Arterioscler Thromb Vasc Biol %D 1997 %T Relationship of C-reactive protein to risk of cardiovascular disease in the elderly. Results from the Cardiovascular Health Study and the Rural Health Promotion Project. %A Tracy, R P %A Lemaitre, R N %A Psaty, B M %A Ives, D G %A Evans, R W %A Cushman, M %A Meilahn, E N %A Kuller, L H %K Aged %K Aging %K C-Reactive Protein %K Cardiovascular Diseases %K Case-Control Studies %K Female %K Humans %K Male %K Prospective Studies %K Sex Factors %X

Markers of inflammation, such as C-reactive protein (CRP), are related to risk of cardiovascular disease (CVD) events in those with angina, but little is known about individuals without prevalent clinical CVD. We performed a prospective, nested case-control study in the Cardiovascular Health Study (CHS; 5201 healthy elderly men and women). Case subjects (n = 146 men and women with incident CVD events including angina, myocardial infarction, and death) and control subjects (n = 146) were matched on the basis of sex and the presence or absence of significant subclinical CVD at baseline (average follow-up, 2.4 years). In women but not men, the mean CRP level was higher for case subjects than for control subjects (P < or = .05). In general, CRP was higher in those with subclinical disease. Most of the association of CRP with female case subjects versus control subjects was in the subgroup with subclinical disease; 3.33 versus 1.90 mg/L, P < .05, adjusted for age and time of follow-up. Case-control differences were greatest when the time between baseline and the CVD event was shortest. The strongest associations were with myocardial infarction, and there was an overall odds ratio for incident myocardial infarction for men and women with subclinical disease (upper quartile versus lower three quartiles) of 2.67 (confidence interval [CI] = 1.04 to 6.81), with the relationship being stronger in women (4.50 [CI = 0.97 to 20.8]) than in men (1.75 [CI = 0.51 to 5.98]). We performed a similar study in the Rural Health Promotion Project, in which mean values of CRP were higher for female case subjects than for female control subjects, but no differences were apparent for men. Comparing the upper quintile with the lower four, the odds ratio for CVD case subjects was 2.7 (CI = 1.10 to 6.60). In conclusion, CRP was associated with incident events in the elderly, especially in those with subclinical disease at baseline.

%B Arterioscler Thromb Vasc Biol %V 17 %P 1121-7 %8 1997 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/9194763?dopt=Abstract %0 Journal Article %J Thromb Haemost %D 1998 %T Correlates of antithrombin, protein C, protein S, and TFPI in a healthy elderly cohort. %A Sakkinen, P A %A Cushman, M %A Psaty, B M %A Kuller, L H %A Bajaj, S P %A Sabharwal, A K %A Boineau, R %A Macy, E %A Tracy, R P %K Aged %K Aged, 80 and over %K Analysis of Variance %K Anticoagulants %K Antithrombin III %K Biomarkers %K Cross-Sectional Studies %K Disease Susceptibility %K Female %K Humans %K Lipoproteins %K Male %K Prevalence %K Protein C %K Protein S %K Reference Values %K Risk Factors %K Thrombosis %X

The majority of fatal acute myocardial infarctions occur in the elderly. Since these events are predominantly thrombotic, we studied the cross-sectional associations of the anticoagulant proteins Antithrombin, Protein C, Protein S. and Tissue Factor Pathway Inhibitor (TFPI) in a subgroup (n = 400) of the Cardiovascular Health Study (a study of healthy men and women > or = 65 years) free of clinical cardiovascular disease (CVD). We did not observe any strong age-associated trends, although Protein C was lower in older women (p < or = 0.001), and TFPI was higher in older men (p < or = 0.01). The inhibitors were highly intercorrelated, and were associated with increased levels of inflammation-sensitive proteins (e.g., fibrinogen. plasminogen), lipids (especially total and LDL-cholesterol), and coagulation factors, such as Factors VIIc, IXc, and Xc. None was associated with the procoagulant markers Prothrombin Fragment F1-2 or Fibrinopeptide A. Only TFPI was associated with subclinical atherosclerosis: ankle-arm index and internal carotid artery stenosis, p trend < or = 0.01; and carotid wall thickness, p trend < or = 0.05. In multivariate analysis the independent predictors of TFPI were levels of fibrinogen; the fibrinolytic marker plasmin-antiplasmin complex; LDL-cholesterol; and carotid wall thickness (R2 for the model = 0.35). In summary, the inhibitors did not appear to increase with age, and were predominantly associated with inflammation markers and lipids. Since markers of thrombin production do increase with age, we hypothesize that an age-related hemostatic imbalance may ensue, with associated increased thrombotic risk. Only TFPI was associated with subclinical CVD, suggesting that it may more closely reflect endothelial damage.

%B Thromb Haemost %V 80 %P 134-9 %8 1998 Jul %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/9684799?dopt=Abstract %0 Journal Article %J Arterioscler Thromb Vasc Biol %D 1998 %T Differences in prevalence of and risk factors for subclinical vascular disease among black and white participants in the Cardiovascular Health Study. %A Kuller, L %A Fisher, L %A McClelland, R %A Fried, L %A Cushman, M %A Jackson, S %A Manolio, T %K African Americans %K Aged %K Cardiovascular Physiological Phenomena %K Cohort Studies %K European Continental Ancestry Group %K Female %K Health Status %K Humans %K Male %K Multivariate Analysis %K Prevalence %K Regression Analysis %K Risk Factors %K Vascular Diseases %X

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

%B Arterioscler Thromb Vasc Biol %V 18 %P 283-93 %8 1998 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/9484995?dopt=Abstract %0 Journal Article %J Thromb Haemost %D 1998 %T Factor V Leiden is not a risk factor for arterial vascular disease in the elderly: results from the Cardiovascular Health Study. %A Cushman, M %A Rosendaal, F R %A Psaty, B M %A Cook, E F %A Valliere, J %A Kuller, L H %A Tracy, R P %K Adult %K Age Factors %K Aged %K Arteries %K Factor V %K Female %K Humans %K Male %K Middle Aged %K Mutation %K Risk Factors %K Thrombosis %X

Coagulation factor V Leiden is a risk marker for venous thrombosis. For arterial thrombosis no large study to date has included population-based elderly patients. The Cardiovascular Health Study is a longitudinal study of 5,201 men and women over age 65. With 3.4-year follow-up, we studied 373 incident cases of myocardial infarction (MI), angina, stroke. or transient ischemic attack (TIA), and 482 controls. The odds ratios for each event with heterozygous factor V Leiden were: MI, 0.46 (95% CI 0.17 to 1.25); angina, 1.0 (95% CI 0.45 to 2.23); stroke, 0.77 (95% CI 0.35 to 1.70): TIA, 1.33 (95% CI 0.5 to 3.55); any outcome, 0.83 (95% CI 0.48 to 1.44). Adjustment for cardiovascular risk factors did not change relationships. In older adults factor V Leiden is not a risk factor for future arterial thrombosis.

%B Thromb Haemost %V 79 %P 912-5 %8 1998 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/9609219?dopt=Abstract %0 Journal Article %J Am J Clin Nutr %D 1998 %T High body fatness, but not low fat-free mass, predicts disability in older men and women: the Cardiovascular Health Study. %A Visser, M %A Langlois, J %A Guralnik, J M %A Cauley, J A %A Kronmal, R A %A Robbins, J %A Williamson, J D %A Harris, T B %K Adipose Tissue %K Aged %K Aged, 80 and over %K Body Composition %K Cross-Sectional Studies %K Disability Evaluation %K Female %K Geriatric Assessment %K Health Surveys %K Humans %K Male %K Obesity %K Predictive Value of Tests %K Walking %X

Using data from the Cardiovascular Health Study, we studied the relation between body composition (fat mass and fat-free mass, assessed by bioelectrical impedance) and self-reported, mobility-related disability (difficulty walking or stair climbing) in 2714 women and 2095 men aged 65-100 y. In a cross-sectional analysis at baseline (1989-1990), disability was reported by 26.5% of the women and 16.9% of the men. A positive association was observed between fat mass and disability. The odds ratio for disability in the highest quintile of fat mass was 3.04 (95% CI: 2.18, 4.25) for women and 2.77 (95% CI: 1.82, 4.23) for men compared with those in the lowest quintile. Low fat-free mass was not associated with a higher prevalence of disability. In a longitudinal analysis among persons not reporting disability at baseline, 20.3% of the women and 14.8% of the men reported disability 3 y later. Fat mass at baseline was predictive of disability 3 y later, with odds ratios of 2.83 (95% CI: 1.80, 4.46) for women and 1.72 (95% CI: 1.03, 2.85) for men in the highest quintile of fat. The increased risk was not explained by age, physical activity, chronic disease, or other potential confounders. Low fat-free mass was not predictive of disability. The results showed that high body fatness is an independent predictor of mobility-related disability in older men and women. These findings suggest that high body fatness in old age should be avoided to decrease the risk of disability.

%B Am J Clin Nutr %V 68 %P 584-90 %8 1998 Sep %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/9734734?dopt=Abstract %R 10.1093/ajcn/68.3.584 %0 Journal Article %J Arch Neurol %D 1998 %T Sex differences in brain aging: a quantitative magnetic resonance imaging study. %A Coffey, C E %A Lucke, J F %A Saxton, J A %A Ratcliff, G %A Unitas, L J %A Billig, B %A Bryan, R N %K Age Distribution %K Aged %K Aged, 80 and over %K Aging %K Atrophy %K Brain %K Cerebrospinal Fluid %K Diagnosis, Computer-Assisted %K Female %K Health Status %K Humans %K Magnetic Resonance Imaging %K Male %K Regression Analysis %K Sex Characteristics %K Sex Distribution %X

BACKGROUND: Little is known about the effect of sex on age-related changes in brain structure.

METHODS: Quantitative magnetic resonance imaging of the brain was performed in 330 elderly (age range, 66-96 years) volunteers living independently in the community, all of whom were participants in the Cardiovascular Health Study. Blinded measurements of global and regional brain size were made from T1-weighted axial images by means of computer-assisted edge detection and trace methods. High measurement reliabilities were obtained.

RESULTS: Age-specific changes in brain size were significantly greater in men than women for the peripheral (sulcal) cerebrospinal fluid volume, the lateral (sylvian) fissure cerebrospinal fluid volume, and the parieto-occipital region area. Main effects of age were observed for all the remaining brain regions examined (cerebral hemisphere volume, frontal region area, temporoparietal region area, lateral ventricular volume, and third ventricle volume), but these effects were similar in men and women. Asymmetries in brain structures were not affected by aging in either sex.

CONCLUSIONS: Our results are generally consistent with the few published studies on sex differences in brain aging and suggest that, for at least some structures, aging effects may be more apparent in men than women. The neurobiological bases and functional correlates of these sex differences require further investigation.

%B Arch Neurol %V 55 %P 169-79 %8 1998 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/9482358?dopt=Abstract %0 Journal Article %J Am J Epidemiol %D 1999 %T Analytical and biologic variability in measures of hemostasis, fibrinolysis, and inflammation: assessment and implications for epidemiology. %A Sakkinen, P A %A Macy, E M %A Callas, P W %A Cornell, E S %A Hayes, T E %A Kuller, L H %A Tracy, R P %K Adult %K Aged %K Analysis of Variance %K Cardiovascular Diseases %K Cholesterol %K Epidemiology %K Female %K Fibrinolysis %K Hemostasis %K Humans %K Inflammation %K Male %K Middle Aged %K Models, Statistical %K Multivariate Analysis %K Risk Factors %X

An increasing number of cardiovascular epidemiologic studies are measuring non-traditional risk markers of disease, most of which do not have established biovariability characteristics. When biovariability data have been reported, they usually represent a short time period, and, in any case, there is little consensus on how the information should be used. The authors performed a long-term (6-month) repeated measures study on 26 healthy individuals, and, using a nested analysis of variance (ANOVA) approach, report on the analytical (CVA), intraindividual (CVI), and between individual (CVG) variability of 12 procoagulant, fibrinolysis, and inflammation assays, including total cholesterol for comparison. The results suggest acceptable analytical variability (CVA < or = 1/2 CVI) for all assays. However, there was a large range of intraindividual variation as a proportion of total variance (2-78%), and adjusting for intraindividual and between individual variation in bivariate correlations increased the observed correlation by more than 30 percent for three of these assays. Overall, the assays showed a significant increase in intraindividual variation over 6 months (p < 0.05). While these findings suggest that most of these assays have biovariability characteristics similar to cholesterol, there is variation among assays. Some assays may be better suited to epidemiologic studies, and knowledge of an assay's biovariability data may be useful in interpreting simple statistics, and in designing multivariate models.

%B Am J Epidemiol %V 149 %P 261-7 %8 1999 Feb 01 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/9927222?dopt=Abstract %0 Journal Article %J Arterioscler Thromb Vasc Biol %D 1999 %T Ankle-arm index as a predictor of cardiovascular disease and mortality in the Cardiovascular Health Study. The Cardiovascular Health Study Group. %A Newman, A B %A Shemanski, L %A Manolio, T A %A Cushman, M %A Mittelmark, M %A Polak, J F %A Powe, N R %A Siscovick, D %K Age Distribution %K Aged %K Aged, 80 and over %K Ankle %K Arm %K Blood Pressure Determination %K Cardiovascular Diseases %K Cohort Studies %K Female %K Humans %K Hypertension %K Male %K Predictive Value of Tests %K Risk Factors %K Sex Distribution %K Survival Analysis %X

Peripheral arterial disease (PAD) in the legs, measured noninvasively by the ankle-arm index (AAI) is associated with clinically manifest cardiovascular disease (CVD) and its risk factors. To determine risk of total mortality, coronary heart disease, or stroke mortality and incident versus recurrent CVD associated with a low AAI, we examined the relationship of the AAI to subsequent CVD events in 5888 older adults with and without CVD. The AAI was measured in 5888 participants >/=65 years old at the baseline examination of the Cardiovascular Health Study. All participants had a detailed assessment of prevalent CVD and were contacted every 6 months for total mortality and CVD events (including CVD mortality, fatal and nonfatal myocardial infarction, congestive heart failure, angina, stroke, and hospitalized PAD). The crude mortality rate at 6 years was highest (32.3%) in those participants with prevalent CVD and a low AAI (P<0.9), and it was lowest in those with neither of these findings (8.7%, P<0.01). Similar patterns emerged from analysis of recurrent CVD and incident CVD. The risk for incident congestive heart failure (relative risk [RR]=1.61) and for total mortality (RR=1.62) in those without CVD at baseline but with a low AAI remained significantly elevated after adjustment for cardiovascular risk factors. Hospitalized PAD events occurred months to years after the AAI was measured, with an adjusted RR of 5.55 (95% CI, 3.08 to 9.98) in those at risk for incident events. A statistically significant decline in survival was seen at each 0.1 decrement in the AAI. An AAI of <0.9 is an independent risk factor for incident CVD, recurrent CVD, and mortality in this group of older adults in the Cardiovascular Health Study.

%B Arterioscler Thromb Vasc Biol %V 19 %P 538-45 %8 1999 Mar %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/10073955?dopt=Abstract %R 10.1161/01.atv.19.3.538 %0 Journal Article %J Lancet %D 1999 %T Cardiovascular disease in older adults with glucose disorders: comparison of American Diabetes Association criteria for diabetes mellitus with WHO criteria. %A Barzilay, J I %A Spiekerman, C F %A Wahl, P W %A Kuller, L H %A Cushman, M %A Furberg, C D %A Dobs, A %A Polak, J F %A Savage, P J %K Age Factors %K Aged %K Blood Glucose %K Cardiovascular Diseases %K Cross-Sectional Studies %K Diabetes Complications %K Diabetes Mellitus %K Fasting %K Female %K Glucose Intolerance %K Humans %K Longitudinal Studies %K Male %K Prospective Studies %K Risk Factors %K Sensitivity and Specificity %K Societies, Medical %K United States %K World Health Organization %X

BACKGROUND: The new fasting American Diabetes Association (ADA) criteria for the diagnosis of diabetes mellitus rely mainly on fasting blood glucose concentrations and use a lower cut-off value for diagnosis than the WHO criteria. We aimed to assess the sensitivity of these criteria for the detection of cardiovascular disease, the main complication of diabetes mellitus in the elderly.

METHODS: We did a cross-sectional and prospective analysis of 4515 participants of the Cardiovascular Health Study, an 8 year longitudinal study designed to identify factors related to the onset and course of cardiovascular disease in adults aged at least 65 years. We calculated the prevalence and incidence of cardiovascular disease for the ADA and WHO criteria.

FINDINGS: There was a higher prevalence of cardiovascular disease among individuals with impaired glucose or newly diagnosed diabetes by both criteria than among those with normal glucose concentrations. However, because fewer individuals had abnormal glucose states by the fasting ADA criteria (22.3%) than by the WHO criteria (46.8%), the number of cases of cardiovascular disease attributable to abnormal glucose states was a third of that attributable by the WHO criteria (53 vs 159 cases per 10,000). For the two sets of criteria, the relative risk for incident cardiovascular disease (mean follow-up 5.9 years) was higher in individuals with impaired glucose and newly diagnosed diabetes than in those with normal glucose. Individuals classified as normal by the fasting ADA criteria had a higher absolute number of incident events (455 of 581 events) than those classified as normal by the WHO criteria (269 of 581 events). Fasting ADA criteria were therefore less sensitive than the WHO criteria for predicting cardiovascular disease among individuals with abnormal glucose (sensitivity, 28% vs 54%).

INTERPRETATION: The new fasting ADA criteria seem to be less predictive than the WHO criteria for the burden of cardiovascular disease associated with abnormal glucose in the elderly.

%B Lancet %V 354 %P 622-5 %8 1999 Aug 21 %G eng %N 9179 %1 https://www.ncbi.nlm.nih.gov/pubmed/10466662?dopt=Abstract %R 10.1016/s0140-6736(98)12030-5 %0 Journal Article %J Arterioscler Thromb Vasc Biol %D 1999 %T Fibrinolytic activation markers predict myocardial infarction in the elderly. The Cardiovascular Health Study. %A Cushman, M %A Lemaitre, R N %A Kuller, L H %A Psaty, B M %A Macy, E M %A Sharrett, A R %A Tracy, R P %K Age Factors %K Aged %K Angina Pectoris %K Biomarkers %K Female %K Fibrin Fibrinogen Degradation Products %K Fibrinolysin %K Fibrinolysis %K Follow-Up Studies %K Heart Arrest %K Humans %K Male %K Myocardial Infarction %K Plasminogen Activator Inhibitor 1 %K Risk Factors %X

Coagulation factor levels predict arterial thrombosis in epidemiological studies, but studies of older persons are needed. We studied 3 plasma antigenic markers of fibrinolysis, viz, plasminogen activator inhibitor-1 (PAI-1), fibrin fragment D-dimer, and plasmin-antiplasmin complex (PAP) for the prediction of arterial thrombosis in healthy elderly persons over age 65. The study was a nested case-control study in the Cardiovascular Health Study cohort of 5201 men and women >/=65 years of age who were enrolled from 1989 to 1990. Cases were 146 participants without baseline clinical vascular disease who developed myocardial infarction, angina, or coronary death during a follow-up of 2.4 years. Controls remained free of cardiovascular events and were matched 1:1 to cases with respect to sex, duration of follow-up, and baseline subclinical vascular disease status. With increasing quartile of D-dimer and PAP levels but not of PAI-1, there was an independent increased risk of myocardial infarction or coronary death, but not of angina. The relative risk for D-dimer above versus below the median value (>/=120 microg/L) was 2.5 (95% confidence interval, 1.1 to 5.9) and for PAP above the median (>/=5.25 nmol/L), 3.1 (1.3 to 7.7). Risks were independent of C-reactive protein and fibrinogen concentrations. There were no differences in risk by sex or presence of baseline subclinical disease. D-dimer and PAP, but not PAI-1, predicted future myocardial infarction in men and women over age 65. Relationships were independent of other risk factors, including inflammation markers. Results indicate a major role for these markers in identifying a high risk of arterial disease in this age group.

%B Arterioscler Thromb Vasc Biol %V 19 %P 493-8 %8 1999 Mar %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/10073948?dopt=Abstract %R 10.1161/01.atv.19.3.493 %0 Journal Article %J Arterioscler Thromb Vasc Biol %D 1999 %T Hormone replacement therapy, inflammation, and hemostasis in elderly women. %A Cushman, M %A Meilahn, E N %A Psaty, B M %A Kuller, L H %A Dobs, A S %A Tracy, R P %K Aged %K Biomarkers %K Case-Control Studies %K Cross-Sectional Studies %K Estrogens %K Female %K Hemostasis %K Hormone Replacement Therapy %K Humans %K Inflammation %K Progestins %K Random Allocation %K United Kingdom %K United States %X

Lipid-lowering by postmenopausal hormone therapy (HRT) explains only partly the assumed coronary risk reduction associated with therapy. To explore other possible mechanisms, we studied associations of HRT use with inflammation and hemostasis risk markers in women >/=65 years of age. Subjects were selected from 3393 participants in the fourth year examination of the Cardiovascular Health Study, an observational study of vascular disease risk factors. After excluding women with vascular disease, we compared levels of inflammation and hemostasis variables in the 230 women using unopposed estrogen and 60 using estrogen/progestin, with those of 196 nonusers selected as controls. Compared with nonusers, unopposed estrogen use was associated with 59% higher mean C-reactive protein (P<0.001), but with modestly lower levels of other inflammation indicators, fibrinogen, and alpha-1 acid glycoprotein (P<0.001). Factor VIIc was 16% higher among estrogen users (P<0.001), but this was not associated with higher thrombin production (prothrombin fragment 1-2), or increased fibrin breakdown (D-dimer). Concentration of plasminogen activator inhibitor-1 was 50% lower in both using groups (P<0.001) compared with nonusers, and this was associated with higher plasmin-antiplasmin complex: 8% higher in estrogen and 18% higher in estrogen/progestin users (P<0. 05). Relationships between the markers and hormone use were less pronounced in estrogen/progestin users, with no association for C-reactive protein except in women in upper 2 tertiles of body mass index (P for interaction, 0.02). The direction and strength of the associations of HRT use with inflammation markers differed depending on the protein, so it is not clear whether HRT confers coronary risk reduction through an inflammation-sensitive mechanism. Associations with hemostasis markers indicated no association with evidence of procoagulation and a possible association with increased fibrinolytic activity.

%B Arterioscler Thromb Vasc Biol %V 19 %P 893-9 %8 1999 Apr %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/10195915?dopt=Abstract %R 10.1161/01.atv.19.4.893 %0 Journal Article %J J Natl Cancer Inst %D 1999 %T Increased blood glucose and insulin, body size, and incident colorectal cancer. %A Schoen, R E %A Tangen, C M %A Kuller, L H %A Burke, G L %A Cushman, M %A Tracy, R P %A Dobs, A %A Savage, P J %K Adipose Tissue %K Aged %K Blood Glucose %K Body Constitution %K Cholesterol, HDL %K Colorectal Neoplasms %K Female %K Humans %K Incidence %K Insulin %K Male %K Prospective Studies %K Risk %K Triglycerides %K Viscera %X

BACKGROUND: Abdominal obesity--an elevated level of visceral adipose tissue--has been linked to colorectal cancer. Furthermore, elevated levels of visceral adipose tissue have been associated with hyperinsulinemia, and insulin is a growth factor in the colon. We assessed whether waist circumference, a surrogate measure of visceral adipose tissue, and metabolic parameters associated with visceral adipose tissue were related to colorectal cancer.

METHODS: In the Cardiovascular Health Study cohort, we examined the relationship of baseline measurements of body size, glucose, insulin, and lipoproteins to incident colorectal cancer. All P values are two-sided.

RESULTS: Among 5849 participants, 102 incident cases of colorectal cancer were identified. Individuals in the highest quartile of fasting glucose had a nearly twofold increased risk of colorectal cancer (relative risk [RR] = 1.8; 95% confidence interval [CI] = 1.0-3.1), and the linear trend RR (LT RR = 1.2; 95% CI = 1.0-1.5) for fasting glucose level was statistically significant (P =. 02). Glucose and insulin levels 2 hours after oral glucose challenge also exhibited statistically significant associations with colorectal cancer (2-hour glucose levels: RR = 2.4 [95% CI = 1.2-4. 7]/LT RR = 1.3 [95% CI = 1.0-1.6; P =.02]; 2-hour insulin levels: RR = 2.0 [95% CI = 1.0-3.8]/LT RR = 1.2 [95% CI = 1.0-1.5; P =.04]). Analysis of fasting insulin levels suggested a threshold effect, with values above the median associated with colorectal cancer (RR = 1.6; 95% CI = 1.1-2.4; P =.02). Higher levels of waist circumference were also statistically significantly associated with colorectal cancer (RR = 1.9; 95% CI = 1.1-3.3; P =.02).

CONCLUSIONS: These data provide, to our knowledge, the first direct evidence of an association between elevated visceral adipose tissue level, its associated metabolic effects, and colorectal cancer.

%B J Natl Cancer Inst %V 91 %P 1147-54 %8 1999 Jul 07 %G eng %N 13 %1 https://www.ncbi.nlm.nih.gov/pubmed/10393723?dopt=Abstract %R 10.1093/jnci/91.13.1147 %0 Journal Article %J Neurology %D 1999 %T Relation of education to brain size in normal aging: implications for the reserve hypothesis. %A Coffey, C E %A Saxton, J A %A Ratcliff, G %A Bryan, R N %A Lucke, J F %K Aged %K Aged, 80 and over %K Atrophy %K Brain %K Cerebral Cortex %K Cerebrospinal Fluid %K Educational Status %K Female %K Functional Laterality %K Health Status %K Humans %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Regression Analysis %K Sex Characteristics %X

OBJECTIVE: To examine the relations between education and age-related changes in brain structure in a nonclinical sample of elderly adults.

BACKGROUND: Education may protect against cognitive decline in late life--an observation that has led to the "reserve" hypothesis of brain aging. Little is known, however, about the effect of education on age-related changes in brain structure.

METHODS: Quantitative MRI of the brain was performed in 320 elderly volunteers (age range, 66 to 90 years) living independently in the community (Mini-Mental State Examination scores > or =24), all of whom were participants in the Cardiovascular Health Study. Blinded measurements of global and regional brain size were made from T1-weighted axial images using computer-assisted edge detection and trace methodology. High measurement reliabilities were obtained.

RESULTS: Regression analyses (adjusting for the effects of intracranial size, sex, age, age-by-sex interactions, and potential confounders) revealed significant main effects of education on peripheral (sulcal) CSF volume-a marker of cortical atrophy. Each year of education was associated with an increase in peripheral CSF volume of 1.77 mL (p<0.03). As reported previously, main effects of age (but not education) were observed for all of the remaining brain regions examined, including cerebral hemisphere volume, frontal region area, temporoparietal region area, parieto-occipital region area, lateral (Sylvian) fissure volume, lateral ventricular volume, and third ventricle volume.

CONCLUSIONS: The authors' findings demonstrate a relation between education and age-related cortical atrophy in a nonclinical sample of elderly persons, and are consistent with the reserve hypothesis as well as with a small number of brain imaging studies in patients with dementia. The neurobiological basis and functional correlates of this education effect require additional investigation.

%B Neurology %V 53 %P 189-96 %8 1999 Jul 13 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/10408558?dopt=Abstract %R 10.1212/wnl.53.1.189 %0 Journal Article %J Arterioscler Thromb Vasc Biol %D 1999 %T Relationship of plasmin generation to cardiovascular disease risk factors in elderly men and women. %A Sakkinen, P A %A Cushman, M %A Psaty, B M %A Rodriguez, B %A Boineau, R %A Kuller, L H %A Tracy, R P %K Aged %K Aged, 80 and over %K alpha-2-Antiplasmin %K Antifibrinolytic Agents %K Asian Continental Ancestry Group %K Cohort Studies %K Coronary Disease %K Diabetes Mellitus, Type 2 %K European Continental Ancestry Group %K Female %K Fibrinolysin %K Fibrinolysis %K Humans %K Insulin Resistance %K Male %K Multivariate Analysis %K Myocardial Infarction %K Plasminogen Activator Inhibitor 1 %K Risk Factors %X

Plasmin-alpha2-antiplasmin complex (PAP) marks plasmin generation and fibrinolytic balance. We recently observed that elevated levels of PAP predict acute myocardial infarction in the elderly, yet little is known about the correlates of PAP. We measured PAP in 800 elderly subjects who were free of clinical cardiovascular disease in 2 cohort studies: the Cardiovascular Health Study and the Honolulu Heart Program. Median PAP levels did not differ between the Cardiovascular Health Study (6.05+/-1.46 nmol/L) and the Honolulu Heart Program (6.11+/-1.44 nmol/L), and correlates of PAP were similar in both cohorts. In CHS, PAP levels increased with age (r=0. 30), procoagulant factors (eg, factor VIIc, r=0.15), thrombin activity (prothrombin fragment F1+2, r=0.29), and inflammation-sensitive proteins (eg, fibrinogen, r=0.44; factor VIIIc, r=0.37). PAP was associated with increased atherosclerosis as measured by the ankle-arm index (AAI) (P for trend, %B Arterioscler Thromb Vasc Biol %V 19 %P 499-504 %8 1999 Mar %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/10073949?dopt=Abstract %R 10.1161/01.atv.19.3.499 %0 Journal Article %J J Clin Epidemiol %D 1999 %T The reliability of medication inventory methods compared to serum levels of cardiovascular drugs in the elderly. %A Smith, N L %A Psaty, B M %A Heckbert, S R %A Tracy, R P %A Cornell, E S %K Aged %K Aspirin %K Cardiovascular Agents %K Digoxin %K Humans %K Hydrochlorothiazide %K Patient Compliance %K Propranolol %K Reproducibility of Results %X

Medication inventory is more reliable than self-report in assessing prescription drug use in elderly populations. It is not known how strongly medication inventory reflects actual medication use as measured by serum drug levels. In the Cardiovascular Health Study, medication data were collected annually by study interviewers from medication containers brought to the clinic visit. At the fourth clinic visit, venipuncture was performed under 12-hour fasting conditions. Participants were told to take medications as usual. Based on medication inventory results, we randomly selected 55 users and 55 non-users of four cardiovascular drugs: aspirin, propranolol, hydrochlorothiazide, and digoxin. All 110 blood samples for each of the four drugs were analyzed; cut points were based on detectable levels given laboratory limitations. Kappa statistics (K) tested degree of agreement between medication inventory findings and serum detection. Assays were completed on 400 samples (91%). Agreement for aspirin (n=102) was poor: K=0.16 (95% CI: 0.0-0.32). Agreement for propranolol (n = 98) was fair: K=0.43 (95% CI: 0.27-0.59). Agreement for hydrochlorothiazide (n=100) was good: K=0.62 (95% CI: 0.53-0.91). Agreement for digoxin (n=100) was excellent: K=0.94 (95% CI: 0.74-1.0). For four all drugs, lack of agreement was confined primarily to participants who reported use but did not have detectable levels. Excluding aspirin users, only one non-user (0.7%) had drug detected in serum. The medication inventory is a reasonably sensitive and a fairly reliable method for ascertaining non-aspirin cardiovascular drug use in the elderly even though this method may overestimate use as assessed by serum level.

%B J Clin Epidemiol %V 52 %P 143-6 %8 1999 Feb %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/10201655?dopt=Abstract %R 10.1016/s0895-4356(98)00141-3 %0 Journal Article %J J Gen Intern Med %D 1999 %T Stroke risk in an elderly population with atrial fibrillation. %A Feinberg, W M %A Kronmal, R A %A Newman, A B %A Kraut, M A %A Bovill, E G %A Cooper, L %A Hart, R G %K Aged %K Atrial Fibrillation %K Cerebrovascular Disorders %K Cohort Studies %K Humans %K Male %K Poisson Distribution %K Proportional Hazards Models %K Risk Factors %X

Patients with nonvalvular atrial fibrillation (AF) have an increased risk of stroke, but the absolute rate of stroke varies widely depending on coexistent vascular disease. We assessed the stroke rate and predictive value of two published schemes for stroke risk stratification in a population-derived cohort of 259 elderly people with nonvalvular AF followed for a median of 5.3 years. The rate of ischemic stroke was 2.8% per year (95% confidence interval [CI] 1.9, 3.9). Thirty-one percent were predicted to be at low risk, and their stroke rate was 1.7% per year (95% CI 0.6, 3.8). Many people with AF in this population-derived cohort had relatively low rates of stroke. Further studies to reliably stratify stroke risk in patients with AF are needed.

%B J Gen Intern Med %V 14 %P 56-9 %8 1999 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/9893092?dopt=Abstract %0 Journal Article %J Circulation %D 2000 %T Chlamydia pneumoniae, herpes simplex virus type 1, and cytomegalovirus and incident myocardial infarction and coronary heart disease death in older adults : the Cardiovascular Health Study. %A Siscovick, D S %A Schwartz, S M %A Corey, L %A Grayston, J T %A Ashley, R %A Wang, S P %A Psaty, B M %A Tracy, R P %A Kuller, L H %A Kronmal, R A %K Adult %K Age Factors %K Aged %K Antibodies, Bacterial %K Antibodies, Viral %K Case-Control Studies %K Chlamydophila pneumoniae %K Coronary Disease %K Cytomegalovirus %K Female %K Herpesvirus 1, Human %K HIV Antibodies %K Humans %K Immunoglobulin G %K Male %K Myocardial Infarction %K Risk Factors %X

BACKGROUND: Whether serological evidence of prior infection with Chlamydia pneumoniae, herpes simplex virus type 1 (HSV-1), and cytomegalovirus (CMV) is associated with myocardial infarction (MI) and coronary heart disease (CHD) death remains a source of controversy.

METHODS AND RESULTS: We conducted a nested case-control study among participants in the Cardiovascular Health Study, a cohort study of persons aged >/=65 years. Cases experienced an incident MI and CHD death (n=213). Control subjects were matched to cases by age, sex, clinic, year of enrollment, and month of blood draw (n=405). Serum was analyzed for IgG antibodies to C pneumoniae, HSV-1, and CMV. After adjustment for other risk factors, the risk of MI and CHD death was associated with the presence of IgG antibodies to HSV-1 (odds ratio [OR] 2.0, 95% CI 1.1 to 3.6) but was not associated with the presence of IgG antibodies to either C pneumoniae (OR 1.1, 95% CI 0.7 to 1.8) or CMV (OR 1.2, 95% CI 0.7 to 1.9). Although there was little association with low to moderate C pneumoniae antibody titers (

CONCLUSIONS: Among older adults, the presence of IgG antibodies to HSV-1 was associated with a 2-fold increase in the risk of incident MI and CHD death. For C pneumoniae, only high-titer IgG antibodies were associated with an increased risk of MI and CHD death. The presence of IgG antibodies to CMV was not associated with risk among the elderly.

%B Circulation %V 102 %P 2335-40 %8 2000 Nov 07 %G eng %N 19 %1 https://www.ncbi.nlm.nih.gov/pubmed/11067785?dopt=Abstract %R 10.1161/01.cir.102.19.2335 %0 Journal Article %J Am J Epidemiol %D 2000 %T Clustering of procoagulation, inflammation, and fibrinolysis variables with metabolic factors in insulin resistance syndrome. %A Sakkinen, P A %A Wahl, P %A Cushman, M %A Lewis, M R %A Tracy, R P %K Aged %K Aged, 80 and over %K Antigens %K Blood Coagulation %K Cardiovascular Diseases %K Cluster Analysis %K Factor Analysis, Statistical %K Factor VII %K Female %K Fibrinogen %K Fibrinolysis %K Humans %K Inflammation %K Insulin Resistance %K Male %K Middle Aged %K Plasminogen Activator Inhibitor 1 %K Risk Factors %X

The known metabolic cardiovascular disease risk factors associated with insulin resistance syndrome (IRS) do not adequately explain the excess cardiovascular disease risk attributed to this syndrome, and abnormalities in hemostatic variables may contribute to this excess risk. Using data from 322 nondiabetic elderly men and women (aged 65-100 years) participating in the Cardiovascular Health Study during 1989-1990, the authors performed factor analysis on 10 metabolic risk factors associated with IRS and 11 procoagulation, inflammation, and fibrinolysis variables to examine the clustering of the metabolic and hemostatic risk markers. Factor analysis of the metabolic variables confirmed four uncorrelated factors: body mass, insulin/glucose, lipids, and blood pressure. Adding the hemostatic variables yielded three new factors interpreted as inflammation, vitamin K-dependent proteins, and procoagulant activity. Plasminogen activator inhibitor-1 clustered with the body mass factor, supporting the hypothesis that obesity is related to impaired fibrinolysis. Fibrinogen clustered with the inflammation summary factor rather than procoagulant activity, supporting the position that fibrinogen principally reflects underlying inflammation rather than procoagulant potential. The authors conclude that should hemostatic variables be shown to contribute to IRS-related cardiovascular disease, apart from plasminogen activator inhibitor-1, they may do so independently of the established metabolic abnormalities.

%B Am J Epidemiol %V 152 %P 897-907 %8 2000 Nov 15 %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/11092431?dopt=Abstract %R 10.1093/aje/152.10.897 %0 Journal Article %J Circulation %D 2000 %T Depressive symptoms and risks of coronary heart disease and mortality in elderly Americans. Cardiovascular Health Study Collaborative Research Group. %A Ariyo, A A %A Haan, M %A Tangen, C M %A Rutledge, J C %A Cushman, M %A Dobs, A %A Furberg, C D %K Aged %K Aged, 80 and over %K Cohort Studies %K Coronary Disease %K Depression %K Female %K Humans %K Male %K Prospective Studies %K Risk Factors %K United States %X

BACKGROUND: Several epidemiological studies have associated depressive symptoms with cardiovascular disease. We investigated whether depressive symptoms constituted a risk for coronary heart disease (CHD) and total mortality among an apparently healthy elderly cohort.

METHODS AND RESULTS: In a prospective cohort of 5888 elderly Americans (>/=65 years) who were enrolled in the Cardiovascular Health Study, 4493 participants who were free of cardiovascular disease at baseline provided annual information on their depressive status, which was assessed using the Depression Scale of the Center for Epidemiological Studies. These 4493 subjects were followed for 6 years for the development of CHD and mortality. The cumulative mean depression score was assessed for each participant up to the time of event (maximum 6-year follow-up). Using time-dependent, proportional-hazards models, the unadjusted hazard ratio associated with every 5-unit increase in mean depression score for the development of CHD was 1.15 (P:=0.006); the ratio for all-cause mortality was 1.29 (P:<0.0001). In multivariate analyses adjusted for age, race, sex, education, diabetes, hypertension, cigarette smoking, total cholesterol, triglyceride level, congestive heart failure, and physical inactivity, the hazard ratio for CHD was 1.15 (P:=0.006) and that for all-cause mortality was 1.16 (P:=0.006). Among participants with the highest cumulative mean depression scores, the risk of CHD increased by 40% and risk of death by 60% compared with those who had the lowest mean scores.

CONCLUSIONS: Among elderly Americans, depressive symptoms constitute an independent risk factor for the development of CHD and total mortality.

%B Circulation %V 102 %P 1773-9 %8 2000 Oct 10 %G eng %N 15 %1 https://www.ncbi.nlm.nih.gov/pubmed/11023931?dopt=Abstract %R 10.1161/01.cir.102.15.1773 %0 Journal Article %J J Am Geriatr Soc %D 2000 %T Estrogen replacement therapy and MRI-demonstrated cerebral infarcts, white matter changes, and brain atrophy in older women: the Cardiovascular Health Study. %A Luoto, R %A Manolio, T %A Meilahn, E %A Bhadelia, R %A Furberg, C %A Cooper, L %A Kraut, M %K Aged %K Aged, 80 and over %K Atrophy %K Brain %K Brain Infarction %K Estrogen Replacement Therapy %K Female %K Humans %K Intelligence Tests %K Life Style %K Magnetic Resonance Imaging %K Population Surveillance %K Prevalence %K Prospective Studies %K Social Class %K United States %X

OBJECTIVE: We studied the relationship between the use of estrogen replacement therapy (ERT) and cerebral magnetic resonance imaging (MRI) abnormalities among older women.

DESIGN: A population-based prospective study (Cardiovascular Health Study).

SETTING: Four regions in the United States.

PARTICIPANTS: A total of 2133 (62.9% of the eligible) women aged 65 to 95 years (mean age 74.8), on whom MRI was performed in 1992-1994.

MEASUREMENTS: Presence of global brain atrophy, white matter changes, small infarct-like lesion (ILL) (<3 mm), MRI infarcts (> or =3 mm, mostly small and asymptomatic), and cognitive function as measured by Mini-Mental State Exam (MMSE), and by ERT use (current/past/never), adjusted for a number of socioeconomic, lifestyle, and reproductive covariates.

RESULTS: Current use of ERT was reported by 15% and past use by another 23% of participants; 35% of all women had MRI infarcts. The prevalence of MRI infarcts did not differ in current or past users from those who had never used ERT (nonusers). Bifrontal distance, the largest distance between frontal horns, and the size of ventricles were larger among current ERT users compared to past users or nonusers (P (trend) = .01), adjusted for all other covariates, but no dose-response relationship to current or past ERT use was found. Duration of estrogen use was not associated with any atrophy measure. Cortical atrophy measure, sulcal widening, or white matter disease did not differ significantly by ERT use or duration of use. Central measures of atrophy, bifrontal distance, and ventricular size were significantly associated with cognition as measured by MMSE.

CONCLUSIONS: Current ERT users had much more clinically significant central atrophy than nonusers, but the implications remained unclear.

%B J Am Geriatr Soc %V 48 %P 467-72 %8 2000 May %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/10811537?dopt=Abstract %R 10.1111/j.1532-5415.2000.tb04990.x %0 Journal Article %J Clin Neuropsychol %D 2000 %T Normative data on the Boston Naming Test and two equivalent 30-item short forms. %A Saxton, J %A Ratcliff, G %A Munro, C A %A Coffey, E C %A Becker, J T %A Fried, L %A Kuller, L %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Female %K Humans %K Male %K Neuropsychological Tests %K Population Surveillance %K Reference Values %X

Because of the significance of the Boston Naming Test (BNT) in the differential diagnosis of the dementias, especially Alzheimer's disease, adequate norms from community-dwelling elderly individuals are essential. The present study describes the development of two new empirically derived equivalent short forms (30 items each) of the test. Normative data for the total BNT and the two equivalent 30-item halves based on item difficulty are presented using the performance of 314 community-dwelling individuals aged 65 and over. Age and education norms are presented using an overlapping midpoint interval strategy.

%B Clin Neuropsychol %V 14 %P 526-34 %8 2000 Nov %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/11262721?dopt=Abstract %R 10.1076/clin.14.4.526.7204 %0 Journal Article %J Stroke %D 2001 %T Alcohol consumption and subclinical findings on magnetic resonance imaging of the brain in older adults: the cardiovascular health study. %A Mukamal, K J %A Longstreth, W T %A Mittleman, M A %A Crum, R M %A Siscovick, D S %K Aged %K Aging %K Alcohol Drinking %K Atrophy %K Brain %K Brain Diseases %K Cerebral Infarction %K Comorbidity %K Demography %K Female %K Health Surveys %K Humans %K Logistic Models %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Nerve Fibers, Myelinated %K Odds Ratio %K Prospective Studies %K Sensitivity and Specificity %K United States %X

BACKGROUND AND PURPOSE: Subclinical findings on MRI of the brain are associated with poorer cognitive and neurological function among older adults. We sought to determine how alcohol consumption is related to these findings.

METHODS: As part of the Cardiovascular Health Study, 3660 adults aged 65 years and older underwent MRI of the brain from 1992 to 1994. We excluded 284 participants with a confirmed history of cerebrovascular disease. We assessed self-reported intake of beer, wine, and liquor at the annual clinic visit closest to the date of the MRI and grouped participants into 6 categories: abstainers, former drinkers, <1 drink weekly, 1 to <7 drinks weekly, 7 to <15 drinks weekly, and >/=15 drinks weekly. Neuroradiologists assessed white matter grade, infarcts, ventricular size, and sulcal size in a standardized and blinded manner. We used multivariate regression to control for sociodemographic and clinical characteristics.

RESULTS: We found a U-shaped relationship between alcohol consumption and white matter abnormalities. Compared with abstainers, individuals consuming 1 to <7 drinks had an OR of 0.68, and those consuming >/=15 drinks weekly had an OR of 0.95 (p for quadratic term=0.01). Heavier alcohol consumption was associated with a lower prevalence of infarcts (OR for >/=15 drinks weekly relative to abstainers 0.59; P for trend=0.004), but larger ventricular size (OR for >/=15 drinks weekly relative to abstainers 1.32; P for trend=0.006) and sulcal size (OR for >/=15 drinks weekly relative to abstainers 1.53; P for trend=0.007).

CONCLUSIONS: Moderate alcohol consumption is associated with a lower prevalence of white matter abnormalities and infarcts, thought to be of vascular origin, but with a dose-dependent higher prevalence of brain atrophy on MRI among older adults. The extent to which these competing associations influence overall brain function will require further study.

%B Stroke %V 32 %P 1939-46 %8 2001 Sep %G eng %N 9 %1 https://www.ncbi.nlm.nih.gov/pubmed/11546878?dopt=Abstract %R 10.1161/hs0901.095723 %0 Journal Article %J Arch Intern Med %D 2001 %T Association between blood pressure level and the risk of myocardial infarction, stroke, and total mortality: the cardiovascular health study. %A Psaty, B M %A Furberg, C D %A Kuller, L H %A Cushman, M %A Savage, P J %A Levine, D %A O'Leary, D H %A Bryan, R N %A Anderson, M %A Lumley, T %K Aged %K Blood Pressure %K Female %K Humans %K Male %K Myocardial Infarction %K Prognosis %K Proportional Hazards Models %K Prospective Studies %K Risk Factors %K Stroke %K Survival Rate %K United States %X

BACKGROUND: Recent reports have drawn attention to the importance of pulse pressure as a predictor of cardiovascular events. Pulse pressure is used neither by clinicians nor by guidelines to define treatable levels of blood pressure.

METHODS: In the Cardiovascular Health Study, 5888 adults 65 years and older were recruited from 4 US centers. At baseline in 1989-1990, participants underwent an extensive examination, and all subsequent cardiovascular events were ascertained and classified.

RESULTS: At baseline, 1961 men and 2941 women were at risk for an incident myocardial infarction or stroke. During follow-up that averaged 6.7 years, 572 subjects had a coronary event, 385 had a stroke, and 896 died. After adjustment for potential confounders, systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure were directly associated with the risk of incident myocardial infarction and stroke. Only SBP was associated with total mortality. Importantly, SBP was a better predictor of cardiovascular events than DBP or pulse pressure. In the adjusted model for myocardial infarction, a 1-SD change in SBP, DBP, and pulse pressure was associated with hazard ratios (95% confidence intervals) of 1.24 (1.15-1.35), 1.13 (1.04-1.22), and 1.21 (1.12-1.31), respectively; and adding pulse pressure or DBP to the model did not improve the fit. For stroke, the hazard ratios (95% confidence intervals) were 1.34 (1.21-1.47) with SBP, 1.29 (1.17-1.42) with DBP, and 1.21 (1.10-1.34) with pulse pressure. The association between blood pressure level and cardiovascular disease risk was generally linear; specifically, there was no evidence of a J-shaped relationship. In those with treated hypertension, the hazard ratios for the association of SBP with the risks for myocardial infarction and stroke were less pronounced than in those without treated hypertension.

CONCLUSION: In this population-based study of older adults, although all measures of blood pressure were strongly and directly related to the risk of coronary and cerebrovascular events, SBP was the best single predictor of cardiovascular events.

%B Arch Intern Med %V 161 %P 1183-92 %8 2001 May 14 %G eng %N 9 %1 https://www.ncbi.nlm.nih.gov/pubmed/11343441?dopt=Abstract %R 10.1001/archinte.161.9.1183 %0 Journal Article %J Am J Epidemiol %D 2001 %T Association between physical activity and markers of inflammation in a healthy elderly population. %A Geffken, D F %A Cushman, M %A Burke, G L %A Polak, J F %A Sakkinen, P A %A Tracy, R P %K Aged %K Analysis of Variance %K Biomarkers %K C-Reactive Protein %K Cardiovascular Diseases %K Factor VIII %K Female %K Fibrinogen %K Humans %K Inflammation %K Leukocyte Count %K Male %K Physical Exertion %K Sex Factors %K Smoking %X

Higher levels of physical activity are associated with lower risk of cardiovascular disease. There is growing evidence that the development of the atherosclerotic plaque is associated with inflammation. In this study, the authors investigated the cross-sectional association between physical activity and markers of inflammation in a healthy elderly population. Data obtained in 1989-1990 and 1992-1993 from the Cardiovascular Health Study, a cohort of 5,888 men and women aged >/=65 years, were analyzed. Concentrations of the inflammation markers-C-reactive protein, fibrinogen, Factor VIII activity, white blood cells, and albumin-were compared cross-sectionally by quartile of self-reported physical activity. Compared with persons in the lowest quartile, those in the highest quartile of physical activity had 19%, 6%, 4%, and 3% lower concentrations of C-reactive protein, white blood cells, fibrinogen, and Factor VIII activity, respectively, after adjustment for gender, the presence of cardiovascular disease, age, race, smoking, body mass index, diabetes, and hypertension. Multivariate regression models suggested that the association of higher levels of physical activity with lower levels of inflammation markers may be mediated by body mass index and glucose. There was no association between physical activity and albumin. Higher levels of physical activity were associated with lower concentrations of four out of five inflammation markers in this elderly cohort. These data suggest that increased exercise is associated with reduced inflammation. Prospective studies will be required for verification of these findings.

%B Am J Epidemiol %V 153 %P 242-50 %8 2001 Feb 01 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/11157411?dopt=Abstract %R 10.1093/aje/153.3.242 %0 Journal Article %J J Am Geriatr Soc %D 2001 %T The association of bone mineral density and depression in an older population. %A Robbins, J %A Hirsch, C %A Whitmer, R %A Cauley, J %A Harris, T %K Absorptiometry, Photon %K Aged %K Analysis of Variance %K Black People %K Body Mass Index %K Bone Density %K Bone Diseases, Metabolic %K California %K Cross-Sectional Studies %K Depression %K Energy Metabolism %K Exercise %K Female %K Follow-Up Studies %K Fractures, Bone %K Humans %K Linear Models %K Male %K Osteoporosis %K Pennsylvania %K Population Surveillance %K Psychiatric Status Rating Scales %K Radionuclide Imaging %K Risk Factors %K Sex Distribution %K Single-Blind Method %K White People %X

OBJECTIVE: To evaluate the association between bone mineral density (BMD) and measurements of depression in an older population.

DESIGN: Population-based, cross-sectional study.

SETTING: Study subjects were participants in the Cardiovascular Health Study (CHS), a longitudinal, long-term, follow-up study, at the University of California Davis (Sacramento, California) and the University of Pittsburgh (Pittsburgh, Pennsylvania) clinical centers.

PARTICIPANTS: A random sample of 1,566 Medicare enrollees age 65 and older enrolled in the CHS.

MEASUREMENTS: Total hip BMD, measured using dual energy x-ray absorptiometry (DEXA), after adjustment for multiple covariates, was compared with depression evaluated with the Center for Epidemiological Studies 10-item Depression Scale (CES-Dm). Risk factors for osteoporosis were compared in depressed and nondepressed participants. Potential correlates were entered into a regression model. Depression scores were compared in normal, osteopenic, and osteoporotic individuals.

RESULTS: Sixteen percent of participants were clinically depressed; 9% had BMDs in the osteoporotic range. Mean BMD was 40 mg/cm2 lower in those with clinical depression. High CES-Dm scores were associated with lower BMD (P < .001) when adjusted for body mass index (BMI), age, kilocalories of activity, estrogen use, gender, race, smoking and drinking. When stratified by race, this remained true for all Caucasians (P < .01), all African Americans (P < .05), and when stratified by race and gender the association remained only for all Caucasian women (P < .001). In women and Caucasian men there was an increase in depression scores among individuals with osteoporotic-range BMDs.

CONCLUSIONS: A significant association was found between BMD and depressive symptoms after adjustment for osteoporosis risk factors. In Caucasians, depressive symptoms were associated with both osteoporotic and osteopenic levels of BMD. Causality cannot be ascribed, with only one measurement of BMD. We postulate that there may be an unmeasured third factor, such as an endogenous steroid, that is responsible for both low BMD and depression.

%B J Am Geriatr Soc %V 49 %P 732-6 %8 2001 Jun %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/11454111?dopt=Abstract %R 10.1046/j.1532-5415.2001.49149.x %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2001 %T Associations of subclinical cardiovascular disease with frailty. %A Newman, A B %A Gottdiener, J S %A McBurnie, M A %A Hirsch, C H %A Kop, W J %A Tracy, R %A Walston, J D %A Fried, L P %K Aged %K Ankle %K Arm %K Black or African American %K Blood Pressure %K Brain %K Cardiovascular Diseases %K Carotid Artery Diseases %K Cerebral Infarction %K Cerebrovascular Disorders %K Cohort Studies %K Echocardiography %K Electrocardiography %K Frail Elderly %K Health Status %K Heart Failure %K Humans %K Magnetic Resonance Imaging %K United States %K Vascular Diseases %X

BACKGROUND: Frail health in old age has been conceptualized as a loss of physiologic reserve associated with loss of lean mass, neuroendocrine dysregulation, and immune dysfunction. Little work has been done to define frailty and describe the underlying pathophysiology.

METHODS: Frailty status was defined in participants of the Cardiovascular Health Study (CHS), a cohort of 5,201 community-dwelling older adults, based on the presence of three out of five clinical criteria. The five criteria included self-reported weight loss, low grip strength, low energy, slow gait speed, and low physical activity. We examined the spectrum of clinical and subclinical cardiovascular disease in those who were frail (3/5 criteria) or of intermediate frailty status (1 or 2/5 criteria), compared to those who were not frail (0/5). We hypothesized that the severity of frailty would be related to a higher prevalence of reported cardiovascular disease (CVD), as well as to a greater extent of CVD, measured by noninvasive testing.

RESULTS: Of 4,735 eligible participants, 2,289 (48%) were not frail, 299 (6%) were frail, and 2.147 (45%) were of intermediate frailty status. Those who were frail were older (77.2 yrs) compared to those who were not frail (71.5 yrs) or intermediate (73.4 yrs) (p < .001). Frailty status was associated with clinical CVD and most strongly with congestive heart failure (odds ratio [OR] = 7.51 (95% confidence interval [CI] = 4.66-12.12). In those without a history of a CVD event (n = 1.259), frailty was associated with many noninvasive measures of CVD. Those with carotid stenosis >75% (adjusted OR = 3.41), ankle-arm index <0.8 (adjusted OR = 3.17) or 0.8-0.9 (adjusted OR = 2.01), major electrocardiography (ECG) abnormalities (adjusted OR = 1.58), greater left ventricular (LV) mass by echocardiography (adjusted OR = 1.16), and higher degree of infarct-like lesions in the brain (adjusted OR = 1.71), were more likely to be frail compared to those who were not frail. The overall associations of each of these noninvasive measures of CVD with frailty level were significant (all p < .05).

CONCLUSIONS: Cardiovascular disease was associated with an increased likelihood of frail health. In those with no history of CVD, the extent of underlying cardiovascular disease measured by carotid ultrasound and ankle-arm index, LV hypertrophy by ECG and echocardiography, was related to frailty. Infarct-like lesions in the brain on magnet resonance imaging were related to frailty as well.

%B J Gerontol A Biol Sci Med Sci %V 56 %P M158-66 %8 2001 Mar %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/11253157?dopt=Abstract %R 10.1093/gerona/56.3.m158 %0 Journal Article %J J Cardiovasc Risk %D 2001 %T Brachial flow-mediated vasodilator responses in population-based research: methods, reproducibility and effects of age, gender and baseline diameter. %A Herrington, D M %A Fan, L %A Drum, M %A Riley, W A %A Pusser, B E %A Crouse, J R %A Burke, G L %A McBurnie, M A %A Morgan, T M %A Espeland, M A %K Adolescent %K Adult %K Age Factors %K Aged %K Aged, 80 and over %K Blood Circulation %K Brachial Artery %K Female %K Humans %K Male %K Middle Aged %K Observer Variation %K Population Surveillance %K Reproducibility of Results %K Sex Factors %K Vasodilation %K Vasodilator Agents %X

BACKGROUND: Brachial artery ultrasound has been proposed as an inexpensive, accurate way to assess cardiovascular risk in populations. However, analysis and interpretation of these data are not uniform.

METHODS: We analysed the relationship between relative and absolute changes in brachial artery diameter in response to flow-mediated dilation and age, gender and baseline diameter among 4,040 ultrasound examinations from subjects aged 14 to 98 years.

RESULTS: Reproducibility studies demonstrated intra- and interreader and intrasubject correlations from 0.67 to 0.84 for repeated measures of per cent change in diameter. Per cent change in diameter after flow stimulus was 3.58 +/- 0.10% (mean +/- standard deviation). Corresponding values for baseline diameter and absolute change in diameter were 4.43 +/- 0.87 mm and 0.15 +/- 0.01 mm, respectively. Baseline diameter and its variance were inversely related to per cent change in diameter (P< 0.001). In contrast, absolute change in diameter was more uniform throughout the range of baseline diameters. Baseline diameter was directly related, and per cent change in diameter inversely related, to age (P < 0.001 for all three measures). Time to maximum vasodilator response increased with age (P < 0.001). Women (n=2,315) had significantly larger per cent change in diameter than men (n=1,725) (P < 0.001). However, after adjustment for age and baseline diameter, per cent and absolute change were 5% smaller in women than men (P < 0.05 for both). In multivariate analysis, age was overwhelmingly the most important determinant of absolute change in diameter (P < 0.001).

CONCLUSIONS: Automated analysis of brachial flow-mediated vasodilator responses is both feasible and reproducible in large-scale clinical and population-based research.

%B J Cardiovasc Risk %V 8 %P 319-28 %8 2001 Oct %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/11702039?dopt=Abstract %R 10.1177/174182670100800512 %0 Journal Article %J Arch Neurol %D 2001 %T Cluster analysis and patterns of findings on cranial magnetic resonance imaging of the elderly: the Cardiovascular Health Study. %A Longstreth, W T %A Diehr, P %A Manolio, T A %A Beauchamp, N J %A Jungreis, C A %A Lefkowitz, D %K Aged %K Brain %K Cerebral Infarction %K Cerebrovascular Disorders %K Cluster Analysis %K Cohort Studies %K Discriminant Analysis %K Female %K Humans %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Risk Factors %X

OBJECTIVE: To characterize patterns of findings on cranial magnetic resonance imaging (MRI) of the elderly using a statistical technique called cluster analysis.

SUBJECTS AND METHODS: The Cardiovascular Health Study is a population-based, longitudinal study of 5888 people 65 years and older. Of these, 3230 underwent cranial MRI scans, which were coded for presence of infarcts and grades for white matter, ventricles, and sulci. Cluster analysis separated participants into 5 clusters based solely on patterns of MRI findings. Participants comprising each cluster were contrasted with respect to cardiovascular risk factors and clinical manifestations.

RESULTS: One cluster was low on all the MRI findings (normal) and another was high on all of them (complex infarcts). Another cluster had evidence for infarcts alone (simple infarcts), whereas the last 2 clusters lacked infarcts, one having enlarged ventricles and sulci (atrophy) and the other having prominent white matter changes and enlarged ventricles (leukoaraiosis). Factors that distinguished these clusters in a discriminant analysis were age, sex, several measures of hypertension, internal carotid artery wall thickness, smoking, and prevalent claudication before the MRI. The atrophy group had the highest percentage of men and the normal group had the lowest. Cognitive and motor performance also differed across clusters, with the atrophy cluster performing better than may have been expected.

CONCLUSIONS: These MRI patterns identified participants with different vascular disease risk factors and clinical manifestations. Results of these exploratory analyses warrant consideration in other populations of elderly people. Such patterns may provide clues about the pathophysiology of structural brain changes in the elderly.

%B Arch Neurol %V 58 %P 635-40 %8 2001 Apr %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/11295995?dopt=Abstract %R 10.1001/archneur.58.4.635 %0 Journal Article %J Chest %D 2001 %T Correlates of peak expiratory flow lability in elderly persons. %A Enright, P L %A McClelland, R L %A Buist, A S %A Lebowitz, M D %K Aged %K Aged, 80 and over %K Aging %K Asthma %K Female %K Heart Failure %K Humans %K Male %K Monitoring, Ambulatory %K Peak Expiratory Flow Rate %K Predictive Value of Tests %K Pulmonary Disease, Chronic Obstructive %K Reference Values %K Rhinitis, Allergic, Seasonal %K Risk Factors %K Signal Processing, Computer-Assisted %K Spirometry %X

OBJECTIVE: To determine the correlates of the lability of peak expiratory flow (PEF) in the elderly.

METHODS: A community sample of 4,581 persons > or = 65 years old from the Cardiovascular Health Study completed an asthma questionnaire and underwent spirometry. During a follow-up examination of the cohort, 1,836 persons agreed to measure PEF at home twice daily for 2 weeks, and 90% successfully obtained at least 4 days of valid measurements. PEF lability was calculated as the highest daily (PEF maximum - PEF minimum)/mean PEF.

RESULTS: Mean PEF measured at home was accurate when compared to PEF determined by spirometry in the clinic. Mean PEF lability was 18% in those with current asthma (n = 165) vs 12% in healthy nonsmokers (upper limit of normal, 29%). Approximately 26% of those with asthma and 14% of the other participants had abnormally high PEF lability (> 29%). After excluding participants with asthma, other independent predictors of high PEF lability included black race, current and former smoking, airway obstruction on spirometry, daytime sleepiness, recent wheezing, chronic cough, emphysema, and wheezing from lying in a supine position. Despite having a lower mean PEF, those reporting congestive heart failure (n = 82) did not have significantly higher PEF lability.

CONCLUSIONS: Measurement of PEF lability at home is highly successful in elderly persons. PEF lability > or = 30% is abnormal in the elderly and is associated with asthma.

%B Chest %V 120 %P 1861-8 %8 2001 Dec %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/11742914?dopt=Abstract %R 10.1378/chest.120.6.1861 %0 Journal Article %J Arterioscler Thromb Vasc Biol %D 2001 %T Estrogen replacement and brachial artery flow-mediated vasodilation in older women. %A Herrington, D M %A Espeland, M A %A Crouse, J R %A Robertson, J %A Riley, W A %A McBurnie, M A %A Burke, G L %K Aged %K Aged, 80 and over %K Analysis of Variance %K Brachial Artery %K Cardiovascular Diseases %K Drug Therapy, Combination %K Estrogen Replacement Therapy %K Estrogens %K Female %K Humans %K Longitudinal Studies %K Progestins %K Risk Factors %K Ultrasonography %K Vasodilation %X

It remains unclear whether estrogen therapy (with or without progestin) improves endothelial function in older postmenopausal women with or at risk for coronary heart disease. To address this issue, we analyzed brachial artery flow-mediated vasodilation in the Cardiovascular Health Study, a longitudinal study of cardiovascular risk factors in subjects over 65 years of age. At the tenth annual Cardiovascular Health Study examination, 1662 women returned for follow-up. Eighteen percent (n=291) were current users of estrogen replacement, most of whom (75.9%, n=221) took unopposed estrogen. Brachial artery ultrasound examinations measuring vasodilation in response to a flow stimulus (hyperemia) were performed on 1636 women. There were no statistical differences in brachial flow-mediated vasodilator responses between users and nonusers, even after adjustment for potential confounders. Absence of an effect was most notable in women over 80 years old and in those with established cardiovascular disease. However, among women without clinical or subclinical cardiovascular disease or its risk factors, there was a significant association between hormone replacement therapy use and flow-mediated vasodilator responses (P=0.01). Among older postmenopausal women, favorable vascular effects of estrogen may be limited to those who have not yet developed atherosclerotic vascular disease. These data emphasize the importance of ongoing efforts to determine the role of hormone replacement therapy for primary prevention of cardiovascular disease.

%B Arterioscler Thromb Vasc Biol %V 21 %P 1955-61 %8 2001 Dec %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/11742870?dopt=Abstract %R 10.1161/hq1201.100241 %0 Journal Article %J J Am Geriatr Soc %D 2001 %T Factors associated with healthy aging: the cardiovascular health study. %A Burke, G L %A Arnold, A M %A Bild, D E %A Cushman, M %A Fried, L P %A Newman, A %A Nunn, C %A Robbins, J %K Aged %K Aged, 80 and over %K Aging %K Cardiovascular Diseases %K Cohort Studies %K Diet %K Exercise %K Female %K Health Status %K Humans %K Incidence %K Life Style %K Longitudinal Studies %K Lung Diseases, Obstructive %K Male %K Neoplasms %K Probability %K Reference Values %K Risk Factors %K Sex Distribution %K Socioeconomic Factors %K Survival Rate %K United States %X

OBJECTIVES: To identify factors associated with remaining healthy in older adults.

DESIGN: Longitudinal cohort study.

SETTING: Data were collected at the four Cardiovascular Health Study field centers.

PARTICIPANTS: 5,888 participants age 65 years and older in the Cardiovascular Health Study.

MEASUREMENTS: Presence of chronic disease was assessed at baseline and over a maximum 7-year follow-up period. Participants who were free of chronic disease (no cardiovascular disease (CVD), chronic obstructive pulmonary disease, or self-reported cancer, except nonmelanoma skin cancer) at the baseline examination were then monitored for the onset of incident cancer, cardiovascular disease, and fatal outcomes.

RESULTS: A high proportion of these older adults was healthy at the initial examination and remained healthy over the follow-up period. Numerous behavioral factors were associated with continued health, including physical activity, refraining from cigarette smoking, wine consumption (women), higher educational status, and lower waist circumference. A number of CVD risk factors and subclinical disease measures were associated with continued health, including higher high-density lipoprotein (HDL) cholesterol, lack of diabetes, thinner common carotid intimal nmedial thickness, lower blood pressure, lower C-reactive protein, and higher ankle-arm blood pressure ratio. Among the behavioral factors, exercise, not smoking, and not taking aspirin remained significant predictors of health even after controlling for CVD risk factors and subclinical disease in older adults.

CONCLUSIONS: These data suggest that a number of modifiable behavioral factors (physical activity, smoking, and obesity) and cardiovascular risk factors (diabetes, HDL cholesterol, and blood pressure) are associated with maintenance of good health in older adults.

%B J Am Geriatr Soc %V 49 %P 254-62 %8 2001 Mar %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/11300235?dopt=Abstract %R 10.1046/j.1532-5415.2001.4930254.x %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2001 %T Frailty in older adults: evidence for a phenotype. %A Fried, L P %A Tangen, C M %A Walston, J %A Newman, A B %A Hirsch, C %A Gottdiener, J %A Seeman, T %A Tracy, R %A Kop, W J %A Burke, G %A McBurnie, M A %K Aged %K Aged, 80 and over %K Cohort Studies %K Disabled Persons %K Fatigue %K Female %K Frail Elderly %K Humans %K Incidence %K Male %K Muscle Weakness %K Phenotype %K Prevalence %K Sex Distribution %K United States %K Weight Loss %X

BACKGROUND: Frailty is considered highly prevalent in old age and to confer high risk for falls, disability, hospitalization, and mortality. Frailty has been considered synonymous with disability, comorbidity, and other characteristics, but it is recognized that it may have a biologic basis and be a distinct clinical syndrome. A standardized definition has not yet been established.

METHODS: To develop and operationalize a phenotype of frailty in older adults and assess concurrent and predictive validity, the study used data from the Cardiovascular Health Study. Participants were 5,317 men and women 65 years and older (4,735 from an original cohort recruited in 1989-90 and 582 from an African American cohort recruited in 1992-93). Both cohorts received almost identical baseline evaluations and 7 and 4 years of follow-up, respectively, with annual examinations and surveillance for outcomes including incident disease, hospitalization, falls, disability, and mortality.

RESULTS: Frailty was defined as a clinical syndrome in which three or more of the following criteria were present: unintentional weight loss (10 lbs in past year), self-reported exhaustion, weakness (grip strength), slow walking speed, and low physical activity. The overall prevalence of frailty in this community-dwelling population was 6.9%; it increased with age and was greater in women than men. Four-year incidence was 7.2%. Frailty was associated with being African American, having lower education and income, poorer health, and having higher rates of comorbid chronic diseases and disability. There was overlap, but not concordance, in the cooccurrence of frailty, comorbidity, and disability. This frailty phenotype was independently predictive (over 3 years) of incident falls, worsening mobility or ADL disability, hospitalization, and death, with hazard ratios ranging from 1.82 to 4.46, unadjusted, and 1.29-2.24, adjusted for a number of health, disease, and social characteristics predictive of 5-year mortality. Intermediate frailty status, as indicated by the presence of one or two criteria, showed intermediate risk of these outcomes as well as increased risk of becoming frail over 3-4 years of follow-up (odds ratios for incident frailty = 4.51 unadjusted and 2.63 adjusted for covariates, compared to those with no frailty criteria at baseline).

CONCLUSIONS: This study provides a potential standardized definition for frailty in community-dwelling older adults and offers concurrent and predictive validity for the definition. It also finds that there is an intermediate stage identifying those at high risk of frailty. Finally, it provides evidence that frailty is not synonymous with either comorbidity or disability, but comorbidity is an etiologic risk factor for, and disability is an outcome of, frailty. This provides a potential basis for clinical assessment for those who are frail or at risk, and for future research to develop interventions for frailty based on a standardized ascertainment of frailty.

%B J Gerontol A Biol Sci Med Sci %V 56 %P M146-56 %8 2001 Mar %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/11253156?dopt=Abstract %R 10.1093/gerona/56.3.m146 %0 Journal Article %J Neurology %D 2001 %T Frequency and predictors of stroke death in 5,888 participants in the Cardiovascular Health Study. %A Longstreth, W T %A Bernick, C %A Fitzpatrick, A %A Cushman, M %A Knepper, L %A Lima, J %A Furberg, C D %K Aged %K Aged, 80 and over %K Clinical Trials as Topic %K Female %K Humans %K Longitudinal Studies %K Male %K Predictive Value of Tests %K Stroke %K Survival Analysis %K United States %X

BACKGROUND: Few population-based studies have examined in detail issues of stroke-related deaths in elderly people.

METHODS: Participants in the Cardiovascular Health Study (CHS) are 65 years of age or older, have had extensive baseline evaluations, and have been followed-up for fatal and nonfatal cardiovascular and cerebrovascular disease outcomes. Investigators adjudicated these outcomes and classified strokes by types and subtypes.

RESULTS: Over 7 years, 1,310 (22.2%) of 5,888 participants died, and 455 (7.7%) experienced incident stroke. For the 5,888, stroke mortality was 3.2 per 1,000 person-years. For the 455, it was 36.1 per 1,000 person-years, with the most lethal type being hemorrhagic and the ischemic subtype being cardioembolic. After controlling for age and stroke type, the only other independent predictor of death after any stroke was poor performance on a timed walk measured before the incident stroke. Considering only ischemic stroke, the independent predictors of death were African American race and poor performance on timed walk.

CONCLUSION: In CHS, death attributable to stroke is common. As in other studies, the most lethal stroke type was hemorrhagic, and ischemic stroke subtype, cardioembolic. Slow walking, possibly a measure of frailty, was associated with an increased risk of death of stroke. Finally, African Americans faced a greater risk of death than others after an ischemic stroke.

%B Neurology %V 56 %P 368-75 %8 2001 Feb 13 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/11171903?dopt=Abstract %R 10.1212/wnl.56.3.368 %0 Journal Article %J J Am Geriatr Soc %D 2001 %T Gait variability in community-dwelling older adults. %A Brach, J S %A Berthold, R %A Craik, R %A VanSwearingen, J M %A Newman, A B %K Aged %K Aged, 80 and over %K Aging %K Body Height %K Body Weight %K Cross-Sectional Studies %K Disability Evaluation %K Female %K Gait %K Humans %K Male %K Residence Characteristics %K Risk Factors %K Time Factors %K Walking %X

OBJECTIVES: To describe gait variability at usual and fast walking speeds in community-dwelling older adults and to describe the effects of increasing gait speed on gait variability.

DESIGN: Cross-sectional, descriptive study.

SETTING: The Cardiovascular Health Study at the University of Pittsburgh.

PARTICIPANTS: Ninety-five community-living older adults, 54 women and 41 men, age 65 and older (mean age +/- standard deviation 79.4 +/- 3.37).

MEASUREMENTS: Gait measured at participant's usual and fast walking speed collected using an instrumented walkway. Step-length and step-width variability were determined using the coefficient of variation.

RESULTS: Step-length variability was greatest in those who walked the slowest (r = -0.66, P < .001); step-width variability was smallest in those who walked the slowest (r -0.37, P < .001). Individuals who could not increase their walking speed (<0.10 m/second) on command had an increase in step-length variability and a decrease in step-width variability, whereas those who could increase their speed (>0.10 m/second) had an increase in step-width variability when walking at a faster speed.

CONCLUSIONS: Step-length and step-width variability have opposite associations with gait speed in older adults. Improvement in step-length and step-width variability with attempted acceleration might be a key factor to examine in future studies of disability risk and therapeutic interventions.

%B J Am Geriatr Soc %V 49 %P 1646-50 %8 2001 Dec %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/11843998?dopt=Abstract %R 10.1046/j.1532-5415.2001.t01-1-49274.x %0 Journal Article %J Am J Respir Crit Care Med %D 2001 %T Hormone replacement therapy is associated with higher FEV1 in elderly women. %A Carlson, C L %A Cushman, M %A Enright, P L %A Cauley, J A %A Newman, A B %K Aged %K Aged, 80 and over %K Cohort Studies %K Estrogen Replacement Therapy %K Female %K Forced Expiratory Volume %K Humans %K Longitudinal Studies %K Spirometry %K Vital Capacity %X

Estrogen and progesterone use have been associated with improved pulmonary function in premenopausal women. However, little research has examined the relationship between hormone replacement therapy (HRT) and pulmonary function in postmenopausal women. We examined the relationship of HRT with spirometry in 2,353 women aged 65 yr and older participating in the Cardiovascular Health Study in 1993/1994. Current use of HRT was hypothesized to be associated with higher FEV1, higher FVC, and less pulmonary obstruction (FEV1/FVC < 65%). FEV1 was higher among current HRT users compared to noncurrent users in the following groups: overall (1.82 L versus 1.66 L, p < 0.0001), among women without asthma (1.85 L versus 1.69 L, p < 0.0001), among former smokers (1.76 L versus 1.60 L, p = 0.013), and among never smokers (1.90 L versus 1.72 L, p < 0.0001). Overall, HRT use was associated with a lower prevalence of pulmonary obstruction (OR 0.75 [95% CI 0.55, 0.99]). After controlling for potential confounders, HRT use was significantly associated with higher FEV(1) (p = 0.031) and with a lower prevalence of obstruction (OR 0.67 [95% CI 0.48, 0.95]). We conclude that postmenopausal women who use HRT have higher levels of FEV1 and less obstruction, which could not be explained by their lower rates of smoking and other health factors associated with HRT use.

%B Am J Respir Crit Care Med %V 163 %P 423-8 %8 2001 Feb %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/11179117?dopt=Abstract %R 10.1164/ajrccm.163.2.2003040 %0 Journal Article %J Am J Cardiol %D 2001 %T Importance of heart failure with preserved systolic function in patients > or = 65 years of age. CHS Research Group. Cardiovascular Health Study. %A Kitzman, D W %A Gardin, J M %A Gottdiener, J S %A Arnold, A %A Boineau, R %A Aurigemma, G %A Marino, E K %A Lyles, M %A Cushman, M %A Enright, P L %K Aged %K Aged, 80 and over %K Analysis of Variance %K Chi-Square Distribution %K Echocardiography, Doppler %K Female %K Health Status %K Heart Failure %K Humans %K Logistic Models %K Longitudinal Studies %K Male %K Prevalence %K Risk Factors %K Surveys and Questionnaires %K United States %K Ventricular Function, Left %X

Although congestive heart failure (CHF) is a common syndrome among the elderly, there is a relative paucity of population-based data, particularly regarding CHF with normal systolic left ventricular function. A total of 4,842 independent living, community-dwelling subjects aged 66 to 103 years received questionnaires on medical history, family history, personal habits, physical activity, and socioeconomic status, confirmation of pre-existing cardiovascular and cerebrovascular disease, anthropometric measurements, casual seated random-zero blood pressure, forced vital capacity and expiratory volume in 1 second, 12-lead supine electrocardiogram, fasting glucose, creatinine, plasma lipids, carotid artery wall thickness by ultrasonography, and echocardiography-Doppler examinations. Participants with at least 1 confirmed episode of CHF by Cardiovascular Health Study criteria were considered prevalent for CHF. The prevalence of CHF was 8.8% and was associated with increased age, particularly for women, in whom it increased more than twofold from age 65 to 69 years (6.6%) to age > or = 85 years (14%). In multivariate analysis, subjects with CHF were more likely to be older (odds ratio [OR] 1.2 for 5-year difference, men OR 1.1), and more often had a history of myocardial infarction (OR 7.3), atrial fibrillation (OR 3.0), diabetes mellitus (OR 2.1), renal dysfunction (OR 2.0 for creatinine < or = 1.5 mg/ dl), and chronic pulmonary disease (OR 1.8; women only). The echocardiographic correlates of CHF were increased left atrial and ventricular dimensions. Importantly, 55% of subjects with CHF had normal left ventricular systolic function and 80% had either normal or only mildly reduced systolic function. Among subjects with CHF, women had normal systolic function more frequently than men (67% vs 42%; p < 0.001). Thus, CHF is common among community-dwelling elderly. It increases with age and is usually associated with normal systolic LV function, particularly among women. The finding that a large proportion of elderly with CHF have preserved LV systolic function is important because there is a paucity of data to guide management in this dominant subset.

%B Am J Cardiol %V 87 %P 413-9 %8 2001 Feb 15 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/11179524?dopt=Abstract %R 10.1016/s0002-9149(00)01393-x %0 Journal Article %J J Natl Med Assoc %D 2001 %T Incidence and predictors of coronary heart disease among older African Americans--the Cardiovascular Health Study. %A Jackson, S A %A Burke, G L %A Thach, C %A Cushman, M %A Ives, D %A Powe, N %A Manolio, T A %K Age Distribution %K Aged %K Black or African American %K Coronary Disease %K Female %K Health Status %K Humans %K Incidence %K Male %K Predictive Value of Tests %X

Although coronary heart disease (CHD) is the leading cause of death and morbidity in older African Americans, relatively little is known about the incidence and predictors of CHD in this population. This study was undertaken to determine the incidence and predictors of CHD in African-American men and women aged 65 years and older. The participants in this study included a total of 924 African-American men and women aged 65 years of age and older who participated in the Cardiovascular Health Study (CHS). The overall CHD incidence was 26.6 per 1,000 person-years of risk. Rates were higher in men than women (35.3 vs. 21.6) and in those 75 years or older than in those less than 75 years (31.3 vs. 24.5). In multivariate analysis, factors associated with higher risk of incident disease were male gender [relative risk (RR) = 1.8, 95% confidence interval (CI) = 1.1, 2.7], diabetes mellitus (RR = 1.9, 95% CI = 1.2, 2.9), total cholesterol (RR for 40 mg/dL increment = 1.3, 95% CI = 1.0, 1.5), and low (i.e., <0.9) ankle-arm index (RR = 2.1, 95% CI = 1.3, 3.4) after adjusting for age. Within this cohort of older African Americans, male gender, diabetes mellitus, total cholesterol, and low ankle-arm index and were independently predictive of incident events. These results suggest that the ankle-arm index, a measure of advanced atherosclerosis, should be further evaluated for its efficacy in identifying older African Americans at risk for incident clinical events.

%B J Natl Med Assoc %V 93 %P 423-9 %8 2001 Nov %G eng %N 11 %1 https://www.ncbi.nlm.nih.gov/pubmed/11730114?dopt=Abstract %0 Journal Article %J Br J Haematol %D 2001 %T Post-menopausal hormone therapy and concentrations of protein C and antithrombin in elderly women. %A Cushman, M %A Psaty, B M %A Meilahn, E N %A Dobs, A S %A Kuller, L H %K Aged %K Antithrombins %K Black People %K Body Mass Index %K Cross-Sectional Studies %K Estrogen Replacement Therapy %K Female %K Humans %K Logistic Models %K Postmenopause %K Progestins %K Protein C %K Risk Factors %K Venous Thrombosis %K White People %X

The effects of post-menopausal hormone therapy (HRT) on blood coagulation in elderly women are not well defined. We studied associations of HRT use with levels of natural anticoagulant proteins in a cross-sectional study of 3393 women > or = 65 years of age participating in the Cardiovascular Health Study. Protein C antigen and antithrombin were measured in all users (n = 230 unopposed oestrogen; 60 oestrogen/progestin) and a comparison group of 196 age- and race-matched non-users. Compared with non-users, oestrogen use was associated with higher protein C (4.80 vs. 4.30 microg/ml, P < 0.01). Results were similar for oestrogen/progestin (P > 0.05). In both user groups, antithrombin was lower than in non-users (109% for each vs. 115% in non-users, P < 0.001). Adjustment for factors related to prescription of HRT and to anticoagulant protein levels had little impact on the results. For antithrombin, associations with HRT were larger for thinner Caucasian women and black women. Venous thrombosis from HRT may be mediated partly by alterations in antithrombin, but not protein C concentrations. This study extends previous observations to older women, the group at highest risk of venous thromboembolism. Studies of HRT-induced alterations in anticoagulant function in relation to the occurrence of thrombosis with HRT are required.

%B Br J Haematol %V 114 %P 162-8 %8 2001 Jul %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/11472362?dopt=Abstract %R 10.1046/j.1365-2141.2001.02911.x %0 Journal Article %J Diabetes Care %D 2001 %T Prevalence of clinical and isolated subclinical cardiovascular disease in older adults with glucose disorders: the Cardiovascular Health Study. %A Barzilay, J I %A Spiekerman, C F %A Kuller, L H %A Burke, G L %A Bittner, V %A Gottdiener, J S %A Brancati, F L %A Orchard, T J %A O'Leary, D H %A Savage, P J %K Aged %K Angina Pectoris %K Cardiovascular Diseases %K Cerebrovascular Disorders %K Cohort Studies %K Diabetes Mellitus %K Diabetes Mellitus, Type 1 %K Diabetes Mellitus, Type 2 %K Electrocardiography %K Female %K Glucose Intolerance %K Heart Diseases %K Humans %K Male %K Peripheral Vascular Diseases %K Prevalence %K United States %X

OBJECTIVE: Clinical cardiovascular disease (CVD) is highly prevalent among people with diabetes. However, there is little information regarding the prevalence of subclinical CVD and its relation to clinical CVD in diabetes and in the glucose disorders that precede diabetes.

RESEARCH DESIGN AND METHODS: Participants in the Cardiovascular Health Study, aged > or = 65 years (n = 5,888), underwent vascular and metabolic testing. Individuals with known disease in the coronary, cerebral, or peripheral circulations were considered to have clinical disease. Those without any clinical disease in whom CVD was detected by ultrasonography, electrocardiography, or ankle arm index in any of the three vascular beds were considered to have isolated subclinical disease.

RESULTS: Approximately 30% of the cohort had clinical disease, and approximately 60% of the remainder had isolated subclinical disease. In those with normal glucose status, isolated subclinical disease made up most of the total CVD. With increasing glucose severity, the proportion of total CVD that was clinical disease increased; 75% of men and 66% of women with normal fasting glucose status had either clinical or subclinical CVD. Among those with known diabetes, the prevalence was approximately 88% (odds ratio [OR] 2.46 for men and 4.22 for women, P < 0.0001). There were intermediate prevalences and ORs for those with impaired fasting glucose status and newly diagnosed diabetes.

CONCLUSIONS: Isolated subclinical CVD is common among older adults. Glucose disorders are associated with an increased prevalence of total CVD and an increased proportion of clinical disease relative to subclinical disease.

%B Diabetes Care %V 24 %P 1233-9 %8 2001 Jul %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/11423508?dopt=Abstract %R 10.2337/diacare.24.7.1233 %0 Journal Article %J J Hypertens %D 2001 %T Relation of hemodynamics and risk factors to ventricular-vascular interactions in the elderly: the Cardiovascular Health Study. %A de Simone, G %A McClelland, R %A Gottdiener, J S %A Celentano, A %A Kronmal, R A %A Gardin, J M %K Aged %K Aged, 80 and over %K Blood Pressure %K Carotid Arteries %K Compliance %K Cross-Sectional Studies %K Echocardiography %K Female %K Hemodynamics %K Humans %K Hypertension %K Hypertrophy, Left Ventricular %K Male %K Reference Values %K Risk Factors %K Stroke Volume %K Tunica Intima %K Tunica Media %K Ventricular Function, Left %X

OBJECTIVE: To investigate the interaction between left ventricular (LV) geometry, carotid structure and arterial compliance in relation to hemodynamic stimuli and risk factors (plasma cholesterol, body mass index, insulin resistance, smoking habit, age, sex and race).

DESIGN: Cross-sectional.

METHODS: Echocardiography and carotid ultrasound were performed in 2375 elderly subjects without signs or history of prevalent cardiovascular disease, diabetes or renal disease (795 men; 298 non-whites; 1215 hypertensive), from the cohort of the Cardiovascular Health Study. Arterial compliance was estimated by the prognostically validated ratio of stroke volume to pulse pressure (SV/PP) as the percent deviation (Delta%) from the value predicted by individual age, heart rate and body weight.

RESULTS: Intima-medial thickness (IMT) was higher in the presence of LV hypertrophy (LVH) in normotensive and hypertensive subjects and was greatest in the presence of concentric LVH. Maximum carotid lumen diameter (CLD) was also higher in the presence of LVH (and was greatest with eccentric LVH, in association with relatively high values for stroke volume). After adjusting for blood pressure, maximum carotid lumen diameter was directly correlated with stroke volume, and IMT to LV mass (all P < 0.001). Similarly, IMT was also related to maximum carotid lumen diameter, independently of prevalent risk factors (P < 0.001). SV/PP-Delta% was reduced in both groups with concentric LV remodeling (both P < 0.0001) or concentric LVH (both P < 0.05). Adjusting for risk factors did not affect these associations in normotensives, but made them insignificant in hypertensives. In normotensives, IMT was inversely related to SV/PP-Delta% (P < 0.001), independently of risk factors, whereas no significant relation was found in hypertensives.

CONCLUSIONS: The magnitudes of carotid intima-medial thickness and lumen diameter parallel levels of LV mass and geometry, and are directly related to stroke volume and arterial stiffness; this interaction is most evident in the presence of normal blood pressure, whereas it is affected by other cardiovascular risk factors when arterial hypertension is present.

%B J Hypertens %V 19 %P 1893-903 %8 2001 Oct %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/11593112?dopt=Abstract %R 10.1097/00004872-200110000-00026 %0 Journal Article %J Diabetes %D 2001 %T The relation of markers of inflammation to the development of glucose disorders in the elderly: the Cardiovascular Health Study. %A Barzilay, J I %A Abraham, L %A Heckbert, S R %A Cushman, M %A Kuller, L H %A Resnick, H E %A Tracy, R P %K Aged %K Biomarkers %K Blood Glucose %K C-Reactive Protein %K Cardiovascular Diseases %K Cohort Studies %K Diabetes Mellitus %K Female %K Humans %K Hypoglycemia %K Inflammation %K Longitudinal Studies %K Male %K Reference Values %K Risk Factors %X

Several studies suggest that inflammation plays a role in the pathogenesis of some glucose disorders in adults. We tested this hypothesis in a longitudinal cohort study of older individuals who had normal fasting glucose (FG) values at baseline. We compared the baseline levels of six inflammatory markers in participants who had developed glucose disorders at follow-up with those of participants whose FG remained normal at follow-up. Participants were members of the Cardiovascular Health Study, a prospective study of risk factors for cardiovascular disease in adults > or =65 years. All 5,888 participants had baseline testing, including FG and markers of inflammation: white blood cell and platelet counts and albumin, fibrinogen, C-reactive protein (CRP), and factor VIIIc levels. At 3-4 years of follow-up, 4,481 (84.5%) of those who were alive had FG levels retested. Participants who developed diabetes (n = 45) had higher median levels of CRP at baseline than those who remained normoglycemic. On multivariate analysis, those with elevated CRP levels (75th percentile [2.86 mg/l] vs. 25th percentile [0.82 mg/l]) were 2.03 times (95% confidence intervals, 1.44-2.86) more likely to have diabetes on follow-up. Adjustment for confounders and other inflammatory markers did not appreciably change this finding. There was no relationship between the development of diabetes and other markers of inflammation. Inflammation, as measured by CRP levels, is associated with the development of diabetes in the elderly. Understanding the role of inflammation in the pathogenesis of glucose disorders in this age-group may lead to better classification and treatment of glucose disorders among them.

%B Diabetes %V 50 %P 2384-9 %8 2001 Oct %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/11574423?dopt=Abstract %R 10.2337/diabetes.50.10.2384 %0 Journal Article %J J Clin Epidemiol %D 2001 %T The role of comorbidity in the assessment of intermittent claudication in older adults. %A Newman, A B %A Naydeck, B L %A Sutton-Tyrrell, K %A Polak, J F %A Kuller, L H %K Aged %K Angina Pectoris %K Arterial Occlusive Diseases %K Cerebrovascular Disorders %K Cohort Studies %K Comorbidity %K Diabetes Mellitus %K Female %K Humans %K Intermittent Claudication %K Leg %K Male %K Prevalence %K Sensitivity and Specificity %K Surveys and Questionnaires %X

The prevalence of intermittent claudication (IC) in older adults by questionnaire is less than 5% while the prevalence of peripheral arterial disease (PAD) by non-invasive testing is 2-4-fold higher. Comorbid conditions may result in under-reporting intermittent claudication (IC) as assessed by the Rose Questionnaire. We examined characteristics of those who report leg pain in relationship to other comorbid conditions and disability in 5888 participants of the Cardiovascular Health Study (CHS). Older adults with exertional leg pain, not meeting criteria for IC, had a higher prevalence of PAD on non-invasive testing with the ankle-arm index than those without pain, as well as a higher prevalence of arthritis. The pattern of responses suggested that pain for both conditions was reported together. The Rose Questionnaire for IC is specific for PAD, but a negative questionnaire does not indicate a lack of symptoms, rather the presence of PAD along with other conditions that can cause pain.

%B J Clin Epidemiol %V 54 %P 294-300 %8 2001 Mar %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/11223327?dopt=Abstract %R 10.1016/s0895-4356(00)00308-5 %0 Journal Article %J Neurology %D 2001 %T Silent MRI infarcts and the risk of future stroke: the cardiovascular health study. %A Bernick, C %A Kuller, L %A Dulberg, C %A Longstreth, W T %A Manolio, T %A Beauchamp, N %A Price, T %K Aged %K Cerebral Infarction %K Cohort Studies %K Female %K Follow-Up Studies %K Humans %K Incidence %K Magnetic Resonance Imaging %K Male %K Predictive Value of Tests %K Risk Factors %K Stroke %X

BACKGROUND: Silent infarcts are commonly discovered on cranial MRI in the elderly.

OBJECTIVE: To examine the association between risk of stroke and presence of silent infarcts, alone and in combination with other stroke risk factors.

METHODS: Participants (3,324) in the Cardiovascular Health Study (CHS) without a history of stroke underwent cranial MRI scans between 1992 and 1994. Silent infarcts were defined as focal lesions greater than 3 mm that were hyperintense on T2 images and, if subcortical, hypointense on T1 images. Incident strokes were identified and classified over an average follow-up of 4 years. The authors evaluated the risk of subsequent symptomatic stroke and how it was modified by other potential stroke risk factors among those with silent infarcts.

RESULTS: Approximately 28% of CHS participants had evidence of silent infarcts (n = 923). The incidence of stroke was 18.7 per 1,000 person-years in those with silent infarcts (n = 67) compared with 9.5 per 1,000 person-years in the absence of silent infarcts. The adjusted relative risk of incident stroke increased with multiple (more than one) silent infarcts (hazard ratio 1.9 [1.2 to 2.8]). Higher values of diastolic and systolic blood pressure, common and internal carotid wall thickness, and the presence of atrial fibrillation were associated with an increased risk of strokes in those with silent infarcts (n = 53 strokes).

CONCLUSION: The presence of silent cerebral infarcts on MRI is an independent predictor of the risk of symptomatic stroke over a 4-year follow- up in older individuals without a clinical history of stroke.

%B Neurology %V 57 %P 1222-9 %8 2001 Oct 09 %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/11591840?dopt=Abstract %R 10.1212/wnl.57.7.1222 %0 Journal Article %J J Am Geriatr Soc %D 2001 %T Weight change in old age and its association with mortality. %A Newman, A B %A Yanez, D %A Harris, T %A Duxbury, A %A Enright, P L %A Fried, L P %K Aged %K Analysis of Variance %K Body Weight %K Chi-Square Distribution %K Female %K Health Status %K Humans %K Longitudinal Studies %K Male %K Mortality %K Proportional Hazards Models %K Risk Factors %K United States %K Weight Gain %K Weight Loss %X

OBJECTIVES: Previous studies of weight change and mortality in older adults have relied on self-reported weight loss, have not evaluated weight gain, or have had limited information on health status. Our objective was to determine whether 5% weight gain or loss in 3 years was predictive of mortality in a large sample of older adults.

DESIGN: Longitudinal observational cohort study.

SETTING: Four U.S. communities.

PARTICIPANTS: Four thousand seven hundred fourteen community-dwelling older adults, age 65 and older.

MEASUREMENTS: Weight gain or loss of 5% in a 3-year period was examined in relationship to baseline health status and interim health events. Risk for subsequent mortality was estimated in those with weight loss or weight gain compared with the group whose weight was stable.

RESULTS: Weight changes occurred in 34.6% of women and 27.3% of men, with weight loss being more frequent than gain. Weight loss was associated with older age, black race, higher weight, lower waist circumference, current smoking, stroke, any hospitalization, death of a spouse, activities of daily living disability, lower grip strength, and slower gait speed. Weight loss but not weight gain of 5% or more was associated with an increased risk of mortality that persisted after multivariate adjustment (Hazard ratio (HR) = 1.67, 95% CI = 1.29-2.15) and was similar in those with no serious illness in the period of weight change. Those with weight loss and low baseline weight had the highest crude mortality rate, although the HR for weight loss was similar for all tertiles of baseline weight and for those with or without a special diet, compared with those whose weight was stable.

CONCLUSIONS: This study confirms that even modest decline in body weight is an important and independent marker of risk of mortality in older adults.

%B J Am Geriatr Soc %V 49 %P 1309-18 %8 2001 Oct %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/11890489?dopt=Abstract %R 10.1046/j.1532-5415.2001.49258.x %0 Journal Article %J Br J Haematol %D 2002 %T Anticardiolipin antibodies as a risk factor for venous thromboembolism in a population-based prospective study. %A Runchey, Shauna S %A Folsom, Aaron R %A Tsai, Michael Y %A Cushman, Mary %A McGovern, Paul D %K Aged %K Aged, 80 and over %K Antibodies, Anticardiolipin %K Case-Control Studies %K Female %K Humans %K Immunoglobulin G %K Immunoglobulin M %K Longitudinal Studies %K Male %K Middle Aged %K Odds Ratio %K Prospective Studies %K Reference Values %K Risk Factors %K Thromboembolism %K Venous Thrombosis %X

Anticardiolipin antibodies, one of the family of 'antiphospholipid' antibodies, increase the risk of venous thromboembolism in the presence of autoimmune disease. Our objective was to determine prospectively whether there is a positive association between anticardiolipin antibodies and venous thromboembolism in ostensibly healthy adults. We conducted a nested case-control study (n = 317 patients and n = 655 control subjects) in a longitudinal study of over 20 000 participants. Baseline (prediagnosis) anticardiolipin IgG and IgM antibodies were assessed by enzyme-linked immunoassays. Venous thromboembolism was validated using standardized criteria for venous thrombosis and pulmonary embolism. There was no association between anticardiolipin antibodies and subsequent venous thromboembolism occurrence, overall or in any subgroup. For example, the multivariate-adjusted relative risk was 0.88 (95% confidence interval, 0.43, 1.78) for greater than versus less than the 95th percentile of anticardiolipin IgG. In conclusion, in this general population sample, an elevated anticardiolipin antibody level was not a risk factor for venous thromboembolism.

%B Br J Haematol %V 119 %P 1005-10 %8 2002 Dec %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/12472581?dopt=Abstract %R 10.1046/j.1365-2141.2002.03949.x %0 Journal Article %J Age Ageing %D 2002 %T Calcium channel blocker use and gastrointestinal tract bleeding among older adults. %A Kaplan, Robert C %A Heckbert, Susan R %A Koepsell, Thomas D %A Rosendaal, Frits R %A Furberg, Curt D %A Cooper, Lawton S %A Psaty, Bruce M %K Aged %K Antihypertensive Agents %K Calcium Channel Blockers %K Gastrointestinal Hemorrhage %K Geriatric Assessment %K Health Services for the Aged %K Humans %K Hypertension %K Prospective Studies %K Risk Factors %B Age Ageing %V 31 %P 217-8 %8 2002 May %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/12006312?dopt=Abstract %R 10.1093/ageing/31.3.217 %0 Journal Article %J Kidney Int %D 2002 %T Cardiovascular disease risk status in elderly persons with renal insufficiency. %A Shlipak, Michael G %A Fried, Linda F %A Crump, Casey %A Bleyer, Anthony J %A Manolio, Teri A %A Tracy, Russell P %A Furberg, Curt D %A Psaty, Bruce M %K Age Distribution %K Aged %K Cholesterol, HDL %K Cholesterol, LDL %K Coronary Disease %K Creatinine %K Cross-Sectional Studies %K Female %K Humans %K Kidney Failure, Chronic %K Male %K Prevalence %K Prospective Studies %K Risk Factors %X

BACKGROUND: Renal insufficiency has been independently associated with incident cardiovascular disease events in some, but not all, prospective studies. We determined the prevalence of elevated cardiovascular disease risk status among elderly persons with renal insufficiency.

METHODS: This study is a cross-sectional analysis using data collected at the baseline visit of the Cardiovascular Health Study, which enrolled 5888 community dwelling adults aged 65 years or older from four clinical centers in the United States. Renal insufficiency was defined as a serum creatinine level > or =1.3 mg/dL in women and > or =1.5 mg/dL in men. The outcomes of this study included prevalent cardiovascular disease [prior coronary heart disease (CHD) or stroke], subclinical cardiovascular disease (abnormal values of ankle-arm index, carotid ultrasound, and echocardiography) and elevated cardiovascular risk based upon a diagnosis of diabetes and the Framingham equations. The association between renal insufficiency and cardiovascular risk status was estimated with and without adjustment for other cardiovascular predictors.

RESULTS: Among the 5808 participants with creatinine levels measured at entry, 15.9% of men (N = 394), and 7.6% of women (N = 254) had renal insufficiency. The prevalence of either clinical or subclinical cardiovascular disease was 64% in persons with renal insufficiency compared with 43% in those without it [odds ratio (OR) 2.34; 95% confidence interval (95% CI), 1.96, 2.80]. After adjustment for other cardiovascular risk factors, renal insufficiency remained significantly associated with clinical and subclinical cardiovascular disease (adjusted OR 1.43; 95% CI, 1.18, 1.75), but the magnitude of association was substantially reduced. After combining clinical and subclinical cardiovascular disease, diabetes, and an estimated risk>20% by the Framingham equations, 78% of men and 61% of women with renal insufficiency had elevated cardiovascular risk status.

CONCLUSIONS: Renal insufficiency is a marker for elevated cardiovascular disease risk in community dwelling elderly adults.

%B Kidney Int %V 62 %P 997-1004 %8 2002 Sep %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/12164883?dopt=Abstract %R 10.1046/j.1523-1755.2002.00522.x %0 Journal Article %J Arch Intern Med %D 2002 %T Cardiovascular risk factors and venous thromboembolism incidence: the longitudinal investigation of thromboembolism etiology. %A Tsai, Albert W %A Cushman, Mary %A Rosamond, Wayne D %A Heckbert, Susan R %A Polak, Joseph F %A Folsom, Aaron R %K Aged %K Arteriosclerosis %K Female %K Humans %K Incidence %K Male %K Middle Aged %K Multivariate Analysis %K Proportional Hazards Models %K Prospective Studies %K Pulmonary Embolism %K Risk Factors %K United States %K Venous Thrombosis %X

BACKGROUND: The association between traditional cardiovascular risk factors and risk of venous thromboembolism (VTE) has not been extensively examined in prospective studies.

METHODS: To determine whether atherosclerotic risk factors are also associated with increased incidence of VTE, we conducted a prospective study of 19 293 men and women without previous VTE in 6 US communities between 1987 and 1998.

RESULTS: There were 215 validated VTE events (1.45 per 1000 person-years) during a median of 8 years of follow-up. The age-adjusted hazard ratio was 1.4 (95% confidence interval [CI], 1.1-1.9) for men vs women, 1.6 (95% CI, 1.2-2.2) for blacks vs whites, and 1.7 (95% CI, 1.5-2.0) per decade of age. Cigarette smoking, hypertension, dyslipidemia, physical inactivity, and alcohol consumption were not associated with risk of VTE. Age-, race-, and sex-adjusted hazard ratios for body mass index categories (calculated as the weight in kilograms divided by the height in meters squared) of less than 25, 25 to less than 30, 30 to less than 35, 35 to less than 40, and 40 or more were 1.0, 1.5, 2.2, 1.5, and 2.7, respectively (P<.001 for the trend). Diabetes was also associated with an increased risk of VTE (adjusted hazard ratio, 1.5 [95% CI, 1.0-2.1]).

CONCLUSIONS: Our data showing no relationship of some arterial risk factors with VTE corroborate the view that the etiology of VTE differs from atherosclerotic cardiovascular disease. In addition, the findings suggest a hypothesis that avoidance of obesity and diabetes or vigilance in prophylaxis in patients with those conditions may prevent some venous thromboses.

%B Arch Intern Med %V 162 %P 1182-9 %8 2002 May 27 %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/12020191?dopt=Abstract %R 10.1001/archinte.162.10.1182 %0 Journal Article %J Stroke %D 2002 %T Cerebrovascular disease and evolution of depressive symptoms in the cardiovascular health study. %A Steffens, David C %A Krishnan, K Ranga Rama %A Crump, Casey %A Burke, Gregory L %K Aged %K Aged, 80 and over %K Basal Ganglia Cerebrovascular Disease %K Brain %K Cerebrovascular Disorders %K Cohort Studies %K Comorbidity %K Depression %K Disease Progression %K Female %K Health Surveys %K Humans %K Incidence %K Logistic Models %K Magnetic Resonance Imaging %K Male %K Neuropsychological Tests %K Odds Ratio %K United States %X

BACKGROUND AND PURPOSE: Previous studies have reported an association between cerebrovascular disease and depressive symptoms. The Cardiovascular Health Study (CHS) provides an opportunity to examine the relationship between vascular brain pathology seen on neuroimaging and changes in depressive symptoms.

METHODS: The sample included 3236 CHS participants who had an MRI brain scan. Demographic variables, medical history, functional status, and apolipoprotein E genotype were obtained at baseline. Annual scores on a modified version of the Centers for Epidemiologic Studies Depression (CES-D) scale were obtained initially and up to 7 years subsequently.

RESULTS: After controlling for important covariates, occurrence of depressive symptoms (defined as modified CES-D score of >7) was associated with small lesions in the basal ganglia, large cortical white-matter lesions, and severe subcortical white-matter grade. Neuroimaging variables did not predict incident depression among those who were nondepressive at the time of MRI. Persistence of depressive symptoms across 2 consecutive time points was associated with small basal ganglia lesions and large cerebral cortical white-matter lesions. Worsening of depression (increase in CES-D score of > or =5) was associated with subcortical white-matter lesions.

CONCLUSIONS: These findings suggest that cerebrovascular disease at baseline is related to depression symptoms over time. Further studies are needed to investigate the differential effects of subcortical white- versus gray-matter lesions on mood.

%B Stroke %V 33 %P 1636-44 %8 2002 Jun %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/12053004?dopt=Abstract %R 10.1161/01.str.0000018405.59799.d5 %0 Journal Article %J Am J Med %D 2002 %T Coagulation factors, inflammation markers, and venous thromboembolism: the longitudinal investigation of thromboembolism etiology (LITE). %A Tsai, Albert W %A Cushman, Mary %A Rosamond, Wayne D %A Heckbert, Susan R %A Tracy, Russell P %A Aleksic, Nena %A Folsom, Aaron R %K Aged %K Biomarkers %K Blood Coagulation Factors %K C-Reactive Protein %K Cohort Studies %K Confidence Intervals %K Factor VII %K Female %K Fibrinogen %K Humans %K Inflammation Mediators %K Longitudinal Studies %K Male %K Middle Aged %K Multivariate Analysis %K Prospective Studies %K Risk Assessment %K Risk Factors %K Sensitivity and Specificity %K Thromboembolism %K Venous Thrombosis %K von Willebrand Factor %X

PURPOSE: We sought to assess prospectively whether higher levels of blood coagulation factors and inflammation markers are risk factors for venous thromboembolism.

SUBJECTS AND METHODS: In two pooled population-based cohort studies, we measured levels of factor VII, factor VIII, von Willebrand factor, fibrinogen, and C-reactive protein, and white blood cell count, in samples obtained from 19,237 adults with no baseline history of venous thromboembolism, cancer, or warfarin use. The endpoint was validated venous thromboembolism during follow-up (median, 7.8 years).

RESULTS: A total of 159 venous thromboembolism events occurred. Factor VIII and von Willebrand factor were linearly associated with increased risk of venous thromboembolism (P for trend <0.0001). As compared with those in the lowest quartile, the multivariate-adjusted hazard ratio (HR) of venous thromboembolism was 2.6 (95% confidence interval [CI]: 1.6 to 4.3) for factor VIII levels in the highest quartile and 3.8 (95% CI: 2.0 to 7.2) for the highest fifth percentile. For von Willebrand factor, the hazard ratios in middle-aged subjects were 4.6 (95% CI: 2.2 to 9.2) for the highest quartile and 7.6 (95% CI: 3.1 to 18) for the highest fifth percentile. Factor VII levels above the 95th percentile, as compared with the lowest quartile, also conveyed a higher risk of venous thromboembolism (HR = 2.4; 95% CI: 1.2 to 4.8). In contrast, there was no association of venous thromboembolism with fibrinogen or C-reactive protein levels, or white cell count.

CONCLUSIONS: In this prospective study, elevated factor VIII and von Willebrand factor levels were common, independent, and dose-dependent risk factors for venous thromboembolism, and an elevated factor VII level was a possible risk factor. Venous thromboembolism, unlike arterial disease, was not related to inflammatory markers.

%B Am J Med %V 113 %P 636-42 %8 2002 Dec 01 %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/12505113?dopt=Abstract %R 10.1016/s0002-9343(02)01345-1 %0 Journal Article %J Arch Intern Med %D 2002 %T Frailty and activation of the inflammation and coagulation systems with and without clinical comorbidities: results from the Cardiovascular Health Study. %A Walston, Jeremy %A McBurnie, Mary Ann %A Newman, Anne %A Tracy, Russell P %A Kop, Willem J %A Hirsch, Calvin H %A Gottdiener, John %A Fried, Linda P %K Aged %K Aged, 80 and over %K Blood Coagulation Disorders %K Cardiovascular Diseases %K Cohort Studies %K Diabetes Complications %K Diabetes Mellitus %K Female %K Frail Elderly %K Geriatric Assessment %K Humans %K Inflammation %K Longitudinal Studies %K Male %X

BACKGROUND: The biological basis of frailty has been difficult to establish owing to the lack of a standard definition, its complexity, and its frequent coexistence with illness.

OBJECTIVE: To establish the biological correlates of frailty in the presence and absence of concurrent cardiovascular disease and diabetes mellitus.

METHODS: Participants were 4735 community-dwelling adults 65 years and older. Frail, intermediate, and nonfrail subjects were identified by a validated screening tool and exclusion criteria. Bivariate relationships between frailty level and physiological measures were evaluated by Pearson chi2 tests for categorical variables and analysis of variance F tests for continuous variables. Multinomial logistic regression was performed to evaluate multivariable relationships between frailty status and physiological measures.

RESULTS: Of 4735 Cardiovascular Health Study participants, 299 (6.3%) were identified as frail, 2147 (45.3%) as intermediate, and 2289 (48.3%) as not frail. Frail vs nonfrail participants had increased mean +/- SD levels of C-reactive protein (5.5 +/- 9.8 vs 2.7 +/- 4.0 mg/L), factor VIII (13 790 +/- 4480 vs 11 860 +/- 3460 mg/dL), and, in a smaller subset, D dimer (647 +/- 1033 vs 224 +/- 258 ng/mL) (P< or =.001 for all, chi2 test for trend). These differences persisted when individuals with cardiovascular disease and diabetes were excluded and after adjustment for age, sex, and race.

CONCLUSIONS: These findings support the hypothesis that there is a specific physiological basis to the geriatric syndrome of frailty that is characterized in part by increased inflammation and elevated markers of blood clotting and that these physiological differences persist when those with diabetes and cardiovascular disease are excluded.

%B Arch Intern Med %V 162 %P 2333-41 %8 2002 Nov 11 %G eng %N 20 %1 https://www.ncbi.nlm.nih.gov/pubmed/12418947?dopt=Abstract %R 10.1001/archinte.162.20.2333 %0 Journal Article %J Stroke %D 2002 %T Incidence, manifestations, and predictors of brain infarcts defined by serial cranial magnetic resonance imaging in the elderly: the Cardiovascular Health Study. %A Longstreth, W T %A Dulberg, Corinne %A Manolio, Teri A %A Lewis, Michael R %A Beauchamp, Norman J %A O'Leary, Daniel %A Carr, Jeff %A Furberg, Curt D %K Aged %K Brain Infarction %K California %K Cohort Studies %K Creatinine %K Follow-Up Studies %K Humans %K Incidence %K Longitudinal Studies %K Magnetic Resonance Imaging %K Maryland %K Multivariate Analysis %K Neuropsychological Tests %K North Carolina %K Odds Ratio %K Pennsylvania %K Predictive Value of Tests %K Risk Factors %X

BACKGROUND AND PURPOSE: MRI-defined infarcts are common in the elderly. We sought to explore incidence, manifestations, and predictors of such infarcts.

METHODS: The Cardiovascular Health Study (CHS) is a population-based, longitudinal study of 5888 people aged > or =65 years. Participants have had extensive baseline and follow-up evaluations; 1433 participants underwent 2 MRI scans separated by 5 years and had no infarcts on initial MRI.

RESULTS: On follow-up MRI, 254 participants (17.7%) had 1 or more infarcts. Most were single (75.6%), subcortical (79.9%), and small (3 to 20 mm in 87.0%). Only 11.4% of those with infarcts experienced a documented transient ischemic attack or stroke between the scans. Although participants were similar at initial MRI, those with MRI-defined infarcts on follow-up experienced greater decline than those without infarcts on the Modified Mini-Mental State Examination and Digit-Symbol Substitution test (both P<0.01). Severity of white matter changes on initial MRI was the strongest predictor of incident infarcts. When it was excluded from stepwise multivariable models, predictors were serum creatinine, age, and ankle-arm index.

CONCLUSIONS: Incident MRI-defined infarcts commonly affect the elderly. Most are small, subcortical, and not associated with acute symptoms recognized as a transient ischemic attack or stroke. Nonetheless, they cannot be considered silent because of their association with subtle cognitive deficits. These covert infarcts are associated with white matter changes, which may share a common pathophysiology. Whether control of vascular risk factors, such as blood pressure, would reduce the risk of developing these infarcts and associated cognitive decline deserves further investigation.

%B Stroke %V 33 %P 2376-82 %8 2002 Oct %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/12364724?dopt=Abstract %R 10.1161/01.str.0000032241.58727.49 %0 Journal Article %J Am J Cardiol %D 2002 %T Left atrial dimensions determined by M-mode echocardiography in black and white older (> or =65 years) adults (The Cardiovascular Health Study). %A Manolio, Teri A %A Gottdiener, John S %A Tsang, Teresa S M %A Gardin, Julius M %K African Continental Ancestry Group %K Age Factors %K Aged %K Blood Flow Velocity %K Body Weight %K Cardiovascular Diseases %K Echocardiography %K Electrocardiography %K European Continental Ancestry Group %K Evidence-Based Medicine %K Female %K Heart Atria %K Heart Ventricles %K Humans %K Male %K Multivariate Analysis %K Prospective Studies %K Risk Factors %K Statistics as Topic %K Ventricular Function, Left %X

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

%B Am J Cardiol %V 90 %P 983-7 %8 2002 Nov 01 %G eng %N 9 %1 https://www.ncbi.nlm.nih.gov/pubmed/12398966?dopt=Abstract %R 10.1016/s0002-9149(02)02665-6 %0 Journal Article %J Thromb Haemost %D 2002 %T No association of plasma prothrombin concentration or the G20210A mutation with incident cardiovascular disease: results from the Cardiovascular Health Study. %A Smiles, Adam M %A Jenny, Nancy S %A Tang, Zhonghua %A Arnold, Alice %A Cushman, Mary %A Tracy, Russell P %K 3' Untranslated Regions %K Aged %K Aged, 80 and over %K Alleles %K Angina Pectoris %K Blood Proteins %K Cardiovascular Diseases %K Case-Control Studies %K Comorbidity %K Diabetes Mellitus %K Female %K Genetic Predisposition to Disease %K Humans %K Hyperlipidemias %K Hypertension %K Male %K Mutation %K Myocardial Infarction %K Obesity %K Promoter Regions, Genetic %K Prothrombin %K Risk Factors %K Smoking %K Stroke %K Vermont %X

Prothrombin is a key factor in blood clotting, a process intimately involved in thrombotic disease. We assessed prothrombin levels and G20210A genotype in a case-control study within the Cardiovascular Health Study. Cases included angina, myocardial infarction, stroke, and the presence of MRI-detectable infarcts (n approximately 250 each). Population-based controls free of clinical cardiovascular disease (CVD) (n approximately 500) and a subset free of clinical and subclinical CVD (n approximately 250) were used for comparison. The 20210 A allele, frequency 2.9%, was associated with higher mean prothrombin levels: 166.3 vs. 139.5 microg/ml (P <0.001). Significant correlates of prothrombin included gender, plasma lipids, other vitamin K-dependent proteins, and inflammatory markers, but not race, smoking, hypertension, diabetes, measures of subclinical CVD, or markers of procoagulant activity. Compared to controls, neither genotype nor prothrombin level was associated with any CVD case group. We conclude that, in the elderly, neither prothrombin level nor 20210 genotype were associated with either CVD risk factors or events. This is consistent with the lack of association of prothrombin levels with measures of underlying CVD or procoagulant markers.

%B Thromb Haemost %V 87 %P 614-21 %8 2002 Apr %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/12008943?dopt=Abstract %0 Journal Article %J Ann Intern Med %D 2002 %T Outcome of congestive heart failure in elderly persons: influence of left ventricular systolic function. The Cardiovascular Health Study. %A Gottdiener, John S %A McClelland, Robyn L %A Marshall, Robert %A Shemanski, Lynn %A Furberg, Curt D %A Kitzman, Dalane W %A Cushman, Mary %A Polak, Joseph %A Gardin, Julius M %A Gersh, Bernard J %A Aurigemma, Gerard P %A Manolio, Teri A %K Aged %K Cause of Death %K Echocardiography %K Female %K Heart Failure %K Humans %K Longitudinal Studies %K Male %K Myocardial Infarction %K Prevalence %K Prognosis %K Risk Factors %K Stroke %K Ventricular Dysfunction, Right %K Ventricular Function, Left %X

BACKGROUND: Most persons with congestive heart failure are elderly, and many elderly persons with congestive heart failure have normal left ventricular systolic function.

OBJECTIVE: To evaluate the relationship between left ventricular systolic function and outcome of congestive heart failure in elderly persons.

DESIGN: Population-based longitudinal study of coronary heart disease and stroke.

SETTING: Four U.S. sites: Forsyth County, North Carolina; Sacramento County, California; Allegheny County, Pennsylvania; and Washington County, Maryland.

PARTICIPANTS: 5888 persons who were at least 65 years of age and were recruited from the community.

MEASUREMENTS: Total mortality and cardiovascular morbidity and mortality.

RESULTS: Of 5532 participants, 269 (4.9%) had congestive heart failure. Among these, left ventricular function was normal in 63%, borderline decreased in 15%, and overtly impaired in 22%. The mortality rate was 25 deaths per 1000 person-years in the reference group (no congestive heart failure and normal left ventricular function at baseline); 154 deaths per 1000 person-years in participants with congestive heart failure and impaired left ventricular systolic function; 87 and 115 deaths per 1000 person-years in participants with congestive heart failure and normal or borderline systolic function, respectively; and 89 deaths per 1000 person-years in persons with impaired left ventricular function but no congestive heart failure. Although the risk for death from congestive heart failure was lower in persons with normal systolic function than in those with impaired function, more deaths were associated with normal systolic function because more persons with heart failure fall into this category.

CONCLUSIONS: Community-dwelling elderly persons, especially those with impaired left ventricular function, have a substantial risk for death from congestive heart failure. However, more deaths occur from heart failure in persons with normal systolic function because left ventricular function is more often normal than impaired in elderly persons with heart failure.

%B Ann Intern Med %V 137 %P 631-9 %8 2002 Oct 15 %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/12379062?dopt=Abstract %R 10.7326/0003-4819-137-8-200210150-00006 %0 Journal Article %J J Vasc Surg %D 2002 %T Prevalence of renovascular disease in the elderly: a population-based study. %A Hansen, Kimberley J %A Edwards, Matthew S %A Craven, Timothy E %A Cherr, Gregory S %A Jackson, Sharon A %A Appel, Richard G %A Burke, Gregory L %A Dean, Richard H %K Age Factors %K Aged %K Aged, 80 and over %K Cohort Studies %K Ethnic Groups %K Female %K Humans %K Longitudinal Studies %K Male %K Prevalence %K Prospective Studies %K Renal Artery %K Renal Artery Obstruction %K Risk Factors %K Sex Factors %K Ultrasonography, Doppler, Duplex %X

PURPOSE: The purpose of this investigation was to estimate the population-based prevalence of renovascular disease (RVD), defined as > or = 60% diameter-reducing renal artery stenosis or occlusion, and to define its associations with age, gender, race, and other potential risk factors among participants in the Cardiovascular Health Study (CHS).

METHODS: The CHS is a multicenter, longitudinal cohort study of cardiovascular disease risk factors, morbidity, and mortality among free-living adults of more than 65 years of age. As part of an ancillary investigation, participants in the Forsyth County cohort of the CHS were invited to undergo renal duplex sonography (RDS) to define the presence or absence of RVD. RVD was defined as stenosis with a focal renal artery peak systolic velocity exceeding 1.8 m/s in the main renal artery and defined as occlusion when an imaged renal artery lacked a Doppler signal. Demographic and atherosclerotic risk factor data were gathered as part of the baseline CHS examination. Univariable tests of association were performed with chi(2) and Student t tests and logistic regression analysis. Multivariate associations were examined with logistic regression analysis.

RESULTS: Eight hundred seventy CHS participants underwent RDS. Of these examinations, 834 (96%) were technically adequate to define the presence or absence of RVD. The RDS study cohort had a mean age of 77.2 +/- 4.9 years and consisted of 63% women and 37% men. Participant race was 76% white and 23% African American. The overall prevalence rate of RVD was 6.8%. Among the 57 patients with RVD, 50 (88%) had unilateral disease and seven (12%) had bilateral disease. Seven cases were seen of renal artery occlusion, including one case with contralateral renal artery stenosis. The mean ages of patients with and without RVD were 78.7 +/- 5.7 years and 77.1 +/- 4.9 years (P =.018). RVD was present in 5.5% of women and 9.1% of men (P =.053). RVD was present in 6.9% of white participants and 6.7% of African American participants (P =.933). Multivariate analysis revealed increasing participant age (P =.028; odds ratio, 1.34; 95% CI, 1.03, 1.73), high-density lipoprotein cholesterol levels of less than 40 mg/dL (P =.003; odds ratio, 2.63; 95% CI, 1.40, 4.93), and increasing systolic blood pressure (P =.007; odds ratio, 1.44; 95% CI, 1.10, 1.87) to be significantly and independently associated with the presence of RVD.

CONCLUSION: This investigation provides the first population-based estimate of the prevalence of RVD among free-living, elderly black and white Americans. RVD was present in 6.8% of the study cohort. RVD showed no association with ethnicity. However, its presence was significantly and independently associated with increasing age, low high-density lipoprotein cholesterol levels, and increasing systolic blood pressure.

%B J Vasc Surg %V 36 %P 443-51 %8 2002 Sep %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/12218965?dopt=Abstract %R 10.1067/mva.2002.127351 %0 Journal Article %J Am J Hematol %D 2002 %T Prospective study of the G20210A polymorphism in the prothrombin gene, plasma prothrombin concentration, and incidence of venous thromboembolism. %A Folsom, Aaron R %A Cushman, Mary %A Tsai, Michael Y %A Heckbert, Susan R %A Aleksic, Nena %K African Continental Ancestry Group %K Age Factors %K Aged %K Case-Control Studies %K European Continental Ancestry Group %K Genotype %K Humans %K Incidence %K Middle Aged %K Odds Ratio %K Polymorphism, Single Nucleotide %K Prospective Studies %K Prothrombin %K Recurrence %K Research Design %K Risk Factors %K Thromboembolism %K United States %X

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

%B Am J Hematol %V 71 %P 285-90 %8 2002 Dec %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/12447958?dopt=Abstract %R 10.1002/ajh.10229 %0 Journal Article %J Blood %D 2002 %T A prospective study of venous thromboembolism in relation to factor V Leiden and related factors. %A Folsom, Aaron R %A Cushman, Mary %A Tsai, Michael Y %A Aleksic, Nena %A Heckbert, Susan R %A Boland, Lori L %A Tsai, Albert W %A Yanez, N David %A Rosamond, Wayne D %K Activated Protein C Resistance %K Aged %K Cohort Studies %K Continental Population Groups %K Factor V %K Genotype %K Haplotypes %K Humans %K Incidence %K Longitudinal Studies %K Middle Aged %K Odds Ratio %K Prospective Studies %K Risk Factors %K Thromboembolism %K Venous Thrombosis %X

The aim of this study was to examine the occurrence of venous thromboembolism (VTE) in relation to factor V-related risk factors. Using a nested case-control design combining 2 population-based prospective studies, we measured factor V Leiden, HR2 haplotype, activated protein C (APC) resistance, and plasma factor V antigen in 335 participants who developed VTE during 8 years of follow-up and 688 controls. The overall odds ratio (OR) of VTE was 3.67 (95% CI, 2.20-6.12) in participants carrying factor V Leiden compared with noncarriers. APC resistance measured after predilution with factor V-deficient plasma conferred an OR of 2.58 (95% CI, 1.62-4.10). All 3 participants homozygous for the HR2 haplotype had a VTE, and the OR of VTE for homozygosity was estimated to be 5.5 (95% CI, 2.45-12.5). Carriers of the HR2 haplotype otherwise were not at increased risk of VTE overall (OR = 1.05; 95% CI, 0.64-1.72), but double heterozygotes for HR2 and factor V Leiden carried an OR of idiopathic VTE of 16.3 (95% CI, 1.7-159) compared with noncarriers. Factor V antigen also was not associated with VTE overall, but for participants with the combination of high factor V antigen plus factor V Leiden the OR of idiopathic VTE was 11.5 (95% CI, 4.2-31.4). In the general population, APC resistance and factor V Leiden were important VTE risk factors; homozygosity for the HR2 haplotype may be a risk factor but was rare; otherwise, HR2 haplotype and factor V antigen were not risk factors except in carriers of factor V Leiden.

%B Blood %V 99 %P 2720-5 %8 2002 Apr 15 %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/11929758?dopt=Abstract %R 10.1182/blood.v99.8.2720 %0 Journal Article %J Arterioscler Thromb Vasc Biol %D 2002 %T Protein C, antithrombin, and venous thromboembolism incidence: a prospective population-based study. %A Folsom, Aaron R %A Aleksic, Nena %A Wang, Lu %A Cushman, Mary %A Wu, Kenneth K %A White, Richard H %K Adult %K Aged %K Aged, 80 and over %K Antithrombins %K Arteriosclerosis %K Cohort Studies %K Humans %K Incidence %K Longitudinal Studies %K Middle Aged %K Odds Ratio %K Population Surveillance %K Prospective Studies %K Protein C %K Protein C Deficiency %K Pulmonary Embolism %K Thromboembolism %K Venous Thrombosis %X

Although deficiencies of protein C and antithrombin, 2 natural plasma anticoagulants, are known risk factors for venous thrombosis, population-based prospective incidence data on these associations are lacking. Venous thromboembolic events have been identified in adults in 2 longitudinal cohort studies, the Atherosclerosis Risk in Communities (ARIC) Study and the Cardiovascular Health Study (CHS). Incidence was examined in relation to prediagnostic plasma levels of protein C (ARIC Study only) and antithrombin. Over a mean of 8.1 years of follow-up, there were 130 incident venous thromboembolic events that were not due to cancer in the ARIC Study. The age-adjusted incidence was elevated 3.36-fold (95% CI 1.24 to 9.11) in the 1.1% of subjects with protein C values <2.0 mg/L compared with subjects with higher values. In contrast, in the ARIC Study and the CHS, there was no association between low plasma antithrombin and venous thromboembolism. In conclusion, in this population-based study, a low protein C, but not antithrombin, level has been determined to be associated with an increased incidence of venous thromboembolism. Attributable risk estimates suggest that low protein C levels account for approximately 2.5% of venous thromboembolic events in the ARIC population.

%B Arterioscler Thromb Vasc Biol %V 22 %P 1018-22 %8 2002 Jun 01 %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/12067914?dopt=Abstract %R 10.1161/01.atv.0000017470.08363.ab %0 Journal Article %J Ann Epidemiol %D 2002 %T A regression model for longitudinal change in the presence of measurement error. %A Yanez, N David %A Kronmal, Richard A %A Shemanski, Lynn R %A Psaty, Bruce M %K Aged %K Bias %K Coronary Disease %K Humans %K Lipoproteins %K Models, Statistical %K Regression Analysis %K Risk Factors %X

PURPOSE: The analysis of change in measured variables has become quite popular in studies where data are collected repeatedly over time. The authors describe some of the potential pitfalls in the analysis of change when the variable for change is measured with error. They show that regression analysis is often biased, possibly leading to erroneous results.

METHODS: A simple method to correct for measurement error bias in regression models that model change is presented.

RESULTS AND CONCLUSIONS: The two examples illustrate how measurement error can adversely affect an analysis. The bias-corrected approach yields valid results.

%B Ann Epidemiol %V 12 %P 34-8 %8 2002 Jan %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/11750238?dopt=Abstract %R 10.1016/s1047-2797(01)00280-0 %0 Journal Article %J Addiction Research and Theory %D 2002 %T Reproducibility of two approaches for assessing alcohol consumption among older adults. %A Crum, RM %A Puddey, I %A Gilbert, CG %A Fried, LP %K alcohol %K elderly %K measurement %K questionnaire %X Objectives: In this study, we hypothesized that there is greater disclosure in self reports of alcohol intake when details of quantity-frequency measures of alcohol consumption are ascertained in the context of a general health and life style questionnaire as compared to a directed interview on usual drinking habits. Methods: Data are from the 1993 to 1994 follow-up of the Washington County cohort of men and women 65 years and older, participating in the Cardiovascular Health Study. A total of 918 subjects completed a questionnaire evaluation of their usual alcohol consumption by two separate approaches: (1) alcohol intake was derived from responses to questions contained within a medical and personal history questionnaire; (2) the same questions were within a medical and personal history questionnaire. Results: The mean alcohol intake for the entire cohort, and for drinkers alone were almost identical when assessed by either questionnaire, with high correlation between the two estimates, irrespective of beverage type. There was 89% agreement classifying drinkers versus nondrinkers by both approaches, with the strength of the agreement good (k=0.76). This agreement became moderate if drinkers were further categorized into three levels of alcohol intake. Predictors of the differences in alcohol intake between the two questionnaires were explored by multiple regression. Differences were largest for those who stated that the reason they drank was because they were no longer working, and for those drinking on average more than 24g (greater than approximately 2 drinks) of alcohol daily. Discussion: Although agreement between the two approaches was generally comparable, some findings may indicate that older adults who are problem drinkers or drink heavily report lower consumption patterns when administered a more directed questionnaire specifically focusing on drinking behavior. These findings have implications in the design of studies measuring alcohol consumption among elderly persons with a relatively low background alcohol intake. %B Addiction Research and Theory %V 10 %P 385 %8 2002-01-01 %G eng %N 4 %& 373 %0 Journal Article %J Neurology %D 2002 %T Serum potassium level and dietary potassium intake as risk factors for stroke. %A Green, D M %A Ropper, A H %A Kronmal, R A %A Psaty, B M %A Burke, G L %K Aged %K Cohort Studies %K Confidence Intervals %K Diuretics %K Humans %K Linear Models %K Male %K Potassium %K Potassium, Dietary %K Proportional Hazards Models %K Prospective Studies %K Risk Factors %K Stroke %X

BACKGROUND: Numerous studies have found that low potassium intake and low serum potassium are associated with increased stroke mortality, but data regarding stroke incidence have been limited. Serum potassium levels, dietary potassium intake, and diuretic use in relation to risk for stroke in a prospectively studied cohort were investigated.

METHODS: The study comprised 5,600 men and women older than 65 years who were free of stroke at enrollment. Baseline data included serum potassium level, dietary potassium intake, and diuretic use. Participants were followed for 4 to 8 years, and the incidence and types of strokes were recorded. Low serum potassium was defined as less than 4.1 mEq/L, and low potassium intake as less than 2.4 g/d.

RESULTS: Among diuretic users, there was an increased risk for stroke associated with lower serum potassium (relative risk [RR]: 2.5, p < 0.0001). Among individuals not taking diuretics, there was an increased risk for stroke associated with low dietary potassium intake (RR: 1.5, p < 0.005). The small number of diuretic users with lower serum potassium and atrial fibrillation had a 10-fold greater risk for stroke compared with those with higher serum potassium and normal sinus rhythm.

CONCLUSIONS: A lower serum potassium level in diuretic users, and low potassium intake in those not taking diuretics were associated with increased stroke incidence among older individuals. Lower serum potassium was associated with a particularly high risk for stroke in the small number of diuretic users with atrial fibrillation. Further study is required to determine if modification of these factors would prevent strokes.

%B Neurology %V 59 %P 314-20 %8 2002 Aug 13 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/12177362?dopt=Abstract %R 10.1212/wnl.59.3.314 %0 Journal Article %J J Clin Epidemiol %D 2002 %T A stroke prediction score in the elderly: validation and Web-based application. %A Lumley, Thomas %A Kronmal, Richard A %A Cushman, Mary %A Manolio, Teri A %A Goldstein, Steven %K Aged %K Aged, 80 and over %K Blood Pressure %K Female %K Follow-Up Studies %K Humans %K Incidence %K Male %K Models, Cardiovascular %K Predictive Value of Tests %K Risk Factors %K ROC Curve %K Stroke %K United States %X

The objective of this study was to construct a prediction model for predicting stroke in an elderly U.S. population, and to assess the accuracy in this population of other previously published prediction models. The subjects were participants in the Cardiovascular Health Study: 2,495 men and 3,393 women age 65 years and older at baseline, and followed for 6.3 years. Among 5,711 participants free of baseline stroke, 399 strokes occurred. Sex-specific prediction equations were constructed using study variables that were most importantly related to incident stroke: age, systolic blood pressure, diabetes, ECG diagnosis of atrial fibrillation or left ventricular hypertrophy, confirmed history of cardiovascular disease, diabetes, time to walk 15 ft, and serum creatinine. The prediction rule was implemented as a risk score and in a Web-based interactive Java applet. Overall, the model predicted 5-year stroke risks ranging from less than 1 to 59%. The 20% of subjects in the highest predicted risk group had a 5-year actual stroke incidence rate of 15%, while the 20% lowest risk group had a 1% incidence. Risk scores from two other studies performed well in these study participants. Effective discrimination between low and high stroke risk in the elderly was possible in this cohort with data that are easy to obtain. Evaluation of the generalizability and clinical usefulness of this prediction model requires further research.

%B J Clin Epidemiol %V 55 %P 129-36 %8 2002 Feb %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/11809350?dopt=Abstract %R 10.1016/s0895-4356(01)00434-6 %0 Journal Article %J Arch Intern Med %D 2002 %T Time trends in high blood pressure control and the use of antihypertensive medications in older adults: the Cardiovascular Health Study. %A Psaty, Bruce M %A Manolio, Teri A %A Smith, Nicholas L %A Heckbert, Susan R %A Gottdiener, John S %A Burke, Gregory L %A Weissfeld, Joel %A Enright, Paul %A Lumley, Thomas %A Powe, Neil %A Furberg, Curt D %K Age Factors %K Aged %K Antihypertensive Agents %K Awareness %K Cohort Studies %K Drug Therapy %K Female %K Health Knowledge, Attitudes, Practice %K Humans %K Hypertension %K Male %K Prospective Studies %K Time Factors %X

BACKGROUND: Control of high blood pressure (BP) in older adults is an important part of public health efforts at prevention.

OBJECTIVE: To assess recent time trends in the awareness, treatment, and control of high BP and in the use of medications to treat high BP.

METHODS: In the Cardiovascular Health Study, 5888 adults 65 years and older were recruited from 4 US centers. At baseline, participants underwent an extensive examination that included the measurement of BP, use of medications, and other risk factors. Participants were followed up with annual visits that assessed BP and medication use from baseline in 1989-1990 through the examination in 1998-1999. The primary outcome measures were control of BP to levels lower than than 140/90 mm Hg and the prevalence of use of various classes of antihypertensive medications.

RESULTS: The awareness, treatment, and control of high BP improved during the 1990s. The proportions aware and treated were higher among blacks than whites, though control prevalences were similar. For both groups combined, the control of high BP to lower than 140/90 mm Hg increased from 37% at baseline to 49% in 1999. The 51% whose BP was not controlled generally had isolated mild to moderate elevations in systolic BP. Among treated persons, the improvement in control was achieved in part by a mean increase of 0.2 antihypertensive medications per person over the course of 9 years. Improved control was also achieved by increasing the proportion of the entire Cardiovascular Health Study population that was treated for hypertension, from 34.5% in 1990 to 51.1% in 1999. Time trends in antihypertensive drug use were pronounced. Among those without coronary disease, the use of low-dose diuretics and beta-blockers decreased, while the use of newer agents, such as calcium channel blockers, angiotensin-converting enzyme inhibitors, and alpha-blockers increased.

CONCLUSIONS: While control of high BP improved in the 1990s, about half the participants with hypertension had uncontrolled BP, primarily mild to moderate elevations in systolic BP. Low-dose diuretics and beta-blockers--the preferred agents since 1993 according to the recommendations of the Joint National Committee on the Detection, Evaluation and Treatment of High Blood Pressure--remained underused. More widespread use of these agents will be an important intervention to prevent the devastating complications of hypertension, including stroke, myocardial infarction, and heart failure.

%B Arch Intern Med %V 162 %P 2325-32 %8 2002 Nov 11 %G eng %N 20 %1 https://www.ncbi.nlm.nih.gov/pubmed/12418946?dopt=Abstract %R 10.1001/archinte.162.20.2325 %0 Journal Article %J Chest %D 2003 %T The 6-min walk test: a quick measure of functional status in elderly adults. %A Enright, Paul L %A McBurnie, Mary Ann %A Bittner, Vera %A Tracy, Russell P %A McNamara, Robert %A Arnold, Alice %A Newman, Anne B %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Cohort Studies %K Coronary Disease %K Cross-Sectional Studies %K Diabetes Mellitus, Type 2 %K Exercise Test %K Female %K Humans %K Ischemic Attack, Transient %K Linear Models %K Male %K Mass Screening %K Sensitivity and Specificity %K Stroke %K United States %K Walking %X

OBJECTIVES: To determine the correlates of the total 6-min walk distance (6MWD) in a population sample of adults > or = 68 years old.

METHODS: The standardized 6-min walk test (6MWT) was administered to the Cardiovascular Health Study cohort during their seventh annual examination.

RESULTS: Of the 3,333 participants with a clinic visit, 2,281 subjects (68%) performed the 6MWT. There were no untoward events. The mean 6MWD was 344 m (SD, 88 m). Independent general correlates of a shorter 6MWD in linear regression models in women and men included the following: older age, higher weight, larger waist, weaker grip strength, symptoms of depression, and decreased mental status. Independent disease or risk factor correlates of a shorter 6MWD included the following: a low ankle BP, use of angiotensin-converting enzyme inhibitors, and arthritis in men and women; higher C-reactive protein, diastolic hypertension, and lower FEV(1) in women; and the use of digitalis in men. Approximately 30% of the variance in 6MWD was explained by the linear regression models. Newly described bivariate associations of a shorter 6MWD included impaired activities of daily living; self-reported poor health; less education; nonwhite race; a history of coronary heart disease, transient ischemic attacks, stroke, or diabetes; and higher levels of C-reactive protein, fibrinogen, or WBC count.

CONCLUSIONS: Most community-dwelling elderly persons can quickly and safely perform this functional status test in the outpatient clinic setting. The test may be used clinically to measure the impact of multiple comorbidities, including cardiovascular disease, lung disease, arthritis, diabetes, and cognitive dysfunction and depression, on exercise capacity and endurance in older adults. Expected values should be adjusted for the patient's age, gender, height, and weight.

%B Chest %V 123 %P 387-98 %8 2003 Feb %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/12576356?dopt=Abstract %R 10.1378/chest.123.2.387 %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 J Am Geriatr Soc %D 2003 %T The association between time since last meal and blood pressure in older adults: the cardiovascular health study. %A Smith, Nicholas L %A Psaty, Bruce M %A Rutan, Gale H %A Lumley, Thomas %A Yanez, David %A Chaves, Paulo H M %A Kronmal, Richard A %K Aged %K Blood Pressure %K Cardiovascular Diseases %K Cohort Studies %K Eating %K Female %K Humans %K Hypotension %K Male %K Postprandial Period %K Prospective Studies %K Risk Factors %K Time Factors %X

OBJECTIVES: To demonstrate a postprandial hypotensive (PPH) phenomenon in older adults.

DESIGN: Observational, prospective cohort study composed of baseline and nine follow-up visits.

SETTING: Cardiovascular Health Study, an epidemiological study of risk factors for cardiovascular disease in older adults.

PARTICIPANTS: Five thousand eight hundred eighty-eight community-dwelling adults aged 65 and older.

MEASUREMENTS: Blood pressure and time since last meal were recorded synchronously at baseline and at follow-up clinic visits. Generalized estimating equations were used to estimate associations between time since last meal and blood pressure and to adjust variance estimates to account for repeated blood pressure measures within subjects across fasting times.

RESULTS: Mean systolic and diastolic blood pressures were lower in the first hour after the last meal and were progressively higher through the fourth hour after the last meal than blood pressures measured immediately after the last meal (0 hour: 133.7/68.8 mmHg; 1st hour: 130.1/66.6 mmHg; 4th hour: 136.5/71.1 mmHg). Changes were significant for systolic and diastolic measures (P <.001 for both). Exploratory analyses suggested that the systolic PPH association was more pronounced in women. Little evidence was found that the degree of systolic or diastolic PPH varied by age, race, prevalent cardiovascular disease, heart rate, ejection fraction, treated hypertension or diabetes mellitus, or body mass index.

CONCLUSION: These data support previous observations that there is a significant drop in blood pressure within 1 hour after a meal in older adults. Time since last meal may be an important factor to consider when measuring blood pressure in older adults, and perhaps national standards need to be set.

%B J Am Geriatr Soc %V 51 %P 824-8 %8 2003 Jun %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/12757570?dopt=Abstract %R 10.1046/j.1365-2389.2003.51264.x %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 Circulation %D 2003 %T C-reactive protein, carotid intima-media thickness, and incidence of ischemic stroke in the elderly: the Cardiovascular Health Study. %A Cao, Jie J %A Thach, Chau %A Manolio, Teri A %A Psaty, Bruce M %A Kuller, Lewis H %A Chaves, Paulo H M %A Polak, Joseph F %A Sutton-Tyrrell, Kim %A Herrington, David M %A Price, Thomas R %A Cushman, Mary %K Aged %K Brain Ischemia %K C-Reactive Protein %K California %K Carotid Arteries %K Cohort Studies %K Comorbidity %K Female %K Follow-Up Studies %K Humans %K Incidence %K Longitudinal Studies %K Male %K Maryland %K North Carolina %K Odds Ratio %K Pennsylvania %K Proportional Hazards Models %K Risk Assessment %K Risk Factors %K Stroke %K Tunica Intima %K Tunica Media %K Ultrasonography %X

BACKGROUND: Increased carotid artery intima-media thickness (IMT) and elevated C-reactive protein (CRP) are both associated with the occurrence of stroke. We investigated whether elevated CRP is a risk factor for ischemic stroke independent of carotid IMT and studied the interaction between CRP and IMT.

METHODS AND RESULTS: We studied 5417 participants aged 65 years or older without preexisting stroke or chronic atrial fibrillation who were participants in the Cardiovascular Health Study. The hazard ratio of incident ischemic stroke was estimated by Cox proportional hazards regression. During 10.2 years of follow-up, 469 incident ischemic strokes occurred. The adjusted hazard ratios for ischemic stroke in the 2nd to 4th quartiles of baseline CRP, relative to the 1st quartile, were 1.19 (95% CI 0.92 to 1.53), 1.05 (95% CI 0.81 to 1.37), and 1.60 (95% CI 1.23 to 2.08), respectively. With additional adjustment for carotid IMT, there was little confounding. The association of CRP with stroke was significantly different depending on IMT (P<0.02), with no association of CRP with stroke among those in the lowest IMT tertile and a significant association among those with higher levels of IMT.

CONCLUSIONS: We conclude that elevated CRP is a risk factor for ischemic stroke, independent of atherosclerosis severity as measured by carotid IMT. The association of CRP with stroke is more apparent in the presence of a higher carotid IMT. CRP and carotid IMT may each be independent integrals in determining the risk of ischemic stroke.

%B Circulation %V 108 %P 166-70 %8 2003 Jul 15 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/12821545?dopt=Abstract %R 10.1161/01.CIR.0000079160.07364.6A %0 Journal Article %J Circulation %D 2003 %T Elevations of inflammatory and procoagulant biomarkers in elderly persons with renal insufficiency. %A Shlipak, Michael G %A Fried, Linda F %A Crump, Casey %A Bleyer, Anthony J %A Manolio, Teri A %A Tracy, Russell P %A Furberg, Curt D %A Psaty, Bruce M %K Aged %K alpha-2-Antiplasmin %K Biomarkers %K Blood Coagulation Factors %K C-Reactive Protein %K Cardiovascular Diseases %K Cohort Studies %K Creatinine %K Cross-Sectional Studies %K Female %K Fibrin Fibrinogen Degradation Products %K Fibrinogen %K Fibrinolysin %K Humans %K Inflammation %K Interleukin-6 %K Male %K Prospective Studies %K Renal Insufficiency %K Risk Factors %X

BACKGROUND: Renal insufficiency has been associated with cardiovascular disease events and mortality in several prospective studies, but the mechanisms for the elevated risk are not clear. Little is known about the association of renal insufficiency with inflammatory and procoagulant markers, which are potential mediators for the cardiovascular risk of kidney disease.

METHODS AND RESULTS: The cross-sectional association of renal insufficiency with 8 inflammatory and procoagulant factors was evaluated using baseline data from the Cardiovascular Health Study, a population-based cohort study of 5888 subjects aged > or =65 years. C-reactive protein, fibrinogen, factor VIIc, and factor VIIIc levels were measured in nearly all participants; interleukin-6, intercellular adhesion molecule-1, plasmin-antiplasmin complex, and D-dimer levels were measured in nearly half of participants. Renal insufficiency was defined as a serum creatinine level > or =1.3 mg/dL in women and > or =1.5 mg/dL in men. Multivariate linear regression was used to compare adjusted mean levels of each biomarker in persons with and without renal insufficiency after adjustment for other baseline characteristics. Renal insufficiency was present in 647 (11%) of Cardiovascular Health Study participants. After adjustment for baseline differences, levels of C-reactive protein, fibrinogen, interleukin-6, factor VIIc, factor VIIIc, plasmin-antiplasmin complex, and D-dimer were significantly greater among persons with renal insufficiency (P<0.001). In participants with clinical, subclinical, and no cardiovascular disease at baseline, the positive associations of renal insufficiency with these inflammatory and procoagulant markers were similar.

CONCLUSION: Renal insufficiency was independently associated with elevations in inflammatory and procoagulant biomarkers. These pathways may be important mediators leading to the increased cardiovascular risk of persons with kidney disease.

%B Circulation %V 107 %P 87-92 %8 2003 Jan 07 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/12515748?dopt=Abstract %R 10.1161/01.cir.0000042700.48769.59 %0 Journal Article %J Blood %D 2003 %T Fibrin fragment D-dimer and the risk of future venous thrombosis. %A Cushman, Mary %A Folsom, Aaron R %A Wang, Lu %A Aleksic, Nena %A Rosamond, Wayne D %A Tracy, Russell P %A Heckbert, Susan R %K Aged %K Body Mass Index %K Cohort Studies %K Continental Population Groups %K Factor V %K Factor VIII %K Female %K Fibrin Fibrinogen Degradation Products %K Humans %K Longitudinal Studies %K Male %K Middle Aged %K Odds Ratio %K Prospective Studies %K Prothrombin %K Risk Factors %K Venous Thrombosis %X

Plasma D-dimer concentration rises more than 100-fold during acute deep vein thrombosis, but there are no prospective data concerning D-dimer as a risk factor for incident venous thrombosis in a general population. Incident venous thrombosis was ascertained in 2 prospective observational studies, the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study. Of 21 690 participants enrolled between 1987 and 1993, after 8 years of follow-up, D-dimer was measured using baseline stored plasma of 307 participants who developed venous thrombosis and 616 who did not. Relative to the first quintile of the distribution of D-dimer, the age-adjusted odds ratios for future venous thrombosis for the second to fifth quintiles of D-dimer were 1.6, 2.3, 2.3, and 4.2, respectively (P for trend <.0001). Following added adjustment for sex, race, body mass index, factor V Leiden, prothrombin 20210A, and elevated factor VIII coagulant activity (factor VIII:c), these odds ratios were 1.5, 2.1, 1.9, and 3.0, respectively (P for trend <.0001). Among those with idiopathic thrombosis or secondary thrombosis unrelated to cancer, the adjusted fifth quintile odds ratios were 3.5 and 4.8, respectively. By contrast, D-dimer in the fifth versus first quintile was not related to occurrence of cancer-associated thrombosis (odds ratio, 1.1). Odds ratios for elevated D-dimer were consistently elevated in subgroups defined by age, sex, race, duration of follow-up, and thrombosis type (deep vein thrombosis or pulmonary embolus). D-dimer is strongly and positively related to the occurrence of future venous thrombosis.

%B Blood %V 101 %P 1243-8 %8 2003 Feb 15 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/12393393?dopt=Abstract %R 10.1182/blood-2002-05-1416 %0 Journal Article %J J Womens Health (Larchmt) %D 2003 %T Hormone replacement therapy and the risk of incident congestive heart failure: the Cardiovascular Health Study. %A Rea, Thomas D %A Psaty, Bruce M %A Heckbert, Susan R %A Cushman, Mary %A Meilahn, Elaine %A Olson, Jean L %A Lemaitre, Rozenn N %A Smith, Nicholas L %A Sotoodehnia, Nona %A Chaves, Paulo H M %K Aged %K Aged, 80 and over %K Body Mass Index %K Cohort Studies %K Estrogen Replacement Therapy %K Female %K Heart Failure %K Humans %K Incidence %K Life Style %K Middle Aged %K Multivariate Analysis %K Obesity %K Osteoporosis, Postmenopausal %K Proportional Hazards Models %K Prospective Studies %K Risk %K Risk Factors %K United States %K Women's Health %X

BACKGROUND: The development of congestive heart failure (CHF) in older persons is related to a variety of mechanisms. Hormone replacement therapy (HRT) affects several of the pathways that may be important in the development of CHF. We hypothesized that HRT would be associated with a decreased risk of incident CHF.

METHODS: Using Cox proportional-hazards regression, we assessed the risk of incident CHF (n = 304) associated with time-dependent past and current use of HRT compared to never use. The Cardiovascular Health Study is a prospective cohort study of community-dwelling adults aged 65 years and older. This analysis included female participants without a history of CHF at baseline (n = 3223).

RESULTS: At baseline, 62% were never users, 26% were past users, and 12% were current users of HRT. Compared with never users, the multivariable relative risk (RR) of CHF was 1.01 (95% confidence interval [95% CI] 0.76,1.34) for past users and 1.34 (0.93,1.94) for current users. Results were similar among most treatment and clinical subgroups, except that the association of current HRT with CHF appeared to depend on body mass index (BMI) or osteoporosis status. The RR was 0.82 (0.43,1.60) for normal weight women, 1.65 (0.95,2.88) for overweight women, and 2.22 (1.06,4.67) for obese women (p = 0.01 for interaction). Similarly, the RR was 0.15 (0.04,0.65) for women with osteoporosis and 1.82 (1.25,2.65) for women without osteoporosis (p = 0.001 for interaction).

CONCLUSIONS: Overall, HRT was not associated with the risk of incident CHF, although BMI and osteoporosis appeared to modify the association of HRT with CHF. The risk of CHF was lower in patients with lower BMI or osteoporosis.

%B J Womens Health (Larchmt) %V 12 %P 341-50 %8 2003 May %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/12804341?dopt=Abstract %R 10.1089/154099903765448853 %0 Journal Article %J Circulation %D 2003 %T Inflammation as a risk factor for atrial fibrillation. %A Aviles, Ronnier J %A Martin, David O %A Apperson-Hansen, Carolyn %A Houghtaling, Penny L %A Rautaharju, Pentti %A Kronmal, Richard A %A Tracy, Russell P %A Van Wagoner, David R %A Psaty, Bruce M %A Lauer, Michael S %A Chung, Mina K %K Aged %K Atrial Fibrillation %K C-Reactive Protein %K Cross-Sectional Studies %K Female %K Humans %K Inflammation %K Longitudinal Studies %K Male %K Risk Factors %X

BACKGROUND: The presence of systemic inflammation determined by elevations in C-reactive protein (CRP) has been associated with persistence of atrial fibrillation (AF). The relationship between CRP and prediction of AF has not been studied in a large population-based cohort.

METHODS AND RESULTS: CRP measurement and cardiovascular assessment were performed at baseline in 5806 subjects enrolled in the Cardiovascular Health Study. Patients were followed up for a mean of 6.9+/-1.6 (median 7.8) years. AF was identified by self-reported history and ECGs at baseline and by ECGs and hospital discharge diagnoses at follow-up. Univariate and multivariate analyses were used to assess CRP as a predictor of baseline and future development of AF. At baseline, 315 subjects (5%) had AF. Compared with subjects in the first CRP quartile (<0.97 mg/L), subjects in the fourth quartile (>3.41 mg/L) had more AF (7.4% versus 3.7%, adjusted OR 1.8, 95% CI 1.2 to 2.5; P=0.002). Of 5491 subjects without AF at baseline, 897 (16%) developed AF during follow-up. Baseline CRP predicted higher risk for developing future AF (fourth versus first quartile adjusted hazard ratio 1.31, 95% CI 1.08 to 1.58; P=0.005). When treated as a continuous variable, elevated CRP predicted increased risk for developing future AF (adjusted hazard ratio for 1-SD increase, 1.24; 95% CI 1.11 to 1.40; P<0.001).

CONCLUSIONS: CRP is not only associated with the presence of AF but may also predict patients at increased risk for future development of AF.

%B Circulation %V 108 %P 3006-10 %8 2003 Dec 16 %G eng %N 24 %1 https://www.ncbi.nlm.nih.gov/pubmed/14623805?dopt=Abstract %R 10.1161/01.CIR.0000103131.70301.4F %0 Journal Article %J J Thromb Haemost %D 2003 %T Lack of association of the plasminogen activator inhibitor-1 4G/5G promoter polymorphism with cardiovascular disease in the elderly. %A Crainich, P %A Jenny, N S %A Tang, Z %A Arnold, A M %A Kuller, L H %A Manolio, T %A Sharrett, A R %A Tracy, R P %K African Continental Ancestry Group %K Aged %K Alleles %K Cardiovascular Diseases %K Case-Control Studies %K Cohort Studies %K European Continental Ancestry Group %K Female %K Genotype %K Homozygote %K Humans %K Male %K Myocardial Infarction %K Plasminogen Activator Inhibitor 1 %K Polymorphism, Genetic %K Promoter Regions, Genetic %K Risk %X

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

%B J Thromb Haemost %V 1 %P 1799-804 %8 2003 Aug %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/12911596?dopt=Abstract %R 10.1046/j.1538-7836.2003.00255.x %0 Journal Article %J N Engl J Med %D 2003 %T Lp(a) lipoprotein, vascular disease, and mortality in the elderly. %A Ariyo, Abraham A %A Thach, Chau %A Tracy, Russell %K Aged %K Coronary Disease %K Female %K Humans %K Incidence %K Lipoprotein(a) %K Male %K Mortality %K Proportional Hazards Models %K Prospective Studies %K Risk Factors %K Sex Factors %K Stroke %K Survival Analysis %K United States %K Vascular Diseases %X

BACKGROUND: As compared with what is known about predictors of vascular events in middle-aged persons, less is known about these events in the elderly. Lp(a) lipoprotein, which plays an important part in atherothrombogenesis, has been associated with an increased risk of vascular disease. We investigated this relation among older U.S. adults.

METHODS: In a prospective study of 5888 community-dwelling older adults (65 years of age or older) in the United States, 2375 women and 1597 men who were free of vascular disease provided base-line serum samples for analysis for levels of Lp(a) lipoprotein. These 3972 subjects were followed for a median of 7.4 years to evaluate the development of stroke and to track deaths from vascular causes and all causes. The men and women were divided into quintile groups according to the Lp(a) lipoprotein level at base line.

RESULTS: Using Cox proportional-hazards models, we determined the risk associated with each quintile level of Lp(a) lipoprotein, with the lowest quintile serving as the reference group. As compared with those in the lowest quintile, men in the highest quintile had three times the unadjusted risk of stroke (relative risk, 3.00; 95 percent confidence interval, 1.59 to 5.65), almost three times the risk of death associated with vascular events (relative risk, 2.54; 95 percent confidence interval, 1.59 to 4.08), and nearly twice the risk of death from all causes (relative risk, 1.76; 95 percent confidence interval, 1.31 to 2.36). Adjustment for age; sex; the levels of total cholesterol, low-density lipoprotein cholesterol, and triglycerides; carotid-wall thickness; smoking status; the presence or absence of diabetes and systolic and diastolic hypertension; body-mass index; and other traditional risk factors had little effect on the final assessments. Similar analyses for women, which also included adjustment for estrogen use or nonuse, revealed no such relation.

CONCLUSIONS: Among older adults in the United States, an elevated level of Lp(a) lipoprotein is an independent predictor of stroke, death from vascular disease, and death from any cause in men but not in women. These data support the use of Lp(a) lipoprotein levels in predicting the risk of these events in older men.

%B N Engl J Med %V 349 %P 2108-15 %8 2003 Nov 27 %G eng %N 22 %1 https://www.ncbi.nlm.nih.gov/pubmed/14645638?dopt=Abstract %R 10.1056/NEJMoa001066 %0 Journal Article %J Arch Neurol %D 2003 %T Prevalence and classification of mild cognitive impairment in the Cardiovascular Health Study Cognition Study: part 1. %A Lopez, Oscar L %A Jagust, William J %A DeKosky, Steven T %A Becker, James T %A Fitzpatrick, Annette %A Dulberg, Corinne %A Breitner, John %A Lyketsos, Constantine %A Jones, Beverly %A Kawas, Claudia %A Carlson, Michelle %A Kuller, Lewis H %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Cognition Disorders %K Cohort Studies %K Dementia %K Female %K Humans %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Memory Disorders %K Neuropsychological Tests %K Pennsylvania %K Population %K Psychiatric Status Rating Scales %X

OBJECTIVE: To examine the prevalence of mild cognitive impairment (MCI) and its diagnostic classification in the Cardiovascular Health Study (CHS) Cognition Study.

DESIGN: The CHS Cognition Study is an ancillary study of the CHS that was conducted to determine the presence of MCI and dementia in the CHS cohort.

SETTING: Multicenter population study.

PATIENTS: We examined 3608 participants in the CHS who had undergone detailed neurological, neuropsychological, neuroradiological, and psychiatric testing to identify dementia and MCI.

MAIN OUTCOME MEASURES: The prevalence of MCI was determined for the whole cohort, and specific subtypes of MCI were examined in detail only at the Pittsburgh, Pa, center (n = 927). Mild cognitive impairment was classified as either MCI amnestic-type or MCI multiple cognitive deficits-type.

RESULTS: The overall prevalence of MCI was 19% (465 of 2470 participants); prevalence increased with age from 19% in participants younger than 75 years to 29% in those older than 85 years. The overall prevalence of MCI at the Pittsburgh center was 22% (130 of 599 participants); prevalence of the MCI amnesic-type was 6% and of the MCI multiple cognitive deficits-type was 16%.

CONCLUSIONS: Twenty-two percent of the participants aged 75 years or older had MCI. Mild cognitive impairment is a heterogeneous syndrome, where the MCI amnestic-type is less frequent than the MCI multiple cognitive deficits-type. Most of the participants with MCI had comorbid conditions that may affect their cognitive functions.

%B Arch Neurol %V 60 %P 1385-9 %8 2003 Oct %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/14568808?dopt=Abstract %R 10.1001/archneur.60.10.1385 %0 Journal Article %J J Clin Epidemiol %D 2003 %T Prospective study of fibrinolytic markers and venous thromboembolism. %A Folsom, Aaron R %A Cushman, Mary %A Heckbert, Susan R %A Rosamond, Wayne D %A Aleksic, Nena %K Aged %K alpha-2-Antiplasmin %K Antifibrinolytic Agents %K Biomarkers %K Caenorhabditis elegans Proteins %K Case-Control Studies %K Female %K Fibrinolysin %K Fibrinolysis %K Humans %K Male %K Middle Aged %K Odds Ratio %K Plasminogen Activator Inhibitor 1 %K Prognosis %K Prospective Studies %K Protein-Tyrosine Kinases %K Risk Factors %K Thromboembolism %K Venous Thrombosis %X

Prior research has conflicted on whether increased levels of plasma fibrinolytic factors may identify patients at risk of venous thromboembolism (VTE). We therefore performed a nested case-control study of VTE within two prospective population-based studies. In 308 participants who developed VTE and 640 controls, we measured PAI-1 antigen, tPA/PAI-1 complex, plasmin-alpha 2-antiplasmin (PAP), and the PAI-1 -675 4G/5G promoter polymorphism on pre-event blood samples. There was no overall association between any of these fibrinolytic variables and VTE, after adjustment for age or for multiple VTE risk factors. There was weak evidence for an interaction of PAP with elevated factor VIIIc and elevated D-dimer in augmenting VTE risk. We conclude that, for the most part, these fibrinolytic markers do not identify healthy subjects at risk for VTE.

%B J Clin Epidemiol %V 56 %P 598-603 %8 2003 Jun %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/12873656?dopt=Abstract %R 10.1016/s0895-4356(03)00052-0 %0 Journal Article %J J Thromb Haemost %D 2003 %T Prospective study of the A455V polymorphism in the thrombomodulin gene, plasma thrombomodulin, and incidence of venous thromboembolism: the LITE Study. %A Aleksic, N %A Folsom, A R %A Cushman, M %A Heckbert, S R %A Tsai, M Y %A Wu, K K %K Age Factors %K Aged %K Amino Acid Substitution %K Case-Control Studies %K Female %K Genotype %K Humans %K Incidence %K Male %K Polymorphism, Genetic %K Prevalence %K Prospective Studies %K Risk Factors %K Thromboembolism %K Thrombomodulin %K Venous Thrombosis %X

Plasma thrombomodulin (soluble TM; sTM) is considered to be a marker of endothelial injury, but a recent report indicated that the relationship of sTM with thrombosis is complex. Venous thromboembolic events were identified in adults in two longitudinal cohort studies, the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study, totaling 21 690 participants. After 8 years of follow-up, sTM was measured in baseline plasma of 305 participants who developed venous thrombosis and 607 who did not. Thrombomodulin A455V genotype was determined in 302 cases and 626 controls. There was no difference in the prevalence of the three TM genotypes between cases and controls and no difference in age-adjusted mean values of sTM by genotype. There were no associations of age-adjusted sTM or TMA455V genotype with overall venous thromboembolism or with thrombosis in any subtype of venous thromboembolism.

%B J Thromb Haemost %V 1 %P 88-94 %8 2003 Jan %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/12871544?dopt=Abstract %R 10.1046/j.1538-7836.2003.00029.x %0 Journal Article %J Am J Kidney Dis %D 2003 %T Relationships between renovascular disease, blood pressure, and renal function in the elderly: a population-based study. %A Edwards, Matthew S %A Hansen, Kimberley J %A Craven, Timothy E %A Cherr, Gregory S %A Bleyer, Anthony J %A Burke, Gregory L %A Dean, Richard H %K Aged %K Blood Pressure %K Female %K Humans %K Hypertension %K Kidney %K Kidney Diseases %K Male %K Prospective Studies %K Ultrasonography, Doppler, Duplex %K Vascular Diseases %X

BACKGROUND: The purpose of this study is to examine the associations between renovascular disease (RVD) and cross-sectional measures of blood pressure and renal function among participants in the Cardiovascular Health Study (CHS).

METHODS: The CHS is a prospective cohort study of cardiovascular disease among elderly Americans. As part of an ancillary study, participants in the Forsyth County, NC, cohort of the CHS were invited to undergo renal duplex sonography (RDS) to define the presence or absence of RVD (defined as any focal peak systolic velocity > or = 1.8 milliseconds or the absence of a Doppler shifted signal from an imaged artery). Demographic, risk factor, blood pressure, and serum creatinine data were obtained at the time of RDS and from the annual CHS examination.

RESULTS: Eight hundred thirty-four CHS participants (including 525 women [63%], 309 men [37%], 194 African Americans [23%], and 635 Caucasians [76%]) with a mean age of 77.2 +/- 4.9 years underwent successful RDS. RVD was present in 57 participants (6.8%). When examined according to the presence or absence of RVD, significant univariate differences were observed in the prevalence of clinical hypertension (72% versus 50%; P = 0.001), systolic blood pressure (145 versus 136 mm Hg; P = 0.001), and renal insufficiency (16% versus 8%; P = 0.041). Multivariate analyses showed significant and independent associations for the presence of RVD with increasing systolic blood pressure (P = 0.034), clinical hypertension (odds ratio, 2.68; 95% confidence interval, 1.44 to 4.99; P = 0.002), increasing serum creatinine level, and renal insufficiency (odds ratio, 2.21; 95% confidence interval, 1.02 to 4.79; P = 0.043). A significant interaction was observed between the presence of RVD and increasing systolic blood pressure in association with increasing serum creatinine levels (P = 0.041).

CONCLUSION: These results suggest important population-based associations between RVD and cross-sectional measures of blood pressure and renal function. Furthermore, the observed relationship between RVD and increasing serum creatinine level was influenced strongly by increasing blood pressure.

%B Am J Kidney Dis %V 41 %P 990-6 %8 2003 May %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/12722033?dopt=Abstract %R 10.1016/s0272-6386(03)00196-3 %0 Journal Article %J J Am Coll Cardiol %D 2003 %T Renal insufficiency as a predictor of cardiovascular outcomes and mortality in elderly individuals. %A Fried, Linda F %A Shlipak, Michael G %A Crump, Casey %A Bleyer, Anthony J %A Gottdiener, John S %A Kronmal, Richard A %A Kuller, Lewis H %A Newman, Anne B %K Aged %K Cardiovascular Diseases %K Confidence Intervals %K Creatinine %K Female %K Heart Failure %K Humans %K Intermittent Claudication %K Kidney Failure, Chronic %K Male %K Odds Ratio %K Predictive Value of Tests %K Survival Analysis %X

OBJECTIVES: This study was designed to evaluate the relationship between elevated creatinine levels and cardiovascular events.

BACKGROUND: End-stage renal disease is associated with high cardiovascular morbidity and mortality. The association of mild to moderate renal insufficiency with cardiovascular outcomes remains unclear.

METHODS: We analyzed data from the Cardiovascular Health Study, a prospective population-based study of subjects, aged >65 years, who had a serum creatinine measured at baseline (n = 5,808) and were followed for a median of 7.3 years. Proportional hazards models were used to examine the association of creatinine to all-cause mortality and incident cardiovascular mortality and morbidity. Renal insufficiency was defined as a creatinine level > or =1.5 mg/dl in men or > or =1.3 mg/dl in women.

RESULTS: An elevated creatinine level was present in 648 (11.2%) participants. Subjects with elevated creatinine had higher overall (76.7 vs. 29.5/1,000 years, p < 0.001) and cardiovascular (35.8 vs. 13.0/1,000 years, p < 0.001) mortality than those with normal creatinine levels. They were more likely to develop cardiovascular disease (54.0 vs. 31.8/1,000 years, p < 0.001), stroke (21.1 vs. 11.9/1,000 years, p < 0.001), congestive heart failure (38.7 vs. 17/1,000 years, p < 0.001), and symptomatic peripheral vascular disease (10.6 vs. 3.5/1,000 years, p < 0.001). After adjusting for cardiovascular risk factors and subclinical disease measures, elevated creatinine remained a significant predictor of all-cause and cardiovascular mortality, total cardiovascular disease (CVD), claudication, and congestive heart failure (CHF). A linear increase in risk was observed with increasing creatinine.

CONCLUSIONS: Elevated creatinine levels are common in older adults and are associated with increased risk of mortality, CVD, and CHF. The increased risk is apparent early in renal disease.

%B J Am Coll Cardiol %V 41 %P 1364-72 %8 2003 Apr 16 %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/12706933?dopt=Abstract %R 10.1016/s0735-1097(03)00163-3 %0 Journal Article %J Arch Neurol %D 2003 %T Risk factors for mild cognitive impairment in the Cardiovascular Health Study Cognition Study: part 2. %A Lopez, Oscar L %A Jagust, William J %A Dulberg, Corinne %A Becker, James T %A DeKosky, Steven T %A Fitzpatrick, Annette %A Breitner, John %A Lyketsos, Constantine %A Jones, Beverly %A Kawas, Claudia %A Carlson, Michelle %A Kuller, Lewis H %K Aged %K Apolipoprotein E4 %K Apolipoproteins E %K Brain %K Cardiovascular Diseases %K Cognition Disorders %K Cohort Studies %K Depressive Disorder %K Female %K Humans %K Logistic Models %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Mood Disorders %K Pennsylvania %K Population %K Risk Factors %X

OBJECTIVE: To examine the risk factors for mild cognitive impairment (MCI) in a longitudinal population study-the Cardiovascular Health Study Cognition Study.

DESIGN: We examined the factors that in the period 1991 through 1994 predicted the development of MCI in all participants of the Cardiovascular Health Study Cognition Study. Further examination was conducted in the Pittsburgh, Pa, cohort (n = 927), where participants with MCI were classified as having either the MCI amnestic-type or the MCI multiple cognitive deficits-type.

SETTING: Multicenter population study.

PATIENTS: This study includes all participants of the Cardiovascular Health Study Cognition Study (n = 3608) who had a magnetic resonance imaging (MRI) scan of the brain between 1991 and 1994, and detailed neuropsychological, neurological, and medical evaluations to identify the presence of MCI or dementia in the period 1998 to 1999. The mean time between the closest clinical examination to the MRI and the diagnostic evaluation for cognitive disorders was 5.8 years for the Cardiovascular Health Study Cognition Study cohort and 6.0 years for the Pittsburgh cohort.

MAIN OUTCOME MEASURES: Risk factors for MCI at the time of the MRI were identified using logistic regression, controlling for age, race, educational level, baseline Modified Mini-Mental State Examination and Digit Symbol Test scores, measurements of depression, MRI findings (atrophy, ventricular volume, white matter lesions, and infarcts), the presence of the apolipoprotein E (APOE) epsilon4 allele, hypertension, diabetes mellitus, and heart disease.

RESULTS: Mild cognitive impairment (n = 577) was associated with race (African American), low educational level, low Modified Mini-Mental State Examination and Digit Symbol Test scores, cortical atrophy, MRI-identified infarcts, and measurements of depression. The MCI amnestic-type was associated with MRI-identified infarcts, the presence of the APOE epsilon4 allele, and low Modified Mini-Mental State Examination scores. The MCI multiple cognitive deficits-type was associated with low Modified Mini-Mental State Examination and Digit Symbol Test scores.

CONCLUSIONS: The development of MCI is associated with measurements of cognition and depression, racial and constitutional factors, and cerebrovascular disease. Early cognitive deficits seem to be a common denominator for the 2 forms of MCI; the presence of cerebrovascular disease and the APOE epsilon4 allele is associated with the amnestic type of MCI.

%B Arch Neurol %V 60 %P 1394-9 %8 2003 Oct %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/14568809?dopt=Abstract %R 10.1001/archneur.60.10.1394 %0 Journal Article %J Am J Hematol %D 2003 %T Serum homocysteine, thermolabile variant of methylene tetrahydrofolate reductase (MTHFR), and venous thromboembolism: Longitudinal Investigation of Thromboembolism Etiology (LITE). %A Tsai, Albert W %A Cushman, Mary %A Tsai, Michael Y %A Heckbert, Susan R %A Rosamond, Wayne D %A Aleksic, Nena %A Yanez, N David %A Psaty, Bruce M %A Folsom, Aaron R %K Aged %K Aging %K Animals %K Case-Control Studies %K Cohort Studies %K Factor V %K Female %K Genotype %K Homocysteine %K Humans %K Longitudinal Studies %K Male %K Methylenetetrahydrofolate Reductase (NADPH2) %K Middle Aged %K Odds Ratio %K Oxidoreductases Acting on CH-NH Group Donors %K Polymorphism, Genetic %K Prospective Studies %K Risk Factors %K Venous Thrombosis %X

We sought to examine prospectively the association of serum homocysteine and the methylene tetrahydrofolate reductase (MTHFR) C677T gene polymorphism with risk of venous thromboembolism (VTE). We studied these relationships in a nested case-control study of 303 VTE cases and 635 matched controls from a population-based cohort of 21,680 adults from six U.S. communities. The highest quintile of serum homocysteine carried a non-statistically significant adjusted odds ratio of 1.55 (95% CI, 0.93-2.58) compared to the lowest quintile in the overall cohort but a significant association among adults aged 45-64 years (OR = 2.05, 95% CI, 1.10-3.83) and an inverse association in those > or = 65 years of age. Carriers of the MTHFR C677T polymorphism were not at higher risk for VTE than those with normal genotype (OR = 0.74, 95% CI = 0.56-0.98). Our prospective data showed, at most, a weak relationship between homocysteine and VTE risk, with associations larger among younger participants. MTHFR C677T was not a risk factor for VTE.

%B Am J Hematol %V 72 %P 192-200 %8 2003 Mar %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/12605391?dopt=Abstract %R 10.1002/ajh.10287 %0 Journal Article %J Arch Intern Med %D 2003 %T "Successful aging": effect of subclinical cardiovascular disease. %A Newman, Anne B %A Arnold, Alice M %A Naydeck, Barbara L %A Fried, Linda P %A Burke, Gregory L %A Enright, Paul %A Gottdiener, John %A Hirsch, Calvin %A O'Leary, Daniel %A Tracy, Russell %K Aged %K Aged, 80 and over %K Aging %K C-Reactive Protein %K Cardiovascular Diseases %K Female %K Health Status %K Humans %K Longitudinal Studies %K Male %K Quality of Life %K Regression Analysis %K Risk Factors %X

BACKGROUND: Cardiovascular diseases are the primary cause of death in older adults. Among those without clinical disease, high levels of subclinical disease are associated with poor survival. The effect of the extent of subclinical cardiovascular disease on the quality of the remaining years has not been defined.

METHODS: In a longitudinal cohort study, 2932 men and women aged 65 years and older were followed up for 8 years to determine the likelihood of maintaining intact health and functioning. Successful aging was defined as remaining free of cardiovascular disease, cancer, and chronic obstructive pulmonary disease and with intact physical and cognitive functioning.

RESULTS: Younger age at study entry and a lower extent of subclinical cardiovascular disease were independently associated with the likelihood of maintaining successful aging. In age-stratified summaries, those with subclinical disease had a trajectory of decline similar to subjects 5 years older without subclinical vascular disease. Regression analyses showed that the decline associated with subclinical disease was equivalent to 6.5 (95% confidence interval, 6.4-6.6) years of aging for women and 5.6 (95% confidence interval, 5.4-5.8) years of aging for men. Individual measures of the extent of cardiovascular disease, diabetes mellitus, smoking, and higher C-reactive protein level were also independently predictive of fewer years of successful aging, but none of these factors substantially attenuated the effect of age itself.

CONCLUSIONS: There is a graded relationship between the extent of vascular disease measured noninvasively and the likelihood of maintaining intact health and function. Prevention of subclinical vascular disease may increase the quality and the quantity of years in late life.

%B Arch Intern Med %V 163 %P 2315-22 %8 2003 Oct 27 %G eng %N 19 %1 https://www.ncbi.nlm.nih.gov/pubmed/14581251?dopt=Abstract %R 10.1001/archinte.163.19.2315 %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 J Natl Med Assoc %D 2004 %T Associates of bone mineral density in older African Americans. %A Robbins, John %A Hirsch, Calvin %A Cauley, Jane %K Aged %K Body Weight %K Bone Density %K Cross-Sectional Studies %K Female %K Humans %K Male %K Osteoporosis %K Risk Factors %X

OBJECTIVES: To assess correlates of bone mineral density (BMD) in older African Americans.

PARTICIPANTS: 189 women and 115 men over age 64.

METHODS: Variables investigated: BMD by dual X-ray absorptiometry (DXA), medications, cardiovascular disease risk factors, demographic, lifestyle factors and functional status. Variables showing univariate correlation with BMD (p < or = 0.1) were entered into sex-stratified linear regression models.

RESULTS: Age range 67-96 (mean 75). The mean BMD (gm/ cm2 +/- standard deviation) is reported for three sites. Total body: 1.03 (+/- 0.12) in women, 1.21 (+/- 0.11) in men. Spine: 1.05 (+/- 0.24) in women, 1.22 (+/- 0.26) in men. Total hip: 0.85 (+/- 0.15) in women, 1.04 (+/- 0.17) in men. Gender was significantly associated with BMD (t-test, p < 0.001). The R2 for tested variables were highly significant only for weight. Age was only significant for total hip in women (p < 0.05). Each kilogram of weight change was associated with a 5.3-6.8 mg/cm2 change in BMD.

CONCLUSIONS: In a population-based cohort of older African Americans, average BMD was significantly greater in men than women. Weight accounted for most of the explained variability (R2) in BMD; age added little to the overall R2. Lower-weight, older African-American men and women are at significantly increased risk for low BMD and, thus, likely to be at greater risk for osteoporotic fracture.

%B J Natl Med Assoc %V 96 %P 1609-15 %8 2004 Dec %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/15622691?dopt=Abstract %0 Journal Article %J J Am Coll Cardiol %D 2004 %T The association of fasting glucose levels with congestive heart failure in diabetic adults > or =65 years: the Cardiovascular Health Study. %A Barzilay, Joshua I %A Kronmal, Richard A %A Gottdiener, John S %A Smith, Nicholas L %A Burke, Gregory L %A Tracy, Russell %A Savage, Peter J %A Carlson, Michelle %K Aged %K Biomarkers %K Blood Glucose %K Blood Pressure %K Coronary Disease %K Diabetes Mellitus %K Diabetic Angiopathies %K Fasting %K Female %K Follow-Up Studies %K Heart Failure %K Humans %K Incidence %K Male %K Proportional Hazards Models %K Risk Factors %K Statistics as Topic %K Stroke Volume %K Ventricular Function, Left %X

OBJECTIVES: The purpose of this study was to determine if fasting glucose levels are an independent risk factor for congestive heart failure (CHF) in elderly individuals with diabetes mellitus (DM) with or without coronary heart disease (CHD).

BACKGROUND: Diabetes mellitus and CHF frequently coexist in the elderly. It is not clear whether fasting glucose levels in the setting of DM are a risk factor for incident CHF in the elderly.

METHODS: A cohort of 829 diabetic participants, age > or =65 years, without prevalent CHF, was followed for five to eight years. The Cox proportional hazards modeling was used to determine the risk of CHF by fasting glucose levels. The cohort was categorized by the presence or absence of prevalent CHD.

RESULTS: For a 1 standard deviation (60.6 mg/dl) increase in fasting glucose, the adjusted hazard ratios for incident CHF among participants without CHD at baseline, with or without an incident myocardial infarction (MI) or CHD event on follow-up, was 1.41 (95% confidence interval 1.24 to 1.61; p < 0.0001). Among those with prevalent CHD at baseline, with or without another incident MI or CHD event on follow-up, the corresponding adjusted hazard ratio was 1.27 (95% confidence interval 1.02 to 1.58; p < 0.05).

CONCLUSIONS: Among older adults with DM, elevated fasting glucose levels are a risk factor for incident CHF. The relationship of fasting glucose to CHF differs somewhat by the presence or absence of prevalent CHD.

%B J Am Coll Cardiol %V 43 %P 2236-41 %8 2004 Jun 16 %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/15193686?dopt=Abstract %R 10.1016/j.jacc.2003.10.074 %0 Journal Article %J Soc Sci Med %D 2004 %T The association of personal and neighborhood socioeconomic indicators with subclinical cardiovascular disease in an elderly cohort. The cardiovascular health study. %A Nordstrom, Cheryl K %A Diez Roux, Ana V %A Jackson, Sharon A %A Gardin, Julius M %K Aged %K California %K Cardiovascular Diseases %K Cohort Studies %K Female %K Geography %K Humans %K Male %K Maryland %K Medicare %K North Carolina %K Pennsylvania %K Residence Characteristics %K Risk Factors %K Social Class %K Socioeconomic Factors %K Surveys and Questionnaires %X

There has been recent interest in determining whether neighborhood characteristics are related to the cardiovascular health of residents. However, there are no data regarding the relationship between neighborhood socioeconomic status (SES) and prevalence of subclinical cardiovascular disease (CVD) in the elderly. We related personal SES (education, income, and occupation type) and neighborhood socioeconomic characteristics (a block-group score summing six variables reflecting neighborhood income and wealth, education, and occupation) to the prevalence of subclinical CVD (asymptomatic peripheral vascular disease or carotid atherosclerosis, electrocardiogram or echocardiogram abnormalities, and/or positive responses to Rose Questionnaire claudication or angina pectoris) among 3545 persons aged 65 and over, without prevalent CVD, in the Cardiovascular Health Study. Sixty percent of participants had at least one indicator of subclinical disease. Compared to those without, those with subclinical disease had significantly lower education, income, and neighborhood scores and were more likely to have blue-collar jobs. After adjustment for age, gender, and race, those in the lowest SES groups had increased prevalence of subclinical disease compared with those in the highest SES groups (OR = 1.50; 95% CI 1.21, 1.86 for income; OR = 1.41; 95% CI 1.18, 1.69 for education; OR = 1.39; 95% CI 1.16, 1.67 for block-group score). Those reporting a blue-collar lifetime occupation had greater prevalence of subclinical disease relative to those reporting a white-collar occupation (OR = 1.29; 95% CI 1.02-1.59). After adjustment for behavioral and biomedical risk factors, all of these associations were reduced. Neighborhood score tended to remain inversely associated with subclinical disease after adjustment for personal socioeconomic indicators but associations were not statistically significant. Personal income and blue-collar occupation remained significantly associated with subclinical disease after simultaneous adjustment for neighborhood score and education. Personal and neighborhood socioeconomic indicators were associated with subclinical disease prevalence in this elderly cohort. These relationships were reduced after controlling for traditional CVD risk factors.

%B Soc Sci Med %V 59 %P 2139-47 %8 2004 Nov %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/15351479?dopt=Abstract %R 10.1016/j.socscimed.2004.03.017 %0 Journal Article %J Vasc Endovascular Surg %D 2004 %T Associations between renovascular disease and prevalent cardiovascular disease in the elderly: a population-based study. %A Edwards, Matthew S %A Hansen, Kimberley J %A Craven, Timothy E %A Bleyer, Anthony J %A Burke, Gregory L %A Levy, Pavel J %A Dean, Richard H %K Aged %K Arteriosclerosis %K Cardiovascular Diseases %K Cohort Studies %K Humans %K Hypertension, Renovascular %K Longitudinal Studies %K Male %K Multivariate Analysis %K Prevalence %K Prospective Studies %K Renal Artery Obstruction %K Ultrasonography %K United States %X

Atherosclerotic renovascular disease (RVD) is a suspected contributor to the morbidity and mortality of cardiovascular disease (CVD) through its potential effects on blood pressure and excretory renal function as well as through its associations with other forms of CVD. However, population-based data regarding the associations between the presence of RVD and prevalent CVD are lacking. The Cardiovascular Health Study (CHS) is a prospective, multicenter cohort study of CVD among elderly Americans. As part of an ancillary study, participants in the Forsyth County, North Carolina, cohort of the CHS were invited to undergo renal duplex sonography (RDS) to establish the presence or absence of RVD (defined as any focal peak systolic velocity >/= 1.8 m/second or the absence of a Doppler-shifted signal from an imaged artery). Demographic, risk factor, and prevalent CVD data were obtained from the CHS coordinating center and matched with ancillary study participants. Eight hundred thirty-four CHS participants (including 525 women [63%], 309 men [37%], 194 African-Americans [23%], and 635 Caucasians [76%]) with a mean age of 77.2 +/-4.9 years underwent RDS examination. RVD was present in 57 participants (6.8%). Overall, clinical and/or subclinical manifestations of CVD were present in 603 participants (72.3%) at the time of RDS. Participants with RVD demonstrated a significantly greater prevalence of angina (p = 0.002), previous myocardial infarction (p < 0.001), >/= 25% diameter-reducing internal carotid artery stenosis (p = 0.010), increased carotid intimal medial thickness (p = 0.003), and major electrocardiographic abnormalities (p = 0.013). Following adjustment for demographics and cardiovascular risk factors, the presence of RVD demonstrated a significant and independent association with prevalent coronary artery disease but not with prevalent cerebrovascular or lower extremity vascular disease. These results suggest important population-based associations between RVD and both clinical and subclinical manifestations of CVD, especially coronary artery disease.

%B Vasc Endovascular Surg %V 38 %P 25-35 %8 2004 Jan-Feb %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/14760474?dopt=Abstract %R 10.1177/153857440403800103 %0 Journal Article %J Am J Public Health %D 2004 %T Barriers to health care access among the elderly and who perceives them. %A Fitzpatrick, Annette L %A Powe, Neil R %A Cooper, Lawton S %A Ives, Diane G %A Robbins, John A %K Aged %K Aged, 80 and over %K Chi-Square Distribution %K Female %K Health Behavior %K Health Services Accessibility %K Humans %K Logistic Models %K Male %K Medicare %K Patients %K Surveys and Questionnaires %K United States %X

OBJECTIVES: We evaluated self-perceived access to health care in a cohort of Medicare beneficiaries.

METHODS: We identified patterns of use and barriers to health care from self-administered questionnaires collected during the 1993-1994 annual examination of the Cardiovascular Health Study.

RESULTS: The questionnaires were completed by 4889 (91.1%) participants, with a mean age of 76.0 years. The most common barriers to seeing a physician were the doctor's lack of responsiveness to patient concerns, medical bills, transportation, and street safety. Low income, no supplemental insurance, older age, and female gender were independently related to perceptions of barriers. Race was not significant after adjustment for other factors.

CONCLUSIONS: Psychological and physical barriers affect access to care among the elderly; these may be influenced by poverty more than by race.

%B Am J Public Health %V 94 %P 1788-94 %8 2004 Oct %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/15451751?dopt=Abstract %R 10.2105/ajph.94.10.1788 %0 Journal Article %J Ann Intern Med %D 2004 %T Cognitive impairment and decline are associated with carotid artery disease in patients without clinically evident cerebrovascular disease. %A Johnston, S Claiborne %A O'Meara, Ellen S %A Manolio, Teri A %A Lefkowitz, David %A O'Leary, Daniel H %A Goldstein, Steven %A Carlson, Michelle C %A Fried, Linda P %A Longstreth, W T %K Aged %K Carotid Stenosis %K Cognition Disorders %K Cohort Studies %K Cross-Sectional Studies %K Female %K Humans %K Male %K Neuropsychological Tests %K Odds Ratio %K Risk Factors %K Tunica Intima %X

BACKGROUND: Whether carotid artery disease is a cause of cognitive impairment in persons who have not had stroke is unknown. If this is the case, diminished performance on the Modified Mini-Mental State Examination should be more common in persons with left carotid artery disease than in those with right carotid artery disease.

OBJECTIVE: To determine whether left carotid artery disease is associated with cognitive impairment.

DESIGN: Cross-sectional and cohort study.

SETTING: Four U.S. communities participating in the Cardiovascular Health Study.

PATIENTS: 4006 right-handed men and women 65 years of age or older without history of stroke, transient ischemic attack, or carotid endarterectomy.

MEASUREMENTS: Internal carotid artery stenosis and intima-media thickness of the common carotid artery were assessed by using duplex ultrasonography. Cognitive impairment was defined as a score less than 80 on the Modified Mini-Mental State Examination, and cognitive decline was defined as an average decrease of more than 1 point annually in Modified Mini-Mental State Examination score during up to 5 years of follow-up. Multivariate logistic regression models were used to estimate the risk for cognitive impairment and decline associated with left internal carotid artery stenosis and intima-media thickness, after adjustment for measures of right-sided disease and risk factors for vascular disease.

RESULTS: After adjustment for right-sided stenosis, high-grade (> or =75% narrowing of diameter) stenosis of the left internal carotid artery (32 patients) was associated with cognitive impairment (odds ratio, 6.7 [95% CI, 2.4 to 18.1] compared with no stenosis) and cognitive decline (odds ratio, 2.6 [CI, 1.1 to 6.3]). Intima-media thickness of the left common carotid artery was associated with cognitive impairment and decline in univariate analysis, but this effect did not persist after adjustment.

CONCLUSIONS: Cognitive impairment and decline are associated with asymptomatic high-grade stenosis of the left internal carotid artery. The persistence of the association after adjustment for right-sided stenosis indicates that the association is not due to underlying vascular risk factors or atherosclerosis in general.

%B Ann Intern Med %V 140 %P 237-47 %8 2004 Feb 17 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/14970146?dopt=Abstract %R 10.7326/0003-4819-140-4-200402170-00005 %0 Journal Article %J Am J Med %D 2004 %T Deep vein thrombosis and pulmonary embolism in two cohorts: the longitudinal investigation of thromboembolism etiology. %A Cushman, Mary %A Tsai, Albert W %A White, Richard H %A Heckbert, Susan R %A Rosamond, Wayne D %A Enright, Paul %A Folsom, Aaron R %K Aged %K Case-Control Studies %K Cohort Studies %K Female %K Follow-Up Studies %K Humans %K Incidence %K Male %K Middle Aged %K Neoplasms %K Population Surveillance %K Pulmonary Embolism %K Recurrence %K Risk Factors %K Survival Rate %K Venous Thrombosis %X

PURPOSE: To determine the incidence of deep vein thrombosis and pulmonary embolism in two cohorts representing regions of the United States.

METHODS: The sample comprised 21,680 participants of the Atherosclerosis Risk in Communities study and the Cardiovascular Health Study. Subjects were aged >/=45 years, resided in six communities, and were followed for 7.6 years. All hospitalizations were identified and thromboses were validated by chart review.

RESULTS: The age-standardized incidence of first-time venous thromboembolism was 1.92 per 1000 person-years. Rates were higher in men than women, and increased with age in both sexes. There was no antecedent trauma, surgery, immobilization, or diagnosis of cancer for 48% (175/366) of events. The 28-day case-fatality rate was 11% (29/265) after a first venous thromboembolism and 25% (17/67) for cancer-associated thrombosis. The recurrence rate 2 years after a first venous thromboembolism was 7.7% per year (95% confidence interval [CI]: 4.5% to 10.9% per year). Cancer was the only factor independently associated with 28-day fatality (relative risk [RR] = 5.2; 95% CI: 1.4 to 19.9) or recurrent thrombosis (RR = 9.2; 95% CI: 2.0 to 41.7).

CONCLUSION: The incidence of venous thromboembolism in this cohort of middle- and older-aged subjects was similar to that observed in more geographically homogeneous samples. Half of cases were idiopathic. Short-term mortality and 2-year recurrence rates were appreciable, especially among subjects with cancer. Based on this study we estimate that 187,000 cases of first-time venous thromboembolism are diagnosed yearly in the United States among those aged 45 years or older.

%B Am J Med %V 117 %P 19-25 %8 2004 Jul 01 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/15210384?dopt=Abstract %R 10.1016/j.amjmed.2004.01.018 %0 Journal Article %J J Am Soc Nephrol %D 2004 %T Inflammatory and prothrombotic markers and the progression of renal disease in elderly individuals. %A Fried, Linda %A Solomon, Cam %A Shlipak, Michael %A Seliger, Stephen %A Stehman-Breen, Catherine %A Bleyer, Anthony J %A Chaves, Paolo %A Furberg, Curt %A Kuller, Lewis %A Newman, Anne %K Aged %K Biomarkers %K C-Reactive Protein %K Creatinine %K Factor VII %K Female %K Fibrinogen %K Follow-Up Studies %K Glomerular Filtration Rate %K Hemoglobins %K Humans %K Leukocyte Count %K Linear Models %K Longitudinal Studies %K Male %K Predictive Value of Tests %K Prospective Studies %K Renal Insufficiency %K Serum Albumin %K Thrombosis %X

Inflammatory and prothrombotic markers are elevated in individuals with mild to moderate renal disease. It was hypothesized that these markers may also be determinants of the progression of renal disease. The association of six markers-serum C-reactive protein (CRP), white blood cell (WBC) count, fibrinogen, factor VII, albumin, and hemoglobin-with subsequent elevations of creatinine and decline in estimated GFR in the Cardiovascular Health Study, a community-based cohort of elderly individuals, was analyzed. Linear regression was used to determine predictors of an annualized change in serum creatinine as the main outcome. Duration of follow-up was 7 yr for the original cohort and 4 yr for the more recently recruited black cohort. A total of 588 (12.7%) individuals had a decline in estimated GFR of at least 3 ml/min per yr per 1.73 m(2). Higher CRP (P < 0.001), WBC count (P < 0.001), fibrinogen (P < 0.001), and factor VII (P < 0.001) levels and lower albumin (P < 0.001) and hemoglobin levels (P < 0.001) were associated with a rise in creatinine, after adjusting for age. With additional adjustments for race, gender, baseline creatinine, systolic and diastolic BP, lipid levels, weight, and pack-years smoking, higher CRP, factor VII, fibrinogen, WBC count, and lower albumin and hemoglobin levels remained associated with a rise in creatinine. Similar results were found for decline in estimated GFR. The decline in GFR was greater with increasing number of inflammatory or prothrombotic markers that were above the median (below for hemoglobin and albumin). Inflammatory and prothrombotic markers are predictors for a change in kidney function in elderly individuals. Interventions that reduce inflammation might confer significant cardiovascular and renal benefits.

%B J Am Soc Nephrol %V 15 %P 3184-91 %8 2004 Dec %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/15579522?dopt=Abstract %R 10.1097/01.ASN.0000146422.45434.35 %0 Journal Article %J J Vasc Surg %D 2004 %T Mesenteric artery disease in the elderly. %A Hansen, Kimberley J %A Wilson, David B %A Craven, Timothy E %A Pearce, Jeffrey D %A English, William P %A Edwards, Matthew S %A Ayerdi, Juan %A Burke, Gregory L %K Age Factors %K Aged %K Aged, 80 and over %K Arteriosclerosis %K Celiac Artery %K Cohort Studies %K Female %K Humans %K Male %K Mesenteric Arteries %K Mesenteric Artery, Superior %K Mesenteric Vascular Occlusion %K Prevalence %K Ultrasonography, Doppler, Duplex %K Weight Loss %X

PURPOSE: The purpose of this study was to estimate the population-based prevalence of mesenteric artery stenosis (MAS) and occlusion among independent elderly Americans.

METHOD: As part of an ancillary investigation to the Cardiovascular Health Study (CHS), participants in the Forsyth County, NC cohort had visceral duplex sonography of the celiac arteries and superior mesenteric arteries (SMAs). Critical MAS was defined by celiac peak systolic velocity >or=2.0 m/s and/or SMA peak systolic velocity >or=2.7 m/s. Occlusion of either vessel was defined by lack of a Doppler-shifted signal within the imaged artery. Demographic data, blood pressures, and blood lipid levels were collected as part of the baseline CHS examination. Participants' weights were measured at baseline and before the duplex exam. Univariate tests of association were performed with two-way contingency tables, Student t tests, and Fisher exact tests. Multivariate associations were examined with logistic regression analysis.

RESULTS: A total of 553 CHS participants had visceral duplex sonography technically adequate to define the presence or absence of MAS. The study group had a mean age of 77.2 +/- 4.9 years and comprised 63% women and 37% men. Participant race was 76% white and 23% African-American. Ninety-seven participants (17.5%) had MAS. There was no significant difference in age, race, gender, body mass index, blood pressure, cholesterol, or low-density lipoproteins for participants with or without MAS. Forward stepwise variable selection found renal artery stenosis (P =.008; odds ratio [OR], 2.85; 95% confidence interval [CI], 1.31, 6.21) and high-density lipoprotein >40 (P =.02; OR, 3.03; 95% CI, 1.17, 7.81) significantly associated with MAS in a multivariate logistic regression model. Eighty-three of the 97 participants with MAS (15.0% of the cohort) had isolated celiac stenosis. Seven participants (1.3% of the cohort) had combined celiac and SMA stenosis. Five participants (0.9% of the cohort) had isolated SMA stenosis. Two participants (0.4% of the cohort) had celiac occlusion. Considering all participants with MAS, there was no association with weight change. However, SMA stenosis and celiac occlusion demonstrated an independent association with annualized weight loss (P =.028; OR, 1.54; 95% CI, 1.05, 2.26) and with renal artery stenosis (P =.001; OR, 9.48; 95% CI, 2.62, 34.47).

CONCLUSION: This investigation provides the first population-based estimate of the prevalence of MAS among independent elderly Americans. MAS existed in 17.5% of the study cohort. The majority had isolated celiac disease. SMA stenosis and celiac artery occlusion demonstrated a significant and independent association with weight loss and concurrent renal artery disease.

%B J Vasc Surg %V 40 %P 45-52 %8 2004 Jul %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/15218461?dopt=Abstract %R 10.1016/j.jvs.2004.03.022 %0 Journal Article %J Arch Neurol %D 2004 %T Plasma total homocysteine levels and cranial magnetic resonance imaging findings in elderly persons: the Cardiovascular Health Study. %A Longstreth, W T %A Katz, Ronit %A Olson, Jean %A Bernick, Charles %A Carr, J Jeffrey %A Malinow, M René %A Hess, David L %A Cushman, Mary %A Schwartz, Stephen M %K Aged %K Aging %K Brain %K Brain Infarction %K Female %K Homocysteine %K Humans %K Magnetic Resonance Imaging %K Male %K Odds Ratio %K Radiography %K Risk Factors %X

BACKGROUND: An elevated plasma total homocysteine (tHcy) level is associated with an increased risk of vascular disease. Some studies have shown associations between tHcy level and small-vessel disease of the brain on magnetic resonance imaging (MRI).

DESIGN: In the Cardiovascular Health Study, 622 elderly participants without a history of transient ischemic attack or stroke had results for tHcy level and cranial MRI. We sought associations between tHcy level and MRI findings of ventricular grade, sulcal grade, white matter grade, and infarcts. We controlled for other factors, including levels of creatinine, folate, and vitamins B(6) and B(12) and methylenetetrahydrofolate reductase genotype.

RESULTS: After controlling for age and sex, tHcy level was not associated with the individual MRI findings. Further adjustments for other factors and other blood tests had little effect on these findings. The only significant finding was a linear trend across quintiles of tHcy level and a pattern of MRI findings combining infarcts and high white matter grade. The linear trend remained significant after controlling for other risk factors and atherosclerotic markers (top quintile vs bottom quintile odds ratio, 3.3; 95% confidence interval, 0.96-11.20; P =.04 for linear trend) but was slightly diminished after further controlling for creatinine, folate, and vitamins B(6) and B(12) (odds ratio, 3.2; 95% confidence interval, 0.81-13.10; P =.07 for linear trend).

CONCLUSION: We were unable to confirm the results of previous studies with respect to tHcy level and individual MRI findings, although an association was seen for an MRI pattern combining infarcts and high white matter grade.

%B Arch Neurol %V 61 %P 67-72 %8 2004 Jan %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/14732622?dopt=Abstract %R 10.1001/archneur.61.1.67 %0 Journal Article %J Neurology %D 2004 %T Preclinical Alzheimer disease: neuropsychological test performance 1.5 to 8 years prior to onset. %A Saxton, J %A Lopez, O L %A Ratcliff, G %A Dulberg, C %A Fried, L P %A Carlson, M C %A Newman, A B %A Kuller, L %K Age of Onset %K Alzheimer Disease %K Cardiovascular Diseases %K Cognition Disorders %K Cohort Studies %K Confounding Factors, Epidemiologic %K Disease Progression %K Early Diagnosis %K Educational Status %K Female %K Follow-Up Studies %K Humans %K Male %K Memory Disorders %K Neuropsychological Tests %K Predictive Value of Tests %K Proportional Hazards Models %K Risk %K Sensitivity and Specificity %K Time Factors %X

OBJECTIVE: To determine if individuals ultimately diagnosed with Alzheimer disease (AD) exhibited evidence of cognitive impairment on neuropsychological tests administered between 1.5 years and 8.1 years before dementia onset.

METHODS: A total of 693 community-dwelling individuals, part of the Cardiovascular Health Study, completed a neuropsychological test battery in 1991/92. Subjects were followed annually over the next 8 years (median follow-up = 7.4 years). Seventy-two individuals were ultimately diagnosed with AD (median follow-up = 4.5 years): 24 with AD onset 1.5 to 3.4 years after baseline neuropsychological testing, 20 with AD onset 3.5 to 5.0 years after testing, and 28 with onset 5.1 to 8.1 years after testing. A total of 621 individuals remained nondemented throughout the 8 years of follow-up (median follow-up = 7.5 years).

RESULTS: Subjects ultimately diagnosed with AD had poorer scores on baseline neuropsychological measures than subjects who remained nondemented. Although individuals closest to AD onset (i.e., 1.5 to 3.4 years) performed the most poorly, cognitive impairment was detected in individuals who did not develop AD until 5 to 8 years later.

CONCLUSIONS: Cognitive changes can be detected well before onset of Alzheimer disease.

%B Neurology %V 63 %P 2341-7 %8 2004 Dec 28 %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/15623697?dopt=Abstract %R 10.1212/01.wnl.0000147470.58328.50 %0 Journal Article %J Ann Epidemiol %D 2004 %T Predictors of falling cholesterol levels in older adults: the Cardiovascular Health Study. %A Manolio, Teri A %A Cushman, Mary %A Gottdiener, John S %A Dobs, Adrian %A Kuller, Lewis H %A Kronmal, Richard A %K African Americans %K Age Factors %K Aged %K Cardiovascular Diseases %K Cholesterol %K European Continental Ancestry Group %K Female %K Forecasting %K Health Status %K Humans %K Male %K Medicare %K Prospective Studies %K Risk Factors %K Sex Distribution %K Sex Factors %K United States %X

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

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

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

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

%B Ann Epidemiol %V 14 %P 325-31 %8 2004 May %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/15177271?dopt=Abstract %R 10.1016/j.annepidem.2003.09.006 %0 Journal Article %J Am Heart J %D 2004 %T Racial differences in endothelial function in postmenopausal women. %A Loehr, Laura R %A Espeland, Mark A %A Sutton-Tyrrell, Kim %A Burke, Gregory L %A Crouse, John R %A Herrington, David M %K African Continental Ancestry Group %K Aged %K Brachial Artery %K Cohort Studies %K Endothelium, Vascular %K European Continental Ancestry Group %K Female %K Humans %K Multivariate Analysis %K Postmenopause %K Risk Factors %K Vasodilation %X

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

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

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

%B Am Heart J %V 148 %P 606-11 %8 2004 Oct %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/15459590?dopt=Abstract %R 10.1016/j.ahj.2004.04.032 %0 Journal Article %J Am J Kidney Dis %D 2004 %T The relationship of cardiovascular risk factors to microalbuminuria in older adults with or without diabetes mellitus or hypertension: the cardiovascular health study. %A Barzilay, Joshua I %A Peterson, Do %A Cushman, Mary %A Heckbert, Susan R %A Cao, Jie J %A Blaum, Caroline %A Tracy, Russell P %A Klein, Ronald %A Herrington, David M %K Age Distribution %K Aged %K Aged, 80 and over %K Albuminuria %K Biomarkers %K Brachial Artery %K Comorbidity %K Coronary Disease %K Cross-Sectional Studies %K Diabetes Mellitus %K Female %K Humans %K Hypertension %K Inflammation %K Logistic Models %K Male %K Multivariate Analysis %K Odds Ratio %K Risk Factors %K Smoking %K Ultrasonography %X

BACKGROUND: Microalbuminuria is a risk factor for coronary heart disease (CHD). It occurs most commonly in the settings of diabetes and hypertension. The mechanisms by which it increases CHD risk are uncertain.

METHODS: We examined the cross-sectional association of microalbuminuria with a broad range of CHD risk factors in 3 groups of adults aged 65 years or older with and without microalbuminuria: those with (1) no diabetes or hypertension (n = 1,098), (2) hypertension only (n = 1,450), and (3) diabetes with or without hypertension (n = 465).

RESULTS: Three factors were related to microalbuminuria in all 3 groups: age, elevated systolic blood pressure, and markers of systemic inflammation. In patients with neither diabetes nor hypertension, increasing C-reactive protein levels were associated with microalbuminuria (odds ratio per 1-mg/L increase, 1.46; 95% confidence interval [CI], 1.15 to 1.84). Among those with diabetes, an increase in white blood cell (WBC) count was associated with microalbuminuria (odds ratio per 1,000-cell/mL increase, 2.57; 95% CI, 1.12 to 5.89). Among those with hypertension, an increase in WBC count (odds ratio per 1,000-cell/mL increase, 1.83; 95% CI, 1.04 to 3.23) and fibrinogen level (odds ratio per 10-mg/dL increase, 1.02; 95% CI, 1.00 to 1.05) were significantly associated with microalbuminuria. In all 3 groups, prevalent CHD was related to an elevated WBC count. In none of the 3 groups was brachial artery reactivity to ischemia, an in vivo marker of endothelial function, related to microalbuminuria.

CONCLUSION: Microalbuminuria is associated with age, systolic blood pressure, and markers of inflammation. These associations reflect potential mechanisms by which microalbuminuria is related to CHD risk.

%B Am J Kidney Dis %V 44 %P 25-34 %8 2004 Jul %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/15211434?dopt=Abstract %R 10.1053/j.ajkd.2004.03.022 %0 Journal Article %J J Am Geriatr Soc %D 2004 %T Risk of congestive heart failure in an elderly population treated with peripheral alpha-1 antagonists. %A Bryson, Chris L %A Smith, Nicholas L %A Kuller, Lewis H %A Chaves, Paulo H M %A Manolio, Teri A %A Lewis, William %A Boyko, Edward J %A Furberg, Curt D %A Psaty, Bruce M %K Adrenergic alpha-Antagonists %K Aged %K Antihypertensive Agents %K Benzothiadiazines %K Blood Pressure %K Cohort Studies %K Diuretics %K Female %K Heart Failure %K Humans %K Hypertension %K Male %K Risk Factors %K Sodium Chloride Symporter Inhibitors %K United States %X

OBJECTIVES: To compare the risk of congestive heart failure (CHF) in elderly individuals treated with any peripheral alpha-1 antagonist for hypertension with any thiazide, test whether the risk persists in subjects without cardiovascular disease (CVD) at baseline, and examine CHF risk in normotensive men with prostatism treated with alpha antagonists.

DESIGN: Prospective cohort study.

SETTING: Four U.S. sites: Washington County, Maryland; Allegheny County, Pennsylvania; Sacramento County, California; and Forsyth County, North Carolina.

PARTICIPANTS: A total of 5,888 community-dwelling subjects aged 65 and older.

MEASUREMENTS: Adjudicated incident CHF.

RESULTS: The 3,105 participants with treated hypertension were at risk for CHF; 22% of men and 8% of women took alpha antagonists during follow-up. The age-adjusted risk of CHF in those receiving monotherapy treated with alpha antagonists was 1.90 (95% confidence interval=1.03-3.50) compared with thiazides. In subjects without CVD at baseline receiving monotherapy, women taking an alpha antagonist had a 3.6 times greater age-adjusted risk of CHF, whereas men had no difference in risk. Adjustment for systolic blood pressure attenuated statistical differences in risk. There were 930 men without hypertension at risk for CHF; 5% used alpha antagonists during follow-up, with no observed increase in CHF risk.

CONCLUSION: Subjects receiving alpha antagonist monotherapy for hypertension had a two to three times greater risk of incident CHF, also seen in lower-risk subjects, but differences in blood pressure control partly explained this.

%B J Am Geriatr Soc %V 52 %P 1648-54 %8 2004 Oct %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/15450040?dopt=Abstract %R 10.1111/j.1532-5415.2004.52456.x %0 Journal Article %J Neurology %D 2004 %T Stroke risk factors and loss of high cognitive function. %A Elkins, J S %A O'Meara, E S %A Longstreth, W T %A Carlson, M C %A Manolio, T A %A Johnston, S C %K Aged %K Aged, 80 and over %K Aging %K Cognition Disorders %K Cohort Studies %K Comorbidity %K Female %K Follow-Up Studies %K Higher Nervous Activity %K Humans %K Incidence %K Male %K Risk Assessment %K Risk Factors %K Sampling Studies %K Sensitivity and Specificity %K Severity of Illness Index %K Stroke %K United States %X

BACKGROUND: Modifiable stroke risk factors may contribute to age-associated declines in cognitive function. Individuals with high levels of cognitive function after midlife may have less exposure to these stroke risk factors or may be less susceptible to their effects on cognition.

METHODS: The Cardiovascular Health Study (CHS)* is a population-based, longitudinal cohort study of 5,888 people age 65 years and older. Participants (n = 4,129) who were free of dementia, stroke, or TIA at the time of baseline cranial MRI were selected for analysis. High cognitive function at baseline was defined by performance at or above midlife norms on the Modified Mini-Mental State Examination (3MS).

RESULTS: The odds of having high cognitive function at baseline decreased by quartile of stroke risk (highest vs lowest risk quartile, adjusted odds ratio [OR] 0.68; 95% CI 0.52 to 0.88; p for trend = 0.005). Stroke risk was a predictor of decline on the 3MS in those with typical levels of cognitive function at baseline, even in the absence of incident stroke or TIA (highest vs lowest risk quartile for 3MS decline, adjusted OR 2.11; 95% CI 1.42 to 3.13; p for trend < 0.001). In contrast, stroke risk was not associated with decline on the 3MS in those with high cognitive function at baseline (p = 0.03 for interaction).

CONCLUSIONS: In a cohort of older adults without stroke, TIA, or dementia, cognitive function and incident cognitive decline were associated with risk for stroke. Additional studies are needed to determine whether modification of stroke risk factors can reduce the cognitive decline that is often attributed to normal aging.

%B Neurology %V 63 %P 793-9 %8 2004 Sep 14 %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/15365125?dopt=Abstract %R 10.1212/01.wnl.0000137014.36689.7f %0 Journal Article %J Am J Geriatr Cardiol %D 2004 %T Subclinical cardiovascular disease in older adults: insights from the Cardiovascular Health Study. %A Chaves, Paulo H M %A Kuller, Lewis H %A O'Leary, Daniel H %A Manolio, Teri A %A Newman, Anne B %K Aged %K Cardiovascular Diseases %K Coronary Artery Disease %K Heart Failure %K Humans %K Longitudinal Studies %K Prevalence %K Risk Assessment %K Risk Factors %X

Knowledge about the epidemiology of subclinical cardiovascular disease (SCVD) in older adults may hold the key for improved opportunities for primary prevention of cardiovascular disease (CVD), a top clinical and public health priority. This review reports findings on the prevalence of SCVD and the ability of SCVD measures to predict incident and adverse outcomes from one of the largest (N=5888) and most comprehensive prospective observational studies on SCVD in older adults, the Cardiovascular Health Study. According to a composite index that combined SCVD measures from different vascular beds, the overall prevalence of SCVD was 37%, making it as common as clinically overt CVD in older adults. SCVD measures strongly predicted incident CVD, stroke, mortality, frailty, and physical and cognitive decline, even after adjustment for traditional CVD risk factors. Ongoing research will address the potential use of SCVD for clinical decision making in older adults.

%B Am J Geriatr Cardiol %V 13 %P 137-51 %8 2004 May-Jun %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/15133417?dopt=Abstract %R 10.1111/j.1076-7460.2004.02120.x %0 Journal Article %J Am Heart J %D 2004 %T Time trends in the use of beta-blockers and other pharmacotherapies in older adults with congestive heart failure. %A Smith, Nicholas L %A Chan, Jeannie D %A Rea, Thomas D %A Wiggins, Kerri L %A Gottdiener, John S %A Lumley, Thomas %A Psaty, Bruce M %K Adrenergic beta-Antagonists %K Aged %K Angiotensin II Type 1 Receptor Blockers %K Angiotensin-Converting Enzyme Inhibitors %K Cohort Studies %K Drug Therapy %K Drug Therapy, Combination %K Female %K Heart Failure %K Humans %K Male %K Multivariate Analysis %K Prevalence %X

BACKGROUND: Evidence supporting pharmacotherapy of congestive heart failure (CHF) has grown substantially over the past decade and includes large, placebo-controlled trials with mortality end points. We describe beta-blocker and other medication temporal treatment trends of CHF in the Cardiovascular Health Study, a community-based cohort study of 5888 adults > or =65 years of age.

METHODS: Prescription medication data were collected from hospital discharge summaries for incident CHF events and at in-study annual clinic visits for prevalent CHF cases from 1989 to 2000. Change in use of agents over time was estimated by using generalized estimating equations while adjusting for potential confounding factors of age, sex, race, and cardiovascular and pulmonary comorbidities.

RESULTS: Among 1033 incident CHF events, beta-blocker use after diagnosis increased an average of 2.4 percentage points annually (95% CI, 1.5 to 3.4 points) from 1989 to 2000. The increasing trend was consistent throughout follow-up. Among participants with coronary disease and/or hypertension and among those with low ejection fractions (<45%), beta-blocker use remained flat from 1989 to 1994 and increased 4.7 points annually (2.5 to 6.9) and 10.0 points annually (6.1 to 13.8), respectively, from 1995 to 2000. Among participants without coronary disease or hypertension, there was no overall increase in use. Use of renin-angiotensin system inhibitors increased 2.3 points annually (1.0 to 3.5), digoxin use decreased 2.4 points annually (-3.6 to -1.1), and loop diuretic use remained flat between 1989 and 2000. In general, treatment trends were similar for prevalent CHF.

CONCLUSIONS: Treatment of CHF has changed gradually in the 1990s and may in part reflect the influence of CHF clinical trial evidence.

%B Am Heart J %V 148 %P 710-7 %8 2004 Oct %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/15459605?dopt=Abstract %R 10.1016/j.ahj.2004.04.002 %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 2004 %T White matter hyperintensity on cranial magnetic resonance imaging: a predictor of stroke. %A Kuller, Lewis H %A Longstreth, W T %A Arnold, Alice M %A Bernick, Charles %A Bryan, R Nick %A Beauchamp, Norman J %K Aged %K Brain %K Female %K Humans %K Leukoaraiosis %K Magnetic Resonance Imaging %K Male %K Radiography %K Risk Factors %K Stroke %X

BACKGROUND AND PURPOSE: We have previously reported that several "silent" infarcts found on magnetic resonance imaging (MRI) were a risk factor for stroke. Several recent reports have shown that high white matter grade (WMG) and increasing WMG over time were risk factors for stroke. We tested the hypothesis that high WMG > or =2 was a predictor of risk for stroke, independent of other risk factors.

METHODS: We examined the extent of white matter hyperintensity on cranial MRI of 3293 participants from the Cardiovascular Health Study (CHS). The degree of white matter hyperintensity was graded from least severe (grade=0) to most severe (grade=9). Participants were followed-up for an average of 7 years for the occurrence of a stroke. Clinical stroke diagnoses were based on hospital records reviewed by an adjudication committee expert in stroke diagnosis. During this period, 278 strokes occurred. Results The relative risk of stroke increased significantly as the WMG increased. The risk of stroke was 2.8% per year for participants with high WMG (grades > or =5), compared with only 0.6% for participants with grades 0 to 1.Conclusions The risk of stroke with high WMG is independent of traditional stroke risk factors and persists when controlling for MRI infarcts, another subclinical imaging marker of cerebrovascular disease. Assessment of white matter disease may be valuable in assessing future risk of stroke.

%B Stroke %V 35 %P 1821-5 %8 2004 Aug %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/15178824?dopt=Abstract %R 10.1161/01.STR.0000132193.35955.69 %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 Heart J %D 2005 %T Association of beta-blocker use with mortality among patients with congestive heart failure in the Cardiovascular Health Study (CHS). %A Chan, Jeannie D %A Rea, Thomas D %A Smith, Nicholas L %A Siscovick, David %A Heckbert, Susan R %A Lumley, Thomas %A Chaves, Paulo %A Furberg, Curt D %A Kuller, Lewis %A Psaty, Bruce M %K Adrenergic beta-Antagonists %K Age Factors %K Aged %K Aged, 80 and over %K Female %K Follow-Up Studies %K Heart Failure %K Humans %K Male %X

BACKGROUND: In clinical trials, beta-blocker therapy reduces all-cause mortality among people with congestive heart failure (CHF) characterized by depressed systolic function, but few trials included large numbers of elderly participants. This study assessed the association between beta-blocker therapy and mortality among community-dwelling older adults with CHF.

METHODS: The Cardiovascular Health Study (CHS) is a longitudinal, population-based study of adults aged > or = 65 years. Recruitment began in 1989 with follow-up extending through June 2000 or death. Cox proportional hazard regression models were used to assess the association between beta-blocker therapy and all-cause mortality among 950 participants who developed new-onset CHF.

RESULTS: beta-Blocker users (n = 157) were more likely than nonusers (n = 793) to have treated hypertension, clinical coronary artery disease, and valvular disease at the time of CHF diagnosis. Death occurred in 67 users and 446 nonusers during a median follow-up of 2.3 years. Compared with nonuse, use of beta-blockers was associated with a multivariable adjusted hazard ratio (HR) of 0.74 (95% CI 0.56-0.98) for all-cause mortality. Among the 520 participants who had left ventricular ejection fraction assessed within 90 days after CHF diagnosis, the risk for all cause mortality associated with beta-blocker use did not differ significantly between those with ejection fraction of < 40% and those with ejection fraction of > or = 40% (HR 0.56, 95% CI 0.27-1.13; HR 0.82, 95% CI 0.56-1.22, respectively; interaction P = .34).

CONCLUSIONS: This observational study suggests that beta-blocker treatment is associated with a reduced risk of all-cause mortality among community-dwelling older adults with CHF.

%B Am Heart J %V 150 %P 464-70 %8 2005 Sep %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/16169325?dopt=Abstract %R 10.1016/j.ahj.2004.12.022 %0 Journal Article %J Am J Kidney Dis %D 2005 %T Associations between retinal microvascular abnormalities and declining renal function in the elderly population: the Cardiovascular Health Study. %A Edwards, Matthew S %A Wilson, David B %A Craven, Timothy E %A Stafford, Jeanette %A Fried, Linda F %A Wong, Tien Y %A Klein, Ronald %A Burke, Gregory L %A Hansen, Kimberley J %K African Americans %K Aged %K Aged, 80 and over %K Aging %K Antihypertensive Agents %K Capillaries %K Cohort Studies %K Comorbidity %K Creatinine %K Diabetes Mellitus %K Disease Progression %K European Continental Ancestry Group %K Female %K Glomerular Filtration Rate %K Humans %K Hypertension %K Kidney %K Male %K Photography %K Prospective Studies %K Proteinuria %K Retina %K Retinal Diseases %K Retinal Vessels %X

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

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

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

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

%B Am J Kidney Dis %V 46 %P 214-24 %8 2005 Aug %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/16112039?dopt=Abstract %R 10.1053/j.ajkd.2005.05.005 %0 Journal Article %J Neurology %D 2005 %T Benefits of fatty fish on dementia risk are stronger for those without APOE epsilon4. %A Huang, T L %A Zandi, P P %A Tucker, K L %A Fitzpatrick, A L %A Kuller, L H %A Fried, L P %A Burke, G L %A Carlson, M C %K Aged %K Alzheimer Disease %K Apolipoprotein E4 %K Apolipoproteins E %K Cohort Studies %K Dementia %K Dietary Fats, Unsaturated %K Fatty Acids, Omega-3 %K Feeding Behavior %K Female %K Fish Oils %K Fish Products %K Food, Formulated %K Genetic Predisposition to Disease %K Humans %K Incidence %K Male %K Risk Factors %K Socioeconomic Factors %K Surveys and Questionnaires %X

OBJECTIVE: To compare associations of lean fish vs fatty fish (tuna or other fish) intake with dementia, Alzheimer disease (AD), and vascular dementia (VaD) and in relation to APOE epsilon4 status in the Cardiovascular Health Cognition Study (CHCS).

METHODS: Fish intake was assessed by food frequency questionnaires. Incident dementia, AD, and VaD were determined through a series of cognitive tests, physician's assessment, and committee consensus. We used Cox proportional hazards regression to calculate hazard ratios of dementia, AD, and VaD with lean fried fish, fatty fish, or total fish intake, which were then stratified by the presence of APOE epsilon4.

RESULTS: Although consumption of lean fried fish had no protective effect, consumption of fatty fish more than twice per week was associated with a reduction in risk of dementia by 28% (95% CI: 0.51 to 1.02), and AD by 41% (95% CI: 0.36 to 0.95) in comparison to those who ate fish less than once per month. Stratification by APOE epsilon4 showed this effect to be selective to those without the epsilon4 allele. Adjustment by education and income attenuated the effect.

CONCLUSION: In the Cardiovascular Health Cognition Study, consumption of fatty fish was associated with a reduced risk of dementia and Alzheimer disease for those without the APOE epsilon4 allele.

%B Neurology %V 65 %P 1409-14 %8 2005 Nov 08 %G eng %N 9 %1 https://www.ncbi.nlm.nih.gov/pubmed/16275829?dopt=Abstract %R 10.1212/01.wnl.0000183148.34197.2e %0 Journal Article %J JAMA %D 2005 %T Cardiovascular mortality risk in chronic kidney disease: comparison of traditional and novel risk factors. %A Shlipak, Michael G %A Fried, Linda F %A Cushman, Mary %A Manolio, Teri A %A Peterson, Do %A Stehman-Breen, Catherine %A Bleyer, Anthony %A Newman, Anne %A Siscovick, David %A Psaty, Bruce %K Aged %K Cardiovascular Diseases %K Chronic Disease %K Humans %K Kidney Diseases %K Longitudinal Studies %K Risk Factors %X

CONTEXT: Elderly persons with chronic kidney disease have substantial risk for cardiovascular mortality, but the relative importance of traditional and novel risk factors is unknown.

OBJECTIVE: To compare traditional and novel risk factors as predictors of cardiovascular mortality.

DESIGN, SETTING, AND PATIENTS: A total of 5808 community-dwelling persons aged 65 years or older living in 4 communities in the United States participated in the Cardiovascular Health Study cohort. Participants were initially recruited from 1989 to June 1990; an additional 687 black participants were recruited in 1992-1993. The average length of follow-up in this longitudinal study was 8.6 years.

MAIN OUTCOME MEASURES: Cardiovascular mortality among those with and without chronic kidney disease. Chronic kidney disease was defined as an estimated glomerular filtration rate of less than 60 mL/min per 1.73 m2.

RESULTS: Among the participants, 1249 (22%) had chronic kidney disease at baseline. The cardiovascular mortality risk rate was 32 deaths/1000 person-years among those with chronic kidney disease vs 16/1000 person-years among those without it. In multivariate analyses, diabetes, systolic hypertension, smoking, low physical activity, nonuse of alcohol, and left ventricular hypertrophy were predictors of cardiovascular mortality in persons with chronic kidney disease (all P values <.05). Among the novel risk factors, only log C-reactive protein (P = .05) and log interleukin 6 (P<.001) were associated with the outcome as linear predictors. Traditional risk factors were associated with the largest absolute increases in risks for cardiovascular deaths among persons with chronic kidney disease: for left ventricular hypertrophy, there were 25 deaths per 1000 person-years; current smoking, 20 per 1000 person-years; physical inactivity, 15 per 1000 person-years; systolic hypertension, 14 per 1000 person-years; diabetes, 14 per 1000 person-years; and nonuse of alcohol, 11 per 1000 person-years vs 5 deaths per 1000 person-years for those with increased C-reactive protein and 5 per 1000 person-years for those with increased interleukin 6 levels. A receiver operating characteristic analysis found that traditional risk factors had an area under the curve of 0.73 (95% confidence interval, 0.70-0.77) among those with chronic kidney disease. Adding novel risk factors only increased the area under the curve to 0.74 (95% confidence interval, 0.71-0.78; P for difference = .15).

CONCLUSIONS: Traditional cardiovascular risk factors had larger associations with cardiovascular mortality than novel risk factors in elderly persons with chronic kidney disease. Future research should investigate whether aggressive lifestyle intervention in patients with chronic kidney disease can reduce their substantial cardiovascular risk.

%B JAMA %V 293 %P 1737-45 %8 2005 Apr 13 %G eng %N 14 %1 https://www.ncbi.nlm.nih.gov/pubmed/15827312?dopt=Abstract %R 10.1001/jama.293.14.1737 %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 Neurology %D 2005 %T Classification of vascular dementia in the Cardiovascular Health Study Cognition Study. %A Lopez, O L %A Kuller, L H %A Becker, J T %A Jagust, W J %A DeKosky, S T %A Fitzpatrick, A %A Breitner, J %A Lyketsos, C %A Kawas, C %A Carlson, M %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Brain %K Cerebral Arteries %K Cohort Studies %K Dementia, Vascular %K Diagnosis, Differential %K Disease Progression %K Female %K Humans %K Magnetic Resonance Imaging %K Male %K Predictive Value of Tests %K Stroke %K United States %X

OBJECTIVE: To describe the diagnostic classification of subjects with incident vascular dementia (VaD) participating in the Cardiovascular Health Study (CHS) Cognition Study.

METHODS: The CHS classified 480 incident cases between 1994 and 1999 among 3,608 CHS participants who had brain MRI in 1992 through 1994 and in 1997 through 1998. The patients were diagnosed before and after reviewing the brain MRI.

RESULTS: The pre-MRI classification showed that 52 participants had VaD and 76 had both Alzheimer disease (AD) and VaD. The post-MRI classification showed that the Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) criteria classified 61 subjects as having VaD, the National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN) criteria classified 43 subjects as having probable VaD and 10 as possible VaD, and the State of California Alzheimer's Disease Diagnostic and Treatment Center (ADDTC) criteria classified 117 as having probable VaD and 96 as possible. The combination of the ADDTC and National Institute of Neurological and Communication Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria was used to examine the spectrum of vascular disease in dementia. The dementia was attributable to only vascular factors in 56 cases (probable VaD); VaD coexisted with AD in 61 cases, although the VaD component was the leading cause of dementia (probable VaD with AD); AD was the leading cause of dementia in 61 cases (possible VaD and probable AD); and in 29 cases, it was not clear that either AD or VaD was the primary diagnosis (possible AD and possible VaD).

CONCLUSIONS: None of the clinical criteria for VaD identified the same group of subjects. The diagnosis of vascular dementia is difficult in epidemiologic studies because poststroke dementia can be due to Alzheimer disease (AD) and evidence of vascular disease can be found in the MRI of dementia cases without clinical strokes. Whether the clinical progression is related to AD pathology or vascular disease is difficult to establish.

%B Neurology %V 64 %P 1539-47 %8 2005 May 10 %G eng %N 9 %1 https://www.ncbi.nlm.nih.gov/pubmed/15883314?dopt=Abstract %R 10.1212/01.WNL.0000159860.19413.C4 %0 Journal Article %J Atherosclerosis %D 2005 %T Common promoter polymorphisms of inflammation and thrombosis genes and longevity in older adults: the cardiovascular health study. %A Reiner, Alexander P %A Diehr, Paula %A Browner, Warren S %A Humphries, Stephen E %A Jenny, Nancy S %A Cushman, Mary %A Tracy, Russell P %A Walston, Jeremy %A Lumley, Thomas %A Newman, Anne B %A Kuller, Lewis H %A Psaty, Bruce M %K Aged %K Aging %K Carboxypeptidase B2 %K Cause of Death %K Cohort Studies %K Female %K Genotype %K Health Status %K Humans %K Inflammation %K Longevity %K Male %K Middle Aged %K Plasminogen Activator Inhibitor 1 %K Polymorphism, Genetic %K Promoter Regions, Genetic %K Prospective Studies %K Risk Factors %K Thrombosis %X

Inflammatory response genes may influence life span or quality at advanced ages. Using data from the population-based cardiovascular health study (CHS) cohort, we examined the associations between promoter polymorphisms of several inflammation and thrombosis genes with longevity. We ascertained genotypes for interleukin (IL)-6 -174 G/C, beta-fibrinogen -455 G/A, plasminogen activator inhibitor (PAI)-1 -675 4G/5G, and thrombin-activatable fibrinolysis inhibitor (TAFI) -438 G/A in 2224 men and women > or = 65 years old at baseline. During 10 years of follow-up, men with the TAFI -438 A/A genotype had decreased mortality due to all causes, and lived, on average, 0.9 more years of life, or 1.1 more years of healthy life, than men with the -438 G allele. The effects of TAFI -438 G/A in women were smaller and not statistically significant. PAI-1 4G/4G genotype appeared to be associated with lower non-cardiovascular mortality in men, but with greater cardiovascular mortality in women. In exploratory analyses, we observed a possible interaction among anti-inflammatory drugs, interleukin-6 -174 C/C genotype, and longevity. These findings suggest that modulators of fibrinolytic activity may have a generalized influence on aging, and merit further investigation in studies of genetic determinants of human longevity.

%B Atherosclerosis %V 181 %P 175-83 %8 2005 Jul %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/15939070?dopt=Abstract %R 10.1016/j.atherosclerosis.2005.01.028 %0 Journal Article %J Circulation %D 2005 %T C-reactive protein and the 10-year incidence of coronary heart disease in older men and women: the cardiovascular health study. %A Cushman, Mary %A Arnold, Alice M %A Psaty, Bruce M %A Manolio, Teri A %A Kuller, Lewis H %A Burke, Gregory L %A Polak, Joseph F %A Tracy, Russell P %K Age Factors %K Aged %K Aged, 80 and over %K Biomarkers %K C-Reactive Protein %K Coronary Disease %K Female %K Humans %K Incidence %K Inflammation %K Male %K Myocardial Infarction %K Predictive Value of Tests %K Risk Factors %X

BACKGROUND: High C-reactive protein (CRP) is associated with increased coronary heart disease risk. Few long-term data in the elderly are available.

METHODS AND RESULTS: Baseline CRP was measured in 3971 men and women > or =65 years of age without prior vascular diseases; 26% had elevated concentrations (>3 mg/L). With 10 years of follow-up, 547 participants developed coronary heart disease (CHD; defined as myocardial infarction or coronary death). With elevated CRP, the 10-year cumulative CHD incidences were 33% in men and 17% in women. The age-, ethnicity-, and sex-adjusted relative risk of CHD for CRP >3 mg/L compared with <1 mg/L was 1.82 (95% CI, 1.46 to 2.28). Adjusting for conventional risk factors reduced the relative risk to 1.45 (95% CI, 1.14 to 1.86). The population-attributable risk of CHD for elevated CRP was 11%. Risk relationships did not differ in subgroups defined by baseline risk factors. We assessed whether CRP improved prediction by the Framingham Risk Score. Among men with a 10-year Framingham-predicted risk of 10% to 20%, the observed CHD incidence was 32% for elevated CRP. Among women, CRP discriminated best among those with a 10-year predicted risk >20%; the incidences were 31% and 10% for elevated and normal CRP levels, respectively.

CONCLUSIONS: In older men and women, elevated CRP was associated with increased 10-year risk of CHD, regardless of the presence or absence of cardiac risk factors. A single CRP measurement provided information beyond conventional risk assessment, especially in intermediate-Framingham-risk men and high-Framingham-risk women.

%B Circulation %V 112 %P 25-31 %8 2005 Jul 05 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/15983251?dopt=Abstract %R 10.1161/CIRCULATIONAHA.104.504159 %0 Journal Article %J Ann Intern Med %D 2005 %T Cystatin C concentration as a risk factor for heart failure in older adults. %A Sarnak, Mark J %A Katz, Ronit %A Stehman-Breen, Catherine O %A Fried, Linda F %A Jenny, Nancy Swords %A Psaty, Bruce M %A Newman, Anne B %A Siscovick, David %A Shlipak, Michael G %K Aged %K Biomarkers %K Creatinine %K Cystatin C %K Cystatins %K Female %K Follow-Up Studies %K Glomerular Filtration Rate %K Heart Failure %K Humans %K Incidence %K Kidney %K Kidney Function Tests %K Male %K Risk Factors %K United States %X

BACKGROUND: Previous studies that evaluated the association of kidney function with incident heart failure may be limited by the insensitivity of serum creatinine concentration for detecting abnormal kidney function.

OBJECTIVE: To compare serum concentrations of cystatin C (a novel marker of kidney function) and creatinine as predictors of incident heart failure.

DESIGN: Observational study based on measurement of serum cystatin C from frozen sera obtained at the 1992-1993 visit of the Cardiovascular Health Study. Follow-up occurred every 6 months.

SETTING: Adults 65 years of age or older from 4 communities in the United States.

PARTICIPANTS: 4384 persons without previous heart failure who had measurements of serum cystatin C and serum creatinine.

MEASUREMENTS: Incident heart failure.

RESULTS: The mean (+/-SD) serum concentrations of cystatin C and creatinine were 82 +/- 25 nmol/L (1.10 +/- 0.33 mg/L) and 89 +/- 34 micromol/L (1.01 +/- 0.39 mg/dL), respectively. During a median follow-up of 8.3 years (maximum, 9.1 years), 763 (17%) participants developed heart failure. After adjustment for demographic factors, traditional and novel cardiovascular risk factors, cardiovascular disease status, and medication use, sequential quintiles of cystatin C concentration were associated with a stepwise increased risk for heart failure in Cox proportional hazards models (hazard ratios, 1.0 [reference], 1.30 [95% CI, 0.96 to 1.75], 1.44 [CI, 1.07 to 1.94], 1.58 [CI, 1.18 to 2.12], and 2.16 [CI, 1.61 to 2.91]). In contrast, quintiles of serum creatinine concentration were not associated with risk for heart failure in adjusted analysis (hazard ratios, 1.0 [reference], 0.77 [CI, 0.59 to 1.01], 0.85 [CI, 0.64 to 1.13], 0.97 [CI, 0.72 to 1.29], and 1.14 [CI, 0.87 to 1.49]).

LIMITATIONS: The mechanism by which cystatin C concentration predicts risk for heart failure remains unclear.

CONCLUSIONS: The cystatin C concentration is an independent risk factor for heart failure in older adults and appears to provide a better measure of risk assessment than the serum creatinine concentration. *For a full list of participating Cardiovascular Health Study investigators and institutions, see http://www.chs-nhlbi.org.

%B Ann Intern Med %V 142 %P 497-505 %8 2005 Apr 05 %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/15809461?dopt=Abstract %R 10.7326/0003-4819-142-7-200504050-00008 %0 Journal Article %J Am J Med %D 2005 %T Cystatin-C and inflammatory markers in the ambulatory elderly. %A Shlipak, Michael G %A Katz, Ronit %A Cushman, Mary %A Sarnak, Mark J %A Stehman-Breen, Catherine %A Psaty, Bruce M %A Siscovick, David %A Tracy, Russell P %A Newman, Anne %A Fried, Linda %K Age Factors %K Aged %K Biomarkers %K C-Reactive Protein %K Cross-Sectional Studies %K Cystatin C %K Cystatins %K Female %K Fibrinogen %K Glomerular Filtration Rate %K Humans %K Kidney Diseases %K Male %K Predictive Value of Tests %K Sensitivity and Specificity %X

PURPOSE: Inflammatory factors are elevated in persons with severe renal dysfunction, but their association across all levels of renal function is unclear. We compared cystatin-C, a novel marker of renal function, with creatinine and estimated glomerular filtration rate (eGFR) as predictors of C-reactive protein and fibrinogen levels.

METHODS: This study is a cross-sectional analysis to evaluate cystatin-C, creatinine, and eGFR as predictors of the inflammatory markers C-reactive protein and fibrinogen. Participants included 4637 ambulatory elderly patients from the Cardiovascular Health Study. Multivariate linear regression was used to determine the independent associations of each renal function measurement with the inflammatory marker outcomes.

RESULTS: After adjustment for confounding factors, cystatin-C was correlated with both C-reactive protein (coefficient = 0.13; 95% confidence interval: 0.10-1.16, P <.0001) and fibrinogen levels (0.15; 0.13-0.18, P <.0001). Associations were larger than those for creatinine and C-reactive protein (0.05; 0.02-0.07, P = .003) or fibrinogen (0.07; 0.04-0.10, P <.0001). Adjusted levels of C-reactive protein increased incrementally across quintiles of cystatin-C, from a median of 2.2 mg/L in quintile 1 to 3.7 mg/L in quintile 5. In contrast, both C-reactive protein and fibrinogen had U-shaped associations with quintiles of creatinine and eGFR, because the inflammatory markers were equivalently elevated in quintiles 1 and 5.

CONCLUSIONS: The finding of a significant linear association of cystatin-C and inflammation markers suggests that even small reductions in renal function may be associated with adverse pathophysiologic consequences.

%B Am J Med %V 118 %P 1416 %8 2005 Dec %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/16378798?dopt=Abstract %R 10.1016/j.amjmed.2005.07.060 %0 Journal Article %J J Am Soc Nephrol %D 2005 %T Kidney function as a predictor of noncardiovascular mortality. %A Fried, Linda F %A Katz, Ronit %A Sarnak, Mark J %A Shlipak, Michael G %A Chaves, Paulo H M %A Jenny, Nancy Swords %A Stehman-Breen, Catherine %A Gillen, Dan %A Bleyer, Anthony J %A Hirsch, Calvin %A Siscovick, David %A Newman, Anne B %K Age Factors %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Cause of Death %K Cohort Studies %K Confidence Intervals %K Creatinine %K Cystatin C %K Cystatins %K Female %K Glomerular Filtration Rate %K Humans %K Kidney Failure, Chronic %K Kidney Function Tests %K Longitudinal Studies %K Male %K Probability %K Proportional Hazards Models %K Risk Assessment %K Severity of Illness Index %K Survival Analysis %K United States %X

Chronic kidney disease is associated with a higher risk for cardiovascular mortality, as well as all-cause mortality. Whether chronic kidney disease is a predictor of noncardiovascular mortality is less clear. To further explore the latter, the association of kidney function with total noncardiovascular mortality and cause-specific mortality was assessed in the Cardiovascular Health Study, a community-based cohort of older individuals. Kidney disease was assessed using cystatin C and estimated GFR in 4637 participants in 1992 to 1993. Participants were followed until June 30, 2001. Deaths were adjudicated as cardiovascular or noncardiovascular disease by committee, and an underlying cause of death was assigned. The associations of kidney function with total noncardiovascular mortality and cause-specific mortality were analyzed by proportional hazards regression. Noncardiovascular mortality rates increased with higher cystatin C quartiles (16.8, 17.1, 21.6, and 50.0 per 1000 person-years). The association of cystatin C with noncardiovascular mortality persisted after adjustment for demographic factors; the presence of diabetes, C-reactive protein, hemoglobin, and prevalent cardiovascular disease; and measures of atherosclerosis (hazard ratio 1.69; 95% confidence interval 1.33 to 2.15, for the fourth quartile versus the first quartile). Results for estimated GFR were similar. The risk for noncardiac deaths attributed to pulmonary disease, infection, cancer, and other causes was similarly associated with cystatin C levels. Kidney function predicts noncardiovascular mortality from multiple causes in the elderly. Further research is needed to understand the mechanisms and evaluate interventions to reduce the high mortality rate in chronic kidney disease.

%B J Am Soc Nephrol %V 16 %P 3728-35 %8 2005 Dec %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/16251239?dopt=Abstract %R 10.1681/ASN.2005040384 %0 Journal Article %J Neuroepidemiology %D 2005 %T Morphometric analysis of gray matter volume in demented older adults: exploratory analysis of the cardiovascular health study brain MRI database. %A Rosano, C %A Becker, J %A Lopez, O %A Lopez-Garcia, P %A Carter, C S %A Newman, A %A Kuller, L %A Aizenstein, H %K Aged %K Aged, 80 and over %K Brain %K Dementia %K Educational Status %K Feasibility Studies %K Female %K Health Status %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Organ Size %K Reproducibility of Results %X

We tested the feasibility of a fully automated brain MRI voxel count technique--automated labeling pathway (ALP)--in a sample of 15 demented and 13 cognitively normal women (age 75-85 years) participating to the Cardiovascular Health Study (CHS). We hypothesized that ALP would replicate well-established findings of the anatomical correlates of dementia. In particular, we hypothesized that ALP volumetric measures would: (1) significantly differ between cognitively normal and demented women in those brain areas that are established markers for diagnosis of dementia (temporal and medial temporal lobes, hippocampus, amygdala and parahippocampus) but not in other brain areas (e.g., occipital lobe, visual cortex, motor cortex) and (2) correlate with visual ratings of brain disease which have been previously collected as part of the CHS. ALP required minimal operator intervention (input of brain images and verification of misalignments) and employed computer time of about 1 h per brain. ALP detected significant focal volumetric differences in the limbic system (p values between groups for hippocampus and parahippocampus: 0.002 and 0.005, respectively), temporal lobe (p < 0.0001) and caudate (p = 0.009), but not in other brain areas (e.g. occipital lobe, visual or motor cortex). Furthermore, ALP measures of medial temporal lobe atrophy strongly correlated with CHS visual ratings of ventricular enlargement (r(2) = 0.6, p = 0.002 for medial temporal lobe). In conclusion, ALP-detected focal brain atrophy was strongly associated with dementia. Because of its fully automated design, ALP technique is an ideal candidate to assess whether volumetric measures of specific areas can discriminate dementia better than currently available measures of global brain atrophy in large epidemiological studies.

%B Neuroepidemiology %V 24 %P 221-9 %8 2005 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/15832060?dopt=Abstract %R 10.1159/000085140 %0 Journal Article %J Am J Epidemiol %D 2005 %T Physical activity, APOE genotype, and dementia risk: findings from the Cardiovascular Health Cognition Study. %A Podewils, Laura Jean %A Guallar, Eliseo %A Kuller, Lewis H %A Fried, Linda P %A Lopez, Oscar L %A Carlson, Michelle %A Lyketsos, Constantine G %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Apolipoproteins E %K Dementia %K Dementia, Vascular %K Female %K Genotype %K Humans %K Male %K Motor Activity %K Proportional Hazards Models %K Prospective Studies %K Risk Factors %K United States %X

Physical activity may help preserve cognitive function and decrease dementia risk, but epidemiologic findings are inconsistent. The authors conducted a prospective study to determine the association between physical activity and risk of dementia, Alzheimer's disease, and vascular dementia. The US study population comprised 3,375 men and women aged 65 years or older, free of dementia at baseline, who participated in the Cardiovascular Health Cognition Study in 1992-2000. Leisure-time energy expenditure and an activity index reflecting number of different physical activities were calculated. Analyses were based on Cox proportional hazards models. There were 480 incident cases of dementia over an average of 5.4 years of follow-up. After multivariate adjustment, participants in the highest quartile of physical energy expenditure had a relative risk of dementia of 0.85 (95% confidence interval: 0.61, 1.19) compared with those in the lowest quartile, and participants engaging in >or=4 activities had a relative risk of dementia of 0.51 (95% confidence interval: 0.33, 0.79) compared with those engaging in 0-1 activity. These associations were more marked in apolipoprotein E genotype (APOE) epsilon4 allele noncarriers but were absent in carriers. A similar pattern was observed for Alzheimer's disease and vascular dementia. Mechanisms to explain the observed relations deserve further study.

%B Am J Epidemiol %V 161 %P 639-51 %8 2005 Apr 01 %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/15781953?dopt=Abstract %R 10.1093/aje/kwi092 %0 Journal Article %J Am J Hum Genet %D 2005 %T Population structure, admixture, and aging-related phenotypes in African American adults: the Cardiovascular Health Study. %A Reiner, Alexander P %A Ziv, Elad %A Lind, Denise L %A Nievergelt, Caroline M %A Schork, Nicholas J %A Cummings, Steven R %A Phong, Angie %A Burchard, Esteban González %A Harris, Tamara B %A Psaty, Bruce M %A Kwok, Pui-Yan %K African Americans %K Aged %K Aging %K Algorithms %K Cardiovascular Diseases %K Cohort Studies %K Female %K Genetics, Population %K Genotype %K Humans %K Male %K Models, Genetic %K Phenotype %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Risk Factors %K Socioeconomic Factors %X

U.S. populations are genetically admixed, but surprisingly little empirical data exists documenting the impact of such heterogeneity on type I and type II error in genetic-association studies of unrelated individuals. By applying several complementary analytical techniques, we characterize genetic background heterogeneity among 810 self-identified African American subjects sampled as part of a multisite cohort study of cardiovascular disease in older adults. On the basis of the typing of 24 ancestry-informative biallelic single-nucleotide-polymorphism markers, there was evidence of substantial population substructure and admixture. We used an allele-sharing-based clustering algorithm to infer evidence for four genetically distinct subpopulations. Using multivariable regression models, we demonstrate the complex interplay of genetic and socioeconomic factors on quantitative phenotypes related to cardiovascular disease and aging. Blood glucose level correlated with individual African ancestry, whereas body mass index was associated more strongly with genetic similarity. Blood pressure, HDL cholesterol level, C-reactive protein level, and carotid wall thickness were not associated with genetic background. Blood pressure and HDL cholesterol level varied by geographic site, whereas C-reactive protein level differed by occupation. Both ancestry and genetic similarity predicted the number and quality of years lived during follow-up, but socioeconomic factors largely accounted for these associations. When the 24 genetic markers were tested individually, there were an excess number of marker-trait associations, most of which were attenuated by adjustment for genetic ancestry. We conclude that the genetic demography underlying older individuals who self identify as African American is complex, and that controlling for both genetic admixture and socioeconomic characteristics will be required in assessing genetic associations with chronic-disease-related traits in African Americans. Complementary methods that identify discrete subgroups on the basis of genetic similarity may help to further characterize the complex biodemographic structure of human populations.

%B Am J Hum Genet %V 76 %P 463-77 %8 2005 Mar %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/15660291?dopt=Abstract %R 10.1086/428654 %0 Journal Article %J Arch Intern Med %D 2005 %T A prospective study of anemia status, hemoglobin concentration, and mortality in an elderly cohort: the Cardiovascular Health Study. %A Zakai, Neil A %A Katz, Ronit %A Hirsch, Calvin %A Shlipak, Michael G %A Chaves, Paulo H M %A Newman, Anne B %A Cushman, Mary %K Age Factors %K Aged %K Anemia %K California %K Female %K Follow-Up Studies %K Health Status %K Hemoglobins %K Humans %K Male %K Maryland %K Multivariate Analysis %K North Carolina %K Observation %K Pennsylvania %K Prospective Studies %K Risk Factors %K Severity of Illness Index %K Survival Rate %X

BACKGROUND: Anemia is viewed as a negative prognostic factor in the elderly population; its independent impact on survival is unclear.

METHODS: Baseline hemoglobin quintiles and anemia, as defined by the World Health Organization criteria, were assessed in relation to mortality in the Cardiovascular Health Study, a prospective cohort study with 11.2 years of follow-up of 5888 community-dwelling men and women 65 years or older, enrolled in 1989-1990 or 1992-1993 in 4 US communities.

RESULTS: A total of 1205 participants were in the lowest hemoglobin quintile (<13.7 g/dL for men; <12.6 g/dL for women), and 498 (8.5%) were anemic (<13 g/dL for men; <12 g/dL for women). A reverse J-shaped relationship with mortality was observed; age-, sex-, and race-adjusted hazard ratios (95% confidence interval [CI]) in the first and fifth quintiles, compared with the fourth quintile, were 1.42 (95% CI, 1.25-1.62) and 1.24 (95% CI, 1.09-1.42). After multivariate adjustment, these hazard ratios were 1.33 (95% CI, 1.15-1.54) and 1.17 (95% CI, 1.01-1.36). The demographic- and fully-adjusted hazard ratios of anemia for mortality were 1.57 (95% CI, 1.38-1.78) and 1.38 (95% CI, 1.19-1.54). Adjustment for causes and consequences of anemia (renal function, inflammation, or frailty) did not reduce associations.

CONCLUSIONS: Lower and higher hemoglobin concentrations and anemia by World Health Organization criteria were independently associated with increased mortality. The World Health Organization criteria did not identify risk as well as a lower hemoglobin value. Additional study is needed on the clinically valid definition for and causes of anemia in the elderly and on the increased mortality at the extremes of hemoglobin concentrations.

%B Arch Intern Med %V 165 %P 2214-20 %8 2005 Oct 24 %G eng %N 19 %1 https://www.ncbi.nlm.nih.gov/pubmed/16246985?dopt=Abstract %R 10.1001/archinte.165.19.2214 %0 Journal Article %J Cancer %D 2005 %T Prostate carcinoma incidence in relation to prediagnostic circulating levels of insulin-like growth factor I, insulin-like growth factor binding protein 3, and insulin. %A Chen, Chu %A Lewis, S Kay %A Voigt, Lynda %A Fitzpatrick, Annette %A Plymate, Stephen R %A Weiss, Noel S %K Aged %K Aged, 80 and over %K Carcinoma %K Case-Control Studies %K Humans %K Hypoglycemic Agents %K Incidence %K Insulin %K Insulin-Like Growth Factor Binding Protein 3 %K Insulin-Like Growth Factor I %K Male %K Prostatic Neoplasms %K Risk Factors %X

BACKGROUND: There have been several epidemiologic studies investigating the association between circulating levels of insulin-like growth factor I (IGF-I), insulin-like growth factor binding protein 3 (IGFBP-3), and insulin in relation to the risk of prostate carcinoma, with conflicting results. To examine this issue further, the authors conducted a nested case-control study within the Cardiovascular Health Study cohort.

METHODS: In men who were diagnosed with prostate carcinoma (cases) between 1990 and 1999 (n=174), the levels of IGF-I, IGFBP-3, and insulin were measured on blood samples that were obtained 1-9 years prior to diagnosis (mean, 3.4 years). Similar measurements were made on 174 male participants without prostate carcinoma (controls) who were matched to cases based on the year blood was drawn, survival until the date of diagnosis, race, and age.

RESULTS: Relative to the men with IGF-I levels in the first (lowest) quartile of the distribution, the risk of prostate carcinoma for men in the second, third, and fourth (upper) quartiles were 0.77 (95% confidence interval [95% CI], 0.43-1.38), 0.73 (95% CI, 0.41-1.30), and 0.67 (95% CI, 0.37-1.25), respectively. The results were influenced little by adjustment for levels of IGFBP-3 or, instead, by evaluating the molar IGF-I/IGFBP-3 ratio. An analysis that was restricted to men who had plasma prostate-specific antigen levels <4 ng/mL at the time of the blood draw yielded similar results. The corresponding relative risks for IGFBP-3 were 0.91 (95% CI, 0.49-1.68), 0.47 (95% CI, 0.25-0.94), and 0.65 (95% CI, 0.35-1.20), respectively. The distribution of serum insulin levels in cases and controls were nearly identical.

CONCLUSIONS: The IGF-I level was not associated positively with the risk of prostate carcinoma; however, an increase in the IGFBP-3 level was associated with a modest decrease in risk.

%B Cancer %V 103 %P 76-84 %8 2005 Jan 01 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/15540247?dopt=Abstract %R 10.1002/cncr.20727 %0 Journal Article %J Am J Kidney Dis %D 2005 %T Renal duplex parameters, blood pressure, and renal function in elderly people. %A Pearce, Jeffrey D %A Edwards, Matthew S %A Craven, Timothy E %A English, William P %A Mondi, Matthew M %A Reavis, Scott W %A Hansen, Kimberley J %K African Americans %K Aged %K Aging %K Arteriosclerosis %K Blood Pressure %K Cardiovascular Diseases %K Cohort Studies %K Creatinine %K Cross-Sectional Studies %K Diastole %K Disease Progression %K European Continental Ancestry Group %K Female %K Humans %K Hypertension, Renovascular %K Kidney %K Kidney Diseases %K Kidney Function Tests %K Male %K Renal Artery %K Renal Artery Obstruction %K Renal Circulation %K Risk Factors %K Sampling Studies %K Systole %K Ultrasonography, Doppler, Duplex %K United States %X

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

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

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

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

%B Am J Kidney Dis %V 45 %P 842-50 %8 2005 May %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/15861349?dopt=Abstract %R 10.1053/j.ajkd.2005.01.028 %0 Journal Article %J Arch Intern Med %D 2005 %T Renovascular disease and the risk of adverse coronary events in the elderly: a prospective, population-based study. %A Edwards, Matthew S %A Craven, Timothy E %A Burke, Gregory L %A Dean, Richard H %A Hansen, Kimberley J %K Age Distribution %K Aged %K Aged, 80 and over %K Analysis of Variance %K Cohort Studies %K Comorbidity %K Coronary Disease %K Female %K Geriatric Assessment %K Heart Function Tests %K Humans %K Hypertension, Renovascular %K Incidence %K Kidney Function Tests %K Male %K Multivariate Analysis %K Probability %K Prognosis %K Prospective Studies %K Risk Assessment %K Severity of Illness Index %K Sex Distribution %K Survival Rate %K Ultrasonography, Doppler %K United States %X

BACKGROUND: Renovascular disease is a cause of secondary hypertension and renal insufficiency and is suspected to contribute to morbidity and mortality of coronary heart disease. This investigation prospectively examined associations between renovascular disease and adverse coronary events among a population-based sample of elderly Americans.

METHODS: The Cardiovascular Health Study is a prospective, multicenter cohort study of cardiovascular disease risk factors, morbidity, and mortality among Americans older than 65 years. Renal duplex sonography was performed on 870 individuals between January 1995 and February 1997. Renovascular disease was defined as any focal peak systolic velocity of 1.8 m/s or greater (renal artery stenosis) or the absence of a Doppler-shifted signal from an imaged artery (renal artery occlusion). Adverse coronary events were defined as hospitalized angina, fatal or nonfatal myocardial infarction, and coronary revascularization.

RESULTS: During a mean follow-up of 14 months, 68 participants experienced incident or recurrent adverse coronary events. The presence of renovascular disease demonstrated a significant relationship with adverse coronary events (hazard ratio, 1.96; 95% confidence interval, 1.00-3.83; P = .05) that remained after controlling for the effects of coexisting atherosclerotic risk factors and prevalent cardiovascular disease. The relationship between renovascular disease and adverse coronary events was not dependent on the effects of increased blood pressure.

CONCLUSIONS: The presence of renovascular disease was associated with an increase in the risk of adverse coronary events in this sample. The increment in risk was not dependent on the effects of associated atherosclerotic risk factors, other prevalent cardiovascular disease, or increased blood pressure.

%B Arch Intern Med %V 165 %P 207-13 %8 2005 Jan 24 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/15668368?dopt=Abstract %R 10.1001/archinte.165.2.207 %0 Journal Article %J Arch Intern Med %D 2005 %T Risk factors for declining ankle-brachial index in men and women 65 years or older: the Cardiovascular Health Study. %A Kennedy, Margaret %A Solomon, Cam %A Manolio, Teri A %A Criqui, Michael H %A Newman, Anne B %A Polak, Joseph F %A Burke, Gregory L %A Enright, Paul %A Cushman, Mary %K Aged %K Aged, 80 and over %K Ankle %K Brachial Artery %K Cardiovascular Diseases %K Female %K Humans %K Male %K Peripheral Vascular Diseases %K Risk Assessment %K Risk Factors %X

BACKGROUND: An ankle-brachial index (ABI) of less than 0.9 is a noninvasive measure of lower extremity arterial disease and a predictor of cardiovascular events. Little information is available on longitudinal change in ABI or on risk factors for declining ABI in a community-based population.

METHODS: To assess risk factors for ABI decline, we studied 5888 participants in the Cardiovascular Health Study cohort (men and women 65 years or older). We measured ABI in 1992-1993 and again in 1998-1999. At baseline, we excluded individuals with an ABI less than 0.9, ABI greater than 1.4, or confirmed symptomatic lower extremity arterial disease (n = 823). The group with ABI decline included 218 participants with decline greater than 0.15 and to 0.9 or less. The comparison group comprised the remaining 2071 participants with follow-up ABI.

RESULTS: The percentage of participants with ABI decline was 9.5% over 6 years of follow-up. The mean +/- SD decline was 0.33 +/- 0.12 in cases of ABI decline and 0.02 +/- 0.13 in non-cases. Independent predictors of ABI decline, reported as odds ratios, were age, 1.96 (95% confidence interval [CI], 1.42-2.71) for 75 to 84 years and 3.79 (95% CI, 1.36-10.5) for those older than 85 years compared with those younger than 75 years; current cigarette use, 1.74 (95% CI, 1.02-2.96); hypertension, 1.64 (95% CI, 1.18-2.28); diabetes, 1.77 (95% CI, 1.14-2.76); higher low-density lipoprotein cholesterol level, 1.60 (95% CI, 1.03-2.51), and lipid-lowering drug use 1.74 (95% CI, 1.05-2.89).

CONCLUSION: Worsening lower extremity arterial disease, assessed as ABI decline, occurred in 9.5% of this elderly cohort over 6 years and was associated with modifiable vascular disease risk factors.

%B Arch Intern Med %V 165 %P 1896-902 %8 2005 Sep 12 %G eng %N 16 %1 https://www.ncbi.nlm.nih.gov/pubmed/16157835?dopt=Abstract %R 10.1001/archinte.165.16.1896 %0 Journal Article %J Neurology %D 2005 %T Statins and cognitive function in the elderly: the Cardiovascular Health Study. %A Bernick, C %A Katz, R %A Smith, N L %A Rapp, S %A Bhadelia, R %A Carlson, M %A Kuller, L %K Aged %K Aged, 80 and over %K Aging %K Anticholesteremic Agents %K Atrophy %K Brain %K Cholesterol %K Cognition Disorders %K Cohort Studies %K Dementia %K Female %K Humans %K Hydroxymethylglutaryl-CoA Reductase Inhibitors %K Longitudinal Studies %K Male %K Memory Disorders %K Nootropic Agents %K Treatment Outcome %X

OBJECTIVE: To examine the association of statin drug use on cognitive and MRI change in older adults.

METHODS: Participants in the Cardiovascular Health Study, a longitudinal study of people age 65 or older, were classified into three groups determined by whether they were taking statin drugs on a continuous basis, intermittently, or not at all. The untreated group was further divided into categories based on National Cholesterol Education Program recommendations for lipid-lowering treatment. Participants with prevalent or incident clinical TIA or stroke or with baseline Modified Mini-Mental State Examination (3MS) scores at or below 80 were excluded. Outcomes examined included rate of change on the 3MS over an average observational period of 7 years, along with changes in MRI white matter grade and measures of atrophy.

RESULTS: Three thousand three hundred thirty-four participants had adequate data for analysis. At baseline, the untreated group in which lipid-lowering drug treatment was recommended were slightly older, less likely to be on estrogen replacement, and had higher serum cholesterol and lower 3MS scores than the statin-treated group. The rate of decline on the 3MS was 0.48 point/year less in those taking statins compared with the untreated group for which treatment was recommended (p = 0.069) and 0.49 point/year less in statin users compared with the group in which lipid-lowering treatment was not recommended (p = 0.009). This effect remained after controlling for serum cholesterol levels. One thousand seven hundred thirty participants with baseline 3MS scores of > 80 underwent cranial MRI scans on two occasions separated by 5 years. There was no significant difference in white matter grade change or atrophy measures between groups.

CONCLUSION: Statin drug use was associated with a slight reduction in cognitive decline in an elderly population. This relationship could not be completely explained by the effect of statins on lowering of serum cholesterol.

%B Neurology %V 65 %P 1388-94 %8 2005 Nov 08 %G eng %N 9 %1 https://www.ncbi.nlm.nih.gov/pubmed/16275825?dopt=Abstract %R 10.1212/01.wnl.0000182897.18229.ec %0 Journal Article %J J Am Geriatr Soc %D 2005 %T Subclinical brain magnetic resonance imaging abnormalities predict physical functional decline in high-functioning older adults. %A Rosano, Caterina %A Kuller, Lewis H %A Chung, Hyoju %A Arnold, Alice M %A Longstreth, William T %A Newman, Anne B %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Brain %K Female %K Follow-Up Studies %K Gait %K Humans %K Incidence %K Magnetic Resonance Imaging %K Male %K Proportional Hazards Models %K Psychomotor Disorders %K Risk Factors %K United States %X

OBJECTIVES: To determine whether severity of subclinical brain magnetic resonance imaging (MRI) abnormalities predicts incident self-reported physical impairment or rate of decline in motor performance.

DESIGN: Longitudinal analysis, average follow-up time: 4.0 years.

SETTING: Cardiovascular Health Study (CHS).

PARTICIPANTS: CHS participants with modified Mini-Mental State Examination (3MS) score of 80 or greater, no self-reported disability, no history of stroke, and at least one assessment of mobility (n=2,450, mean age=74.4).

MEASUREMENTS: Brain MRI abnormalities (ventricular enlargement, white matter hyperintensities, subcortical and basal ganglia small brain infarcts), self-reported physical impairment (difficulty walking half a mile or with one or more activities of daily living), and motor performance (gait speed, timed chair stand).

RESULTS: After adjusting for demographics, cardiovascular risk factors, and diseases, risk of incident self-reported physical impairment was 35% greater for those with severe ventricular enlargement than for those with minimal ventricular enlargement, 22% greater for those with moderate white matter hyperintensities than for those with minimal white matter hyperintensities, and 26% greater for participants with at least one brain infarct than for those with no infarcts. Those with moderate to severe brain abnormalities experienced faster gait speed decline (0.02 m/s per year) than those with no MRI abnormalities (0.01 m/s per year). Further adjustment for incident stroke, incident dementia, and 3MS score did not substantially attenuate hazard ratios for incident self-reported physical impairment or coefficients for decline in gait speed.

CONCLUSION: Subclinical structural brain abnormalities in high-functioning older adults can increase the risk of developing physical disabilities and declining in motor performance.

%B J Am Geriatr Soc %V 53 %P 649-54 %8 2005 Apr %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/15817012?dopt=Abstract %R 10.1111/j.1532-5415.2005.53214.x %0 Journal Article %J Arch Intern Med %D 2006 %T 10-year follow-up of subclinical cardiovascular disease and risk of coronary heart disease in the Cardiovascular Health Study. %A Kuller, Lewis H %A Arnold, Alice M %A Psaty, Bruce M %A Robbins, John A %A O'Leary, Daniel H %A Tracy, Russell P %A Burke, Gregory L %A Manolio, Teri A %A Chaves, Paolo H M %K African Continental Ancestry Group %K Aged %K Blood Chemical Analysis %K Cardiovascular Diseases %K Comorbidity %K Coronary Disease %K Echocardiography %K European Continental Ancestry Group %K Female %K Follow-Up Studies %K Humans %K Incidence %K Male %K Multivariate Analysis %K Prevalence %K Proportional Hazards Models %K Regression Analysis %K Risk Factors %K Sex Distribution %K United States %X

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

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

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

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

%B Arch Intern Med %V 166 %P 71-8 %8 2006 Jan 09 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/16401813?dopt=Abstract %R 10.1001/archinte.166.1.71 %0 Journal Article %J J Am Geriatr Soc %D 2006 %T Adjusted mortality after hip fracture: From the cardiovascular health study. %A Robbins, John A %A Biggs, Mary L %A Cauley, Jane %K Aged %K Cohort Studies %K Female %K Health Status %K Health Surveys %K Hip Fractures %K Humans %K Male %K Mortality %K Multicenter Studies as Topic %K Proportional Hazards Models %K Sex Distribution %K Time Factors %K United States %X

OBJECTIVES: To estimate the risk of death associated with hip fracture (HFx), stratifying by sex and time since fracture.

DESIGN: Prospective cohort study compared participants with and without hip fracture, matched on sex, age, race, recruitment period, and time since enrollment.

SETTING: The Cardiovascular Health Study, a more-than-15-year longitudinal study of 5,888 older individuals from four U.S. sites.

PARTICIPANTS: Three hundred seventy-nine individuals with HFx were compared with 1,134 without HFx.

MEASUREMENTS: Extended Cox models were used to estimate mortality hazard ratios (HRs) for different periods after fracture, adjusting for prefracture health.

RESULTS: Age- and race-adjusted excess mortality was 9% in women and 24% in men 1 year after fracture, and 24% in women and 26% men 5 years postfracture. Multivariable-adjusted HRs of mortality associated with HFx in women were 7.1 (95% confidence interval (CI) = 2.3-21.5), 2.1 (95% CI = 1.0-4.1), 1.4 (95% CI = 1.1-2.0), and 1.0 (95% CI = 0.6-1.5) for 0 to 1 months, 2 to 6 months, 7 months to 4 years, and 5 to 8 years, respectively, after index date. In men, respective HRs for the same time periods were 39.9 (95% CI = 5.2-308.7), 3.8 (95% CI = 1.4-10.3), 1.1 (95% CI = 0.7-1.8), and 1.0 (95% CI = 0.3-2.7). HRs adjusted for age and race were 20% to 40% higher.

CONCLUSION: The risk of mortality was highest in the first 6 months after HFx. In men, the risk of death approximated that of men without HFx after 6 months; in women, a moderately greater risk persisted through the fourth year. Although the mortality pattern was different in women and men, excess mortality 5 years postfracture was similar for both sexes.

%B J Am Geriatr Soc %V 54 %P 1885-91 %8 2006 Dec %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/17198494?dopt=Abstract %R 10.1111/j.1532-5415.2006.00985.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 Int J Obes (Lond) %D 2006 %T The association of markers of inflammation with weight change in older adults: the Cardiovascular Health Study. %A Barzilay, J I %A Forsberg, C %A Heckbert, S R %A Cushman, M %A Newman, A B %K Aged %K Biomarkers %K C-Reactive Protein %K Cardiovascular Diseases %K Factor VIII %K Female %K Fibrinogen %K Humans %K Inflammation %K Interleukin-6 %K Leukocyte Count %K Male %K Platelet Count %K Weight Gain %K Weight Loss %X

OBJECTIVE: Elevated levels of inflammation factors often precede weight loss and may be causally related to it. Newer studies suggest that elevated levels of inflammation factors also precede weight gain. In this study, we examined whether inflammation factors are elevated in individuals, age >or=65 years, who lost or gained >5% weight over a 3 year follow-up period compared to those with stable weight.

SUBJECTS: In total, 3254 participants in the Cardiovascular Health Study whose weight was stable; 661 who gained >5% weight; and 842 who lost >5% weight.

MEASUREMENTS: C-reactive protein (CRP), fibrinogen, factor VIIIc, white blood cell (WBC) and platelet counts, and interleukin-6 (IL-6) levels.

RESULTS: As compared to participants whose weight was stable, those who lost >5% weight had higher baseline CRP concentration (1.05 (95% CI, 1.02, 1.08) per interquartile increase) and WBC count (1.10 (1.01, 1.19) per interquartile increase) on adjusted analyses. Those who gained >5% weight had higher baseline CRP (1.05 (1.01, 1.08)), fibrinogen (1.13 (1.01, 1.27)), and factor VIIIc (1.15 (1.03, 1.30)).

CONCLUSIONS: Inflammation factors are associated with weight gain and weight loss in older individuals. These findings suggest that subclinical inflammation, or unknown factors associated with subclinical inflammation, contribute to weight change.

%B Int J Obes (Lond) %V 30 %P 1362-7 %8 2006 Sep %G eng %N 9 %1 https://www.ncbi.nlm.nih.gov/pubmed/16534520?dopt=Abstract %R 10.1038/sj.ijo.0803306 %0 Journal Article %J Atherosclerosis %D 2006 %T The association of microalbuminuria with clinical cardiovascular disease and subclinical atherosclerosis in the elderly: the Cardiovascular Health Study. %A Cao, Jie J %A Barzilay, Joshua I %A Peterson, Do %A Manolio, Teri A %A Psaty, Bruce M %A Kuller, Lewis %A Wexler, Jason %A Bleyer, Anthony J %A Cushman, Mary %K Aged %K Aged, 80 and over %K Albuminuria %K Atherosclerosis %K Cardiovascular Diseases %K Coronary Disease %K Diabetes Mellitus %K Female %K Humans %K Hypertension %K Male %K Peripheral Vascular Diseases %K Prevalence %K Risk Factors %K Stroke %K United States %X

PURPOSE: Microalbuminuria (MA) is a risk factor for cardiovascular disease (CVD). It is not known whether this association is due to the effect of MA on the development of subclinical atherosclerosis or whether MA destabilizes subclinical atherosclerosis, leading to clinical events.

METHODS: In a cross-sectional analysis we evaluated 3312 Cardiovascular Health Study participants, age >or=65 years, who had MA testing. Participants were divided into three groups: those without diabetes or hypertension (33%), those with hypertension (52%) and those with diabetes, with or without hypertension (15%). Clinical CVD was defined as presence of coronary heart disease (angina, MI, CABG, PTCA), cerebrovascular disease (stroke, TIA) and peripheral arterial disease (requiring intervention). Among those without clinical disease, subclinical atherosclerosis was defined as increased carotid artery intima-media thickness, decreased ankle arm index or increased left ventricular mass.

RESULTS: In each of the three groups of participants, the adjusted odds of prevalent clinical CVD in the presence of MA was 1.70-1.80-fold increased, independent of other risk factors. MA was not associated with risk of subclinical atherosclerosis in those without hypertension or diabetes (OR 1.14 [95% CI 0.59, 2.23]), whereas it was associated with subclinical atherosclerosis in those with hypertension (OR 1.58 [95% CI 1.08, 2.30]) or diabetes (OR 2.51 [95% CI 1.27, 4.94]).

CONCLUSION: In the absence of hypertension or diabetes, MA was associated with clinical CVD but not with subclinical atherosclerosis. Thus, a hypothesis may be made that the mechanism of association of MA with clinical vascular disease involves destabilization of the vasculature, leading to clinical disease.

%B Atherosclerosis %V 187 %P 372-7 %8 2006 Aug %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/16242696?dopt=Abstract %R 10.1016/j.atherosclerosis.2005.09.015 %0 Journal Article %J JAMA %D 2006 %T Association of polymorphisms in the CRP gene with circulating C-reactive protein levels and cardiovascular events. %A Lange, Leslie A %A Carlson, Christopher S %A Hindorff, Lucia A %A Lange, Ethan M %A Walston, Jeremy %A Durda, J Peter %A Cushman, Mary %A Bis, Joshua C %A Zeng, Donglin %A Lin, Danyu %A Kuller, Lewis H %A Nickerson, Deborah A %A Psaty, Bruce M %A Tracy, Russell P %A Reiner, Alexander P %K African Continental Ancestry Group %K Aged %K C-Reactive Protein %K Cardiovascular Diseases %K Carotid Arteries %K European Continental Ancestry Group %K Female %K Genotype %K Humans %K Male %K Myocardial Infarction %K Polymorphism, Single Nucleotide %K Proportional Hazards Models %K Risk %K Stroke %K Tunica Intima %X

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

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

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

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

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

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

%B JAMA %V 296 %P 2703-11 %8 2006 Dec 13 %G eng %N 22 %1 https://www.ncbi.nlm.nih.gov/pubmed/17164456?dopt=Abstract %R 10.1001/jama.296.22.2703 %0 Journal Article %J Ann Epidemiol %D 2006 %T The association of race with frailty: the cardiovascular health study. %A Hirsch, Calvin %A Anderson, Melissa L %A Newman, Anne %A Kop, Willem %A Jackson, Sharon %A Gottdiener, John %A Tracy, Russell %A Fried, Linda P %K African Americans %K Aged %K Asthenia %K Cardiovascular Diseases %K Cohort Studies %K Cross-Sectional Studies %K European Continental Ancestry Group %K Female %K Frail Elderly %K Health Status %K Humans %K Male %K Middle Aged %K Motor Activity %K Odds Ratio %K United States %K Weight Loss %X

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

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

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

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

%B Ann Epidemiol %V 16 %P 545-53 %8 2006 Jul %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/16388967?dopt=Abstract %R 10.1016/j.annepidem.2005.10.003 %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 Am J Cardiol %D 2006 %T Cardiovascular morbidity and mortality in community-dwelling elderly individuals with calcification of the fibrous skeleton of the base of the heart and aortosclerosis (The Cardiovascular Health Study). %A Barasch, Eddy %A Gottdiener, John S %A Marino Larsen, Emily K %A Chaves, Paulo H M %A Newman, Anne B %K Aged %K Aortic Valve %K Calcinosis %K Echocardiography %K Female %K Follow-Up Studies %K Heart Failure %K Heart Valve Diseases %K Humans %K Male %K Mitral Valve %K Prospective Studies %K Risk Factors %K Sclerosis %K Severity of Illness Index %K United States %X

In the elderly, mitral annular calcification (MAC) and aortic valve sclerosis (AVS) are associated with increased cardiovascular morbidity and mortality. Aortic annular calcification (AAC) commonly occurs with MAC. However, the prognostic value of AAC, singly or in combination with MAC and AVS, for incident cardiovascular disease and mortality is unknown. From the Cardiovascular Health Study, we analyzed 3,782 participants (76 +/- 5 years of age, 60% women) who had an echocardiogram at the 1994 to 1995 examination and who were prospectively followed for an average of 6.6 years (range 0.01 to 8.5). All 3 calcification categories were associated with incident congestive heart failure (MAC: hazard ratio [HR] 1.71, 95% confidence interval [CI] 1.35 to 2.18, AAC: HR 1.62, 95% CI 1.28 to 2.06, and AVS: HR 1.50, 95% CI 1.19 to 1.89) and death. A stronger association with incident cardiovascular disease and mortality was observed with a larger number of calcification categories and with increased MAC severity. Moreover, in the participants with prevalent cardiovascular disease at echocardiographic examination (n = 1,054), MAC and AAC were still associated with cardiovascular mortality (MAC: HR 1.91, 95% CI 1.04 to 3.50; AAC: HR 2.11, 95% CI 1.16 to 3.85) even in fully adjusted models. In conclusion, MAC, AAC, and AVS are associated with a significant risk of incident congestive heart failure, cardiovascular and all-cause mortalities, and worse outcome in older patients with preexisting cardiovascular disease. Elderly patients with these findings represent a high-risk group and may require close medical attention.

%B Am J Cardiol %V 97 %P 1281-6 %8 2006 May 01 %G eng %N 9 %1 https://www.ncbi.nlm.nih.gov/pubmed/16635596?dopt=Abstract %R 10.1016/j.amjcard.2005.11.065 %0 Journal Article %J Hum Mol Genet %D 2006 %T CFH, ELOVL4, PLEKHA1 and LOC387715 genes and susceptibility to age-related maculopathy: AREDS and CHS cohorts and meta-analyses. %A Conley, Yvette P %A Jakobsdottir, Johanna %A Mah, Tammy %A Weeks, Daniel E %A Klein, Ronald %A Kuller, Lewis %A Ferrell, Robert E %A Gorin, Michael B %K Aged %K Aged, 80 and over %K Case-Control Studies %K Cohort Studies %K Complement Factor H %K Eye Proteins %K Female %K Genetic Predisposition to Disease %K Humans %K Intracellular Signaling Peptides and Proteins %K Macular Degeneration %K Male %K Membrane Proteins %K Proteins %X

Age-related maculopathy (ARM) is an important cause of visual impairment in the elderly population. It is of crucial importance to identify genetic factors and their interactions with environmental exposures for this disorder. This study was aimed at investigating the CFH, ELOVL4, PLEKHA1 and LOC387715 genes in independent cohorts collected using different ascertainment schemes. The study used a case-control design with subjects originally recruited through the Cardiovascular Health Study (CHS) and the Age-Related Eye Disease Study (AREDS). CFH was significantly associated with ARM in both cohorts (P %B Hum Mol Genet %V 15 %P 3206-18 %8 2006 Nov 01 %G eng %N 21 %1 https://www.ncbi.nlm.nih.gov/pubmed/17000705?dopt=Abstract %R 10.1093/hmg/ddl396 %0 Journal Article %J Am J Epidemiol %D 2006 %T Cigarette smoking and nocturnal sleep architecture. %A Zhang, Lin %A Samet, Jonathan %A Caffo, Brian %A Punjabi, Naresh M %K Aged %K Arousal %K Chi-Square Distribution %K Female %K Humans %K Male %K Middle Aged %K Polysomnography %K Prevalence %K Regression Analysis %K Risk Factors %K Sleep Stages %K Sleep Wake Disorders %K Smoking %K United States %X

Cigarette smoking has been associated with a high prevalence of sleep-related complaints. However, its effects on sleep architecture have not been fully examined. The primary objective of this investigation was to assess the impact of cigarette smoking on sleep architecture. Polysomnography was used to characterize sleep architecture among 6,400 participants of the Sleep Heart Health Study (United States, 1994-1999). Sleep parameters included total sleep time, latency to sleep onset, sleep efficiency, and percentage of time in each sleep stage. The study sample consisted of 2,916 never smokers, 2,705 former smokers, and 779 current smokers. Compared with never smokers, current smokers had a longer initial sleep latency (5.4 minutes, 95% confidence interval (CI): 2.9, 7.9) and less total sleep time (14.0 minutes, 95% CI: 6.4, 21.7). Furthermore, relative to never smokers, current smokers also had more stage 1 sleep (relative proportion = 1.24, 95% CI: 1.14, 1.33) and less slow wave sleep (relative proportion = 0.86, 95% CI: 0.78, 0.95). Finally, no differences in sleep architecture were noted between former and never smokers. The results of this study show that cigarette smoking is independently associated with disturbances in sleep architecture, including a longer latency to sleep onset and a shift toward lighter stages of sleep. Nicotine in cigarette smoke and acute withdrawal from it may contribute to disturbances in sleep architecture.

%B Am J Epidemiol %V 164 %P 529-37 %8 2006 Sep 15 %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/16829553?dopt=Abstract %R 10.1093/aje/kwj231 %0 Journal Article %J Arch Intern Med %D 2006 %T Clinical course of mesenteric artery stenosis in elderly americans. %A Wilson, David B %A Mostafavi, Kian %A Craven, Timothy E %A Ayerdi, Juan %A Edwards, Matthew S %A Hansen, Kimberley J %K Aged %K Aged, 80 and over %K Cohort Studies %K Comorbidity %K Female %K Humans %K Male %K Mesenteric Arteries %K Mesenteric Vascular Occlusion %K Proportional Hazards Models %K Prospective Studies %K Radiography %K Risk Factors %K Surveys and Questionnaires %K Ultrasonography %X

BACKGROUND: To examine prospectively the relationship between stenosis or occlusion of the celiac and superior mesenteric arteries and symptoms of chronic intestinal ischemia in free-living elderly patients in the United States.

METHODS: As part of an ancillary study to the Cardiovascular Health Study, participants in the Forsyth County (North Carolina) cohort underwent visceral duplex ultrasonography of the celiac and superior mesenteric arteries. Critical mesenteric artery stenosis (MAS) or occlusion was defined by Doppler flow ultrasound-derived criteria. Clinical outcomes were assessed at annual follow-up examinations and review of death certificates. Multivariate associations between the presence of MAS and all-cause mortality and adverse cardiovascular events were analyzed. Participants with MAS were contacted to determine the presence of symptoms consistent with chronic intestinal ischemia.

RESULTS: Of 553 participants who underwent visceral duplex ultrasonography, 97 (17.5%) had disease of the celiac or superior mesenteric artery. At a mean follow-up of 6(1/2) years, 20 participants with MAS (20.6%) and 93 without MAS (20.4%) had died (relative risk, 1.01; 95% confidence interval, 0.66-1.55). No deaths were attributed to intestinal infarction. No association existed between the presence of MAS and prevalent cardiovascular disease, all-cause mortality, or adverse cardiovascular events. A questionnaire was completed by 71% of the surviving participants with MAS. No participant reported symptoms or weight loss consistent with chronic intestinal ischemia.

CONCLUSIONS: Mesenteric artery stenosis was a common finding in free-living elderly patients. At long-term follow-up, the presence of asymptomatic MAS was not associated with death or adverse cardiovascular events. Participants with asymptomatic MAS by duplex ultrasonographic criteria did not experience intestinal infarction or develop chronic intestinal ischemia.

%B Arch Intern Med %V 166 %P 2095-100 %8 2006 Oct 23 %G eng %N 19 %1 https://www.ncbi.nlm.nih.gov/pubmed/17060539?dopt=Abstract %R 10.1001/archinte.166.19.2095 %0 Journal Article %J Am Heart J %D 2006 %T Clinical significance of calcification of the fibrous skeleton of the heart and aortosclerosis in community dwelling elderly. The Cardiovascular Health Study (CHS). %A Barasch, Eddy %A Gottdiener, John S %A Larsen, Emily K Marino %A Chaves, Paulo H M %A Newman, Anne B %A Manolio, Teri A %K Aged %K Aortic Valve %K Calcinosis %K Female %K Heart Valve Diseases %K Humans %K Male %K Mitral Valve %K Prevalence %K Prospective Studies %K Risk Factors %K Sclerosis %K Ultrasonography %X

BACKGROUND: Mitral annular calcification (MAC), aortic annular calcification (AAC), and aortic valve sclerosis (AVS) are associated with aging, and MAC and AVS are markers of advanced atherosclerosis. No studies have examined the prevalence and the clinical relevance of all 3 forms of calcification in a single free-living elderly population.

METHODS: We used 2-dimensional echocardiography to evaluate MAC, AAC, AVS and all 3 combined in 3929 participants, mean age 76 +/- 5 years, 60% women, in the Cardiovascular Health Study, a prospective community-based observational study designed to assess cardiovascular disease (CVD) risk factors and outcomes in elderly persons.

RESULTS: Mitral annular calcification was found in 1640 (42 %) subjects, AAC in 1710 (44 %), AVS in 2114 (54 %), and all 3 combined in 662 (17 %). The participants with these findings were older than those without them, and those with MAC had worse cardiovascular, renal, metabolic, and functional profile than those with AAC and AVS. Age-, sex-, and race-adjusted logistic regression analysis found a significant association between the 3 calcification categories and CVD, the strongest being between the combined group with congestive heart failure (odds ratio 2.04, 95% CI 1.34-3.09). In highly adjusted models, only MAC was associated with CVD, and the strength of association was related to the severity of MAC.

CONCLUSIONS: In free-living elderly, MAC, AAC, and AVS are highly prevalent and are associated with CVD. Mitral annular calcification in particular has strong association with CVD, and with an adverse biomedical profile.

%B Am Heart J %V 151 %P 39-47 %8 2006 Jan %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/16368289?dopt=Abstract %R 10.1016/j.ahj.2005.03.052 %0 Journal Article %J Am J Cardiol %D 2006 %T Comparison of mortality risk for electrocardiographic abnormalities in men and women with and without coronary heart disease (from the Cardiovascular Health Study). %A Rautaharju, Pentti M %A Ge, Sijian %A Nelson, Jennifer C %A Marino Larsen, Emily K %A Psaty, Bruce M %A Furberg, Curt D %A Zhang, Zhu-Ming %A Robbins, John %A Gottdiener, John S %A Chaves, Paulo H M %K Aged %K Coronary Disease %K Electrocardiography %K Female %K Humans %K Male %K Risk %X

Mortality risk associated with electrocardiographic (ECG) abnormalities has been commonly reported to be lower in women than in men. We compared coronary heart disease (CHD) and all-cause mortality risk for ECG variables during a mean 9.1-year follow-up in 4,912 participants in the Cardiovascular Health Study who were > or = 65 years of age. The hypothesis was that mortality risk for ECG abnormalities is not lower in women than in men. Five ECG variables were significant mortality predictors in Cox regression models that were adjusted for demographic, clinical, and medication variables. Gender differences were significant and mortality risk was higher in women for ECG estimates of left ventricular mass for both end points and for nondipolar QRS voltage for all-cause mortality. When evaluated simultaneously in multiple ECG variable risk models in subgroups that were stratified by baseline CHD status, no gender difference was significant. In the latter models, ST depression was a strong predictor of CHD mortality in groups with and without previous CHD. Other significant ECG predictors were previous myocardial infarction in the previous CHD group and nondipolar QRS voltage in the CHD-free group. Four ECG abnormalities were significant predictors of all-cause mortality in the CHD-free group, with risk increases of 18% to 50%. The risk of all-cause mortality in the previous CHD group was significantly increased for ST depression (by 64%), the ECG estimate of left ventricular mass (by 48%), and previous myocardial infarction (by 34%). In conclusion, we found no evidence that the relative risk of mortality for ECG abnormalities is lower in women than in men.

%B Am J Cardiol %V 97 %P 309-15 %8 2006 Feb 01 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/16442387?dopt=Abstract %R 10.1016/j.amjcard.2005.08.046 %0 Journal Article %J J Nutr Health Aging %D 2006 %T A cross-sectional study of vitamin C and cognitive function in older adults: the differential effects of gender. %A Sato, R %A Helzlsouer, K J %A Comstock, G W %A Hoffman, S C %A Norkus, E P %A Fried, L P %K Aged %K Aging %K Ascorbic Acid %K Cognition %K Cross-Sectional Studies %K Diet %K Female %K Health Surveys %K Humans %K Male %K Mental Status Schedule %K Nutrition Surveys %K Nutritional Requirements %K Sex Factors %K Surveys and Questionnaires %X

Previous studies have suggested that vitamin C status may be associated with cognitive function in community-dwelling populations. However, this has not been consistent across all studies due to methodological differences. This cross-sectional study assessed the association between vitamin C and cognitive function in 544 community-dwelling older adults aged 65 or older who participated in both the Cardiovascular Health Study (CHS) and the CLUE II study in 1989. Three percent of the subjects had low plasma vitamin C concentrations (< 40 mg/dL) and 15% had low total vitamin C intake (< 60 mg/day). Most participants (96.7 percent) had normal cognitive function. In the unadjusted analyses, the highest fifth of plasma vitamin C concentration was associated with better Digit Symbol Substitution Test (DSST) scores and marginally associated with Mini-Mental State Examination (MMSE) compared to the lowest fifth. Total vitamin C intake, measured by Block's food frequency questionnaire, was generally associated with higher MMSE scores, though it was not significant. Adjusting for numerous factors did not substantially change results. In a stratified analysis by gender, higher plasma concentrations or intake were associated with higher MMSE scores for men but not for women. These mixed results do not provide strong evidence of an association between vitamin C concentrations or intake and cognitive function.

%B J Nutr Health Aging %V 10 %P 37-44 %8 2006 Jan-Feb %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/16453056?dopt=Abstract %0 Journal Article %J Stroke %D 2006 %T Factors associated with geographic variations in stroke incidence among older populations in four US communities. %A El-Saed, Aiman %A Kuller, Lewis H %A Newman, Anne B %A Lopez, Oscar %A Costantino, Joseph %A McTigue, Kathleen %A Cushman, Mary %A Kronmal, Richard %K Aged %K Brain %K California %K Female %K Humans %K Incidence %K Magnetic Resonance Imaging %K Male %K Maryland %K North Carolina %K Pennsylvania %K Proportional Hazards Models %K Risk Assessment %K Risk Factors %K Stroke %X

BACKGROUND AND PURPOSE: In the Cardiovascular Health Study (CHS), we previously observed lower stroke incidence in Allegheny County, PA compared with the other 3 study sites. The purpose of this study was to study possible reasons for the lower stroke incidence in Allegheny County.

METHODS: CHS participants 65 years or older who were stroke-free at baseline (n=5639) were followed between 1989 to 1990 and 2000 for the development of stroke. Risk factors at baseline and their subsequent control were compared among both groups. Site-specific hazard ratios for stroke incidence were calculated using Cox regression models.

RESULTS: The unadjusted hazard ratio for total stroke incidence in Forsyth County, NC; Sacramento County, CA; and Washington County, MD combined compared with Allegheny County, PA was 1.74 (95% CI: 1.42, 2.14). After adjustment for age and other traditional risk factors, there was modest reduction of the excess hazard in non-Allegheny sites compared with Allegheny County (hazard ratio=1.52, 95% CI: 1.17, 1.98). Between baseline and the seventh-year visits, control of hypertension, diabetes, lipids, smoking, atrial fibrillation and transient ischemic attack were similar across sites. White matter grade > or = 3 on the baseline brain MRI was less common in Allegheny County (25.8% versus 36.3%, respectively; P<0.001) and accounted for 25% of the excess hazard in non-Allegheny sites compared with Allegheny County.

CONCLUSIONS: Site differences in stroke risk factors at baseline and subsequent control only partially explain site differences in stroke incidence. White matter grade as a possible integrated measure of exposure and control of risk factors may help in explaining geographic variations in stroke incidence.

%B Stroke %V 37 %P 1980-5 %8 2006 Aug %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/16794204?dopt=Abstract %R 10.1161/01.STR.0000231454.77745.d9 %0 Journal Article %J Stroke %D 2006 %T Geographic variations in stroke incidence and mortality among older populations in four US communities. %A El-Saed, Aiman %A Kuller, Lewis H %A Newman, Anne B %A Lopez, Oscar %A Costantino, Joseph %A McTigue, Kathleen %A Cushman, Mary %A Kronmal, Richard %K Aged %K Aged, 80 and over %K California %K Female %K Humans %K Incidence %K Male %K Maryland %K North Carolina %K Pennsylvania %K Stroke %X

BACKGROUND AND PURPOSE: Stroke is a leading cause of death and disability in the US. There is limited data on geographic variations in stroke incidence among older US populations who experience the majority of stroke burden. The purpose of this study was to compare stroke incidence and mortality rates in 4 US communities.

METHODS: Participants in the Cardiovascular Health Study (CHS) who had no history of stroke at baseline (n=5639) were followed for 10 or 7 years in predominantly white (n=5002) and black (n=637) participants, respectively. Incident stroke was validated by a stroke adjudication committee after ascertainment at annual visits, interim telephone contacts, and review of Medicare hospitalization data.

RESULTS: The 2000 US population age and sex standardized total stroke incidence rate for all CHS participants was 17.7 per 1000 person-years (95% CI: 15.9, 19.5). The rate was significantly lower in Allegheny County, Pennsylvania 9.6/1000 person-years (95% CI: 7.7, 11.5) than Forsyth County, North Carolina 19.2/1000 person-years (95% CI: 15.6, 22.8), Sacramento County, California 20.7/1000 person-years (95% CI: 16.9, 24.5), and Washington County, Maryland 19.8/1000 person-years (95% CI: 16.1, 23.5). The lower stroke incidence rate in Allegheny County was consistent in gender, race, and age groups. Though not statistically significant, stroke mortality was also lower in Allegheny County than other 3 sites. The 1-month case fatality rate was similar in the 4 sites for all strokes, and by stroke types.

CONCLUSIONS: Understanding geographic variations in stroke incidence may be an important step in improving preventive practices of stroke.

%B Stroke %V 37 %P 1975-9 %8 2006 Aug %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/16794205?dopt=Abstract %R 10.1161/01.STR.0000231453.98473.67 %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2006 %T Kidney function predicts the rate of bone loss in older individuals: the Cardiovascular Health Study. %A Fried, Linda F %A Shlipak, Michael G %A Stehman-Breen, Catherine %A Mittalhenkle, Anuja %A Seliger, Stephen %A Sarnak, Mark %A Robbins, John %A Siscovick, David %A Harris, Tamara B %A Newman, Anne B %A Cauley, Jane A %K Absorptiometry, Photon %K Aged %K Bone Density %K Creatinine %K Cystatin C %K Cystatins %K Female %K Hip %K Humans %K Kidney Diseases %K Kidney Function Tests %K Linear Models %K Longitudinal Studies %K Male %K Osteoporosis %K Predictive Value of Tests %X

BACKGROUND: Results of cross-sectional analyses of the association of kidney function with bone mineral density (BMD) have been conflicting. We examined the association of cystatin-C, a new marker of kidney function that is unrelated to lean mass, with initial and follow-up BMD, in an ancillary study of the Cardiovascular Health Study, a population-based cohort of individuals > or = 65 years old.

METHODS: Two years after measurement of cystatin-C and other covariates, the first BMD was measured in Pittsburgh, Pennsylvania and Davis, California, by using dual energy x-ray absorptiometry. Follow-up BMD was measured in Pittsburgh 4 years later. Associations of cystatin-C with initial BMD and the change in BMD (%/y) at the hip were examined with linear regression. Analyses were conducted separately for men and women.

RESULTS: In 1519 participants who had cystatin-C and initial BMD assessed, 614 had follow-up BMD. The percent annual change in BMD at the total hip by cystatin-C quartiles was -0.24, -0.13, -0.40, and -0.66%/y (first to fourth quartile) in women and -0.02, -0.30, -0.18, and -0.94%/y in men. After adjusting for potential confounders, cystatin-C was marginally associated with initial BMD in men but not women. Cystatin-C was associated with bone loss in men; after adjustment for weight loss, cystatin-C was not associated with bone loss in women.

CONCLUSION: Kidney dysfunction, as assessed by cystatin-C, is associated with a more rapid loss of BMD at the hip, especially in men. Further studies are needed to confirm these findings and to determine whether this loss leads to an elevated risk of fracture.

%B J Gerontol A Biol Sci Med Sci %V 61 %P 743-8 %8 2006 Jul %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/16870638?dopt=Abstract %R 10.1093/gerona/61.7.743 %0 Journal Article %J Circulation %D 2006 %T Mortality and cardiovascular risk across the ankle-arm index spectrum: results from the Cardiovascular Health Study. %A O'Hare, Ann M %A Katz, Ronit %A Shlipak, Michael G %A Cushman, Mary %A Newman, Anne B %K Aged %K Ankle %K Arm %K Blood Pressure %K Body Mass Index %K Cholesterol, LDL %K Female %K Follow-Up Studies %K Humans %K Longitudinal Studies %K Male %K Peripheral Vascular Diseases %K Risk Factors %K Smoking %X

BACKGROUND: A low ankle-arm index (AAI) is a strong predictor of mortality and cardiovascular events. A high AAI also appears to be associated with higher mortality risk in select populations. However, mortality and cardiovascular risk across the AAI spectrum have not been described in a more broadly defined population.

METHODS AND RESULTS: We examined total and cardiovascular mortality and cardiovascular events across the AAI spectrum among 5748 participants in the Cardiovascular Health Study (CHS). The mean age of the sample population was 73+/-6 years, and the sample included 3289 women (57%) and 883 blacks (15%). The median duration of follow-up was 11.1 (0.1 to 12) years for mortality and 9.6 (0.1 to 12.1) years for cardiovascular events. There were 2311 deaths (953 of which were cardiovascular) and 1491 cardiovascular events during follow-up. After adjustment for potential confounders, AAI measurements < or =0.60 (hazard ratio [HR] 1.82, 95% CI 1.42 to 2.32), 0.61 to 0.7 (HR 2.08, 95% CI 1.61 to 2.69), 0.71 to 0.8 (HR 1.80, 95% CI 1.44 to 2.26), 0.81 to 0.9 (HR 1.73 95% CI 1.43 to 2.11), 0.91 to 1.0 (HR 1.40, 95% CI 1.20 to 1.63), and >1.40 (HR 1.57, 95% CI 1.07 to 2.31) were associated with higher mortality risk from all causes compared with the referent group (AAI 1.11 to 1.20). The pattern was similar for cardiovascular mortality. For cardiovascular events, risk was higher at all AAI levels <1 but not for AAI levels >1.4 (HR 1.00, 95% CI 0.57 to 1.74). The association of a high AAI with mortality was stronger in men than in women and in younger than in older cohort members.

CONCLUSIONS: In a cohort of community-dwelling elders, mortality risk was higher than the referent category of 1.11 to 1.2 among participants with AAI values above the traditional cutpoint of 0.9 (ie, 0.91 to 1.0 and >1.4), and the specific association of AAI with mortality varied by age and gender.

%B Circulation %V 113 %P 388-93 %8 2006 Jan 24 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/16432070?dopt=Abstract %R 10.1161/CIRCULATIONAHA.105.570903 %0 Journal Article %J J Neurol Neurosurg Psychiatry %D 2006 %T Neuropsychological characteristics of mild cognitive impairment subgroups. %A Lopez, O L %A Becker, J T %A Jagust, W J %A Fitzpatrick, A %A Carlson, M C %A DeKosky, S T %A Breitner, J %A Lyketsos, C G %A Jones, B %A Kawas, C %A Kuller, L H %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amnesia %K Cognition Disorders %K Female %K Humans %K Male %K Neuropsychological Tests %K Psychometrics %K Reference Values %X

OBJECTIVE: To describe the neuropsychological characteristics of mild cognitive impairment (MCI) subgroups identified in the Cardiovascular Health Study (CHS) cognition study.

METHODS: MCI was classified as MCI-amnestic type (MCI-AT): patients with documented memory deficits but otherwise normal cognitive function; and MCI-multiple cognitive deficits type (MCI-MCDT): impairment of at least one cognitive domain (not including memory), or one abnormal test in at least two other domains, but who had not crossed the dementia threshold. The MCI subjects did not have systemic, neurological, or psychiatric disorders likely to affect cognition.

RESULTS: MCI-AT (n = 10) had worse verbal and non-verbal memory performance than MCI-MCDT (n = 28) or normal controls (n = 374). By contrast, MCI-MCDT had worse language, psychomotor speed, fine motor control, and visuoconstructional function than MCI-AT or normal controls. MCI-MCDT subjects had memory deficits, though they were less pronounced than in MCI-AT. Of the MCI-MCDT cases, 22 (78.5%) had memory deficits, and 6 (21.5%) did not. MCI-MCDT with memory disorders had more language deficits than MCI-MCDT without memory disorders. By contrast, MCI-MCDT without memory deficits had more fine motor control deficits than MCI-MCDT with memory deficits.

CONCLUSIONS: The most frequent form of MCI was the MCI-MCDT with memory deficits. However, the identification of memory impaired MCI groups did not reflect the true prevalence of MCI in a population, as 16% of all MCI cases and 21.5% of the MCI-MCDT cases did not have memory impairment. Study of idiopathic amnestic and non-amnestic forms of MCI is essential for an understanding of the aetiology of MCI.

%B J Neurol Neurosurg Psychiatry %V 77 %P 159-65 %8 2006 Feb %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/16103044?dopt=Abstract %R 10.1136/jnnp.2004.045567 %0 Journal Article %J Sleep Med %D 2006 %T Obstructive sleep apnea-hypopnea and neurocognitive functioning in the Sleep Heart Health Study. %A Quan, Stuart F %A Wright, Ron %A Baldwin, Carol M %A Kaemingk, Kristine L %A Goodwin, James L %A Kuo, Tracy F %A Kaszniak, Alfred %A Boland, Lori L %A Caccappolo, Elise %A Bootzin, Richard R %K Brain %K Cognition Disorders %K Continuous Positive Airway Pressure %K Demography %K Disorders of Excessive Somnolence %K Electromyography %K Electrooculography %K Female %K Health Status %K Humans %K Hypoxia %K Male %K Middle Aged %K Neuropsychological Tests %K Oxygen %K Polysomnography %K Severity of Illness Index %K Sleep Apnea, Obstructive %K Surveys and Questionnaires %X

BACKGROUND AND PURPOSE: Obstructive sleep apnea-hypopnea (OSAH) is associated with sleep fragmentation and nocturnal hypoxemia. In clinical samples, patients with OSAH frequently are found to have deficits in neuropsychological function. However, the nature and severity of these abnormalities in non-clinical populations is less well defined.

PATIENTS AND METHODS: One hundred and forty-one participants from the Tucson, AZ and New York, NY field centers of the Sleep Heart Health Study completed a battery of neuropsychological tests for 9-40 months (mean=24 months, SD=7 months) after an unattended home polysomnogram. Sixty-seven participants had OSAH (AHI>10) and 74 did not have OSAH (control (CTL), apnea-hypopnea index (AHI)<5). In addition to the individual tests, composite variables representing attention, executive function, MotorSpeed and processing speed were constructed from the neuropsychological test battery.

RESULTS: There were no significant differences in any individual neuropsychological test or composite variable between the OSAH and CTL groups. However, when time spent with O(2) saturations less than 85% was dichotomized into those participants in the top quartile of the distribution and those in the lower three quartiles, motor speed was significantly impaired in those who were more hypoxemic. In addition, poorer motor speed (model adjusted R(2)=0.242, P<0.001) and processing speed performance (model adjusted R(2)=0.122, P<0.001) were associated with more severe oxygen desaturation even after controlling for degree of daytime sleepiness, age, gender and educational level.

CONCLUSIONS: Mild to moderate OSAH has little impact on the selected measures of attention, executive function, motor speed and processing speed. However, hypoxemia adversely affects both motor and processing speed. These results suggest that in middle-aged to elderly adults the neuropsychological effects of clinically unrecognized mild to moderate OSAH are neither global nor large.

%B Sleep Med %V 7 %P 498-507 %8 2006 Sep %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/16815753?dopt=Abstract %R 10.1016/j.sleep.2006.02.005 %0 Journal Article %J J Vasc Surg %D 2006 %T Progression of atherosclerotic renovascular disease: A prospective population-based study. %A Pearce, Jeffrey D %A Craven, Brandon L %A Craven, Timothy E %A Piercy, K Todd %A Stafford, Jeanette M %A Edwards, Matthew S %A Hansen, Kimberley J %K Aged %K Aged, 80 and over %K Atherosclerosis %K Blood Flow Velocity %K Blood Pressure %K Disease Progression %K Female %K Follow-Up Studies %K Humans %K Incidence %K Male %K North Carolina %K Population Surveillance %K Prognosis %K Prospective Studies %K Renal Artery Obstruction %K Severity of Illness Index %K Time Factors %K Ultrasonography, Doppler, Duplex %X

OBJECTIVE: Previous reports from select hypertensive patients suggest that atherosclerotic renovascular disease (RVD) is rapidly progressive and associated with a decline in kidney size and kidney function. This prospective, population-based study estimates the incidence of new RVD and progression of established RVD among elderly, free-living participants in the Cardiovascular Health Study (CHS).

METHOD: The CHS is a multicenter, longitudinal cohort study of cardiovascular risk factors, morbidity, and mortality among men and women aged >65 years old. From 1995 through 1996, 834 participants underwent renal duplex sonography (RDS) to define the presence or absence of significant RVD. Between 2002 and 2005, a second RDS study was performed in 119 participants (mean study interval, 8.0 +/- 0.8 years). Significant RVD was defined as hemodynamically significant stenosis (renal artery peak systolic velocity [RA-PSV] exceeding 1.8 m/s) or renal artery occlusion. Prevalent RVD was significant RVD at the first RDS, and incident disease was defined as new significant RVD at the second RDS. Significant change of RVD was defined as a change in RA-PSV of greater than two times the standard deviation of expected change over time, regardless of hemodynamic significance or progression to renal artery occlusion.

RESULTS: The second RDS study cohort included 119 CHS participants with 235 kidneys (35% men; mean age, 82.8 +/- 3.4). On follow-up, no prevalent RVD (n = 13 kidneys; 6.0%) progressed to occlusion. Twenty-nine kidneys without RVD at the first RDS demonstrated significant change in PSV at the second RDS; including nine kidneys with new significant RVD (8 new stenoses; 1 new occlusion). Controlling for within-subject correlation, the overall estimated change in RVD among all 235 kidneys was 14.0% (95% confidence interval [CI], 9.2% to 21.4%), with progression to significant RVD in 4.0% (95% CI, 1.9% to 8.2%). Longitudinal increase in diastolic blood pressure and decrease in renal length were significantly associated with progression to new (ie, incident) significant RVD but not prevalent RVD.

CONCLUSIONS: This is the first prospective, population-based estimate of incident RVD and progression of prevalent RVD among free-living elderly Americans. In contrast to previous reports among select hypertensive patients, CHS participants with a low rate of clinical hypertension demonstrated a significant change of RVD in only 14.0% of kidneys on follow-up of 8 years (annualized rate, 1.3% per year). Progression to significant RVD was observed in only 4.0% (annualized rate, 0.5% per year), and no prevalent RVD progressed to occlusion.

%B J Vasc Surg %V 44 %P 955-62; discussion 962-3 %8 2006 Nov %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/16982169?dopt=Abstract %R 10.1016/j.jvs.2006.07.031 %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 Biostatistics %D 2006 %T The sensitivity and specificity of markers for event times. %A Cai, Tianxi %A Pepe, Margaret Sullivan %A Zheng, Yingye %A Lumley, Thomas %A Jenny, Nancy Swords %K Aged %K Aged, 80 and over %K Biomarkers %K Biometry %K Cardiovascular Diseases %K Female %K Humans %K Male %K Models, Statistical %K Risk Factors %K ROC Curve %K Sensitivity and Specificity %K Time Factors %X

The statistical literature on assessing the accuracy of risk factors or disease markers as diagnostic tests deals almost exclusively with settings where the test, Y, is measured concurrently with disease status D. In practice, however, disease status may vary over time and there is often a time lag between when the marker is measured and the occurrence of disease. One example concerns the Framingham risk score (FR-score) as a marker for the future risk of cardiovascular events, events that occur after the score is ascertained. To evaluate such a marker, one needs to take the time lag into account since the predictive accuracy may be higher when the marker is measured closer to the time of disease occurrence. We therefore consider inference for sensitivity and specificity functions that are defined as functions of time. Semiparametric regression models are proposed. Data from a cohort study are used to estimate model parameters. One issue that arises in practice is that event times may be censored. In this research, we extend in several respects the work by Leisenring et al. (1997) that dealt only with parametric models for binary tests and uncensored data. We propose semiparametric models that accommodate continuous tests and censoring. Asymptotic distribution theory for parameter estimates is developed and procedures for making statistical inference are evaluated with simulation studies. We illustrate our methods with data from the Cardiovascular Health Study, relating the FR-score measured at enrollment to subsequent risk of cardiovascular events.

%B Biostatistics %V 7 %P 182-97 %8 2006 Apr %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/16079162?dopt=Abstract %R 10.1093/biostatistics/kxi047 %0 Journal Article %J J Thromb Haemost %D 2006 %T Subclinical atherosclerosis and the risk of future venous thrombosis in the Cardiovascular Health Study. %A van der Hagen, P B %A Folsom, A R %A Jenny, N S %A Heckbert, S R %A O'Meara, E S %A Reich, L M %A Rosendaal, F R %A Cushman, M %K Aged %K Aged, 80 and over %K Atherosclerosis %K Carotid Artery Thrombosis %K Cohort Studies %K Female %K Humans %K Male %K Proportional Hazards Models %K Risk Factors %K Ultrasonography %K Venous Thrombosis %X

BACKGROUND: Recent reports have suggested an association of atherosclerosis with risk of venous thrombosis.

OBJECTIVE: To confirm whether subclinical atherosclerosis is a risk factor for venous thrombosis (VT) among men and women age 65 and older.

METHODS: Participants of the Cardiovascular Health Study (n = 4,108) without baseline clinical cardiovascular disease, anticoagulant use or previous VT were followed for a median of 11.7 years after non-invasive assessment of subclinical atherosclerosis using carotid ultrasound (intima-media thickness and presence of plaques), ankle-brachial blood pressure index and electrocardiogram. Each event was classified as idiopathic or secondary. We used Cox proportional hazards regression to estimate the relative risk of overall and idiopathic VT for individuals with and without baseline subclinical atherosclerosis.

RESULTS: There were 133 first time VT events. No subclinical atherosclerosis measures were associated with increased risk of overall or idiopathic VT. The adjusted relative risks of overall and idiopathic VT for presence of any type of subclinical disease were 0.60 (95% confidence interval 0.39-0.91) and 0.32 (0.18-0.59), respectively. Most of this association was explained by an inverse association of high-risk carotid plaques (prevalent in 54% of those at risk) with VT.

CONCLUSION: Non-invasively measured subclinical atherosclerosis was not associated with increased risk of overall or idiopathic VT in this observational study. Carotid plaques and arterial events during follow up were inversely associated, a finding that requires further study.

%B J Thromb Haemost %V 4 %P 1903-8 %8 2006 Sep %G eng %N 9 %1 https://www.ncbi.nlm.nih.gov/pubmed/16961598?dopt=Abstract %R 10.1111/j.1538-7836.2006.02096.x %0 Journal Article %J JAMA %D 2006 %T Thyroid status, cardiovascular risk, and mortality in older adults. %A Cappola, Anne R %A Fried, Linda P %A Arnold, Alice M %A Danese, Mark D %A Kuller, Lewis H %A Burke, Gregory L %A Tracy, Russell P %A Ladenson, Paul W %K Aged %K Atrial Fibrillation %K Cardiovascular Diseases %K Female %K Humans %K Hyperthyroidism %K Hypothyroidism %K Male %K Proportional Hazards Models %K Risk Factors %K Thyroid Gland %K Thyrotropin %X

CONTEXT: Previous studies have suggested that subclinical abnormalities in thyroid-stimulating hormone levels are associated with detrimental effects on the cardiovascular system.

OBJECTIVE: To determine the relationship between baseline thyroid status and incident atrial fibrillation, incident cardiovascular disease, and mortality in older men and women not taking thyroid medication.

DESIGN, SETTING, AND PARTICIPANTS: A total of 3233 US community-dwelling individuals aged 65 years or older with baseline serum thyroid-stimulating hormone levels were enrolled in 1989-1990 in the Cardiovascular Health Study, a large, prospective cohort study.

MAIN OUTCOME MEASURES: Incident atrial fibrillation, coronary heart disease, cerebrovascular disease, cardiovascular death, and all-cause death assessed through June 2002. Analyses are reported for 4 groups defined according to thyroid function test results: subclinical hyperthyroidism, euthyroidism, subclinical hypothyroidism, and overt hypothyroidism.

RESULTS: Individuals with overt thyrotoxicosis (n = 4) were excluded because of small numbers. Eighty-two percent of participants (n = 2639) had normal thyroid function, 15% (n = 496) had subclinical hypothyroidism, 1.6% (n = 51) had overt hypothyroidism, and 1.5% (n = 47) had subclinical hyperthyroidism. After exclusion of those with prevalent atrial fibrillation, individuals with subclinical hyperthyroidism had a greater incidence of atrial fibrillation compared with those with normal thyroid function (67 events vs 31 events per 1000 person-years; adjusted hazard ratio, 1.98; 95% confidence interval, 1.29-3.03). No differences were seen between the subclinical hyperthyroidism group and euthyroidism group for incident coronary heart disease, cerebrovascular disease, cardiovascular death, or all-cause death. Likewise, there were no differences between the subclinical hypothyroidism or overt hypothyroidism groups and the euthyroidism group for cardiovascular outcomes or mortality. Specifically, individuals with subclinical hypothyroidism had an adjusted hazard ratio of 1.07 (95% confidence interval, 0.90-1.28) for incident coronary heart disease.

CONCLUSION: Our data show an association between subclinical hyperthyroidism and development of atrial fibrillation but do not support the hypothesis that unrecognized subclinical hyperthyroidism or subclinical hypothyroidism is associated with other cardiovascular disorders or mortality.

%B JAMA %V 295 %P 1033-41 %8 2006 Mar 01 %G eng %N 9 %1 https://www.ncbi.nlm.nih.gov/pubmed/16507804?dopt=Abstract %R 10.1001/jama.295.9.1033 %0 Journal Article %J J Thromb Haemost %D 2007 %T ABO blood group, other risk factors and incidence of venous thromboembolism: the Longitudinal Investigation of Thromboembolism Etiology (LITE). %A Ohira, T %A Cushman, M %A Tsai, M Y %A Zhang, Y %A Heckbert, S R %A Zakai, N A %A Rosamond, W D %A Folsom, A R %K ABO Blood-Group System %K Aged %K Case-Control Studies %K Diabetes Complications %K Factor V %K Factor VIII %K Female %K Humans %K Longitudinal Studies %K Male %K Middle Aged %K Risk Factors %K Thromboembolism %K Venous Thrombosis %K von Willebrand Factor %X

BACKGROUND: Numerous case-control studies have reported higher prevalence of non-O blood type among venous thromboembolism (VTE) patients than controls, but potential mechanisms or effect modifiers for the association are not fully established.

PATIENTS/METHODS: Using a nested case-control design combining the Atherosclerosis Risk in Communities and the Cardiovascular Health Study cohort, ABO blood type and other VTE risk factors were measured on pre-event blood samples of 492 participants who subsequently developed VTE and 1008 participants who remained free of VTE.

RESULTS: A total of 64.4% of cases and 52.5% of controls had non-O blood type. Among controls, mean values of factor VIIIc (FVIIIc) and von Willebrand factor among the non-O blood type group were higher than among the O group. Compared with O blood type, the age-adjusted odds ratio (OR) of VTE for non-O blood type was 1.64 (95% CI, 1.32-2.05) and was similar for the two parent studies and race groups. Further adjustment for sex, race, body mass index, diabetes mellitus and FVIIIc reduced the OR: 1.31 (95% CI, 1.02-1.68). Factor V Leiden (FV Leiden) appeared to modify the non-O blood type association with VTE in a supra-additive fashion, with an age-, sex- and race-adjusted OR of 6.77 (95% CI, 3.65-12.6) for having both risk factors.

CONCLUSIONS: Non-O blood type was independently associated with risk of VTE, and added to the risk associated with FV Leiden.

%B J Thromb Haemost %V 5 %P 1455-61 %8 2007 Jul %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/17425663?dopt=Abstract %R 10.1111/j.1538-7836.2007.02579.x %0 Journal Article %J Neurobiol Aging %D 2007 %T Acceleration of cerebral ventricular expansion in the Cardiovascular Health Study. %A Carmichael, Owen T %A Kuller, L H %A Lopez, O L %A Thompson, P M %A Dutton, R A %A Lu, A %A Lee, S E %A Lee, J Y %A Aizenstein, H J %A Meltzer, C C %A Liu, Y %A Toga, A W %A Becker, J T %K Aged %K Analysis of Variance %K Cardiovascular Diseases %K Cerebral Ventricles %K Female %K Humans %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Reference Values %K Retrospective Studies %K Sex Factors %K Time Factors %X

Interactions between prevalent late-life medical conditions and expansion of the cerebral ventricles are not well understood. Thirty elderly subjects received three magnetic resonance (MR) scans each, in 1997-1999, 2002-2004, and 2003-2005. A linear expansion model of MR-measured lateral ventricle volume was estimated for each subject by fitting a line to a plot of their 1997-1999 and 2002-2004 volumes as a function of time. Acceleration in ventricular expansion was defined as the deviation between the 2003-2005 volumes measured from MR and the 2003-2005 volumes predicted by the linear expansion model. Ventricular acceleration was analyzed in a multivariate model with age, race, history of heart disease, diabetes, and hypertension as fixed effects. Ventricular acceleration was significantly higher in non-whites, diabetics, and those without heart disease (p<0.05). Ventricular acceleration was higher in subjects with a history of hypertension, but the difference was not statistically significant (p=0.08). Acceleration of ventricular expansion in the elderly may be related to demographic and cardiovascular factors.

%B Neurobiol Aging %V 28 %P 1316-21 %8 2007 Sep %G eng %N 9 %1 https://www.ncbi.nlm.nih.gov/pubmed/16875759?dopt=Abstract %R 10.1016/j.neurobiolaging.2006.06.016 %0 Journal Article %J Osteoporos Int %D 2007 %T Alcohol consumption, bone density, and hip fracture among older adults: the cardiovascular health study. %A Mukamal, K J %A Robbins, J A %A Cauley, J A %A Kern, L M %A Siscovick, D S %K Absorptiometry, Photon %K Aged %K Alcohol Drinking %K Alcoholic Beverages %K Apolipoproteins E %K Bone Density %K Female %K Femur Neck %K Genotype %K Hip %K Hip Fractures %K Humans %K Longitudinal Studies %K Male %K Risk Assessment %K Risk Factors %K Sex Distribution %K United States %X

INTRODUCTION: Previous studies have found inconsistent relationships of alcohol consumption with risk of hip fracture, and the importance of bone mineral density and risk of falls in mediating such a relationship has not been determined.

METHODS: As part of the Cardiovascular Health Study, a population-based cohort study of adults aged 65 years and older from four U.S. communities, 5,865 participants reported their use of beer, wine, and liquor yearly. We identified cases of hip fracture unrelated to malignancy or motor vehicle accidents using hospitalization discharge diagnoses. A subgroup of 1,567 participants in two communities underwent dual-energy x-ray absorptiometry scans to assess bone mineral density.

RESULTS: A total of 412 cases of hip fracture occurred during an average of 12 years of follow-up. There was a significant U-shaped relationship between alcohol intake and risk of hip fracture (p quadratic 0.02). Compared with long-term abstainers, the adjusted hazard ratios for hip fracture were 0.78 (95% confidence interval [CI], 0.61-1.00) among consumers of up to 14 drinks per week and 1.18 (95% CI, 0.77-1.81) among consumers of 14 or more drinks per week. Alcohol intake was associated with bone mineral density of the total hip and femoral neck in a stepwise manner, with approximately 5% (95% CI, 1%-9%) higher bone density among consumers of 14 or more drinks per week than among abstainers. These relationships were all similar among men and women.

CONCLUSIONS: Among older adults, moderate alcohol consumption has a U-shaped relationship with risk of hip fracture, but a graded positive relationship with bone mineral density at the hip.

%B Osteoporos Int %V 18 %P 593-602 %8 2007 May %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/17318666?dopt=Abstract %R 10.1007/s00198-006-0287-7 %0 Journal Article %J Thromb Res %D 2007 %T The association of alpha-fibrinogen Thr312Ala polymorphism and venous thromboembolism in the LITE study. %A Rasmussen-Torvik, Laura J %A Cushman, Mary %A Tsai, Michael Y %A Zhang, Yan %A Heckbert, Susan R %A Rosamond, Wayne D %A Folsom, Aaron R %K African Continental Ancestry Group %K Aged %K Case-Control Studies %K European Continental Ancestry Group %K Female %K Fibrinogen %K Genotype %K Humans %K Logistic Models %K Male %K Middle Aged %K Mutation, Missense %K Polymorphism, Genetic %K Venous Thromboembolism %X

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

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

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

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

%B Thromb Res %V 121 %P 1-7 %8 2007 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/17433418?dopt=Abstract %R 10.1016/j.thromres.2007.02.008 %0 Journal Article %J Circulation %D 2007 %T Association of carotid artery intima-media thickness, plaques, and C-reactive protein with future cardiovascular disease and all-cause mortality: the Cardiovascular Health Study. %A Cao, Jie J %A Arnold, Alice M %A Manolio, Teri A %A Polak, Joseph F %A Psaty, Bruce M %A Hirsch, Calvin H %A Kuller, Lewis H %A Cushman, Mary %K African Americans %K Aged %K Biomarkers %K C-Reactive Protein %K Cardiovascular Diseases %K Carotid Artery Diseases %K Cohort Studies %K Comorbidity %K Diabetes Mellitus %K European Continental Ancestry Group %K Female %K Follow-Up Studies %K Humans %K Hyperlipidemias %K Hypertension %K Incidence %K Inflammation %K Kaplan-Meier Estimate %K Male %K Mass Screening %K Mortality %K Myocardial Infarction %K Obesity %K Predictive Value of Tests %K Proportional Hazards Models %K Prospective Studies %K Risk Assessment %K Risk Factors %K ROC Curve %K Smoking %K Stroke %K Survival Analysis %K Tunica Intima %K Tunica Media %K Ultrasonography %K United States %X

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

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

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

%B Circulation %V 116 %P 32-8 %8 2007 Jul 03 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/17576871?dopt=Abstract %R 10.1161/CIRCULATIONAHA.106.645606 %0 Journal Article %J J Am Soc Nephrol %D 2007 %T Association of kidney function with incident hip fracture in older adults. %A Fried, Linda F %A Biggs, Mary Louise %A Shlipak, Michael G %A Seliger, Stephen %A Kestenbaum, Bryan %A Stehman-Breen, Catherine %A Sarnak, Mark %A Siscovick, David %A Harris, Tamara %A Cauley, Jane %A Newman, Anne B %A Robbins, John %K Aged %K Aged, 80 and over %K Cystatin C %K Cystatins %K Female %K Hip Fractures %K Humans %K Kidney %K Kidney Failure, Chronic %K Longitudinal Studies %K Male %K Osteoporosis %K Prospective Studies %K Risk Factors %K Sex Factors %X

Kidney dysfunction is associated with bone loss, and patients with ESRD have an increased risk for hip fracture. However, the association of mild to moderate kidney disease with hip fracture has not been studied previously. The association of kidney function with incident hip fracture was examined among participants in the Cardiovascular Health Study, a community-based cohort of older individuals. The primary measure of kidney function was serum cystatin C, a measure that does not depend on lean mass. Hip fractures were identified using International Classification of Diseases, Ninth Revision codes for hospitalizations. A total of 4699 individuals had cystatin C measured in 1992 to 1993 and did not have a hip fracture before cystatin C measurement. The association of kidney function with hip fracture was analyzed with Cox proportional hazards models. Analyses were conducted separately for men and women. After a mean follow-up of 7.1 yr, 195 incident hip fractures occurred in women and 79 occurred in men. Higher cystatin C levels were associated with a higher risk for fracture in women (hazard ratio [HR] 1.26; 95% confidence interval [CI] 1.14 to 1.38 per SD) and in men (HR 1.27; 95% CI 1.11 to 1.46). After multivariable adjustment, higher cystatin C levels were significantly associated with hip fracture in women (HR 1.16; 95% CI 1.01, 1.33) but not in men (HR 1.14; 95% CI 0.86 to 1.52), although the magnitude of the association was similar. Kidney dysfunction, as assessed by cystatin C, is associated with an increased risk for hip fracture. Further studies are needed to evaluate potential mediators of this relationship and to assess whether interventions can decrease this risk.

%B J Am Soc Nephrol %V 18 %P 282-6 %8 2007 Jan %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/17167115?dopt=Abstract %R 10.1681/ASN.2006050546 %0 Journal Article %J J Clin Endocrinol Metab %D 2007 %T Association of total insulin-like growth factor-I, insulin-like growth factor binding protein-1 (IGFBP-1), and IGFBP-3 levels with incident coronary events and ischemic stroke. %A Kaplan, Robert C %A McGinn, Aileen P %A Pollak, Michael N %A Kuller, Lewis H %A Strickler, Howard D %A Rohan, Tom E %A Cappola, Anne R %A Xue, XiaoNan %A Psaty, Bruce M %K Aged %K Cardiovascular Diseases %K Case-Control Studies %K Cohort Studies %K Coronary Disease %K Female %K Humans %K Insulin-Like Growth Factor Binding Protein 1 %K Insulin-Like Growth Factor Binding Protein 3 %K Insulin-Like Growth Factor I %K Male %K Multivariate Analysis %K Risk Factors %K Stroke %X

CONTEXT: Prior observational studies have demonstrated that the GH/IGF axis is associated with cardiovascular disease. However, this association has not been extensively studied among older adults.

OBJECTIVE: The objective of this study was to assess the association between levels of total IGF-I and IGF binding proteins (IGFBP-1, IGFBP-3) and risk of incident coronary events and ischemic stroke.

DESIGN AND PARTICIPANTS: A case-cohort analysis was conducted among adults 65 yr and older in the Cardiovascular Health Study.

MAIN OUTCOME MEASURES: A total of 534 coronary events [316 nonfatal myocardial infarctions (MIs), 48 fatal MIs, and 170 fatal coronary heart disease events] and 370 ischemic strokes were identified on follow-up. Comparison subjects were 1122 randomly selected participants from the Cardiovascular Health Study.

RESULTS: Mean follow-up time was 6.7 yr for coronary events, 5.6 yr for strokes, and 9.3 yr for comparison subjects. Hazard ratios (95% confidence intervals) associated with baseline levels of total IGF-I and IGFBPs were estimated using multivariate adjusted Cox proportional hazards models. Neither IGF-I nor IGFBP-1 levels predicted risk of incident coronary events or stroke. IGFBP-3 had an inverse association with risk of coronary events [adjusted hazard ratio per sd=0.88 (0.78-1.00), P=0.05] but was not associated with stroke. Exploratory analyses suggested that low IGF-I and low IGFBP-3 levels were significantly associated with higher risk of nonfatal MI (P<0.05) but not with risk of fatal MI or fatal coronary heart disease.

CONCLUSION: Circulating levels of total IGF-I or IGFBP-1 were not associated with risk of total coronary events or ischemic stroke among older adults, whereas low IGFBP-3 level was associated with increased risk of incident coronary events.

%B J Clin Endocrinol Metab %V 92 %P 1319-25 %8 2007 Apr %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/17264182?dopt=Abstract %R 10.1210/jc.2006-1631 %0 Journal Article %J Circulation %D 2007 %T Brachial flow-mediated dilation predicts incident cardiovascular events in older adults: the Cardiovascular Health Study. %A Yeboah, Joseph %A Crouse, John R %A Hsu, Fang-Chi %A Burke, Gregory L %A Herrington, David M %K Aged %K Aged, 80 and over %K Atherosclerosis %K Biomarkers %K Brachial Artery %K Cardiovascular Diseases %K Cohort Studies %K Disease-Free Survival %K Endothelium, Vascular %K Female %K Hemorheology %K Humans %K Hyperemia %K Male %K Predictive Value of Tests %K Prognosis %K Proportional Hazards Models %K Prospective Studies %K Reproducibility of Results %K Risk Factors %K Stress, Mechanical %K Tourniquets %K Ultrasonography %K United States %K Vasodilation %X

BACKGROUND: The relationship between impaired brachial flow-mediated dilation (FMD) and subsequent clinical cardiovascular events is not well established, especially in older adults whose FMD is often diminished. We assessed the hypothesis that FMD predicts incident cardiovascular events in a population-based cohort of older adults.

METHODS AND RESULTS: FMD was measured at the 1997 to 1998 Cardiovascular Health Study clinic visit in 2792 adults aged 72 to 98 years (82.7% white, 58.6% women) recruited at 4 clinic sites in the United States. Log-rank test and Cox proportional hazard models were used to examine the association between FMD and adjudicated cardiovascular events. A total of 674 subjects (24.1%) had an adjudicated event over the 5-year follow-up period. Event-free survival rates for cardiovascular events were significantly higher in subjects with FMD greater than the sex-specific medians than in subjects with FMD less than or equal to the sex-specific medians (78.3% versus 73.6%, log-rank P=0.006). FMD remained a significant predictor of cardiovascular events after adjustment for age, gender, diabetes mellitus, cigarette smoking, systolic and diastolic blood pressure, baseline cardiovascular disease status, and total cholesterol (hazard ratio, 0.91 [95% CI, 0.83 to 0.99], P=0.02 per unit SD of FMD) but added only approximately 1% to the prognostic accuracy of the best Cox model. Brachial artery diameter was also predictive of CV events in the adjusted Cox proportional hazard model (hazard ratio, 1.12 [95% CI, 1.02 to 1.28], P=0.025) and also added approximately 1% to the accuracy of our best Cox model.

CONCLUSIONS: FMD is a predictor of future cardiovascular events but adds very little to the prognostic accuracy of traditional cardiovascular risk scores/factors in older adults. FMD and brachial artery diameter may have similar predictive values for cardiovascular events in older adults.

%B Circulation %V 115 %P 2390-7 %8 2007 May 08 %G eng %N 18 %1 https://www.ncbi.nlm.nih.gov/pubmed/17452608?dopt=Abstract %R 10.1161/CIRCULATIONAHA.106.678276 %0 Journal Article %J Alzheimer Dis Assoc Disord %D 2007 %T Cerebral ventricular changes associated with transitions between normal cognitive function, mild cognitive impairment, and dementia. %A Carmichael, Owen T %A Kuller, Lewis H %A Lopez, Oscar L %A Thompson, Paul M %A Dutton, Rebecca A %A Lu, Allen %A Lee, Sharon E %A Lee, Jessica Y %A Aizenstein, Howard J %A Meltzer, Carolyn C %A Liu, Yanxi %A Toga, Arthur W %A Becker, James T %K Aged %K Aged, 80 and over %K Case-Control Studies %K Cerebral Ventricles %K Cognition Disorders %K Dementia %K Disease Progression %K Female %K Humans %K Image Processing, Computer-Assisted %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Risk Factors %K Severity of Illness Index %K Time Factors %X

Expansion of the cerebral ventricles may occur at an accelerated rate in subjects with dementia, but the time course of expansion during transitions between normal cognitive function, mild cognitive impairment (MCI), and dementia is not well understood. Furthermore, the effects of cardiovascular risk factors on rate of ventricular expansion are unclear. We used a fully automated segmentation technique to measure change rate in lateral ventricle-to-brain ratio (VBR) on 145 longitudinal pairs of magnetic resonance images of subjects in the Cardiovascular Health Study Cognition Study from the Pittsburgh Center. A multivariate model analyzed VBR change rate, accounting for dementia statuses at both imaging times (normal, MCI, or dementia), age, sex, education, race, magnetic resonance-defined infarcts, Center for Epidemiology Studies Depression Scale, baseline ventricular volume, and cardiovascular risk factors. VBR change was faster in subjects who were demented or transitioned from MCI to dementia, compared with subjects normal at both images and subjects who transitioned from normal to MCI or dementia. Patients with diabetes had faster VBR change. Ventricular expansion may accelerate late in the progression from normal cognitive function to dementia, and may be modulated by diabetes.

%B Alzheimer Dis Assoc Disord %V 21 %P 14-24 %8 2007 Jan-Mar %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/17334268?dopt=Abstract %R 10.1097/WAD.0b013e318032d2b1 %0 Journal Article %J J Am Coll Cardiol %D 2007 %T Clinical factors, but not C-reactive protein, predict progression of calcific aortic-valve disease: the Cardiovascular Health Study. %A Novaro, Gian M %A Katz, Ronit %A Aviles, Ronnier J %A Gottdiener, John S %A Cushman, Mary %A Psaty, Bruce M %A Otto, Catherine M %A Griffin, Brian P %K Aged %K Aged, 80 and over %K Aortic Valve %K Aortic Valve Stenosis %K C-Reactive Protein %K Calcinosis %K Cardiovascular Diseases %K Cohort Studies %K Disease Progression %K Female %K Follow-Up Studies %K Heart Valve Diseases %K Humans %K Male %K Risk Factors %X

OBJECTIVES: The purpose of this study was to examine the relationship between C-reactive protein (CRP) and calcific aortic valve disease in a large, randomly selected, population-based cohort.

BACKGROUND: The pathobiology of calcific aortic stenosis involves an active inflammatory, atheromatous, osteogenic process. Elevations in CRP, a measure of systemic inflammation, have been associated with aortic stenosis.

METHODS: Two-dimensional and Doppler echocardiography and CRP measurement were performed at baseline in 5,621 participants in the Cardiovascular Health Study. Multivariable analysis was used to identify CRP as a predictor of baseline and incident aortic stenosis.

RESULTS: At a mean echocardiographic follow-up of 5 years, 9% of subjects with aortic sclerosis progressed to some degree of aortic stenosis. Increasing age (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.09 to 1.16; p < 0.001) and male gender (OR 3.05, 95% CI 1.76 to 5.27; p < 0.001) were related to risk of incident aortic stenosis, whereas increasing height (OR 0.96, 95% CI 0.94 to 0.99; p = 0.013) and African-American ethnicity conveyed a lower risk (OR 0.49, 95% CI 0.25 to 0.95; p = 0.035). C-reactive protein, treated as a continuous variable, was not associated with baseline aortic stenosis, progression to aortic sclerosis (adjusted OR 0.93, 95% CI 0.85 to 1.02; p = 0.107), or progression to aortic stenosis (adjusted OR 0.85, 95% CI 0.70 to 1.03; p = 0.092).

CONCLUSIONS: In this large population-based cohort, approximately 9% of subjects with aortic sclerosis progressed to aortic stenosis over a 5-year follow-up period. There was no association between CRP levels and the presence of calcific aortic-valve disease or incident aortic stenosis. C-reactive protein appears to be a poor predictor of subclinical calcific aortic-valve disease.

%B J Am Coll Cardiol %V 50 %P 1992-8 %8 2007 Nov 13 %G eng %N 20 %1 https://www.ncbi.nlm.nih.gov/pubmed/17996566?dopt=Abstract %R 10.1016/j.jacc.2007.07.064 %0 Journal Article %J Eur J Cardiovasc Prev Rehabil %D 2007 %T Collaborative meta-analysis of individual participant data from observational studies of Lp-PLA2 and cardiovascular diseases. %A Ballantyne, C %A Cushman, M %A Psaty, B %A Furberg, C %A Khaw, K T %A Sandhu, M %A Oldgren, J %A Rossi, G P %A Maiolino, G %A Cesari, M %A Lenzini, L %A James, S K %A Rimm, E %A Collins, R %A Anderson, J %A Koenig, W %A Brenner, H %A Rothenbacher, D %A Berglund, G %A Persson, M %A Berger, P %A Brilakis, E %A McConnell, J P %A Koenig, W %A Sacco, R %A Elkind, M %A Talmud, P %A Rimm, E %A Cannon, C P %A Packard, C %A Barrett-Connor, E %A Hofman, A %A Kardys, I %A Witteman, J C M %A Criqui, M %A Corsetti, J P %A Rainwater, D L %A Moss, A J %A Robins, S %A Bloomfield, H %A Collins, D %A Packard, C %A Wassertheil-Smoller, S %A Ridker, P %A Ballantyne, C %A Cannon, C P %A Cushman, M %A Danesh, J %A Gu, D %A Hofman, A %A Nelson, J J %A Thompson, S %A Zalewski, A %A Zariffa, N %A Di Angelantonio, E %A Kaptoge, S %A Thompson, A %A Thompson, S %A Walker, M %A Watson, S %A Wood, A %K 1-Alkyl-2-acetylglycerophosphocholine Esterase %K Cardiovascular Diseases %K Humans %K Phospholipases A2 %X

BACKGROUND: A large number of observational epidemiological studies have reported generally positive associations between circulating mass and activity levels of lipoprotein-associated phospholipase A2 (Lp-PLA2) and the risk of cardiovascular diseases. Few studies have been large enough to provide reliable estimates in different circumstances, such as in different subgroups (e.g., by age group, sex, or smoking status) or at different Lp-PLA2 levels. Moreover, most published studies have related disease risk only to baseline values of Lp-PLA2 markers (which can lead to substantial underestimation of any risk relationships because of within-person variability over time) and have used different approaches to adjustment for possible confounding factors.

OBJECTIVES: By combination of data from individual participants from all relevant observational studies in a systematic 'meta-analysis', with correction for regression dilution (using available data on serial measurements of Lp-PLA2), the Lp-PLA2 Studies Collaboration will aim to characterize more precisely than has previously been possible the strength and shape of the age and sex-specific associations of plasma Lp-PLA2 with coronary heart disease (and, where data are sufficient, with other vascular diseases, such as ischaemic stroke). It will also help to determine to what extent such associations are independent of possible confounding factors and to explore potential sources of heterogeneity among studies, such as those related to assay methods and study design. It is anticipated that the present collaboration will serve as a framework to investigate related questions on Lp-PLA2 and cardiovascular outcomes.

METHODS: A central database is being established containing data on circulating Lp-PLA2 values, sex and other potential confounding factors, age at baseline Lp-PLA2 measurement, age at event or at last follow-up, major vascular morbidity and cause-specific mortality. Information about any repeat measurements of Lp-PLA2 and potential confounding factors has been sought to allow adjustment for possible confounding and correction for regression dilution. The analyses will involve age-specific regression models. Synthesis of the available observational studies of Lp-PLA2 will yield information on a total of about 15 000 cardiovascular disease endpoints.

%B Eur J Cardiovasc Prev Rehabil %V 14 %P 3-11 %8 2007 Feb %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/17301621?dopt=Abstract %R 10.1097/01.hjr.0000239464.18509.f1 %0 Journal Article %J Diabetes Care %D 2007 %T Costs of the metabolic syndrome in elderly individuals: findings from the Cardiovascular Health Study. %A Curtis, Lesley H %A Hammill, Bradley G %A Bethel, M Angelyn %A Anstrom, Kevin J %A Gottdiener, John S %A Schulman, Kevin A %K Aged %K Aged, 80 and over %K Cholesterol, HDL %K Continental Population Groups %K Cost of Illness %K Diabetic Angiopathies %K Female %K Humans %K Hypertension %K Interviews as Topic %K Male %K Medicare %K Metabolic Syndrome %K Multivariate Analysis %K Obesity %K Patient Education as Topic %K Prospective Studies %K Regression Analysis %K United States %X

OBJECTIVE: The cardiovascular consequences of the metabolic syndrome and its component risk factors have been documented in elderly individuals. Little is known about how the metabolic syndrome and its individual components translate into long-term medical costs.

RESEARCH DESIGN AND METHODS: We used log-linear regression models to assess the independent contributions of the metabolic syndrome and its individual components to 10-year medical costs among 3,789 individuals aged > or = 65 years in the Cardiovascular Health Study.

RESULTS: As defined by the National Cholesterol Education Program Third Adult Treatment Panel report, the metabolic syndrome was present in 47% of the sample. Total costs to Medicare were 20% higher among participants with the metabolic syndrome ($40,873 vs. $33,010; P < 0.001). Controlling for age, sex, race/ethnicity, and other covariates, we found that abdominal obesity, low HDL cholesterol, and elevated blood pressure were associated with 15% (95% CI 4.3-26.7), 16% (1.7-31.8), and 20% (10.1-31.7) higher costs, respectively. When added to the model, the metabolic syndrome composite variable did not contribute significantly (P = 0.32).

CONCLUSIONS: Abdominal obesity, low HDL cholesterol, and hypertension but not the metabolic syndrome per se are important predictors of long-term costs in the Medicare population.

%B Diabetes Care %V 30 %P 2553-8 %8 2007 Oct %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/17623825?dopt=Abstract %R 10.2337/dc07-0460 %0 Journal Article %J J Am Geriatr Soc %D 2007 %T Depressive symptoms, inflammation, and ischemic stroke in older adults: a prospective analysis in the cardiovascular health study. %A Arbelaez, Jose J %A Ariyo, Abraham A %A Crum, Rosa M %A Fried, Linda P %A Ford, Daniel E %K Aged %K C-Reactive Protein %K Cardiovascular Diseases %K Cerebral Infarction %K Cohort Studies %K Depression %K Female %K Geriatric Assessment %K Humans %K Inflammation %K Kaplan-Meier Estimate %K Longitudinal Studies %K Male %K Multivariate Analysis %K Personality Assessment %K Proportional Hazards Models %K Prospective Studies %K Psychoneuroimmunology %K Risk Factors %K Socioeconomic Factors %K Statistics as Topic %K United States %X

OBJECTIVES: To investigate the mediator role of inflammation in any relationship between depressive symptoms and ischemic stroke.

DESIGN: Longitudinal prospective study.

SETTING: Review of medical records, death certificates, and the Medicare healthcare utilization database for hospitalizations.

PARTICIPANTS: Total of 5,525 elderly men and women aged 65 and older who were prospectively followed from 1989 to 2000 as participants in the Cardiovascular Health Study.

MEASUREMENTS: Depression symptom scores, inflammatory markers.

RESULTS: Greater depressive symptoms were associated with risk of ischemic stroke (unadjusted hazard ratio (HR)=1.32, 95% confidence interval (CI)=1.09-1.59; HR=1.26, 95% CI=1.03-1.54, adjusted for traditional risk factors). When a term for inflammation (C-reactive protein (CRP)) was introduced in the model, the HRs were not appreciably altered (unadjusted HR=1.31, 95% CI=1.08-1.58; adjusted HR=1.25, 95% CI=1.02-1.53), indicating that CRP at baseline was not a mediator in this relationship. In analyses stratified according to CRP levels, a J-shaped relationship between depressive symptoms and stroke was evident in the unadjusted analyses; in the fully adjusted model, only CRP in the highest tertile was associated with a higher risk for stroke in the presence of higher depressive symptoms scores.

CONCLUSION: The analyses from this prospective study provide evidence of a positive association between depressive symptoms and risk of incident stroke. Inflammation, as measured according to CRP at baseline, did not appear to mediate the relationship between depressive symptoms and stroke.

%B J Am Geriatr Soc %V 55 %P 1825-30 %8 2007 Nov %G eng %N 11 %1 https://www.ncbi.nlm.nih.gov/pubmed/17916124?dopt=Abstract %R 10.1111/j.1532-5415.2007.01393.x %0 Journal Article %J J Clin Endocrinol Metab %D 2007 %T Determinants of serum total and free testosterone levels in women over the age of 65 years. %A Cappola, Anne R %A Ratcliffe, Sarah J %A Bhasin, Shalender %A Blackman, Marc R %A Cauley, Jane %A Robbins, John %A Zmuda, Joseph M %A Harris, Tamara %A Fried, Linda P %K Age Distribution %K Aged %K Aged, 80 and over %K Aging %K Body Mass Index %K Cross-Sectional Studies %K Estrogen Replacement Therapy %K Female %K Humans %K Hypogonadism %K Multivariate Analysis %K Nonlinear Dynamics %K Obesity %K Ovariectomy %K Ovary %K Postmenopause %K Predictive Value of Tests %K Prevalence %K Risk Factors %K Testosterone %X

CONTEXT: Little is known about testosterone (T) levels and their determinants in women of late postmenopausal age.

OBJECTIVE: We describe levels of total and free T and selected factors that influence these levels in a random sample of older women.

DESIGN: Levels of serum total T and free T by microdialysis were measured using ultrasensitive assays in 347 community-dwelling women aged 65-98 yr enrolled in the Cardiovascular Health Study. Cross-sectional analyses were performed to define factors associated with total and free T levels.

RESULTS: In adjusted models: 1) total T levels declined with age until 80, whereas free T levels did not vary by age; 2) women with bilateral oophorectomy had 23% lower total T and 16% lower free T levels than those with at least one intact ovary; 3) oral estrogen users had total and free T levels that were 47% lower than never users; 4) obese women had 47% higher total T and 20% higher free T levels, and overweight women had 24% higher total T and 14% higher free T levels, than normal weight women; and 5) free T levels were 51% higher in black women. Corticosteroid users had 75% lower total T and 43% lower free T levels than nonusers.

CONCLUSIONS: Bilateral oophorectomy, estrogen use, corticosteroid use, and low body mass index are independent risk factors for lower T levels in women aged 65 yr and over. Although highly prevalent in women of this age, the physiological significance of low T levels in late postmenopausal women requires further investigation.

%B J Clin Endocrinol Metab %V 92 %P 509-16 %8 2007 Feb %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/17090636?dopt=Abstract %R 10.1210/jc.2006-1399 %0 Journal Article %J BMC Public Health %D 2007 %T The effect of different public health interventions on longevity, morbidity, and years of healthy life. %A Diehr, Paula %A Derleth, Ann %A Cai, Liming %A Newman, Anne B %K Actuarial Analysis %K Cost-Benefit Analysis %K Disease Management %K Health Priorities %K Health Promotion %K Health Services %K Health Status %K Humans %K Life Expectancy %K Medicare %K Models, Biological %K Morbidity %K United States %K United States Public Health Service %X

BACKGROUND: Choosing cost-effective strategies for improving the health of the public is difficult because the relative effects of different types of interventions are not well understood. The benefits of one-shot interventions may be different from the benefits of interventions that permanently change the probability of getting sick, recovering, or dying. Here, we compare the benefits of such types of public health interventions.

METHODS: We used multi-state life table methods to estimate the impact of five types of interventions on mortality, morbidity (years of life in fair or poor health), and years of healthy life (years in excellent, very good, or good health).

RESULTS: A one-shot intervention that makes all the sick persons healthy at baseline would increase life expectancy by 3 months and increase years of healthy life by 6 months, in a cohort beginning at age 65. An equivalent amount of improvement can be obtained from an intervention that either decreases the probability of getting sick each year by 12%, increases the probability of a sick person recovering by 16%, decreases the probability that a sick person dies by 15%, or decreases the probability that a healthy person dies by 14%. Interventions aimed at keeping persons healthy increased longevity and years of healthy life, while decreasing morbidity and medical expenditures. Interventions focused on preventing mortality had a greater effect on longevity, but had higher future morbidity and medical expenditures. Results differed for older and younger cohorts and depended on the value to society of an additional year of sick life.

CONCLUSION: Interventions that promote health and prevent disease performed well, but other types of intervention were sometimes better. The value to society of interventions that increase longevity but also increase morbidity needs further research. More comprehensive screening and treatment of new Medicare enrollees might improve their health and longevity without increasing future medical expenditures.

%B BMC Public Health %V 7 %P 52 %8 2007 Apr 05 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/17411436?dopt=Abstract %R 10.1186/1471-2458-7-52 %0 Journal Article %J Eur J Epidemiol %D 2007 %T The Emerging Risk Factors Collaboration: analysis of individual data on lipid, inflammatory and other markers in over 1.1 million participants in 104 prospective studies of cardiovascular diseases. %A Danesh, J %A Erqou, S %A Walker, M %A Thompson, S G %A Tipping, R %A Ford, C %A Pressel, S %A Walldius, G %A Jungner, I %A Folsom, A R %A Chambless, L E %A Knuiman, M %A Whincup, P H %A Wannamethee, S G %A Morris, R W %A Willeit, J %A Kiechl, S %A Santer, P %A Mayr, A %A Wald, N %A Ebrahim, S %A Lawlor, D A %A Yarnell, J W G %A Gallacher, J %A Casiglia, E %A Tikhonoff, V %A Nietert, P J %A Sutherland, S E %A Bachman, D L %A Keil, J E %A Cushman, M %A Psaty, B M %A Tracy, R P %A Tybjaerg-Hansen, A %A Nordestgaard, B G %A Frikke-Schmidt, R %A Giampaoli, S %A Palmieri, L %A Panico, S %A Vanuzzo, D %A Pilotto, L %A Simons, L %A McCallum, J %A Friedlander, Y %A Fowkes, F G R %A Lee, A J %A Smith, F B %A Taylor, J %A Guralnik, J %A Phillips, C %A Wallace, R %A Blazer, D %A Khaw, K T %A Jansson, J H %A Donfrancesco, C %A Salomaa, V %A Harald, K %A Jousilahti, P %A Vartiainen, E %A Woodward, M %A D'Agostino, R B %A Wolf, P A %A Vasan, R S %A Pencina, M J %A Bladbjerg, E M %A Jorgensen, T %A Moller, L %A Jespersen, J %A Dankner, R %A Chetrit, A %A Lubin, F %A Rosengren, A %A Wilhelmsen, L %A Lappas, G %A Eriksson, H %A Bjorkelund, C %A Cremer, P %A Nagel, D %A Tilvis, R %A Strandberg, T %A Rodriguez, B %A Bouter, L M %A Heine, R J %A Dekker, J M %A Nijpels, G %A Stehouwer, C D A %A Rimm, E %A Pai, J %A Sato, S %A Iso, H %A Kitamura, A %A Noda, H %A Goldbourt, U %A Salomaa, V %A Salonen, J T %A Nyyssönen, K %A Tuomainen, T-P %A Deeg, D %A Poppelaars, J L %A Meade, T %A Cooper, J %A Hedblad, B %A Berglund, G %A Engstrom, G %A Döring, A %A Koenig, W %A Meisinger, C %A Mraz, W %A Kuller, L %A Selmer, R %A Tverdal, A %A Nystad, W %A Gillum, R %A Mussolino, M %A Hankinson, S %A Manson, J %A De Stavola, B %A Knottenbelt, C %A Cooper, J A %A Bauer, K A %A Rosenberg, R D %A Sato, S %A Naito, Y %A Holme, I %A Nakagawa, H %A Miura, H %A Ducimetiere, P %A Jouven, X %A Crespo, C %A Garcia-Palmieri, M %A Amouyel, P %A Arveiler, D %A Evans, A %A Ferrieres, J %A Schulte, H %A Assmann, G %A Shepherd, J %A Packard, C %A Sattar, N %A Cantin, B %A Lamarche, B %A Després, J-P %A Dagenais, G R %A Barrett-Connor, E %A Wingard, D %A Bettencourt, R %A Gudnason, V %A Aspelund, T %A Sigurdsson, G %A Thorsson, B %A Trevisan, M %A Witteman, J %A Kardys, I %A Breteler, M %A Hofman, A %A Tunstall-Pedoe, H %A Tavendale, R %A Lowe, G D O %A Ben-Shlomo, Y %A Howard, B V %A Zhang, Y %A Best, L %A Umans, J %A Onat, A %A Meade, T W %A Njolstad, I %A Mathiesen, E %A Lochen, M L %A Wilsgaard, T %A Gaziano, J M %A Stampfer, M %A Ridker, P %A Ulmer, H %A Diem, G %A Concin, H %A Rodeghiero, F %A Tosetto, A %A Brunner, E %A Shipley, M %A Buring, J %A Cobbe, S M %A Ford, I %A Robertson, M %A He, Y %A Ibanez, A M %A Feskens, E J M %A Kromhout, D %A Collins, R %A Di Angelantonio, E %A Kaptoge, S %A Lewington, S %A Orfei, L %A Pennells, L %A Perry, P %A Ray, K %A Sarwar, N %A Scherman, M %A Thompson, A %A Watson, S %A Wensley, F %A White, I R %A Wood, A M %K Albumins %K Biomarkers %K Cardiovascular Diseases %K Databases, Factual %K Far East %K Humans %K Inflammation %K Leukocyte Count %K Lipids %K Lipoproteins, HDL %K Prospective Studies %K Risk Factors %K Triglycerides %X

Many long-term prospective studies have reported on associations of cardiovascular diseases with circulating lipid markers and/or inflammatory markers. Studies have not, however, generally been designed to provide reliable estimates under different circumstances and to correct for within-person variability. The Emerging Risk Factors Collaboration has established a central database on over 1.1 million participants from 104 prospective population-based studies, in which subsets have information on lipid and inflammatory markers, other characteristics, as well as major cardiovascular morbidity and cause-specific mortality. Information on repeat measurements on relevant characteristics has been collected in approximately 340,000 participants to enable estimation of and correction for within-person variability. Re-analysis of individual data will yield up to approximately 69,000 incident fatal or nonfatal first ever major cardiovascular outcomes recorded during about 11.7 million person years at risk. The primary analyses will involve age-specific regression models in people without known baseline cardiovascular disease in relation to fatal or nonfatal first ever coronary heart disease outcomes. This initiative will characterize more precisely and in greater detail than has previously been possible the shape and strength of the age- and sex-specific associations of several lipid and inflammatory markers with incident coronary heart disease outcomes (and, secondarily, with other incident cardiovascular outcomes) under a wide range of circumstances. It will, therefore, help to determine to what extent such associations are independent from possible confounding factors and to what extent such markers (separately and in combination) provide incremental predictive value.

%B Eur J Epidemiol %V 22 %P 839-69 %8 2007 %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/17876711?dopt=Abstract %R 10.1007/s10654-007-9165-7 %0 Journal Article %J Am J Prev Med %D 2007 %T Ethnic-specific prevalence of peripheral arterial disease in the United States. %A Allison, Matthew A %A Ho, Elena %A Denenberg, Julie O %A Langer, Robert D %A Newman, Anne B %A Fabsitz, Richard R %A Criqui, Michael H %K Adult %K Aged %K Aged, 80 and over %K Databases as Topic %K Female %K Humans %K Male %K Middle Aged %K Peripheral Vascular Diseases %K United States %X

BACKGROUND: Individuals diagnosed with peripheral arterial disease (PAD) are at increased risk for future functional limitations as well as cardiovascular morbidity and mortality. The aim of this study was to estimate the age-, gender-, and ethnic-specific burden of PAD in the United States for the year 2000.

METHODS: Data were collected from seven community-based studies that assessed subjects for the presence of PAD using the ankle-brachial index (ABI). Using standardized weighting criteria, age-, gender-, and ethnic-specific prevalence rates were computed and then multiplied by the corresponding 2000 Census population totals to estimate the burden of PAD in the United States for that year. Evidence-based adjustments for studies which did not consider possible subclavian stenosis, prior revascularization for PAD, or both were employed.

RESULTS: In 2000, it is conservatively estimated that at least 6.8 million (5.8%) individuals aged 40 years or older had PAD based on an ABI of less than 0.9 or previous revascularization for PAD, and that that there are an additional 1.7 million Americans with PAD but "normal" ABIs. Including this group gives a total of 8.5 million (7.2%) individuals with PAD.

CONCLUSIONS: Roughly one in 16 individuals residing in the United States in 2000 who were aged 40 years and older had PAD. Clinicians are encouraged to screen for the presence of PAD using the ABI.

%B Am J Prev Med %V 32 %P 328-33 %8 2007 Apr %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/17383564?dopt=Abstract %R 10.1016/j.amepre.2006.12.010 %0 Journal Article %J J Thromb Haemost %D 2007 %T Factor VII coagulant activity, factor VII -670A/C and -402G/A polymorphisms, and risk of venous thromboembolism. %A Folsom, A R %A Cushman, M %A Heckbert, S R %A Ohira, T %A Rasmussen-Torvik, L %A Tsai, M Y %K Alleles %K Antigens %K Coagulants %K Factor VII %K Female %K Genotype %K Humans %K Male %K Polymorphism, Genetic %K Prospective Studies %K Risk Factors %K Thromboembolism %K Venous Thrombosis %X

BACKGROUND: Most epidemiological studies have found no association between levels of factor (F) VII:C and venous thromboembolism (VTE). Our Longitudinal Investigation of Thromboembolism Etiology (LITE) had, in contrast, reported an independent, increased risk of VTE after 7.8 years of follow-up for those with high baseline levels of FVII:C.

OBJECTIVE: To confirm whether FVII:C is associated with VTE after 12.6 years of follow-up and to examine whether two FVII gene polymorphisms (-670A/C and -402G/A) are related to VTE occurrence.

METHODS: In 19 091 LITE participants with no prior history of VTE or cancer, we measured FVII:C at baseline and identified 404 new VTEs. We also performed a nested case-control study to relate the polymorphisms to VTE (n = 490 without exclusion for cancer or prior VTE).

RESULTS: FVII:C was not independently associated with VTE occurrence after extended follow-up. Multivariable-adjusted rate ratios for VTE were 1.00, 1.00, 0.94, 1.00, and 1.38 (P-trend = 0.48) for the <25th, 25th-49th, 50th-74th, 75th-94th, and >or=95th percentiles of FVII:C, respectively. The -670C and -402A alleles were in high linkage disequilibrium, and both were associated with greater FVII:C levels. However, neither polymorphism was associated with VTE occurrence.

CONCLUSION: After extended follow-up, LITE offers little evidence that a greater FVII level is a risk factor for VTE.

%B J Thromb Haemost %V 5 %P 1674-8 %8 2007 Aug %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/17663738?dopt=Abstract %R 10.1111/j.1538-7836.2007.02620.x %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2007 %T Frailty and risk of venous thromboembolism in older adults. %A Folsom, Aaron R %A Boland, Lori L %A Cushman, Mary %A Heckbert, Susan R %A Rosamond, Wayne D %A Walston, Jeremy D %K Age Factors %K Aged %K Aged, 80 and over %K Female %K Follow-Up Studies %K Frail Elderly %K Humans %K Male %K Morbidity %K Motor Activity %K Prospective Studies %K Risk Factors %K Thromboembolism %K United States %K Venous Thrombosis %X

BACKGROUND: Frailty is a common risk factor for morbidity and mortality in elderly persons. Recent evidence links frailty to activation of coagulation and inflammatory pathways. We aimed to determine whether frailty in community-dwelling older adults is a risk factor for venous thromboembolism (VTE).

METHODS: We conducted a prospective cohort study in four U.S. communities involving 4859 participants 65 years old and older. At baseline, in 1989-1993, we assessed frailty based on weight loss, grip strength, feelings of exhaustion, walk time, and physical activity. Incident VTE (deep vein thrombosis or pulmonary embolus) through 2002 was identified by review of hospital records.

RESULTS: Fifty-two percent of the sample was classified as having intermediate or definite frailty. After adjustment for age, race, sex, body mass index, and diabetes, the relative risk of total VTE (n = 150) for people who were frail compared with no frailty was 1.31 (95% confidence interval [CI], 0.93-1.84). The comparably adjusted relative risk for idiopathic VTE (n = 58) was 1.79 (95% CI, 1.02-3.13).

CONCLUSIONS: The incidence rates of idiopathic VTE was higher in community-dwelling older adults with baseline frailty compared with no frailty. Further studies of the clotting process in frailty may allow the development of an improved strategy to determine VTE risk in this vulnerable subset of older adults.

%B J Gerontol A Biol Sci Med Sci %V 62 %P 79-82 %8 2007 Jan %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/17301042?dopt=Abstract %R 10.1093/gerona/62.1.79 %0 Journal Article %J Hum Genet %D 2007 %T IL-6 gene variation is associated with IL-6 and C-reactive protein levels but not cardiovascular outcomes in the Cardiovascular Health Study. %A Walston, Jeremy D %A Fallin, M Daniele %A Cushman, Mary %A Lange, Leslie %A Psaty, Bruce %A Jenny, Nancy %A Browner, Warren %A Tracy, Russell %A Durda, Peter %A Reiner, Alex %K African Americans %K Aged %K Alleles %K C-Reactive Protein %K Cardiovascular Diseases %K Cohort Studies %K European Continental Ancestry Group %K Female %K Gene Frequency %K Genetic Predisposition to Disease %K Genetic Variation %K Humans %K Interleukin-6 %K Introns %K Longitudinal Studies %K Male %K Polymorphism, Single Nucleotide %K Promoter Regions, Genetic %X

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

%B Hum Genet %V 122 %P 485-94 %8 2007 Dec %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/17851695?dopt=Abstract %R 10.1007/s00439-007-0428-x %0 Journal Article %J Soc Sci Med %D 2007 %T Individual and neighborhood socioeconomic status and progressive chronic kidney disease in an elderly population: The Cardiovascular Health Study. %A Merkin, Sharon Stein %A Diez Roux, Ana V %A Coresh, Josef %A Fried, Linda F %A Jackson, Sharon A %A Powe, Neil R %K Age Factors %K Aged %K Cohort Studies %K Female %K Humans %K Incidence %K Kidney Failure, Chronic %K Male %K Proportional Hazards Models %K Residence Characteristics %K Risk Factors %K Sex Factors %K Social Class %K United States %X

Few studies have focused on the association between socioeconomic status (SES) and progressive chronic kidney disease (pCKD) in an elderly population. We conducted a cohort study of 4735 Cardiovascular Health Study participants, ages 65 and older and living in 4 US communities, to examine the independent risk of pCKD associated with income, education and living in a low SES area. pCKD was defined as creatinine elevation 0.4 mg/dL (35 micromol/L) over a 4-7 year follow-up or CKD hospitalization. Area SES was characterized using measures of income, wealth, education and occupation for 1990 (corresponding to time of enrollment) US Census block groups of residence. Age and study site-adjusted incidence rates (per 1000 person years) of pCKD by quartiles of area-level SES score, income and education showed decreasing rates with increasing SES. Cox proportional hazards models showed that living in the lowest SES area quartile, as opposed to the highest, was associated with 50% greater risk of pCKD, after adjusting for age, gender, study site, baseline creatinine, and individual-level SES. This increased risk and trend persisted after adjusting for lifestyle risk factors, diabetes and hypertension. We found no significant independent associations between pCKD and individual-level income or education (after adjusting for all other SES factors). As such, living in a low SES area is associated with greater risk of pCKD in an elderly US population.

%B Soc Sci Med %V 65 %P 809-21 %8 2007 Aug %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/17499411?dopt=Abstract %R 10.1016/j.socscimed.2007.04.011 %0 Journal Article %J J Thromb Haemost %D 2007 %T Inflammation and hemostasis biomarkers and cardiovascular risk in the elderly: the Cardiovascular Health Study. %A Zakai, N A %A Katz, R %A Jenny, N S %A Psaty, B M %A Reiner, A P %A Schwartz, S M %A Cushman, M %K Aged %K Aging %K Biomarkers %K C-Reactive Protein %K Cardiovascular Diseases %K Cholesterol %K Cohort Studies %K Factor VIII %K Female %K Fibrinogen %K Hemostasis %K Homocysteine %K Humans %K Inflammation Mediators %K Interleukin-6 %K Leukocyte Count %K Lipoprotein(a) %K Male %K Prospective Studies %K Risk Factors %X

BACKGROUND: There are few studies of inflammation and hemostasis biomarkers and cardiovascular disease risk (CVD) in older adults.

OBJECTIVES: To assess multiple biomarkers simultaneously and in combinations for CVD risk assessment in older individuals.

PATIENTS/METHODS: Thirteen biomarkers, interleukin-6 (IL-6), C-reactive protein (CRP), D-dimer, fibrinogen, factor VII, factor VIII, leukocyte count (WBC), platelet count, lipoprotein(a), soluble intercellular adhesion molecule-1 (sICAM-1), albumin, homocysteine and uric acid, were correlated with incident CVD in 4510 individuals in the Cardiovascular Health Study. Baseline biomarkers were analyzed as gender-specific SD increments and quintiles in proportional hazards models adjusted for demographics, CVD risk factors and medications.

RESULTS: Over 9 years with 1700 CVD events, seven biomarkers were associated with CVD. Adjusted hazard ratios (HRs, 95% CI) per SD increment were 1.16 (1.09, 1.23) for IL-6, 1.16 (1.09, 1.23) for CRP, 1.13 (1.05, 1.21) for D-dimer, 1.17 (1.09, 1.25) for homocysteine, 1.06 (1.00, 1.12) for WBC, 1.06 (1.00, 1.12) for factor VIII, and 1.07 (1.00, 1.13) for lipoprotein(a). Fibrinogen was associated with CVD in men only (HR 1.12, 95% CI 1.04, 1.22) and sICAM-1 in women only (HR 1.16, 95% CI 1.05, 1.27). IL-6 and CRP remained associated with CVD when modeled with WBC. Participants were classified by all combinations of two biomarkers being high or low (IL-6, CRP, WBC, factor VIII, cholesterol/HDL). All were associated with CVD when cholesterol/HDL was low and none when CRP was low.

CONCLUSIONS: Seven biomarkers were associated with CVD in older adults, with CRP having some advantages compared with others. Even larger studies are needed to better characterize these associations.

%B J Thromb Haemost %V 5 %P 1128-35 %8 2007 Jun %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/17388967?dopt=Abstract %R 10.1111/j.1538-7836.2007.02528.x %0 Journal Article %J Arch Intern Med %D 2007 %T Longitudinal association between depressive symptoms and incident type 2 diabetes mellitus in older adults: the cardiovascular health study. %A Carnethon, Mercedes R %A Biggs, Mary L %A Barzilay, Joshua I %A Smith, Nicholas L %A Vaccarino, Viola %A Bertoni, Alain G %A Arnold, Alice %A Siscovick, David %K Aged %K Body Mass Index %K C-Reactive Protein %K Depression %K Diabetes Mellitus, Type 2 %K Drinking %K Female %K Humans %K Longitudinal Studies %K Male %K Smoking %X

BACKGROUND: Prospective studies indicate that a single self-report of high depressive symptoms is associated with an increased risk of developing type 2 diabetes mellitus.

METHODS: We tested whether a single report of high depressive symptoms, an increase in depressive symptoms, or persistently high depressive symptoms over time were associated with the development of diabetes in adults 65 years and older. Participants from the Cardiovascular Health Study completed the 10-item Center for Epidemiological Studies-Depression Scale (CES-D) annually from 1989 to 1999. A single report of high depressive symptoms (CES-D score, >/=8), an increase in symptoms during follow-up (>/=5 from baseline), and persistently high symptoms (2 consecutive scores >/=8) were each studied in relation to incident diabetes, defined by initiation of diabetes control medications among participants who were free from diabetes at baseline (n = 4681).

RESULTS: The mean CES-D score at baseline was 4.5 (SD, 4.5). The incidence rate of diabetes was 4.4 per 1000 person-years. Following adjustment for baseline demographic characteristics and measures of physical activity, smoking, alcohol intake, body mass index, and C-reactive protein during follow-up, each measure of depressive symptoms was significantly associated with incident diabetes (high baseline CES-D score: hazard ratio, 1.6 [95% confidence interval, 1.1-2.3]; CES-D score increase: hazard ratio, 1.5 [95% confidence interval, 1.1-2.2]; and persistently high symptoms: hazard ratio, 1.5 [95% confidence interval, 1.1-2.3]).

CONCLUSION: Older adults who reported higher depressive symptoms were more likely to develop diabetes than their counterparts; this association was not fully explained by risk factors for diabetes.

%B Arch Intern Med %V 167 %P 802-7 %8 2007 Apr 23 %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/17452543?dopt=Abstract %R 10.1001/archinte.167.8.802 %0 Journal Article %J Research on Aging %D 2007 %T The number of sick persons in a cohort. %A Diehr, P %A Derleth, A %A Newman, AB %A Cai, L %K Aging %K equilibrium %K transition probabilities %K years of healthy life %X In the Cardiovascular Health Study, a cohort study of older adults followed up to 14 years, the number of sick persons was approximately constant over time. This was true whether we defined “sick” based on self-rated health, ADL or IADL difficulties, the timed walk, bed days, depression, cognitive problems, or cardiovascular disease. To better understand this phenomenon, we estimated the probabilities of transition among the healthy, sick, and dead states, and projected the number who would be in each health state over time for a birth cohort. The estimated number of sick persons in the birth cohort increased slowly over time and was approximately constant from ages 55-75, after which it decreased. The relative excess of older persons who are sick in later life is caused by a decline in the number of healthy persons rather than an increase in the number who are sick. Estimated total medical expenditures for a birth cohort may decline after about age 73. These findings may suggest a different way of thinking about trends in the health and medical expenditures of the population over time. %B Research on Aging %V 29 %8 2007-01-01 %G eng %& 555 %0 Journal Article %J Diabet Med %D 2007 %T The relationship of heart rate and heart rate variability to non-diabetic fasting glucose levels and the metabolic syndrome: the Cardiovascular Health Study. %A Stein, P K %A Barzilay, J I %A Domitrovich, P P %A Chaves, P M %A Gottdiener, J S %A Heckbert, S R %A Kronmal, R A %K Aged %K Aged, 80 and over %K Arrhythmias, Cardiac %K Blood Glucose %K Fasting %K Female %K Glucose Intolerance %K Heart Rate %K Humans %K Male %K Metabolic Syndrome %K Risk Factors %X

BACKGROUND: Increased heart rate (HR) and diminished heart rate variability (HRV) are signs of early cardiovascular autonomic neuropathy. We tested the hypotheses that increased HR and diminished HRV are present in people: (i) with increased fasting glucose (FG) levels not in the range of diabetes mellitus (DM), and (ii) in people with the metabolic syndrome (MetS) independent of elevated FG levels.

METHODS: HR and HRV were determined in 1267 adults (mean age 72 years) who had Holter monitoring and FG measures: 536 had normal FG levels (NORM, FG 4.5-5.5 mmol/l), 363 had mildly impaired FG (IFG-1, FG 5.6-6.0 mmol/l), 182 had significantly impaired FG (IFG-2, FG 6.1-6.9 mmol/l) and 178 had DM (FG > 6.9 mmol/l or use of glucose-lowering agents/insulin). HR and HRV in NORM/IFG-1 was further compared by the number of components of the MetS and compared by the presence or absence of MetS in IFG-2/DM.

RESULTS: HRV indices were more impaired in IFG-2 and DM than in NORM or IFG-1. There were few differences in HRV indices between NORM and IFG-1 or between IFG-2 and DM. In NORM/IFG-1 participants, having > or = 2 components of the MetS was associated with a greater decrease in HRV compared with having no or one components. In IFG-2/DM participants, MetS was associated with decreased HRV compared with no MetS.

CONCLUSIONS: Increased HR and diminished HRV occur in the non-diabetic FG range. Diminished HRV is associated with the MetS, independent of FG levels. Both these results suggest that factors associated with increasing non-diabetic FG levels and the MetS play a role in the onset of cardiac autonomic impairment.

%B Diabet Med %V 24 %P 855-63 %8 2007 Aug %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/17403115?dopt=Abstract %R 10.1111/j.1464-5491.2007.02163.x %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 Risk factors for intracerebral hemorrhage in a pooled prospective study. %A Sturgeon, Jared D %A Folsom, Aaron R %A Longstreth, W T %A Shahar, Eyal %A Rosamond, Wayne D %A Cushman, Mary %K African Americans %K Age Distribution %K Cerebral Hemorrhage %K Cholesterol, LDL %K Female %K Follow-Up Studies %K Humans %K Hypertension %K Incidence %K Male %K Middle Aged %K Multivariate Analysis %K Predictive Value of Tests %K Prevalence %K Prospective Studies %K Risk Factors %K Stroke %K Triglycerides %X

BACKGROUND AND PURPOSE: Few prospective studies have reported risk factors for intracerebral hemorrhage (ICH), and results are inconsistent. We studied risk factors for ICH in a pooled cohort of the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS).

METHODS: The ARIC cohort was recruited in 1987 to 1989 and involves 15 792 men and women, aged 45 to 64 years at baseline, sampled from 4 US communities. The CHS cohort was recruited in 1989 to 1993 and involves 5888 men and women, aged 65 or over at baseline, sampled from 4 US communities. Baseline measurements included many potential vascular risk factors. The cohorts were followed for incident stroke events.

RESULTS: Over 263 489 person-years of follow-up, 135 incident ICH events occurred. In a multivariable model, age, African-American ethnicity (versus Whites), and hypertension were positively associated with incident ICH, whereas low-density lipoprotein cholesterol and triglycerides were inversely related to incident ICH. Participants with systolic blood pressure >or=160 mm Hg or diastolic blood pressure >/=110 mm Hg had 5.55 (95% CI 3.07 to 10.0) times the rate of ICH as nonhypertensives. Sex, smoking, alcohol intake, body mass index, waist-to-hip ratio, waist circumference, and diabetes were not related to ICH.

CONCLUSIONS: In this pooled cohort the risk factors for ICH were older age, African-American ethnicity, hypertension, lower LDL-C, and lower triglycerides.

%B Stroke %V 38 %P 2718-25 %8 2007 Oct %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/17761915?dopt=Abstract %R 10.1161/STROKEAHA.107.487090 %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 Neurobiol Aging %D 2007 %T Ventricular volume and dementia progression in the Cardiovascular Health Study. %A Carmichael, Owen T %A Kuller, Lewis H %A Lopez, Oscar L %A Thompson, Paul M %A Dutton, Rebecca A %A Lu, Allen %A Lee, Sharon E %A Lee, Jessica Y %A Aizenstein, Howard J %A Meltzer, Carolyn Cidis %A Liu, Yanxi %A Toga, Arthur W %A Becker, James T %K Aged %K Aged, 80 and over %K Aging %K Cognition Disorders %K Cross-Sectional Studies %K Dementia %K Disease Progression %K Female %K Follow-Up Studies %K Humans %K Lateral Ventricles %K Linear Models %K Magnetic Resonance Imaging %K Male %K Predictive Value of Tests %K Prospective Studies %K Retrospective Studies %K Time Factors %X

Elevated cerebral ventricular volume may be associated with dementia risk and progression. A fully-automated technique that agreed highly with radiological readings was used to estimate lateral ventricle volume on MR scans done at baseline in 1997-99 of 377 subjects in the Cardiovascular Health Study (CHS) from the Pittsburgh Center. 327 subjects were normal or diagnosed with mild cognitive impairment (MCI) at baseline and were evaluated 4 years later. Baseline ventricular volume was analyzed in multivariate models with age, gender, education level, presence and incidence of cerebral infarcts, and dementia category (normal, MCI, or dementia) at baseline and follow-up as fixed effects. Ventricular volume at baseline was significantly higher among subjects normal at baseline and demented 4 years later. Age, gender, education level, and dementia progression were significant factors affecting ventricular volume. Ventricular volume was higher in dementia compared to MCI, higher in MCI compared to controls, and higher in Possible-Alzheimer's-disease (AD) dementia compared to Probable-AD. Larger ventricles in healthy subjects may indicate susceptibility to, or progression of, dementia-related pathology.

%B Neurobiol Aging %V 28 %P 389-97 %8 2007 Mar %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/16504345?dopt=Abstract %R 10.1016/j.neurobiolaging.2006.01.006 %0 Journal Article %J Stroke %D 2008 %T Abnormal regional cerebral blood flow in cognitively normal elderly subjects with hypertension. %A Dai, Weiying %A Lopez, Oscar L %A Carmichael, Owen T %A Becker, James T %A Kuller, Lewis H %A Gach, H Michael %K Aged %K Aged, 80 and over %K Cerebral Cortex %K Cerebrovascular Circulation %K Cognition %K Cognition Disorders %K Female %K Globus Pallidus %K Gyrus Cinguli %K Humans %K Hypertension %K Magnetic Resonance Imaging %K Male %K Putamen %K Spin Labels %X

BACKGROUND AND PURPOSE: The purpose of this study was to examine regional cerebral blood flow (rCBF) in normal cognitive-performing subjects with hypertension (HTN) using continuous arterial spin-labeled MRI. The most common explanation for the effect of blood pressure on cognition is that HTN increases the risk of cerebrovascular disease, and it may increase the risk for Alzheimer disease possibly through small vessel disease, ischemia, oxidative stress, and inflammation. However, few studies to date have examined the rCBF of cognitively normal subjects with HTN in population-based cohorts, and none have used continuous arterial spin-labeled MRI. This is a noninvasive technique that does not require either injections or ionizing radiation and can measure absolute rCBF rates over the entire brain.

METHODS: rCBF was measured at 1.5 T using continuous arterial spin-labeled MRI in 41 cognitively normal subjects who were participating in the Cardiovascular Health Study Cognition Study. A deformable atrophy-corrected registration method was used to warp the rCBF maps to the standard colin27 brain space. Image and cluster-based statistical analyses were performed between subject groups.

RESULTS: Cognitively normal subjects with HTN (n=19) had decreased rCBF in the putamen, globus pallidus, bilaterally, and in the left hippocampus compared with normotensives (n=22). In addition, decreased rCBF was observed in the right and left anterior cingulate gyrus with extension to the subcallosal region, left posterior cingulate gyrus and medial precuneus, left lateral inferior and superior frontal, and inferior parietal, left orbitofrontal, and left superior temporal cortices.

CONCLUSIONS: rCBF is affected in normal subjects with HTN, not only in the subcortical regions, but also in limbic and paralimbic structures. We hypothesize that the HTN creates a vulnerability state for the development of neurodegenerative disorders, especially Alzheimer disease.

%B Stroke %V 39 %P 349-54 %8 2008 Feb %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/18174483?dopt=Abstract %R 10.1161/STROKEAHA.107.495457 %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 J Am Geriatr Soc %D 2008 %T Anemia is associated with the progression of white matter disease in older adults with high blood pressure: the cardiovascular health study. %A Inzitari, Marco %A Studenski, Stephanie %A Rosano, Caterina %A Zakai, Neil A %A Longstreth, William T %A Cushman, Mary %A Newman, Anne B %K Aged %K Anemia %K Brain %K Cardiovascular Diseases %K Disease Progression %K Female %K Humans %K Hypertension %K Leukoaraiosis %K Magnetic Resonance Imaging %K Male %X

OBJECTIVES: To investigate whether anemia predicts worsening white matter hyperintensities (WMHs) in older community-dwellers.

DESIGN: Prospective cohort study.

SETTING: Older community-dwellers.

PARTICIPANTS: One thousand eight hundred forty-six Cardiovascular Health Study (CHS) participants (mean age 73.7 +/- 4.4, 41% male, 15.6% African American).

MEASUREMENTS: Participants had hemoglobin measured and brain magnetic resonance imaging (MRI) in 1992/93 and a second brain MRI in 1997/98. Anemia was defined according to World Health Organization criteria (hemoglobin <12 g/dL in women and <13 g/dL in men). Worsening WMHs were determined according to standardized side-by-side readings.

RESULTS: After 5 years, WMHs worsened in 517 participants (28%). Progression was not associated with anemia in the whole sample, in sex or race strata, or in other prespecified subgroups (participants with renal dysfunction or diabetes mellitus), except in participants with high blood pressure (>or=140/90 mmHg). Of the 678 participants with high blood pressure, those with anemia (10.5%) had a 1.79 times greater risk of WMHs worsening (95% confidence interval=1.06-2.98; P for interaction between anemia and high blood pressure=.01) independent of demographics, baseline WMHs, cardiovascular risk factors and comorbidities, medications, renal function, inflammation, and incident stroke (logistic regression models). There was no greater risk in participants with anemia with normal blood pressure.

CONCLUSION: Anemia may contribute to worsening of WMHs in older adults with high blood pressure.

%B J Am Geriatr Soc %V 56 %P 1867-72 %8 2008 Oct %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/18811608?dopt=Abstract %R 10.1111/j.1532-5415.2008.01950.x %0 Journal Article %J JAMA %D 2008 %T Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality: a meta-analysis. %A Fowkes, F G R %A Murray, G D %A Butcher, I %A Heald, C L %A Lee, R J %A Chambless, L E %A Folsom, A R %A Hirsch, A T %A Dramaix, M %A deBacker, G %A Wautrecht, J-C %A Kornitzer, M %A Newman, A B %A Cushman, M %A Sutton-Tyrrell, K %A Fowkes, F G R %A Lee, A J %A Price, J F %A D'Agostino, R B %A Murabito, J M %A Norman, P E %A Jamrozik, K %A Curb, J D %A Masaki, K H %A Rodríguez, B L %A Dekker, J M %A Bouter, L M %A Heine, R J %A Nijpels, G %A Stehouwer, C D A %A Ferrucci, L %A McDermott, M M %A Stoffers, H E %A Hooi, J D %A Knottnerus, J A %A Ogren, M %A Hedblad, B %A Witteman, J C %A Breteler, M M B %A Hunink, M G M %A Hofman, A %A Criqui, M H %A Langer, R D %A Fronek, A %A Hiatt, W R %A Hamman, R %A Resnick, H E %A Guralnik, J %A McDermott, M M %K Adult %K Age Factors %K Aged %K Aged, 80 and over %K Ankle %K Atherosclerosis %K Blood Pressure %K Brachial Artery %K Cardiovascular Diseases %K Cohort Studies %K Confidence Intervals %K Female %K Global Health %K Humans %K Male %K Middle Aged %K Odds Ratio %K Predictive Value of Tests %K Risk Assessment %K Risk Factors %K Severity of Illness Index %X

CONTEXT: Prediction models to identify healthy individuals at high risk of cardiovascular disease have limited accuracy. A low ankle brachial index (ABI) is an indicator of atherosclerosis and has the potential to improve prediction.

OBJECTIVE: To determine if the ABI provides information on the risk of cardiovascular events and mortality independently of the Framingham risk score (FRS) and can improve risk prediction.

DATA SOURCES: Relevant studies were identified. A search of MEDLINE (1950 to February 2008) and EMBASE (1980 to February 2008) was conducted using common text words for the term ankle brachial index combined with text words and Medical Subject Headings to capture prospective cohort designs. Review of reference lists and conference proceedings, and correspondence with experts was conducted to identify additional published and unpublished studies.

STUDY SELECTION: Studies were included if participants were derived from a general population, ABI was measured at baseline, and individuals were followed up to detect total and cardiovascular mortality.

DATA EXTRACTION: Prespecified data on individuals in each selected study were extracted into a combined data set and an individual participant data meta-analysis was conducted on individuals who had no previous history of coronary heart disease.

RESULTS: Sixteen population cohort studies fulfilling the inclusion criteria were included. During 480,325 person-years of follow-up of 24,955 men and 23,339 women, the risk of death by ABI had a reverse J-shaped distribution with a normal (low risk) ABI of 1.11 to 1.40. The 10-year cardiovascular mortality in men with a low ABI (< or = 0.90) was 18.7% (95% confidence interval [CI], 13.3%-24.1%) and with normal ABI (1.11-1.40) was 4.4% (95% CI, 3.2%-5.7%) (hazard ratio [HR], 4.2; 95% CI, 3.3-5.4). Corresponding mortalities in women were 12.6% (95% CI, 6.2%-19.0%) and 4.1% (95% CI, 2.2%-6.1%) (HR, 3.5; 95% CI, 2.4-5.1). The HRs remained elevated after adjusting for FRS (2.9 [95% CI, 2.3-3.7] for men vs 3.0 [95% CI, 2.0-4.4] for women). A low ABI (< or = 0.90) was associated with approximately twice the 10-year total mortality, cardiovascular mortality, and major coronary event rate compared with the overall rate in each FRS category. Inclusion of the ABI in cardiovascular risk stratification using the FRS would result in reclassification of the risk category and modification of treatment recommendations in approximately 19% of men and 36% of women.

CONCLUSION: Measurement of the ABI may improve the accuracy of cardiovascular risk prediction beyond the FRS.

%B JAMA %V 300 %P 197-208 %8 2008 Jul 09 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/18612117?dopt=Abstract %R 10.1001/jama.300.2.197 %0 Journal Article %J Stroke %D 2008 %T Antidepressant treatment and worsening white matter on serial cranial magnetic resonance imaging in the elderly: the Cardiovascular Health Study. %A Steffens, David C %A Chung, Hyoju %A Krishnan, K Ranga R %A Longstreth, W T %A Carlson, Michelle %A Burke, Gregory L %K Aged %K Antidepressive Agents %K Antidepressive Agents, Tricyclic %K Cohort Studies %K Disease Progression %K Female %K Follow-Up Studies %K Humans %K Leukoaraiosis %K Magnetic Resonance Imaging %K Male %K Multivariate Analysis %K Risk Assessment %K Serotonin Uptake Inhibitors %X

BACKGROUND AND PURPOSE: In some studies, late life depression is associated with white matter lesions on MRI. The effect of different classes of antidepressants on progression of white matter lesions is unknown. Selective serotonergic reuptake inhibitors (SSRIs) may decrease platelet aggregation. We hypothesized that Cardiovascular Health Study participants taking SSRIs would less often have worsening white matter on serial MRI than participants not on antidepressants.

METHODS: Among 1826 participants who were not using an antidepressant at initial MRI scan, we examined the association of worsening in white matter grade from initial to follow-up MRI scans, 5 years apart on average, and antidepressant use between the scans. Logistic regression models were used, controlling for a variety of potential confounding variables.

RESULTS: Use of any antidepressant during the period of study was associated with worsening white matter. In a multivariable model, risk was slightly increased, not reduced, with use of serotonergic agents (OR 1.36, 95% CI 0.87 to 2.12) and was significantly increased with the use of tricyclic antidepressants (OR 1.77, 95% CI 1.07 to 2.94).

CONCLUSIONS: The association between worsening white matter and use of tricyclic antidepressants was an unexpected finding that may relate to indications for use other than depression or to side effects such as hypotension. Protection against worsening was not seen with use of serotonergic agents.

%B Stroke %V 39 %P 857-62 %8 2008 Mar %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/18239166?dopt=Abstract %R 10.1161/STROKEAHA.107.498097 %0 Journal Article %J Atherosclerosis %D 2008 %T Association between brachial artery reactivity and cardiovascular disease status in an elderly cohort: the cardiovascular health study. %A Yeboah, Joseph %A Sutton-Tyrrell, Kim %A McBurnie, Mary Ann %A Burke, Gregory L %A Herrington, David M %A Crouse, John R %K Aged %K Aged, 80 and over %K Biomarkers %K Brachial Artery %K Cardiovascular Diseases %K Cohort Studies %K Female %K Hemorheology %K Humans %K Male %K Peripheral Vascular Diseases %K ROC Curve %K Ultrasonography %K Vasodilation %X

BACKGROUND AND OBJECTIVES: The association of brachial flow-mediated dilation (FMD) and cardiovascular disease (CVD) status is unclear especially in older adults whose FMD is greatly diminished. We assessed the association of FMD and the presence or absence of subclinical and clinical CVD in a population based cohort of older adults.

METHODS AND RESULTS: FMD was measured in 2971 adults aged 72-98 years (mean age 78.6 years) who participated in the Cardiovascular Health Study. Multiple linear regression analysis was used to examine the association between FMD and CVD status (clinical, subclinical and free of CVD). Out of 2791 with complete data, 82.7% were Caucasians and 59% females. Seven hundred and forty-three were classified as having clinical CVD, 607 as subclinical CVD and 1441 as neither clinical CVD nor subclinical CVD (CVD free). FMD was higher in the CVD free group compared with either the clinical (3.13+/-0.05% vs 2.93+/-0.07%, p=0.025) or the subclinical CVD group (3.13+/-0.05% vs 2.95+/-0.08%, p=0.05) after adjusting for covariates. There was no significant difference between the FMD of subjects with clinical and subclinical CVD (2.93+/-0.07% vs 2.95+/-0.08%, p=0.84). Similar but inverted associations were observed between height adjusted brachial artery diameter (BAD) and CVD status. However, FMD and BAD had poor diagnostic accuracies for identifying older adults with subclinical CVD.

CONCLUSION: Among older adults, those with either clinical or subclinical CVD have lower FMD than CVD free subjects. BAD showed similar but inverted associations with CVD status in this cohort. FMD and BAD had poor diagnostic accuracies for identifying older adults with subclinical CVD.

%B Atherosclerosis %V 197 %P 768-76 %8 2008 Apr %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/17714717?dopt=Abstract %R 10.1016/j.atherosclerosis.2007.07.013 %0 Journal Article %J Thromb Haemost %D 2008 %T Associations between common fibrinogen gene polymorphisms and cardiovascular disease in older adults. The Cardiovascular Health Study. %A Carty, Cara L %A Cushman, Mary %A Jones, Daniel %A Lange, Leslie A %A Hindorff, Lucia A %A Rice, Kenneth %A Jenny, Nancy S %A Durda, J Peter %A Walston, Jeremy %A Carlson, Christopher S %A Nickerson, Debbie %A Tracy, Russell P %A Reiner, Alex P %K African Americans %K Age Factors %K Aged %K Brain Ischemia %K Cardiovascular Diseases %K Carotid Artery Diseases %K European Continental Ancestry Group %K Female %K Fibrinogen %K Gene Frequency %K Genetic Predisposition to Disease %K Haplotypes %K Humans %K Male %K Myocardial Infarction %K Polymorphism, Single Nucleotide %K Population Surveillance %K Proportional Hazards Models %K Prospective Studies %K Reproducibility of Results %K Risk Assessment %K Risk Factors %K Sex Factors %K Stroke %K United States %X

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

%B Thromb Haemost %V 99 %P 388-95 %8 2008 Feb %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/18278190?dopt=Abstract %R 10.1160/TH07-08-0523 %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 Atherosclerosis %D 2008 %T Cardiovascular and mortality risk prediction and stratification using urinary albumin excretion in older adults ages 68-102: the Cardiovascular Health Study. %A Cao, Jie J %A Biggs, Mary L %A Barzilay, Joshua %A Konen, Joseph %A Psaty, Bruce M %A Kuller, Lewis %A Bleyer, Anthony J %A Olson, Jean %A Wexler, Jason %A Summerson, John %A Cushman, Mary %K Aged %K Aged, 80 and over %K Albuminuria %K Biomarkers %K Cohort Studies %K Coronary Disease %K Cross-Sectional Studies %K Female %K Health Surveys %K Humans %K Male %K Predictive Value of Tests %K Risk %X

BACKGROUND: Elevated urinary albumin excretion (UAE) is associated with the risk of cardiovascular disease (CVD) and all-cause mortality. We tested the hypothesis that elevated UAE improves cardiovascular risk stratification in an elderly cohort aged 68-102 years.

METHODS: We evaluated UAE in 3112 participants of the Cardiovascular Health Study who attended the 1996-1997 examination and had median follow up of 5.4 years. Elevated UAE was defined as urinary albumin to creatinine ratio > or =30 microg/mg. Microalbuminuria and macroalbuminuria were defined as urinary albumin to creatinine ratio 30-300 microg/mg and >300 microg/mg, respectively. Outcomes included CVD (myocardial infarction, stroke, cardiovascular death) and all-cause mortality. Cox proportional hazards models were used to assess the risk of outcomes associated with elevated UAE.

RESULTS: The prevalence of elevated UAE was 14.3%, 17.1% and 26.9% in those aged 68-74, 75-84 and 85-102 years, respectively. CVD incidence and all-cause mortality were doubled (7.2% and 8.1% per year) in those with microalbuminuria and tripled (11.1% and 12.3% per year) in those with macroalbuminuria compared to those with normal UAE (3.3% and 3.8% per year). The increased CVD and mortality risks were observed in all age groups after adjustment for conventional risk factors. The adjusted population attributable risk percent of CVD and all-cause mortality for elevated UAE was 11% and 12%, respectively. When participants were cross-classified by UAE and Framingham Risk Score categories, the 5-year cumulative incidence of coronary heart disease among participants with elevated UAE and a 5-year predicted risk of 5-10% was 20%, substantially higher than 6.3% in those with UAE <30m microg/mg.

CONCLUSION: Elevated UAE was associated with an increased risk of CVD and all-cause mortality in all age groups from 68 to 102 years. Combining elevated UAE with the Framingham risk scores may improve risk stratification for CVD in the elderly.

%B Atherosclerosis %V 197 %P 806-13 %8 2008 Apr %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/17875308?dopt=Abstract %R 10.1016/j.atherosclerosis.2007.07.029 %0 Journal Article %J J Am Soc Nephrol %D 2008 %T Chronic kidney disease increases risk for venous thromboembolism. %A Wattanakit, Keattiyoat %A Cushman, Mary %A Stehman-Breen, Catherine %A Heckbert, Susan R %A Folsom, Aaron R %K Aged %K Aged, 80 and over %K Body Mass Index %K Diabetic Nephropathies %K Factor VIII %K Female %K Glomerular Filtration Rate %K Humans %K Hypertension %K Kidney Failure, Chronic %K Longitudinal Studies %K Male %K Middle Aged %K Risk Factors %K Thromboembolism %K Venous Thrombosis %X

Chronic kidney disease (CKD) is associated with increased risk for cardiovascular disease morbidity and mortality, but its association with incident venous thromboembolism (VTE) in non-dialysis-dependent patients has not been evaluated in a community-based population. With the use of data from the Longitudinal Investigation of Thromboembolism Etiology (LITE) study, 19,073 middle-aged and elderly adults were categorized on the basis of estimated GFR, and cystatin C (available in 4734 participants) was divided into quintiles. During a mean follow-up time of 11.8 yr, 413 participants developed VTE. Compared with participants with normal kidney function, relative risk for VTE was 1.28 (95% confidence interval [CI] 1.02 to 1.59) for those with mildly decreased kidney function and 2.09 (95% CI 1.47 to 2.96) for those with stage 3/4 CKD, when adjusted for age, gender, race, and center. After additional adjustment for cardiovascular disease risk factors, an increased risk for VTE was still observed in participants with stage 3/4 CKD, with a multivariable adjusted relative risk of 1.71 (95% CI 1.18 to 2.49). There was no significant association between cystatin C and VTE. In conclusion, middle-aged and elderly patients with CKD (stages 3 through 4) are at increased risk for incident VTE, suggesting that VTE prophylaxis may be particularly important in this population.

%B J Am Soc Nephrol %V 19 %P 135-40 %8 2008 Jan %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/18032796?dopt=Abstract %R 10.1681/ASN.2007030308 %0 Journal Article %J Eur J Epidemiol %D 2008 %T Collaborative pooled analysis of data on C-reactive protein gene variants and coronary disease: judging causality by Mendelian randomisation. %K C-Reactive Protein %K Case-Control Studies %K Cooperative Behavior %K Coronary Disease %K Haplotypes %K Humans %K Inflammation %K Polymorphism, Genetic %K Research Design %X

Many prospective studies have reported associations between circulating C-reactive protein (CRP) levels and risk of coronary heart disease (CHD), but causality remains uncertain. Studies of CHD are being conducted that involve measurement of common polymorphisms of the CRP gene known to be associated with circulating concentrations, thereby utilising these variants as proxies for circulating CRP levels. By analysing data from several studies examining the association between relevant CRP polymorphisms and CHD risk, the present collaboration will undertake a Mendelian randomisation analysis to help assess the likelihood of any causal relevance of CRP levels to CHD risk. A central database is being established containing individual data on CRP polymorphisms, circulating CRP levels, and major coronary outcomes as well as age, sex and other relevant characteristics. Associations between CRP polymorphisms or haplotypes and CHD will be evaluated under different circumstances. This collaboration comprises, at present, about 37,000 CHD outcomes and about 120,000 controls, which should yield suitably precise findings to help judge causality. This work should advance understanding of the relevance of low-grade inflammation to CHD and indicate whether or not CRP itself is involved in long-term pathogenesis.

%B Eur J Epidemiol %V 23 %P 531-40 %8 2008 %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/18425592?dopt=Abstract %R 10.1007/s10654-008-9249-z %0 Journal Article %J J Thromb Haemost %D 2008 %T Common genetic variants associated with plasma fibrin D-dimer concentration in older European- and African-American adults. %A Lange, L A %A Reiner, A P %A Carty, C L %A Jenny, N S %A Cushman, M %A Lange, E M %K Africa %K African Americans %K Aged %K Aged, 80 and over %K Blood Coagulation %K Europe %K European Continental Ancestry Group %K Female %K Fibrin Fibrinogen Degradation Products %K Fibrinogen %K Fibrinolysis %K Genotype %K Humans %K Male %K Middle Aged %K Plasminogen Activator Inhibitor 1 %K Polymorphism, Single Nucleotide %K Prospective Studies %K United States %K Urokinase-Type Plasminogen Activator %X

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

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

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

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

%B J Thromb Haemost %V 6 %P 654-9 %8 2008 Apr %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/18208536?dopt=Abstract %R 10.1111/j.1538-7836.2008.02906.x %0 Journal Article %J Atherosclerosis %D 2008 %T Common variants in the CRP gene in relation to longevity and cause-specific mortality in older adults: the Cardiovascular Health Study. %A Hindorff, Lucia A %A Rice, Kenneth M %A Lange, Leslie A %A Diehr, Paula %A Halder, Indrani %A Walston, Jeremy %A Kwok, Pui %A Ziv, Elad %A Nievergelt, Caroline %A Cummings, Steven R %A Newman, Anne B %A Tracy, Russell P %A Psaty, Bruce M %A Reiner, Alexander P %K African Americans %K Aged %K C-Reactive Protein %K Cardiovascular Diseases %K Cause of Death %K Cohort Studies %K Female %K Genetic Predisposition to Disease %K Haplotypes %K Humans %K Linear Models %K Longevity %K Male %K Polymorphism, Single Nucleotide %K Proportional Hazards Models %K United States %X

Common polymorphisms in the CRP gene are associated with plasma CRP levels in population-based studies, but associations with age-related events are uncertain. A previous study of CRP haplotypes in older adults was broadened to include longevity and cause-specific mortality (all-cause, noncardiovascular (non-CV), and cardiovascular (CV)). Common haplotypes were inferred from four tagSNPs in 4512 whites and five tagSNPs in 812 blacks from the Cardiovascular Health Study, a longitudinal cohort of adults over age 65. Exploratory analyses addressed early versus late mortality. CRP haplotypes were not associated with all-cause mortality or longevity overall in either population, but associations with all-cause mortality differed during early and late periods. In blacks, the haplotype tagged by 3872A (rs1205) was associated with increased risk of non-CV mortality, relative to other haplotypes (adjusted hazard ratio for each additional copy: 1.42, 95% CI: 1.07, 1.87). Relative to other haplotypes, this haplotype was associated with decreased risk of early but not decreased risk of late CV mortality in blacks; among whites, a haplotype tagged by 2667C (rs1800947) gave similar but nonsignificant findings. If confirmed, CRP genetic variants may be weakly associated with CV and non-CV mortality in older adults, particularly in self-identified blacks.

%B Atherosclerosis %V 197 %P 922-30 %8 2008 Apr %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/17888441?dopt=Abstract %R 10.1016/j.atherosclerosis.2007.08.012 %0 Journal Article %J Arch Intern Med %D 2008 %T Cystatin C and aging success. %A Sarnak, Mark J %A Katz, Ronit %A Fried, Linda F %A Siscovick, David %A Kestenbaum, Brian %A Seliger, Stephen %A Rifkin, Dena %A Tracy, Russell %A Newman, Anne B %A Shlipak, Michael G %K Aged %K Aging %K Biomarkers %K Creatinine %K Cystatin C %K Cystatins %K Female %K Follow-Up Studies %K Glomerular Filtration Rate %K Humans %K Kidney %K Male %X

BACKGROUND: To our knowledge, the effect of kidney function on successful aging has not been examined.

METHODS: We evaluated the relationship between cystatin C and aging success during a 6-year follow-up in the Cardiovascular Health Study, a community-based cohort of older adults (aged >or= 65 years). Successful aging was defined as remaining free of cardiovascular disease, cancer, and chronic obstructive pulmonary disease and having intact physical and cognitive functioning. In adjusted analysis, an accelerated failure time model was used to evaluate the percentage reduction in successful years by level of cystatin C. A separate Cox proportional hazards model evaluated whether cystatin C was related to incident physical and cognitive disability.

RESULTS: A total of 2140 participants had cystatin C measured and were free of the previously mentioned conditions at baseline. Their mean age was 74 years. The mean cystatin C level, creatinine level, and estimated glomerular filtration rate were 1.06 mg/L, 0.93 mg/dL, and 78 mL/min/1.73 m(2), respectively (to convert cystatin C to nanomoles per liter, multiply by 75; and to convert creatinine to micromoles per liter, multiply by 88.4). A total of 873 participants reached a first event in follow-up, 138 because of cognitive disability, 238 because of physical disability, 34 because of chronic obstructive pulmonary disease, 146 because of cancer, and 317 because of cardiovascular disease. The adjusted percentage reduction in successful life years in the highest vs the lowest quartile of cystatin C was 27% (95% confidence interval, 11%-39%). The highest vs lowest quartile of cystatin C also was independently associated with incident cognitive or physical disability (hazard ratio, 1.39; 95% confidence interval, 1.00-1.98).

CONCLUSION: A higher cystatin C level, even within a range of relatively normal kidney function, was associated with unsuccessful aging.

%B Arch Intern Med %V 168 %P 147-53 %8 2008 Jan 28 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/18227360?dopt=Abstract %R 10.1001/archinternmed.2007.40 %0 Journal Article %J J Am Geriatr Soc %D 2008 %T Distribution and correlates of lipoprotein-associated phospholipase A2 in an elderly cohort: the Cardiovascular Health Study. %A Furberg, Curt D %A Nelson, Jeanenne J %A Solomon, Cam %A Cushman, Mary %A Jenny, Nancy Swords %A Psaty, Bruce M %K 1-Alkyl-2-acetylglycerophosphocholine Esterase %K Aged %K Atherosclerosis %K Body Mass Index %K Cardiac Output, Low %K Cardiovascular Diseases %K Cholesterol, HDL %K Cholesterol, LDL %K Cohort Studies %K Cross-Sectional Studies %K Electrocardiography %K Female %K Heart Failure %K Humans %K Hypertrophy, Left Ventricular %K Long QT Syndrome %K Male %K Reference Values %K Renal Insufficiency %K Risk Factors %K Statistics as Topic %K Triglycerides %X

OBJECTIVES: To determine whether high levels of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) are associated with prevalent cardiovascular disease (CVD) and to evaluate factors most influencing Lp-PLA(2) levels in a community-based cohort of older adults.

DESIGN: Cross-sectional.

SETTING: The Cardiovascular Health Study (CHS), a population-based cohort study of men and women aged 65 and older.

PARTICIPANTS: Five thousand five hundred thirty-one CHS participants.

MEASUREMENTS: Levels of Lp-PLA(2) activity were determined using stored blood samples from the baseline examination.

RESULTS: Mean Lp-PLA(2) was higher in participants with electrocardiographically determined ventricular conduction defect and major Q-wave abnormality and was positively correlated with left ventricular (LV) mass. It was high in those with echocardiographically determined abnormal LV ejection fraction, which persisted after adjustment. Mean Lp-PLA(2) was also higher in participants with mild renal insufficiency and kidney disease. After multivariable adjustment, there was a modest but significant 27% greater risk of prevalent CHF per standard deviation increment of Lp-PLA(2) and a modest but significant 12% greater risk of prevalent myocardial infarction. Lp-PLA(2) was weakly but mainly most strongly correlated with cholesterol and lipoproteins, but those correlations were not especially strong. Lp-PLA(2) was weakly positively correlated with soluble intercellular adhesion molecule-1 but not interleukin-6. In total, all factors considered could explain only 29% of Lp-PLA(2) activity.

CONCLUSION: Novel findings in the study are the associations, in those aged 65 and older, between Lp-PLA(2) activity and LV dysfunction, CHF, and renal disease. CVD risk factors only minimally explain levels of Lp-PLA(2).

%B J Am Geriatr Soc %V 56 %P 792-9 %8 2008 May %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/18363676?dopt=Abstract %R 10.1111/j.1532-5415.2008.01667.x %0 Journal Article %J Stat Med %D 2008 %T Evaluation of a method for fitting a semi-Markov process model in the presence of left-censored spells using the Cardiovascular Health Study. %A Cai, Liming %A Schenker, Nathaniel %A Lubitz, James %A Diehr, Paula %A Arnold, Alice %A Fried, Linda P %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Cardiovascular System %K Data Interpretation, Statistical %K Disease Progression %K Female %K Humans %K Longitudinal Studies %K Male %K Markov Chains %K Models, Statistical %K Stochastic Processes %K Time Factors %X

We used a longitudinal data set covering 13 years from the Cardiovascular Health Study to evaluate the properties of a recently developed approach to deal with left censoring that fits a semi-Markov process (SMP) model by using an analog to the stochastic EM algorithm--the SMP-EM approach. It appears that the SMP-EM approach gives estimates of duration-dependent probabilities of health changes similar to those obtained by using SMP models that have the advantage of actual duration data. SMP-EM estimates of duration-dependent transition probabilities also appear more accurate and less variable than multi-state life table estimates.

%B Stat Med %V 27 %P 5509-24 %8 2008 Nov 20 %G eng %N 26 %1 https://www.ncbi.nlm.nih.gov/pubmed/18712777?dopt=Abstract %R 10.1002/sim.3382 %0 Journal Article %J Sleep %D 2008 %T Fasting glycemia in sleep disordered breathing: lowering the threshold on oxyhemoglobin desaturation. %A Stamatakis, Katherine %A Sanders, Mark H %A Caffo, Brian %A Resnick, Helaine E %A Gottlieb, Dan J %A Mehra, Reena %A Punjabi, Naresh M %K Aged %K Blood Glucose %K Body Mass Index %K Cohort Studies %K Cross-Sectional Studies %K Diabetes Mellitus, Type 2 %K Fasting %K Female %K Humans %K Male %K Middle Aged %K Odds Ratio %K Oxygen %K Oxyhemoglobins %K Polysomnography %K Reference Values %K Sleep Apnea, Obstructive %X

STUDY OBJECTIVES: Commonly used definitions of sleep-disordered breathing (SDB) are based on identifying discrete events of breathing abnormalities during sleep that are accompanied by an oxyhemoglobin desaturation (delta SaO2) of at least 4%. However, it is not known whether disordered breathing events with oxyhemoglobin desaturation less than 4% are associated with clinical sequelae such as abnormalities in fasting glycemia.

DESIGN: Cross-sectional study.

SUBJECTS AND SETTING: Participants from the Sleep Heart Health Study (SHHS) with a fasting glucose measurement made within a year of the baseline polysomnogram.

MEASUREMENTS AND RESULTS: SDB severity was defined using the apnea-hypopnea index (AHI) and the hypopnea index (HI) by counting events with different levels of oxyhemoglobin desaturation (0.0%-1.9%, 2.0%-2.9%, 3.0%-3.9%, > or = 4.0%). Fasting glucose levels were used to classify individuals into normal (<100 mg/dL), impaired (100-125 mg/dL), and diabetic (> or = 126 mg/dL) groups. Ordinal logistic regression was used to determine the adjusted relative odds of an abnormal glucose value across quartiles of the hypopnea index, independent of factors such as age, body mass index, waist circumference, and usual sleep duration. The prevalence of impaired and diabetic fasting glucose in the analytical sample was 32.9% and 5.8%, respectively. The covariate-adjusted relative odds of impaired or diabetic fasting glucose in the highest versus the lowest AHI quartile was 1.35 (95% CI: 1.04-1.76) for events with a delta SaO2 > or = 4.0%, 1.72 (95% CI: 1.20-2.48) for events with a delta SaO2 between 3.0%-3.9%, 1.41 (95% CI: 1.07-1.86) for events with a delta SaO2 between 2.0%-2.9%, and 1.07 (95% CI: 0.84-1.37) for events with a delta SaO2 between 0.0%-1.9%. The corresponding odds ratios for the HI were 1.47 (95% CI: 1.13-1.92), 2.25 (95% CI: 1.59-3.19), 1.44 (95% CI: 1.09-1.90), and 1.15 (95% CI: 0.90-1.47), respectively.

CONCLUSIONS: The results of this study indicate that SDB events accompanied by oxyhemoglobin desaturation of between 2% to 4% are associated with fasting hyperglycemia. These findings suggest that milder degrees of SDB may predispose to adverse metabolic outcomes.

%B Sleep %V 31 %P 1018-24 %8 2008 Jul %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/18652097?dopt=Abstract %0 Journal Article %J Stroke %D 2008 %T Hemostatic and inflammatory risk factors for intracerebral hemorrhage in a pooled cohort. %A Sturgeon, Jared D %A Folsom, Aaron R %A Longstreth, W T %A Shahar, Eyal %A Rosamond, Wayne D %A Cushman, Mary %K Age Distribution %K Aged %K Biomarkers %K C-Reactive Protein %K Cerebral Hemorrhage %K Cohort Studies %K Factor VIII %K Female %K Fibrinogen %K Follow-Up Studies %K Humans %K Leukocyte Count %K Lipoprotein(a) %K Male %K Middle Aged %K Multivariate Analysis %K Prevalence %K Risk Factors %K Stroke %K United States %K Vasculitis %K von Willebrand Factor %X

BACKGROUND AND PURPOSE: The purpose of this study was to identify novel risk factors for intracerebral hemorrhagic stroke (ICH).

METHODS: Risk factors were assessed at baseline in a pooled cohort of the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS) involving 21,680 adults aged 45 or over. Over 263,489 person-years of follow-up, we identified 135 incident ICH events.

RESULTS: In multivariable models, for each SD higher baseline level of fibrinogen, the relative rate of incident ICH increased 35% (95% CI, 17% to 55%). Fibrinogen was more strongly related to ICH in ARIC than in CHS. In multivariable models, those with von Willebrand factor levels above the median were 1.72 (95% CI, 0.97 to 3.03) times more likely to have an incident ICH as those below the median. Factor VIII was significantly positively related to ICH in ARIC (relative rate per standard deviation of 1.31; 95% CI, 1.07 to 1.62), but not in CHS. There was no relation in multivariable models between lipoprotein (a), Factor VII, white blood cell count, or C-reactive protein and ICH.

CONCLUSIONS: Greater plasma fibrinogen and, to some degree, von Willebrand factor were associated with increased rates of ICH in these prospective studies, whereas Factor VIII was related to ICH in younger ARIC study participants only.

%B Stroke %V 39 %P 2268-73 %8 2008 Aug %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/18535282?dopt=Abstract %R 10.1161/STROKEAHA.107.505800 %0 Journal Article %J Am Heart J %D 2008 %T High insulinlike growth factor binding protein 1 level predicts incident congestive heart failure in the elderly. %A Kaplan, Robert C %A McGinn, Aileen P %A Pollak, Michael N %A Kuller, Lewis %A Strickler, Howard D %A Rohan, Thomas E %A Cappola, Anne R %A Xue, XiaoNan %A Psaty, Bruce M %K Aged %K Aged, 80 and over %K Female %K Heart Failure %K Humans %K Incidence %K Insulin-Like Growth Factor Binding Protein 1 %K Insulin-Like Growth Factor Binding Protein 3 %K Insulin-Like Growth Factor I %K Male %K Predictive Value of Tests %K Prospective Studies %K Risk Factors %X

BACKGROUND: Low levels of insulinlike growth factor 1 (IGF-I) may influence the development of age-related cardiovascular diseases including congestive heart failure (CHF). Insulinlike growth factor binding protein 1 (IGFBP-1), which increases during catabolic states and inhibits anabolic IGF-I effects, is increased in patients with CHF and has been associated prospectively with increased mortality among older adults and survivors of myocardial infarction. We investigated the association between fasting plasma levels of IGF-I, IGFBP-1, IGFBP-3, and insulin and risk of incident CHF in the prospective Cardiovascular Health Study.

METHODS: From among 5,888 adults 65 years old and older in the Cardiovascular Health Study, we studied 566 incident CHF cases and 1,072 comparison subjects after exclusion of underweight individuals (body mass index <18.5 kg/m(2)) and insulin users. Hazard ratios (HRs) with 95% CIs for CHF were estimated after adjustment for age, race, sex, hypertension, systolic blood pressure, lipid levels, left ventricular hypertrophy, coronary disease, C-reactive protein, health status, diabetes, and body mass index.

RESULTS: High baseline IGFBP-1 level was a significant predictor of CHF, independent of established CHF risk factors and inflammation markers. The HR per SD of IGFBP-1 was 1.22 (95% CI 1.07-1.39, P < .01). Relative to the lowest IGFBP-1 tertile, the HR was 1.29 (95% CI 0.96-1.74, P = .09) for the second IGFBP-1 tertile and 1.47 (95% CI 1.06-2.04; P = .02) for the highest IGFBP-1 tertile (tertile cut points 19.5 and 35.8 ng/mL). Total IGF-I, IGFBP-3, or insulin levels had no association with CHF after adjustment for CHF risk factors.

CONCLUSIONS: High circulating IGFBP-1 level may be a CHF risk factor among older adults.

%B Am Heart J %V 155 %P 1006-12 %8 2008 Jun %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/18513511?dopt=Abstract %R 10.1016/j.ahj.2007.12.031 %0 Journal Article %J Blood %D 2008 %T High-density lipoprotein cholesterol and venous thromboembolism in the Longitudinal Investigation of Thromboembolism Etiology (LITE). %A Chamberlain, Alanna M %A Folsom, Aaron R %A Heckbert, Susan R %A Rosamond, Wayne D %A Cushman, Mary %K Aged %K Apolipoprotein A-I %K Cholesterol, HDL %K Female %K Humans %K Incidence %K Longitudinal Studies %K Male %K Middle Aged %K Proportional Hazards Models %K United States %K Venous Thromboembolism %X

We determined prospectively the risk of venous thromboembolism (VTE) in relation to baseline high-density lipoprotein cholesterol (HDL-c) in 19 049 participants of the Longitudinal Investigation of Thromboembolism Etiology (LITE), which was composed of 14 490 participants of the Atherosclerosis Risk in Communities (ARIC) study and 4559 participants of the Cardiovascular Health Study (CHS). In addition, we determined the risk of VTE in relation to baseline subfractions of HDL (HDL(2) and HDL(3)) and apolipoprotein A-I (apoA-I) in 14 488 participants of the ARIC study. Age-adjusted incidence rates of VTE by HDL-c quartile ranged from 1.64 to 1.91 per 1000 person-years in men and 1.40 to 1.94 per 1000 person-years in women; however, there was no apparent trend of VTE incidence across HDL-c quartiles for either sex. The multivariate adjusted hazard ratios of VTE by HDL-c quartiles (with quartile 4 as the reference) were nonsignificant for both sexes and ranged between 0.91 and 0.99 for men and 0.78 and 1.22 for women. Results did not differ in separate evaluations of idiopathic and secondary VTE. In the ARIC study, there was no trend of VTE hazard ratios across quartiles of HDL(2), HDL(3), or apoA-I. Low HDL-c does not appear to be an important VTE risk factor.

%B Blood %V 112 %P 2675-80 %8 2008 Oct 01 %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/18614761?dopt=Abstract %R 10.1182/blood-2008-05-157412 %0 Journal Article %J J Am Geriatr Soc %D 2008 %T Higher levels of inflammation factors and greater insulin resistance are independently associated with higher heart rate and lower heart rate variability in normoglycemic older individuals: the Cardiovascular Health Study. %A Stein, Phyllis K %A Barzilay, Joshua I %A Chaves, Paulo H M %A Traber, Jennifer %A Domitrovich, Peter P %A Heckbert, Susan R %A Gottdiener, John S %K Aged %K C-Reactive Protein %K Cardiovascular Diseases %K Cross-Sectional Studies %K Electrocardiography, Ambulatory %K Female %K Fibrinogen %K Heart Rate %K Humans %K Inflammation Mediators %K Insulin Resistance %K Interleukin-6 %K Male %K Risk Factors %X

OBJECTIVES: To explore the relationship between (1) insulin resistance and inflammation factors with (2) higher heart rate (HR) and lower heart rate variability (HRV) in normoglycemic older adults.

DESIGN: Cross-sectional population-based study.

PARTICIPANTS: Five hundred forty-five adults aged 65 and older with normoglycemia (fasting glucose <100 mg/dL) who participated in the Cardiovascular Health Study.

MEASUREMENTS: Serum levels of three inflammation proteins (C-reactive protein (CRP), interleukin 6 (IL-6), and fibrinogen); insulin resistance, quantified according to the homeostasis assessment model (HOMA-IR); HR; and four representative measures of HRV (the standard deviation of normal beat to beat intervals (SDNN), the root mean square of successive differences (rMSSD), very low frequency power (VLF), and the low- to high-frequency power ratio (LF/HF)) derived from 24-hour Holter recordings.

RESULTS: High CRP and IL-6 levels were associated with higher HR and lower SDNN and VLF after adjustment for multiple covariates, including HOMA-IR and clinical cardiovascular disease. High IL-6 was also associated with lower LF/HF. Significant univariate inverse relationships between HOMA-IR and HR and HRV were also found, but the strengths of these relationships were attenuated after adjustment for inflammation factors.

CONCLUSION: Increased levels of inflammation markers and HOMA-IR are associated with higher HR and lower HRV. These findings suggest that inflammation may contribute to the pathogenesis of cardiovascular autonomic decline in older adults.

%B J Am Geriatr Soc %V 56 %P 315-21 %8 2008 Feb %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/18179502?dopt=Abstract %R 10.1111/j.1532-5415.2007.01564.x %0 Journal Article %J J Am Geriatr Soc %D 2008 %T Incident physical disability in people with lower extremity peripheral arterial disease: the role of cardiovascular disease. %A Brach, Jennifer S %A Solomon, Cam %A Naydeck, Barbara L %A Sutton-Tyrrell, Kim %A Enright, Paul L %A Jenny, Nancy Swords %A Chaves, Paulo M %A Newman, Anne B %K Activities of Daily Living %K Aged %K Cardiovascular Diseases %K Cohort Studies %K Comorbidity %K Disability Evaluation %K Female %K Gait %K Geriatric Assessment %K Humans %K Lower Extremity %K Male %K Mobility Limitation %K Peripheral Vascular Diseases %K Proportional Hazards Models %K Risk Assessment %K Risk Factors %K United States %X

OBJECTIVES: To evaluate the risk of incident physical disability and the decline in gait speed over a 6-year follow-up associated with a low ankle-arm index (AAI) in older adults.

DESIGN: Observational cohort study.

SETTING: Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Allegheny County, Pennsylvania.

PARTICIPANTS: Four thousand seven hundred five older adults, 58% women and 17.6% black, participating in the Cardiovascular Health Study.

MEASUREMENTS: AAI was measured in 1992/93 (baseline). Self-reported mobility, activity of daily living (ADL), and instrumental activity of daily living (IADL) disability and gait speed were recorded at baseline and at 1-year intervals over 6 years of follow-up. Mobility disability was defined as any difficulty walking half a mile and ADL and IADL disability was defined as any difficulty with 11 specific ADL and IADL tasks. Individuals with mobility, ADL, or IADL disability at baseline were excluded from the respective incident disability analyses.

RESULTS: Lower baseline AAI values were associated with increased risk of mobility disability and ADL/IADL disability. Clinical cardiovascular disease (CVD), diabetes mellitus, and interim CVD events partially explained these associations for mobility disability and clinical CVD and diabetes mellitus partially explained these associations for ADL and IADL disability. Individuals with an AAI less than 0.9 had on average a mean decrease in gait speed of 0.02 m/s per year, or a decline of 0.12 m/s over the 6-year follow-up. Prevalent CVD partly explained this decrease but interim CVD events did not further attenuate it.

CONCLUSION: Low AAI serves as marker of future disability risk. Reduction of disability risk in patients with a low AAI should consider cardiovascular comorbidity and the prevention of additional disabling CVD events.

%B J Am Geriatr Soc %V 56 %P 1037-44 %8 2008 Jun %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/18384579?dopt=Abstract %R 10.1111/j.1532-5415.2008.01719.x %0 Journal Article %J Am J Epidemiol %D 2008 %T Inflammatory markers and longitudinal lung function decline in the elderly. %A Jiang, Rui %A Burke, Gregory L %A Enright, Paul L %A Newman, Anne B %A Margolis, Helene G %A Cushman, Mary %A Tracy, Russell P %A Wang, Yuanjia %A Kronmal, Richard A %A Barr, R Graham %K Aged %K C-Reactive Protein %K Cross-Sectional Studies %K Female %K Fibrinogen %K Forced Expiratory Volume %K Geriatric Assessment %K Humans %K Logistic Models %K Longitudinal Studies %K Lung Volume Measurements %K Male %K Multicenter Studies as Topic %K Pulmonary Disease, Chronic Obstructive %K Spirometry %X

Longitudinal studies examining associations of the inflammatory markers fibrinogen and C-reactive protein (CRP) with lung function decline are sparse. The authors examined whether elevated fibrinogen and CRP levels were associated with greater longitudinal lung function decline in the elderly. The Cardiovascular Health Study measured fibrinogen and CRP in 5,790 Whites and African Americans from four US communities aged 65 years or older in 1989-1990 or 1992-1993. Spirometry was performed in 1989-1990 and 4, 7, and 16 years later. Fibrinogen and CRP were inversely associated with lung function at baseline after adjustment for multiple potential confounders. In mixed models, the rate of decline in forced expiratory volume in 1 second (FEV(1))/forced vital capacity (FVC) ratio with increasing age was faster among those with higher baseline fibrinogen (-0.032%/year per standard deviation higher fibrinogen (95% confidence interval: -0.057, -0.0074)) but not among those with higher CRP (-0.0037%/year per standard deviation higher CRP (95% confidence interval: -0.013, 0.0056)). Longitudinal analyses for FEV(1) and FVC yielded results in the direction opposite of that hypothesized, possibly because of the high mortality rate and strong inverse association of FEV(1) and FVC but not FEV(1)/FVC with mortality. An alternative approach to missing data yielded similar results. In conclusion, higher levels of fibrinogen, but not CRP, independently predicted greater FEV(1)/FVC decline in the elderly.

%B Am J Epidemiol %V 168 %P 602-10 %8 2008 Sep 15 %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/18687665?dopt=Abstract %R 10.1093/aje/kwn174 %0 Journal Article %J Growth Horm IGF Res %D 2008 %T Insulin-like growth factor-(IGF)-axis, inflammation, and glucose intolerance among older adults. %A Rajpathak, Swapnil N %A McGinn, Aileen P %A Strickler, Howard D %A Rohan, Thomas E %A Pollak, Michael %A Cappola, Anne R %A Kuller, Lewis %A Xue, XiaoNan %A Newman, Anne B %A Strotmeyer, Elsa S %A Psaty, Bruce M %A Kaplan, Robert C %K Aged %K Aged, 80 and over %K Cohort Studies %K Cross-Sectional Studies %K Female %K Glucose Intolerance %K Humans %K Inflammation %K Insulin-Like Growth Factor Binding Proteins %K Male %K Signal Transduction %K Somatomedins %X

Increasing evidence suggests that the insulin-like growth factor (IGF)-axis may play a role in glucose metabolism and may also be associated with systemic inflammation. The aim of this study was to evaluate the association of insulin-like growth factor-1 (IGF-I) and its binding proteins, IGFBP-1 and IGFBP-3, with glucose intolerance and inflammation among older adults. We conducted a cross-sectional analysis in a in a random subsample (n=922) of the Cardiovascular Health Study (CHS), a prospective cohort of men and women > or = 65 years. Mean IGFBP-1 levels were significantly lower in older adults with impaired glucose tolerance (IGT), impaired fasting glucose (IFG) and diabetes compared to those with normal fasting and post-load glucose. High IGFBP-1 was associated with a reduced prevalence of IGT and IFG; the multivariable OR between extreme quartiles of IGFBP-1 was 0.60 (95% CI: 0.37, 0.95; p-trend: 0.03) for IGT and 0.41 (95% CI: 0.26, 0.64; p-trend: <0.01) for IFG. We did not find any significant association between IGF-I and glucose intolerance in this study and the association for IGFBP-3 was less clear. However, low levels of IGF-I and IGFBP-3 were associated with increased levels of markers of inflammation including C-reactive protein and interleukin-6 levels. We conclude that among adults > or = 65 years, low IGFBP-1 levels are associated with increased prevalence of glucose intolerance. We did not confirm prior associations of low IGF-I with glucose intolerance in this cohort of older individuals.

%B Growth Horm IGF Res %V 18 %P 166-73 %8 2008 Apr %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/17904401?dopt=Abstract %R 10.1016/j.ghir.2007.08.004 %0 Journal Article %J Ann Intern Med %D 2008 %T Insulin-like growth factors, their binding proteins, and prostate cancer risk: analysis of individual patient data from 12 prospective studies. %A Roddam, Andrew W %A Allen, Naomi E %A Appleby, Paul %A Key, Timothy J %A Ferrucci, Luigi %A Carter, H Ballentine %A Metter, E Jeffrey %A Chen, Chu %A Weiss, Noel S %A Fitzpatrick, Annette %A Hsing, Ann W %A Lacey, James V %A Helzlsouer, Kathy %A Rinaldi, Sabina %A Riboli, Elio %A Kaaks, Rudolf %A Janssen, Joop A M J L %A Wildhagen, Mark F %A Schröder, Fritz H %A Platz, Elizabeth A %A Pollak, Michael %A Giovannucci, Edward %A Schaefer, Catherine %A Quesenberry, Charles P %A Vogelman, Joseph H %A Severi, Gianluca %A English, Dallas R %A Giles, Graham G %A Stattin, Pär %A Hallmans, Göran %A Johansson, Mattias %A Chan, June M %A Gann, Peter %A Oliver, Steven E %A Holly, Jeff M %A Donovan, Jenny %A Meyer, François %A Bairati, Isabelle %A Galan, Pilar %K Aged %K Humans %K Insulin-Like Growth Factor Binding Protein 2 %K Insulin-Like Growth Factor Binding Protein 3 %K Insulin-Like Growth Factor Binding Proteins %K Insulin-Like Growth Factor I %K Insulin-Like Growth Factor II %K Male %K Middle Aged %K Prospective Studies %K Prostatic Neoplasms %K Risk Factors %K Somatomedins %X

BACKGROUND: Some, but not all, published results have shown an association between circulating blood levels of some insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) and the subsequent risk for prostate cancer.

PURPOSE: To assess the association between levels of IGFs and IGFBPs and the subsequent risk for prostate cancer.

DATA SOURCES: Studies identified in PubMed, Web of Science, and CancerLit.

STUDY SELECTION: The principal investigators of all studies that published data on circulating concentrations of sex steroids, IGFs, or IGFBPs and prostate cancer risk using prospectively collected blood samples were invited to collaborate.

DATA EXTRACTION: Investigators provided individual participant data on circulating concentrations of IGF-I, IGF-II, IGFBP-II, and IGFBP-III and participant characteristics to a central data set in Oxford, United Kingdom.

DATA SYNTHESIS: The study included data on 3700 men with prostate cancer and 5200 control participants. On average, case patients were 61.5 years of age at blood collection and received a diagnosis of prostate cancer 5 years after blood collection. The greater the serum IGF-I concentration, the greater the subsequent risk for prostate cancer (odds ratio [OR] in the highest vs. lowest quintile, 1.38 [95% CI, 1.19 to 1.60]; P < 0.001 for trend). Neither IGF-II nor IGFBP-II concentrations were associated with prostate cancer risk, but statistical power was limited. Insulin-like growth factor I and IGFBP-III were correlated (r = 0.58), and although IGFBP-III concentration seemed to be associated with prostate cancer risk, this was secondary to its association with IGF-I levels. Insulin-like growth factor I concentrations seemed to be more positively associated with low-grade than high-grade disease; otherwise, the association between IGFs and IGFBPs and prostate cancer risk had no statistically significant heterogeneity related to stage or grade of disease, time between blood collection and diagnosis, age and year of diagnosis, prostate-specific antigen level at recruitment, body mass index, smoking, or alcohol intake.

LIMITATIONS: Insulin-like growth factor concentrations were measured in only 1 sample for each participant, and the laboratory methods to measure IGFs differed in each study. Not all patients had disease stage or grade information, and the diagnosis of prostate cancer may differ among the studies.

CONCLUSION: High circulating IGF-I concentrations are associated with a moderately increased risk for prostate cancer.

%B Ann Intern Med %V 149 %P 461-71, W83-8 %8 2008 Oct 07 %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/18838726?dopt=Abstract %R 10.7326/0003-4819-149-7-200810070-00006 %0 Journal Article %J J Clin Epidemiol %D 2008 %T Item response theory facilitated cocalibrating cognitive tests and reduced bias in estimated rates of decline. %A Crane, Paul K %A Narasimhalu, Kaavya %A Gibbons, Laura E %A Mungas, Dan M %A Haneuse, Sebastien %A Larson, Eric B %A Kuller, Lewis %A Hall, Kathleen %A van Belle, Gerald %K Aged %K Aged, 80 and over %K Cognition Disorders %K Dementia %K Disease Progression %K Epidemiologic Methods %K Female %K Humans %K Male %K Neuropsychological Tests %K Psychometrics %X

OBJECTIVE: To cocalibrate the Mini-Mental State Examination, the Modified Mini-Mental State, the Cognitive Abilities Screening Instrument, and the Community Screening Instrument for Dementia using item response theory (IRT) to compare screening cut points used to identify cases of dementia from different studies, to compare measurement properties of the tests, and to explore the implications of these measurement properties on longitudinal studies of cognitive functioning over time.

STUDY DESIGN AND SETTING: We used cross-sectional data from three large (n>1000) community-based studies of cognitive functioning in the elderly. We used IRT to cocalibrate the scales and performed simulations of longitudinal studies.

RESULTS: Screening cut points varied quite widely across studies. The four tests have curvilinear scaling and varied levels of measurement precision, with more measurement error at higher levels of cognitive functioning. In longitudinal simulations, IRT scores always performed better than standard scoring, whereas a strategy to account for varying measurement precision had mixed results.

CONCLUSION: Cocalibration allows direct comparison of cognitive functioning in studies using any of these four tests. Standard scoring appears to be a poor choice for analysis of longitudinal cognitive testing data. More research is needed into the implications of varying levels of measurement precision.

%B J Clin Epidemiol %V 61 %P 1018-27.e9 %8 2008 Oct %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/18455909?dopt=Abstract %R 10.1016/j.jclinepi.2007.11.011 %0 Journal Article %J Neurology %D 2008 %T Knee height and arm span: a reflection of early life environment and risk of dementia. %A Huang, T L %A Carlson, M C %A Fitzpatrick, A L %A Kuller, L H %A Fried, L P %A Zandi, P P %K Aged %K Aged, 80 and over %K Aging %K Anthropometry %K Arm %K Body Height %K Brain %K Child %K Child, Preschool %K Dementia %K Environment %K Female %K Follow-Up Studies %K Humans %K Infant %K Infant, Newborn %K Knee %K Male %K Middle Aged %K Prospective Studies %K Risk Factors %K Sex Characteristics %K Skeleton %X

OBJECTIVES: To determine if anthropometric measures, as markers of early life environment, are associated with risk of dementia, Alzheimer disease (AD), and vascular dementia (VaD).

METHODS: A total of 2,798 subjects were followed as part of the Cardiovascular Health Cognition Study for an average of 5.4 years; 480 developed dementia. Knee height was measured 3 years prior to and arm span 4 years after the study's baseline. Cox proportional hazard models were used to examine their association with subsequent risk of dementia, AD, and VaD.

RESULTS: Among women, greater knee height and arm span were associated with lower risks of dementia (knee height: HR per 1-inch increase 0.84; 95% CI 0.74-0.96; arm span: HR per 1-inch increase 0.93; 95% CI 0.88-0.98) and AD (knee height: HR per 1-inch increase 0.78; 95% CI 0.65-0.93; arm span: HR per 1-inch increase 0.90; 95% CI 0.85-0.96). Women in the lowest quartile of arm span had approximately 1.5 times greater risk of dementia (HR 1.45; 95% CI 1.03-2.05) and AD (HR 1.70; 95% CI 1.10-2.62) than other women. Among men, only arm span was associated with lower risks of dementia (HR per 1-inch increase 0.94; 95% CI 0.89-1.00) and AD (HR per 1-inch increase 0.92; 95% CI 0.84-1.00). For each gender, knee height was not associated with VaD, while arm span was associated with a nonsignificant lower risk of VaD.

CONCLUSIONS: Our findings with knee height and arm span are consistent with previous reports and suggest early life environment may play an important role in the determination of future dementia risk.

%B Neurology %V 70 %P 1818-26 %8 2008 May 06 %G eng %N 19 Pt 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/18458216?dopt=Abstract %R 10.1212/01.wnl.0000311444.20490.98 %0 Journal Article %J Eur Heart J %D 2008 %T Left ventricular mass predicts heart failure not related to previous myocardial infarction: the Cardiovascular Health Study. %A de Simone, Giovanni %A Gottdiener, John S %A Chinali, Marcello %A Maurer, Mathew S %K Aged %K Aged, 80 and over %K Diabetic Angiopathies %K Echocardiography %K Female %K Heart Failure %K Humans %K Hypertension %K Hypertrophy, Left Ventricular %K Male %K Myocardial Infarction %K Obesity %K Risk Factors %X

AIMS: The relationship of left ventricular hypertrophy (LVH) to incident heart failure (HF) not attributable to myocardial infarction (MI) has not been defined. We assessed whether LVH is an independent predictor of MI-independent HF.

METHODS AND RESULTS: LVH was assessed by echocardiographic LV mass index (in g/m2.7) and excess of LV mass (eLVM, in % of the observed value) relative to the amount predicted by sex, stroke work, and height, using a prognostically validated equation in 2078 participants of Cardiovascular Health Study without prevalent MI and normal systolic function. Increasing eLVM was associated with progressively increasing left atrial dimension and concentric geometry, decreasing systolic (P < 0.0001), and diastolic function (P < 0.04). After adjustment for age, sex, obesity, diabetes, hypertension, and antihypertensive therapy, and accounting for by incident MI, hazard of HF increased by 1% for each 1% increase in eLVM and by 3% for each g/m2.7 increase in LV mass index (both P < 0.0001). The results were confirmed when also C-reactive protein and measures of systolic (endocardial shortening) and diastolic function (categories of E/A ratio) were added to the Cox models.

CONCLUSION: In an elderly population, LVH, measured as LV mass index or eLVM is an independent predictor of incident HF not related to prevalent or incident MI.

%B Eur Heart J %V 29 %P 741-7 %8 2008 Mar %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/18204091?dopt=Abstract %R 10.1093/eurheartj/ehm605 %0 Journal Article %J Circulation %D 2008 %T Left ventricular morphology and systolic function in sleep-disordered breathing: the Sleep Heart Health Study. %A Chami, Hassan A %A Devereux, Richard B %A Gottdiener, John S %A Mehra, Reena %A Roman, Mary J %A Benjamin, Emelia J %A Gottlieb, Daniel J %K Aged %K Echocardiography %K Female %K Humans %K Hypertrophy, Left Ventricular %K Hypoxia %K Male %K Middle Aged %K Odds Ratio %K Sleep Apnea Syndromes %K Systole %K Ventricular Dysfunction, Left %X

BACKGROUND: Whether sleep-disordered breathing (SDB) is a risk factor for left ventricular (LV) hypertrophy and dysfunction is controversial. We assessed the relation of SDB to LV morphology and systolic function in a community-based sample of middle-aged and older adults.

METHODS AND RESULTS: The present study was a cross-sectional observational study of 2058 Sleep Heart Health Study participants (mean age 65+/-12 years; 58% women; 44% ethnic minorities) who had technically adequate echocardiograms. A polysomnographically derived apnea-hypopnea index (AHI) and hypoxemia index (percent of sleep time with oxyhemoglobin saturation < 90%) were used to quantify SDB severity. LV mass index was significantly associated with both AHI and hypoxemia index after adjustment for age, sex, ethnicity, study site, body mass index, current and prior smoking, alcohol consumption, systolic blood pressure, antihypertensive medication use, diabetes mellitus, and prevalent myocardial infarction. Adjusted LV mass index was 41.3 (SD 9.90) g/m(2.7) in participants with AHI < 5 (n=957) and 44.1 (SD 9.90) g/m(2.7) in participants with AHI > or = 30 (n=84) events per hour. Compared with participants with AHI < 5, those with AHI > or = 30 had an adjusted odds ratio of 1.78 (95% confidence interval 1.14 to 2.79) for LV hypertrophy. A higher AHI and higher hypoxemia index were also associated with larger LV diastolic dimension and lower LV ejection fraction, with a trend toward lower LV fractional shortening. LV wall thickness was significantly associated with the hypoxemia index but not with AHI. Left atrial diameter was not associated with either SDB measure.

CONCLUSIONS: In a community-based cohort, SDB is associated with echocardiographic evidence of increased LV mass and reduced LV systolic function.

%B Circulation %V 117 %P 2599-607 %8 2008 May 20 %G eng %N 20 %1 https://www.ncbi.nlm.nih.gov/pubmed/18458174?dopt=Abstract %R 10.1161/CIRCULATIONAHA.107.717892 %0 Journal Article %J Am J Hematol %D 2008 %T Lipoprotein-associated phospholipase A2 and risk of venous thrombosis in older adults. %A Olson, Nels %A O'Meara, Ellen S %A Jenny, Nancy S %A Folsom, Aaron R %A Bovill, Edwin G %A Furberg, Curt D %A Heckbert, Susan R %A Psaty, Bruce M %A Cushman, Mary %K 1-Alkyl-2-acetylglycerophosphocholine Esterase %K Aged %K Female %K Humans %K Male %K Risk Factors %K Venous Thrombosis %X

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an enzyme involved in inflammation and platelet function. Inherited deficiency and elevated levels are associated with atherosclerosis. Given potential common etiologies of atherosclerosis and venous thrombosis (VT), we hypothesized that low and high Lp-PLA2 would be associated with VT risk. Lp-PLA(2) mass and activity were measured in baseline samples of Cardiovascular Health Study participants (5,888 men and women age > or =65), excluding 354 reporting pre-baseline VT. The study endpoint was VT unrelated to cancer after 11.6 years follow-up. Hazard ratios were estimated using Cox proportional hazard models, adjusting for age, race, sex, and body-mass index. With 129 cases of VT, there was no association of Lp-PLA2 activity with risk. Adjusted hazard ratios were 1.19 (CI 0.62, 2.29) and 0.87 (CI 0.43, 1.76) for the lowest and highest decile, respectively, compared to the 10-25th percentile. Corresponding hazard ratios for Lp-PLA2 mass were 1.63 (CI 0.79, 3.34) and 1.33 (CI 0.61, 2.87). Results were robust to several definitions of low or high Lp-PLA2. While the association of Lp-PLA(2) levels with arterial disease events implies a role for this enzyme in atherogenesis, our findings suggest that it is not prothrombotic.

%B Am J Hematol %V 83 %P 524-7 %8 2008 Jul %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/18383322?dopt=Abstract %R 10.1002/ajh.21182 %0 Journal Article %J Neurology %D 2008 %T No advantage of A beta 42-lowering NSAIDs for prevention of Alzheimer dementia in six pooled cohort studies. %A Szekely, C A %A Green, R C %A Breitner, J C S %A Østbye, T %A Beiser, A S %A Corrada, M M %A Dodge, H H %A Ganguli, M %A Kawas, C H %A Kuller, L H %A Psaty, B M %A Resnick, S M %A Wolf, P A %A Zonderman, A B %A Welsh-Bohmer, K A %A Zandi, P P %K Acetaminophen %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Analgesics, Non-Narcotic %K Anti-Inflammatory Agents, Non-Steroidal %K Aspirin %K Cohort Studies %K Female %K Humans %K Male %K Middle Aged %K Neuroprotective Agents %K Peptide Fragments %K Proportional Hazards Models %K Prospective Studies %K Risk Factors %X

INTRODUCTION: Observational studies show reduced incidence of Alzheimer dementia (AD) in users of nonsteroidal anti-inflammatory drugs (NSAIDs). One hypothesis holds that the subset of NSAIDs known as selective A beta(42)-lowering agents (SALAs) is responsible for this apparent reduction in AD risk.

METHODS: We pooled individual-level data from six prospective studies to obtain a sufficient sample to examine AD risk in users of SALA vs non-SALA NSAIDs.

RESULTS: Of 13,499 initially dementia-free participants (70,863 person-years), 820 developed incident AD. Users of NSAIDs (29.6%) showed reduced risk of AD (adjusted hazard ratio [aHR] 0.77, 95% CI 0.65-0.91). The point estimates were similar for SALAs (aHR 0.87, CI 0.72-1.04) and non-SALAs (aHR 0.75, CI 0.56-1.01). Because 573 NSAID users (14.5%) reported taking both a SALA and non-SALA, we examined their use alone and in combination. Resulting aHRs were 0.82 (CI 0.67-0.99) for SALA only, 0.60 (CI 0.40-0.90) for non-SALA only, and 0.87 (CI 0.57-1.33) for both NSAIDs (Wald test for differences, p = 0.32). The 40.7% of participants who used aspirin also showed reduced risk of AD, even when they used no other NSAIDs (aHR 0.78, CI 0.66-0.92). By contrast, there was no association with use of acetaminophen (aHR 0.93, CI 0.76-1.13).

CONCLUSIONS: In this pooled dataset, nonsteroidal anti-inflammatory drug (NSAID) use reduced the risk of Alzheimer dementia (AD). However, there was no apparent advantage in AD risk reduction for the subset of NSAIDs shown to selectively lower A beta(42), suggesting that all conventional NSAIDs including aspirin have a similar protective effect in humans.

%B Neurology %V 70 %P 2291-8 %8 2008 Jun 10 %G eng %N 24 %1 https://www.ncbi.nlm.nih.gov/pubmed/18509093?dopt=Abstract %R 10.1212/01.wnl.0000313933.17796.f6 %0 Journal Article %J J Cardiovasc Electrophysiol %D 2008 %T Novel measures of heart rate variability predict cardiovascular mortality in older adults independent of traditional cardiovascular risk factors: the Cardiovascular Health Study (CHS). %A Stein, Phyllis K %A Barzilay, Joshua I %A Chaves, Paulo H M %A Mistretta, Stephanie Q %A Domitrovich, Peter P %A Gottdiener, John S %A Rich, Michael W %A Kleiger, Robert E %K Aged %K Aged, 80 and over %K Arrhythmias, Cardiac %K Death, Sudden, Cardiac %K Electrocardiography, Ambulatory %K Female %K Heart Rate %K Humans %K Male %K Maryland %K Reproducibility of Results %K Risk Assessment %K Risk Factors %K Sensitivity and Specificity %K Survival Analysis %K Survival Rate %X

UNLABELLED: Novel HRV Predicts CV Mortality in the Elderly.

BACKGROUND: It is unknown whether abnormal heart rate turbulence (HRT) and abnormal fractal properties of heart rate variability identify older adults at increased risk of cardiovascular death (CVdth).

METHODS: Data from 1,172 community-dwelling adults, ages 72 +/- 5 (65-93) years, who participated in the Cardiovascular Health Study (CHS), a study of risk factors for CV disease in people >or=65 years. HRT and the short-term fractal scaling exponent (DFA1) derived from 24-hour Holter recordings. HRT categorized as: normal (turbulence slope [TS] and turbulence onset [TO] normal) or abnormal (TS and/or TO abnormal). DFA1 categorized as low (1). Cox regression analyses stratified by Framingham Risk Score (FRS) strata (low = <10, mid = 10-20, and high >20) and adjusted for prevalent clinical cardiovascular disease (CVD), diabetes, and quartiles of ventricular premature beat counts (VPCs).

RESULTS: CVdths (N = 172) occurred over a median follow-up of 12.3 years. Within each FRS stratum, low DFA1 + abnormal HRT predicted risk of CVdth (RR = 7.7 for low FRS; 3.6, mid FRS; 2.8, high FRS). Among high FRS stratum participants, low DFA1 alone also predicted CVdth (RR = 2.0). VPCs in the highest quartile predicted CVdth, but only in the high FRS group. Clinical CV disease predicted CVdth at each FRS stratum (RR = 2.9, low; 2.6, mid; and 1.9, high). Diabetes predicted CVdth in the highest FRS group only (RR = 2.2).

CONCLUSIONS: The combination of low DFA1 + abnormal HRT is a strong risk factor for CVdth among older adults even after adjustment for conventional CVD risk measures and the presence of CVD.

%B J Cardiovasc Electrophysiol %V 19 %P 1169-74 %8 2008 Nov %G eng %N 11 %1 https://www.ncbi.nlm.nih.gov/pubmed/18631274?dopt=Abstract %R 10.1111/j.1540-8167.2008.01232.x %0 Journal Article %J Curr Med Res Opin %D 2008 %T Pancreatic beta-cell function as a predictor of cardiovascular outcomes and costs: findings from the Cardiovascular Health Study. %A Curtis, Lesley H %A Hammill, Bradley G %A Bethel, M Angelyn %A Anstrom, Kevin J %A Liao, Lawrence %A Gottdiener, John S %A Schulman, Kevin A %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Cohort Studies %K Coronary Disease %K Female %K Follow-Up Studies %K Health Care Costs %K Heart Failure %K Humans %K Insulin-Secreting Cells %K Male %K Myocardial Infarction %K Outcome Assessment, Health Care %K Prognosis %K Prospective Studies %K Stroke %X

OBJECTIVE: To explore relationships between beta-cell function and incident cardiovascular events, death, and medical costs among elderly individuals.

RESEARCH DESIGN AND METHODS: In a prospective, population-based cohort of 4555 elderly individuals, we examined the effect of beta-cell function on incident cardiovascular events and mortality. We also examined costs for 3715 of these individuals. We used the computer-based homeostasis model assessment (HOMA) to calculate indices of beta-cell function (HOMA-%B) and insulin sensitivity (HOMA-%S) using baseline fasting glucose and insulin levels. All subjects were followed from 1992/1993 for 6 years or until death.

MAIN OUTCOME MEASURES: Discrete-time survival model of the effects of beta-cell function on incident cardiovascular events and all-cause mortality; and semiparametric estimators for calculations of mean 6-year costs.

RESULTS: Controlling for HOMA-%S, a 20% decrease in HOMA-%B was associated with increased odds of incident cardiovascular events (odds ratio [OR], 1.09; 95% confidence interval [CI], 1.05-1.14) and death (OR, 1.10; 95% CI, 1.07-1.14). The relationships persisted after controlling for clinical and sociodemographic confounders. A 20% decrease in HOMA-%B was also associated with increased costs (cost ratio, 1.03; 95% CI, 1.01-1.05). The significant association did not persist after controlling for confounders.

LIMITATIONS: The sample comprises relatively healthy elderly individuals and is based on data from 1992 through 1999, which may not reflect current experience. The measure of beta-cell function is an estimate generated from single measures of glucose and insulin.

CONCLUSIONS: Beta-cell function as measured by HOMA-%B is a significant predictor of incident cardiovascular events and mortality but not of costs, controlling for HOMA-%S and sociodemographic and clinical confounders.

%B Curr Med Res Opin %V 24 %P 41-50 %8 2008 Jan %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/18021490?dopt=Abstract %R 10.1185/030079908x253573 %0 Journal Article %J Neurology %D 2008 %T Plasma amyloid levels and the risk of AD in normal subjects in the Cardiovascular Health Study. %A Lopez, O L %A Kuller, L H %A Mehta, P D %A Becker, J T %A Gach, H M %A Sweet, R A %A Chang, Y F %A Tracy, R %A DeKosky, S T %K Age Factors %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Apolipoprotein E4 %K Biomarkers %K Brain %K Cerebrovascular Disorders %K Comorbidity %K Cross-Sectional Studies %K Cystatin C %K Cystatins %K Female %K Humans %K Incidence %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Models, Statistical %K Neuropsychological Tests %K Peptide Fragments %K Predictive Value of Tests %K Prospective Studies %K Reference Values %K Risk Factors %X

OBJECTIVES: To examine the association between incident Alzheimer disease (AD), and plasma A beta 1-40 and A beta 1-42 levels in normal and mild cognitive impairment (MCI) subjects in a subgroup of participants of the Cardiovascular Health Study Cognition Study.

METHODS: We determined the plasma A beta 1-40 and A beta 1-42 levels of 274 nondemented subjects (232 normals and 42 with MCI) in 1998-1999 and repeated the measurements in 2002-2003. The mean age of the subjects at baseline was 79.3 +/- 3.6 years. We examined the association between A beta levels and incident AD over the ensuing 4.5 years, controlling for age, cystatin C level (marker of glomerular function), apolipoprotein E-4 allele, Modified-Mini-Mental State Examination scores, and MRI-identified infarcts.

RESULTS: In an unadjusted prospective model in normal subjects, both A beta 1-40 and A beta 1-42 levels in 1998-1999 were associated with incident AD (n = 55) in 2002-2003 (longitudinal analysis). In the fully adjusted multivariate model, neither A beta 1-42 nor A beta 1-40 nor their ratio was associated with incident AD. However, adjustment had a very small effect on point estimates for A beta 1-42, from an odds ratio (OR) of 1.61 (p = 0.007) in the unadjusted model to an OR of 1.46 (p = 0.08) in the fully adjusted model. In 2002-2003 (cross-sectional analysis), only the unadjusted models showed that both peptides were associated with AD.

CONCLUSIONS: Plasma A beta levels are affected by age and by systemic and CNS vascular risk factors. After controlling for these conditions, A beta-40 and A beta 1-42 are weak predictors of conversion to Alzheimer disease (AD) in normal subjects and are only weakly associated with AD in cross-sectional analysis. Consequently, plasma levels of A beta do not seem to be useful biomarkers for AD.

%B Neurology %V 70 %P 1664-71 %8 2008 May 06 %G eng %N 19 %1 https://www.ncbi.nlm.nih.gov/pubmed/18401021?dopt=Abstract %R 10.1212/01.wnl.0000306696.82017.66 %0 Journal Article %J Am J Hum Genet %D 2008 %T Polymorphisms of the HNF1A gene encoding hepatocyte nuclear factor-1 alpha are associated with C-reactive protein. %A Reiner, Alexander P %A Barber, Mathew J %A Guan, Yongtao %A Ridker, Paul M %A Lange, Leslie A %A Chasman, Daniel I %A Walston, Jeremy D %A Cooper, Gregory M %A Jenny, Nancy S %A Rieder, Mark J %A Durda, J Peter %A Smith, Joshua D %A Novembre, John %A Tracy, Russell P %A Rotter, Jerome I %A Stephens, Matthew %A Nickerson, Deborah A %A Krauss, Ronald M %K Aged %K Bayes Theorem %K C-Reactive Protein %K Female %K Hepatocyte Nuclear Factor 1-alpha %K Humans %K Hydroxymethylglutaryl-CoA Reductase Inhibitors %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Pravastatin %K Simvastatin %X

Data from the Pharmacogenomics and Risk of Cardiovascular Disease (PARC) study and the Cardiovascular Health Study (CHS) provide independent and confirmatory evidence for association between common polymorphisms of the HNF1A gene encoding hepatocyte nuclear factor-1 alpha and plasma C-reactive protein (CRP) concentration. Analyses with the use of imputation-based methods to combine genotype data from both studies and to test untyped SNPs from the HapMap database identified several SNPs within a 5 kb region of HNF1A intron 1 with the strongest evidence of association with CRP phenotype.

%B Am J Hum Genet %V 82 %P 1193-201 %8 2008 May %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/18439552?dopt=Abstract %R 10.1016/j.ajhg.2008.03.017 %0 Journal Article %J Chest %D 2008 %T Power spectral analysis of EEG activity during sleep in cigarette smokers. %A Zhang, Lin %A Samet, Jonathan %A Caffo, Brian %A Bankman, Isaac %A Punjabi, Naresh M %K Electroencephalography %K Female %K Humans %K Logistic Models %K Male %K Middle Aged %K Polysomnography %K Sleep %K Smoking %K Spectroscopy, Fourier Transform Infrared %X

BACKGROUND: Research on the effects of cigarette smoking on sleep architecture is limited. The objective of this investigation was to examine differences in sleep EEG between smokers and nonsmokers.

METHODS: Smokers and nonsmokers who were free of all medical comorbidities were matched on different factors, including age, gender, race, body mass index, and anthropometric measures. Home polysomnography was conducted using a standard recording montage. Sleep architecture was assessed using visual sleep-stage scoring. The discrete fast Fourier transform was used to calculate the EEG power spectrum for the entire night within contiguous 30-s epochs of sleep for the following frequency bandwidths: delta (0.8 to 4.0 Hz); theta (4.1 to 8.0 Hz); alpha (8.1 to 13.0 Hz); and beta (13.1 to 20.0 Hz).

RESULTS: Conventional sleep stages were similar between the two groups. However, spectral analysis of the sleep EEG showed that, compared to nonsmokers, smokers had a lower percentage of EEG power in the delta-bandwidth (59.7% vs 62.6%, respectively; p < 0.04) and higher percentage of EEG power in alpha-bandwidth (15.6% vs 12.5%, respectively; p < 0.001). Differences in the EEG power spectrum between smokers and nonsmokers were greatest in the early part of the sleep period and decreased toward the end. Subjective complaints of lack of restful sleep were also more prevalent in smokers than in nonsmokers (22.5% vs 5.0%, respectively; p < 0.02) and were explained, in part, by the differences in EEG spectral power.

CONCLUSIONS: Cigarette smokers manifest disturbances in the sleep EEG that are not evident in conventional measures of sleep architecture. Nicotine in cigarette smoke and withdrawal from it during sleep may contribute to these changes and the subjective experience of nonrestorative sleep.

%B Chest %V 133 %P 427-32 %8 2008 Feb %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/17925420?dopt=Abstract %R 10.1378/chest.07-1190 %0 Journal Article %J J Thromb Haemost %D 2008 %T PROC, PROCR and PROS1 polymorphisms, plasma anticoagulant phenotypes, and risk of cardiovascular disease and mortality in older adults: the Cardiovascular Health Study. %A Reiner, A P %A Carty, C L %A Jenny, N S %A Nievergelt, C %A Cushman, M %A Stearns-Kurosawa, D J %A Kurosawa, S %A Kuller, L H %A Lange, L A %K Aged %K Aged, 80 and over %K Aging %K Antigens, CD %K Blood Coagulation Factor Inhibitors %K Cardiovascular Diseases %K Coronary Disease %K Endothelial Protein C Receptor %K Female %K Humans %K Inflammation %K Male %K Middle Aged %K Mortality %K Polymorphism, Genetic %K Protein C %K Protein S %K Receptors, Cell Surface %K Risk %K Stroke %K Thrombosis %X

BACKGROUND AND OBJECTIVES: Genes encoding protein C anticoagulant pathways are candidates for atherothrombotic and other aging-related disorders.

METHODS: Using a tagSNP approach, and data from the Cardiovascular Health Study (CHS), we assessed associations of common polymorphisms of PROC, PROS1 and PROCR with: (i) plasma protein C, soluble protein C endothelial receptor (sEPCR) and protein S levels measured in a subsample of 336 participants at study entry; and (ii) risk of incident clinical outcomes [coronary heart disease (CHD), stroke, and mortality] in 4547 participants during follow-up. Secondarily, we explored associations between plasma protein C, protein S and sEPCR levels and other candidate genes involved in thrombosis, inflammation, and aging.

RESULTS: The PROCR Ser219Gly polymorphism (rs867186) was strongly associated with higher sEPCR levels, explaining 75% of the phenotypic variation. The PROCR Ser219Gly variant was also associated with higher levels of circulating protein C antigen. An IL10 polymorphism was associated with higher free protein S levels. The minor alleles of PROC rs2069901 and PROS1 rs4857343 were weakly associated with lower protein C and free protein S levels, respectively. There was no association between PROCR Ser219Gly and risk of CHD, stroke, or mortality. The minor allele of another common PROCR tagSNP, rs2069948, was associated with lymphoid PROCR mRNA expression and with increased risk of incident stroke and all-cause mortality, and decreased healthy survival during follow-up.

CONCLUSIONS: A common PROCR variant may be associated with decreased healthy survival in older adults. Additional studies are warranted to establish the role of PROCR variants in ischemic and aging-related disorders.

%B J Thromb Haemost %V 6 %P 1625-32 %8 2008 Oct %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/18680534?dopt=Abstract %R 10.1111/j.1538-7836.2008.03118.x %0 Journal Article %J Arch Intern Med %D 2008 %T Rapid kidney function decline and mortality risk in older adults. %A Rifkin, Dena E %A Shlipak, Michael G %A Katz, Ronit %A Fried, Linda F %A Siscovick, David %A Chonchol, Michel %A Newman, Anne B %A Sarnak, Mark J %K Aged %K Cardiovascular Diseases %K Creatinine %K Cystatins %K Female %K Glomerular Filtration Rate %K Humans %K Kidney %K Male %K Mortality %X

BACKGROUND: Impaired kidney function is associated with increased mortality risk in older adults. It remains unknown, however, whether longitudinal declines in kidney function are independently associated with increased cardiovascular and all-cause mortality in older adults.

METHODS: The Cardiovascular Health Study evaluated a cohort of community-dwelling older adults enrolled from 1989 to 1993 in 4 US communities with follow-up through 2005. Among 4380 participants, the slope of annual decline in estimated glomerular filtration rate (eGFR) was estimated using both serum creatinine (eGFR(creat)) and cystatin C (eGFR(cys)) rates, which were measured at baseline, year 3, and year 7 of follow-up. Rapid decline in eGFR was defined as a loss greater than 3 mL/min/1.73 m(2) per year, and cardiovascular and all-cause mortality were assessed over a mean of 9.9 years of follow-up.

RESULTS: Mean (SD) levels of creatinine and cystatin C were 0.93 (0.30) mg/dL and 1.03 (0.25) mg/L, respectively; mean (SD) eGFR(creat) and eGFR(cys) were 79 (23) mL/min/1.73 m(2) and 79 (19) mL/min/1.73 m(2), respectively. Individuals with rapid decline measured by eGFR(creat) (n = 714; 16%) had increased risk of cardiovascular (adjusted hazard ratio [AHR], 1.70; 95% confidence interval [CI], 1.40-2.06) and all-cause (AHR, 1.73; 95% CI, 1.54-1.94) mortality. Individuals with rapid decline measured by eGFR(cys) (n = 1083; 25%) also had increased risk of cardiovascular (AHR, 1.53; 95% CI, 1.29-1.80) and all-cause (AHR, 1.53; 95% CI, 1.38-1.69) mortality. The association of rapid decline in eGFR with elevated mortality risk did not differ across subgroups based on baseline kidney function, age, sex, race, or prevalent coronary heart disease.

CONCLUSION: Rapid decline in eGFR is associated with an increased risk of cardiovascular and all-cause mortality in older adults, independent of baseline eGFR and other demographic variables.

%B Arch Intern Med %V 168 %P 2212-8 %8 2008 Nov 10 %G eng %N 20 %1 https://www.ncbi.nlm.nih.gov/pubmed/19001197?dopt=Abstract %R 10.1001/archinte.168.20.2212 %0 Journal Article %J Atherosclerosis %D 2008 %T Relationship between brachial flow-mediated dilation and carotid intima-media thickness in an elderly cohort: the Cardiovascular Health Study. %A Yeboah, Joseph %A Burke, Gregory L %A Crouse, John R %A Herrington, David M %K Age Factors %K Aged %K Aged, 80 and over %K Brachial Artery %K Carotid Arteries %K Carotid Artery Diseases %K Cohort Studies %K Female %K Hemorheology %K Humans %K Male %K Tunica Intima %K Tunica Media %K Ultrasonography %K Vasodilation %X

OBJECTIVE: The aim of this study was to determine the relationship between brachial flow-mediated dilation (FMD) and carotid intima-media thickness (IMT) in a large multi-ethnic elderly cohort.

BACKGROUND: Brachial flow-mediated dilation (FMD) is a physiologic measure and carotid IMT is an anatomic structural measure of subclinical atherosclerosis. Both brachial FMD and carotid IMT have been associated with cardiovascular risk factors and cardiovascular events. The relationship between brachial FMD and carotid IMT is less clear especially in older adults.

METHODS: Brachial FMD, carotid IMT and traditional cardiovascular risk factors were measured in 2338 adults, age 72-98 years who were participants in the Cardiovascular Health Study. The relationship between FMD and IMT was assessed both unadjusted and also after adjusting for age, gender and race/ethnicity, BMI, HDL, LDL, systolic and diastolic blood pressure, serum creatinine, current smoking, diabetes mellitus, hormone therapy and prior CVD.

RESULTS: Both brachial FMD and carotid IMT correlated significantly with age, HDL levels, waist/hip ratio, serum cholesterol and number of CV risk factors. Brachial FMD was not associated with CCA IMT in this elderly cohort (Pearson partial correlation coefficient=-0.0252, p=0.222). In the adjusted linear regression model with CCA IMT as the dependent variable, brachial FMD was also not associated with CCA IMT (beta coefficient=-0.006, p=0.470).

CONCLUSION: Brachial FMD and CCA IMT are not related in population-based older adults. Brachial FMD and CCA IMT may be distinct and independent stages in the complex atherosclerotic process.

%B Atherosclerosis %V 197 %P 840-5 %8 2008 Apr %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/17804000?dopt=Abstract %R 10.1016/j.atherosclerosis.2007.07.032 %0 Journal Article %J J Am Geriatr Soc %D 2008 %T The relationship between exercise and risk of venous thrombosis in elderly people. %A van Stralen, Karlijn J %A Doggen, Carine J M %A Lumley, Thomas %A Cushman, Mary %A Folsom, Aaron R %A Psaty, Bruce M %A Siscovick, David %A Rosendaal, Frits R %A Heckbert, Susan R %K Aged %K Aged, 80 and over %K Case-Control Studies %K Cohort Studies %K Energy Metabolism %K Exercise %K Female %K Humans %K Male %K Prevalence %K Risk Factors %K United States %K Venous Thrombosis %X

OBJECTIVES: To study whether exercise is associated with the risk of venous thrombosis in elderly people.

DESIGN: Observational study with a median follow-up of 11.6 years.

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

PARTICIPANTS: People aged 65 and older without prior venous thrombosis (deep venous thrombosis or pulmonary embolism).

MEASUREMENTS: Self-reported exercise was measured two or three times during follow-up and was defined as expending more than 500 kcal/wk on exercise, including walking for exercise. Venous thrombosis cases were verified using medical record review.

RESULTS: Of 5,534 participants, 171 developed a first venous thrombosis. Self-reported exercise at baseline was not related to the risk of venous thrombosis after adjustment for sex, age, race, self-reported health, and body mass index (adjusted hazard ratio (HR(adj))=1.16, 95% confidence interval (CI)=0.84-1.61), although with exercise modeled as a time-varying exposure, overall results were in the direction of greater risk of venous thrombosis (HR(adj)=1.38, 95% CI=0.99-1.91). For mild-intensity exercise, such as walking, there was a nonsignificant finding in the direction of benefit (HR(adj)=0.75, 95% CI=0.49-1.16), but strenuous exercise, such as jogging, was associated with greater risk of venous thrombosis (HR(adj)=1.75, 95% CI=1.08-2.83) than no exercise at all.

CONCLUSION: In elderly people, strenuous exercise was associated with a higher risk of venous thrombosis than no exercise at all. Future studies are needed to explain this unexpected higher risk.

%B J Am Geriatr Soc %V 56 %P 517-22 %8 2008 Mar %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/18179500?dopt=Abstract %R 10.1111/j.1532-5415.2007.01588.x %0 Journal Article %J J Am Coll Cardiol %D 2008 %T Subclinical thyroid dysfunction, cardiac function, and the risk of heart failure. The Cardiovascular Health study. %A Rodondi, Nicolas %A Bauer, Douglas C %A Cappola, Anne R %A Cornuz, Jacques %A Robbins, John %A Fried, Linda P %A Ladenson, Paul W %A Vittinghoff, Eric %A Gottdiener, John S %A Newman, Anne B %K Aged %K Aged, 80 and over %K Cohort Studies %K Echocardiography %K Female %K Heart %K Heart Failure %K Heart Function Tests %K Humans %K Hyperthyroidism %K Hypertrophy, Left Ventricular %K Hypothyroidism %K Male %K Risk Factors %K Time Factors %X

OBJECTIVES: The goal of this study was to determine whether subclinical thyroid dysfunction was associated with incident heart failure (HF) and echocardiogram abnormalities.

BACKGROUND: Subclinical hypothyroidism and hyperthyroidism have been associated with cardiac dysfunction. However, long-term data on the risk of HF are limited.

METHODS: We studied 3,044 adults>or=65 years of age who initially were free of HF in the Cardiovascular Health Study. We compared adjudicated HF events over a mean 12-year follow-up and changes in cardiac function over the course of 5 years among euthyroid participants, those with subclinical hypothyroidism (subdivided by thyroid-stimulating hormone [TSH] levels: 4.5 to 9.9, >or=10.0 mU/l), and those with subclinical hyperthyroidism.

RESULTS: Over the course of 12 years, 736 participants developed HF events. Participants with TSH>or=10.0 mU/l had a greater incidence of HF compared with euthyroid participants (41.7 vs. 22.9 per 1,000 person years, p=0.01; adjusted hazard ratio: 1.88; 95% confidence interval: 1.05 to 3.34). Baseline peak E velocity, which is an echocardiographic measurement of diastolic function associated with incident HF in the CHS cohort, was greater in those patients with TSH>or=10.0 mU/l compared with euthyroid participants (0.80 m/s vs. 0.72 m/s, p=0.002). Over the course of 5 years, left ventricular mass increased among those with TSH>or=10.0 mU/l, but other echocardiographic measurements were unchanged. Those patients with TSH 4.5 to 9.9 mU/l or with subclinical hyperthyroidism had no increase in risk of HF.

CONCLUSIONS: Compared with euthyroid older adults, those adults with TSH>or=10.0 mU/l have a moderately increased risk of HF and alterations in cardiac function but not older adults with TSH<10.0 mU/l. Clinical trials should assess whether the risk of HF might be ameliorated by thyroxine replacement in individuals with TSH>or=10.0 mU/l.

%B J Am Coll Cardiol %V 52 %P 1152-9 %8 2008 Sep 30 %G eng %N 14 %1 https://www.ncbi.nlm.nih.gov/pubmed/18804743?dopt=Abstract %R 10.1016/j.jacc.2008.07.009 %0 Journal Article %J Am J Kidney Dis %D 2008 %T Subjective and objective sleep quality in patients on conventional thrice-weekly hemodialysis: comparison with matched controls from the sleep heart health study. %A Unruh, Mark L %A Sanders, Mark H %A Redline, Susan %A Piraino, Beth M %A Umans, Jason G %A Chami, Hassan %A Budhiraja, Rohit %A Punjabi, Naresh M %A Buysse, Daniel %A Newman, Anne B %K Aged %K Aged, 80 and over %K Body Mass Index %K Cross-Sectional Studies %K Disease Progression %K Female %K Follow-Up Studies %K Heart Rate %K Humans %K Incidence %K Kidney Failure, Chronic %K Male %K Middle Aged %K Odds Ratio %K Pennsylvania %K Polysomnography %K Prognosis %K Renal Dialysis %K Retrospective Studies %K Risk Factors %K Severity of Illness Index %K Sleep %K Sleep Apnea Syndromes %K Surveys and Questionnaires %X

BACKGROUND: Studies examining sleep in the hemodialysis (HD) population have largely lacked an adequate comparison group. It therefore is uncertain whether poor sleep quality in the HD population reflects age, chronic health conditions, or effects of conventional HD therapy.

STUDY DESIGN: Cross-sectional matched-group study.

SETTING & PARTICIPANTS: Forty-six in-center HD patients were compared with 137 community participants participating in the Sleep Heart Health Study matched for age, sex, body mass index, and race.

PREDICTOR: HD patients compared with community-dwelling non-HD participants.

OUTCOMES & MEASUREMENTS: Home unattended polysomnography was performed and scored by using similar protocols. Sleep habits and sleepiness were assessed by using the Sleep Habits Questionnaire and Epworth Sleepiness Scale.

RESULTS: Average age of study samples was 63 years, 72% were white, and average body mass index was 28 +/- 5 kg/m(2). HD patients were significantly more likely than community participants to have short sleep (odds ratio, 3.27; 95% confidence interval, 1.16 to 9.25) and decreased sleep efficiency (odds ratio, 5.5; 95% confidence interval, 1.5 to 19.6). HD patients reported more difficulty getting back to sleep (odds ratio, 2.25; 95% confidence interval, 1.11 to 4.60) and waking up too early (odds ratio, 2.39; 95% confidence interval, 1.01 to 5.66). There was no association between polysomnography sleep time and self-reported sleep time (r = 0.09; P = 0.6) or between the Epworth Sleepiness Scale and severity of sleep apnea (r = 0.10; P = 0.5) in the HD population.

LIMITATIONS: The study was limited to participants older than 45 years.

CONCLUSIONS: Kidney failure treated with thrice-weekly HD is significantly associated with poor subjective and objective sleep quality.

%B Am J Kidney Dis %V 52 %P 305-13 %8 2008 Aug %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/18617308?dopt=Abstract %R 10.1053/j.ajkd.2008.04.019 %0 Journal Article %J Neurology %D 2009 %T Age, Alzheimer disease, and brain structure. %A Raji, C A %A Lopez, O L %A Kuller, L H %A Carmichael, O T %A Becker, J T %K Aged %K Aged, 80 and over %K Aging %K Alzheimer Disease %K Brain %K Brain Mapping %K Cognition Disorders %K Female %K Humans %K Image Processing, Computer-Assisted %K Linear Models %K Magnetic Resonance Imaging %K Male %K Neuropsychological Tests %K Retrospective Studies %X

BACKGROUND: Lack of clear understanding remains on the overlapping atrophy patterns of aging and early Alzheimer disease (AD) pathology in gray matter (GM) of the brain in vivo.

OBJECTIVE: To evaluate the independent and overlapping patterns of GM atrophy in normal aging and AD.

METHODS: A total of 169 cognitively normal subjects and 33 persons with probable AD enrolled in the longitudinal Cardiovascular Health Study-Cognition Study underwent 3-dimensional volumetric MRI scans. Controls remained cognitively normal for at least 5 years after their MRI scans and the probable AD subjects were relatively early in their clinical course with an average modified Mini-Mental State Examination score of 76/100. The scans were analyzed using voxel-based morphometry adjusting for total intracranial volume, gender, education, and race.

RESULTS: With older age, GM volume was lower in the sensorimotor and heteromodal association areas in frontal, temporal, occipital, and parietal lobes, as well as in the cerebellum (false discovery rate p = 0.05). Additional atrophy was observed in the posterior hippocampus, thalamus, and middle cingulate gyrus. By contrast, atrophy was seen in subjects with AD in the anterior hippocampal/parahippocampal regions and the precuneus. Normal aging and AD overlapped in the hippocampal body and the entorhinal cortex.

CONCLUSION: Brain atrophy with aging was observed in supratentorial and infratentorial areas, as well in primary motor, sensory, and heteromodal association regions. Age and Alzheimer disease exert independent gray matter atrophy patterns but these effects overlapped substantially in the hippocampus and entorhinal cortex.

%B Neurology %V 73 %P 1899-905 %8 2009 Dec 01 %G eng %N 22 %1 http://www.ncbi.nlm.nih.gov/pubmed/19846828?dopt=Abstract %R 10.1212/WNL.0b013e3181c3f293 %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 Aging Cell %D 2009 %T Association of common genetic variation in the insulin/IGF1 signaling pathway with human longevity. %A Pawlikowska, Ludmila %A Hu, Donglei %A Huntsman, Scott %A Sung, Andrew %A Chu, Catherine %A Chen, Justin %A Joyner, Alexander H %A Schork, Nicholas J %A Hsueh, Wen-Chi %A Reiner, Alexander P %A Psaty, Bruce M %A Atzmon, Gil %A Barzilai, Nir %A Cummings, Steven R %A Browner, Warren S %A Kwok, Pui-Yan %A Ziv, Elad %K Aged %K Aged, 80 and over %K Female %K Follow-Up Studies %K Forkhead Box Protein O3 %K Forkhead Transcription Factors %K Genome, Human %K Genotype %K Humans %K Insulin %K Insulin-Like Growth Factor I %K Longevity %K Male %K Osteoporosis %K Polymorphism, Single Nucleotide %K Proto-Oncogene Proteins c-akt %K Signal Transduction %X

The insulin/IGF1 signaling pathways affect lifespan in several model organisms, including worms, flies and mice. To investigate whether common genetic variation in this pathway influences lifespan in humans, we genotyped 291 common variants in 30 genes encoding proteins in the insulin/IGF1 signaling pathway in a cohort of elderly Caucasian women selected from the Study of Osteoporotic Fractures (SOF). The cohort included 293 long-lived cases (lifespan > or = 92 years (y), mean +/- standard deviation (SD) = 95.3 +/- 2.2y) and 603 average-lifespan controls (lifespan < or = 79y, mean = 75.7 +/- 2.6y). Variants were selected for genotyping using a haplotype-tagging approach. We found a modest excess of variants nominally associated with longevity. Nominally significant variants were then replicated in two additional Caucasian cohorts including both males and females: the Cardiovascular Health Study and Ashkenazi Jewish Centenarians. An intronic single nucleotide polymorphism in AKT1, rs3803304, was significantly associated with lifespan in a meta-analysis across the three cohorts (OR = 0.78 95%CI = 0.68-0.89, adjusted P = 0.043); two intronic single nucleotide polymorphisms in FOXO3A demonstrated a significant lifespan association among women only (rs1935949, OR = 1.35, 95%CI = 1.15-1.57, adjusted P = 0.0093). These results demonstrate that common variants in several genes in the insulin/IGF1 pathway are associated with human lifespan.

%B Aging Cell %V 8 %P 460-72 %8 2009 Aug %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/19489743?dopt=Abstract %R 10.1111/j.1474-9726.2009.00493.x %0 Journal Article %J J Atheroscler Thromb %D 2009 %T Association of genetic variation in serum amyloid-A with cardiovascular disease and interactions with IL6, IL1RN, IL1beta and TNF genes in the Cardiovascular Health Study. %A Carty, Cara L %A Heagerty, Patrick %A Heckbert, Susan R %A Enquobahrie, Daniel A %A Jarvik, Gail P %A Davis, Scott %A Tracy, Russell P %A Reiner, Alexander P %K Aged %K Cardiovascular Diseases %K Cholesterol, HDL %K Cytokines %K Female %K Gene Regulatory Networks %K Humans %K Inflammation Mediators %K Interleukin 1 Receptor Antagonist Protein %K Interleukin-1beta %K Interleukin-6 %K Male %K Polymorphism, Single Nucleotide %K Proportional Hazards Models %K Serum Amyloid A Protein %K Tumor Necrosis Factor-alpha %K Tunica Intima %X

AIM: Since inflammation is an important contributor to atherosclerosis, gene variants mediating inflammation are of interest. We investigated gene variants in acute phase serum amyloid-A (SAA), a sensitive indicator of inflammatory activity, and their associations with cardiovascular disease (CVD) and HDL cholesterol. Interaction of the SAA genes with genetic variants of their regulators, IL-1, IL-6 and TNF-alpha in influencing CVD was also explored.

METHODS: SNPs characterizing common variation in the SAA1 and SAA2 genes were genotyped in European-(EA) and African-American (AA) participants (n=3969 and n=719) of the Cardiovascular Health Study. Using linear and Cox proportional hazards regression, we assessed associations of SNPs with baseline carotid artery intima-media thickness (cIMT) and risk of incident myocardial infarction, ischemic stroke, total CVD events or mortality during 14 years of follow-up.

RESULTS: No associations between SAA SNPs and outcomes were observed in EA, with the exception of total CVD events; each rs4638289 minor allele was associated with an increased risk in obese individuals, HR=1.2 (95%CI: 0.981.4; p=0.086) and decreased risk among non-obese, HR=0.9 (95%CI: 0.80.99; p=0.026). In AA, we observed modest associations between SAA SNPs and cIMT, potentially modified by HDL. SAA SNPs were also associated with lower HDL in EA and AA. Suggestive gene-gene interaction findings for cIMT in AA and CVD mortality in EA were not significant in subsequent model selection tests.

CONCLUSION: Associations of SAA SNPs with cIMT, HDL and total CVD events were identified, unadjusted for multiple testing. These findings should be regarded as hypothesis-generating until confirmed by other studies.

%B J Atheroscler Thromb %V 16 %P 419-30 %8 2009 Aug %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/19729864?dopt=Abstract %0 Journal Article %J Circ Cardiovasc Genet %D 2009 %T Association of novel genetic Loci with circulating fibrinogen levels: a genome-wide association study in 6 population-based cohorts. %A Dehghan, Abbas %A Yang, Qiong %A Peters, Annette %A Basu, Saonli %A Bis, Joshua C %A Rudnicka, Alicja R %A Kavousi, Maryam %A Chen, Ming-Huei %A Baumert, Jens %A Lowe, Gordon D O %A McKnight, Barbara %A Tang, Weihong %A de Maat, Moniek %A Larson, Martin G %A Eyhermendy, Susana %A McArdle, Wendy L %A Lumley, Thomas %A Pankow, James S %A Hofman, Albert %A Massaro, Joseph M %A Rivadeneira, Fernando %A Kolz, Melanie %A Taylor, Kent D %A van Duijn, Cornelia M %A Kathiresan, Sekar %A Illig, Thomas %A Aulchenko, Yurii S %A Volcik, Kelly A %A Johnson, Andrew D %A Uitterlinden, André G %A Tofler, Geoffrey H %A Gieger, Christian %A Psaty, Bruce M %A Couper, David J %A Boerwinkle, Eric %A Koenig, Wolfgang %A O'Donnell, Christopher J %A Witteman, Jacqueline C %A Strachan, David P %A Smith, Nicholas L %A Folsom, Aaron R %K Adult %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Cohort Studies %K European Continental Ancestry Group %K Female %K Fibrinogen %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Pedigree %K Polymorphism, Single Nucleotide %K Young Adult %X

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

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

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

%B Circ Cardiovasc Genet %V 2 %P 125-33 %8 2009 Apr %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/20031576?dopt=Abstract %R 10.1161/CIRCGENETICS.108.825224 %0 Journal Article %J Vasc Med %D 2009 %T Brachial artery diameter, blood flow and flow-mediated dilation in sleep-disordered breathing. %A Chami, Hassan A %A Keyes, Michelle J %A Vita, Joseph A %A Mitchell, Gary F %A Larson, Martin G %A Fan, Shuxia %A Vasan, Ramachandran S %A O'Connor, George T %A Benjamin, Emelia J %A Gottlieb, Daniel J %K Adult %K Aged %K Aged, 80 and over %K Blood Flow Velocity %K Brachial Artery %K Cross-Sectional Studies %K Female %K Humans %K Hyperemia %K Hypoxia %K Laser-Doppler Flowmetry %K Male %K Middle Aged %K Polysomnography %K Regional Blood Flow %K Severity of Illness Index %K Sleep Apnea Syndromes %K Ultrasonography %K Vasodilation %X

Clinic-based, case-control studies linked sleep-disordered breathing (SDB) to markers of endothelial dysfunction. We attempted to validate this association in a large community-based sample, and evaluate the relation of SDB to arterial diameter and peripheral blood flow. This community-based, cross-sectional observational study included 327 men and 355 women, aged 42-83 years, from the Framingham Heart Study site of the Sleep Heart Health Study. The polysomnographically derived apnea-hypopnea index and the hypoxemia index (percent sleep time with oxyhemoglobin saturation below 90%) were used to quantify the severity of SDB. Brachial artery ultrasound measurements included baseline diameter, percent flow-mediated dilation, and baseline and hyperemic flow velocity and volume. The baseline brachial artery diameter was significantly associated with both the apnea-hypopnea index and the hypoxemia index. The association was diminished by adjustment for body mass index, but remained significant for the apnea-hypopnea index. Age-, sex-, race- and body mass index-adjusted mean diameters were 4.32, 4.33, 4.33, 4.56, 4.53 mm for those with apnea-hypopnea index < 1.5, 1.5-4.9, 5-14.9, 15-29.9, >/= 30, respectively; p = 0.03. Baseline flow measures were associated with the apnea-hypopnea index but this association was non-significant after adjusting for body mass index. No significant association was observed between measures of SDB and percent flow-mediated dilation or hyperemic flow in any model. In conclusion, this study supports a moderate association of SDB and larger baseline brachial artery diameter, which may reflect SDB-induced vascular remodeling. This study does not support a link between SDB and endothelial dysfunction as measured by brachial artery flow-mediated dilation.

%B Vasc Med %V 14 %P 351-60 %8 2009 Nov %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/19808720?dopt=Abstract %R 10.1177/1358863X09105132 %0 Journal Article %J Am J Nephrol %D 2009 %T Change in cardiovascular risk factors with progression of kidney disease. %A Fried, Linda F %A Katz, Ronit %A Cushman, Mary %A Sarnak, Mark %A Shlipak, Michael G %A Kuller, Lewis %A Newman, Anne B %K Aged %K Aged, 80 and over %K Biomarkers %K C-Reactive Protein %K Cholesterol, HDL %K Creatinine %K Diabetes Mellitus %K Factor VIII %K Female %K Follow-Up Studies %K Humans %K Hypertension, Renal %K Interleukin-6 %K Logistic Models %K Male %K Prevalence %K Renal Insufficiency, Chronic %K Risk Factors %K Vasculitis %X

BACKGROUND: Prior studies evaluating the relationship of kidney disease with cardiovascular risk factors have been limited by their cross-sectional design. We evaluated the change in lipids, inflammatory and procoagulant biomarkers with decline in kidney function in a nested case-cohort study in the Cardiovascular Health Study, a community-based study of adults aged >65 years.

METHODS: Individuals with an increase in serum creatinine >or=0.3 mg/dl (baseline to 3 years later, n = 207) were matched to controls of similar age, race, gender, diabetes and baseline serum creatinine, but whose change in creatinine was <0.3 mg/dl. Baseline and change in risk factors were analyzed with conditional logistic regression.

RESULTS: Changes in C-reactive protein were similar. In contrast, cases had larger increases in fibrinogen (OR 1.38 per standard deviation, 95% confidence interval 1.08-1.76) and factor VIII [1.38 (1.10-1.72)] and larger decreases in HDL [OR 0.80 (0.64, 1.00)]. Change in interleukin-6 was greater in cases than controls, but this did not persist after multivariate adjustment. However, in linear regression, change in interleukin-6 was correlated with change in creatinine.

CONCLUSION: Cardiovascular risk factors and kidney function may change concurrently. This could lead to an increased risk of cardiovascular disease as kidney function worsens.

%B Am J Nephrol %V 29 %P 334-41 %8 2009 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/18948687?dopt=Abstract %R 10.1159/000166598 %0 Journal Article %J Blood %D 2009 %T Coagulation factors IX through XIII and the risk of future venous thrombosis: the Longitudinal Investigation of Thromboembolism Etiology. %A Cushman, Mary %A O'Meara, Ellen S %A Folsom, Aaron R %A Heckbert, Susan R %K Aged %K Aged, 80 and over %K Case-Control Studies %K Factor IX %K Factor X %K Factor XI %K Factor XII %K Factor XIII %K Female %K Humans %K Longitudinal Studies %K Male %K Middle Aged %K Odds Ratio %K Prospective Studies %K Risk Factors %K Venous Thromboembolism %X

Higher levels of procoagulant factors and factor XII deficiency may be risk factors for first venous thromboembolism (VTE). We studied associations of coagulation factors IX through XIII with risk of future VTE in 2 general population samples. Using a nested case-control study combining the 21 860 participants of the Atherosclerosis Risk in Communities study and the Cardiovascular Health Study, we determined antigenic levels of these coagulation factors in primarily pre-event blood samples from 462 participants who subsequently developed VTE and 1047 participants who remained free of VTE. Only elevated levels of factors IX and XI were associated with increased risk of VTE after adjustment for age, sex, race, and study. For factor IX, the odds ratio (OR) was 1.4 (95% confidence interval [CI], 1.0-2.0) comparing the top to bottom quintile. The OR for factor XI was higher: 2.0 (95% CI, 1.4-2.9). With further adjustment for body mass index and diabetes, only elevated factor XI remained associated with VTE risk: OR 1.8 (95% CI, 1.3-2.7). Associations were similar by study and whether the thrombosis was idiopathic or secondary. Factor XII deficiency was not related to VTE risk. Among these procoagulant factors, only elevated factor XI was a risk factor for VTE.

%B Blood %V 114 %P 2878-83 %8 2009 Oct 01 %G eng %N 14 %1 http://www.ncbi.nlm.nih.gov/pubmed/19617576?dopt=Abstract %R 10.1182/blood-2009-05-219915 %0 Journal Article %J Circ Cardiovasc Genet %D 2009 %T Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium: Design of prospective meta-analyses of genome-wide association studies from 5 cohorts. %A Psaty, Bruce M %A O'Donnell, Christopher J %A Gudnason, Vilmundur %A Lunetta, Kathryn L %A Folsom, Aaron R %A Rotter, Jerome I %A Uitterlinden, André G %A Harris, Tamara B %A Witteman, Jacqueline C M %A Boerwinkle, Eric %K Adult %K Aged %K Aging %K Cohort Studies %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Heart Diseases %K Humans %K Male %K Meta-Analysis as Topic %K Middle Aged %K Phenotype %K Research Design %K Risk Factors %X

BACKGROUND: The primary aim of genome-wide association studies is to identify novel genetic loci associated with interindividual variation in the levels of risk factors, the degree of subclinical disease, or the risk of clinical disease. The requirement for large sample sizes and the importance of replication have served as powerful incentives for scientific collaboration. Methods- The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium was formed to facilitate genome-wide association studies meta-analyses and replication opportunities among multiple large population-based cohort studies, which collect data in a standardized fashion and represent the preferred method for estimating disease incidence. The design of the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium includes 5 prospective cohort studies from the United States and Europe: the Age, Gene/Environment Susceptibility-Reykjavik Study, the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study. With genome-wide data on a total of about 38 000 individuals, these cohort studies have a large number of health-related phenotypes measured in similar ways. For each harmonized trait, within-cohort genome-wide association study analyses are combined by meta-analysis. A prospective meta-analysis of data from all 5 cohorts, with a properly selected level of genome-wide statistical significance, is a powerful approach to finding genuine phenotypic associations with novel genetic loci.

CONCLUSIONS: The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and collaborating non-member studies or consortia provide an excellent framework for the identification of the genetic determinants of risk factors, subclinical-disease measures, and clinical events.

%B Circ Cardiovasc Genet %V 2 %P 73-80 %8 2009 Feb %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/20031568?dopt=Abstract %R 10.1161/CIRCGENETICS.108.829747 %0 Journal Article %J Circ Cardiovasc Genet %D 2009 %T Common coding variants of the HNF1A gene are associated with multiple cardiovascular risk phenotypes in community-based samples of younger and older European-American adults: the Coronary Artery Risk Development in Young Adults Study and The Cardiovascula %A Reiner, Alexander P %A Gross, Myron D %A Carlson, Christopher S %A Bielinski, Suzette J %A Lange, Leslie A %A Fornage, Myriam %A Jenny, Nancy S %A Walston, Jeremy %A Tracy, Russell P %A Williams, O Dale %A Jacobs, David R %A Nickerson, Deborah A %K Adolescent %K Adult %K African Americans %K Aged %K Aged, 80 and over %K C-Reactive Protein %K Cardiovascular Diseases %K Cholesterol, LDL %K Cohort Studies %K European Continental Ancestry Group %K Female %K Fibrinogen %K gamma-Glutamyltransferase %K Genetic Predisposition to Disease %K Genotype %K Hepatocyte Nuclear Factor 1-alpha %K Humans %K Male %K Middle Aged %K Phenotype %K Polymorphism, Single Nucleotide %K Risk Factors %X

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

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

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

%B Circ Cardiovasc Genet %V 2 %P 244-54 %8 2009 Jun %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/20031592?dopt=Abstract %R 10.1161/CIRCGENETICS.108.839506 %0 Journal Article %J J Thromb Haemost %D 2009 %T Common hemostasis and inflammation gene variants and venous thrombosis in older adults from the Cardiovascular Health Study. %A Reiner, A P %A Lange, L A %A Smith, N L %A Zakai, N A %A Cushman, M %A Folsom, A R %K Aged %K Alleles %K Factor V %K Factor VIII %K Female %K Hemostasis %K Humans %K Inflammation %K Male %K Middle Aged %K Models, Genetic %K Plasminogen %K Prothrombin %K Risk %K Serine Endopeptidases %K Venous Thrombosis %X

BACKGROUND/OBJECTIVES: Age-related changes in blood coagulation and fibrinolysis are associated with increased risk of thrombotic events. Inherited deficiencies of coagulation proteins, such as factor V (FV) Leiden and prothrombin G20210A, explain a small fraction of venous thromboembolic disease (VTE). Additional genetic factors are likely to underlie the etiology of VTE, some of which may become manifest at older ages.

METHODS: We tested 290 common SNPs within 51 thrombosis and inflammation genes for association with VTE in the Cardiovascular Health Study, a large, prospective cohort of older adults followed for up to 12 years.

RESULTS: There were 184 VTE events that occurred at mean age of 78 years. TagSNPs within four genes encoding FXIII subunit A (F13A), FVII activating protease (HABP2), protease activated receptor-1 (F2R) and the urokinase receptor (PLAUR) showed the strongest evidence for association with VTE, with each gene having a global P-value < 0.05 and at least one tagSNP false discovery rate (FDR) q-value < 0.05. The rs3024409 variant allele of F13A1 was associated with 1.66-fold increased risk of VTE, while the minor alleles of HABP2 rs6585234 and rs3862019, F2R rs253061 and rs153311, and PLAUR rs344782 were each associated with lower risk of VTE (hazard ratios in the range of 0.49-0.66). Consistent with the observed protective association for VTE risk, the HABP2 rs3862019 variant allele was also associated with lower activity levels of coagulation factors FVIII, FIX, FX and plasminogen. We also confirm previously reported associations between common variants of the coagulation FII, FV, FVIII, FXI, alpha-fibrinogen and protein C genes and risk of VTE.

CONCLUSIONS: These findings suggest that several novel common coagulation gene variants may be related to risk of VTE in older adults. Further studies in older adults are needed to validate these findings and assess functional molecular mechanisms.

%B J Thromb Haemost %V 7 %P 1499-505 %8 2009 Sep %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/19552680?dopt=Abstract %R 10.1111/j.1538-7836.2009.03522.x %0 Journal Article %J Cancer Causes Control %D 2009 %T C-reactive protein, interleukin-6, and prostate cancer risk in men aged 65 years and older. %A Pierce, Brandon L %A Biggs, Mary L %A DeCambre, Marvalyn %A Reiner, Alexander P %A Li, Christopher %A Fitzpatrick, Annette %A Carlson, Christopher S %A Stanford, Janet L %A Austin, Melissa A %K African Americans %K Aged %K Aged, 80 and over %K Biomarkers %K C-Reactive Protein %K European Continental Ancestry Group %K Humans %K Inflammation %K Interleukin-6 %K Male %K Polymorphism, Single Nucleotide %K Prospective Studies %K Prostatic Neoplasms %K Risk Factors %X

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

%B Cancer Causes Control %V 20 %P 1193-203 %8 2009 Sep %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/19267250?dopt=Abstract %R 10.1007/s10552-009-9320-4 %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 Am J Geriatr Psychiatry %D 2009 %T Depressed mood is not a risk factor for incident dementia in a community-based cohort. %A Becker, James T %A Chang, Yue-Fang %A Lopez, Oscar L %A Dew, Mary Amanda %A Sweet, Robert A %A Barnes, Deborah %A Yaffe, Kristine %A Young, Jeffrey %A Kuller, Lewis %A Reynolds, Charles F %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cognition Disorders %K Dementia %K Depression %K Female %K Follow-Up Studies %K Humans %K Incidence %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Prospective Studies %K Psychiatric Status Rating Scales %K Residence Characteristics %K Risk Factors %X

OBJECTIVES: To determine the relationship between depressed mood and the development of Alzheimer disease in cognitively normal individuals.

DESIGN: Longitudinal and observational.

SETTING: Community-based cohort study.

PARTICIPANTS: A total of 288 participants in the Cardiovascular Health Study-Cognition Study (mean age: 77.52, SD =3.65, range: 70-89). All of the participants were adjudicated as cognitively normal in 1998/1999, and all had at least three visits before 1998/1999 with measures of cognition and mood state. The mean length of follow-up from 1998-1999 to 2007 was 7.1 years (range: 1-9 years, median =9 years).

MEASUREMENTS: The Center for Epidemiological Studies-Depression Scale (CESD) was used to index mood state, and the Modified Mini-Mental State Examination (3MSE) was the index of cognitive function among participants before 1998/1999. These measures were considered in two ways: participants were classified according to: 1) whether they showed a high-negative correlation between their CESD and 3MSE scores (i.e., indicating that greater depression was linked to poorer cognition) and 2) whether they showed persistently elevated CESD scores. The study outcome, development of dementia (N = 48), was based on consensus classifications, which was based on detailed neuropsychological and neurological exams.

RESULTS: The authors could find no consistent relationship between mood state, either alone or in relation to cognitive status, and the subsequent development of dementia. Those individuals whose cognitive functions were highly correlated with their mood state were no more likely to develop dementia than other participants. Those who had persistently depressed mood were also no more likely to develop dementia than those without persistently depressed mood.

CONCLUSION: Within the confines of this prospective, community-based study of elderly adults, the authors could not find strong evidence to support the hypothesis that mood disturbance was linked with the development of dementia.

%B Am J Geriatr Psychiatry %V 17 %P 653-63 %8 2009 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/19634208?dopt=Abstract %0 Journal Article %J Med Care %D 2009 %T External validity of the cardiovascular health study: a comparison with the Medicare population. %A DiMartino, Lisa D %A Hammill, Bradley G %A Curtis, Lesley H %A Gottdiener, John S %A Manolio, Teri A %A Powe, Neil R %A Schulman, Kevin A %K Aged %K Cardiovascular Diseases %K Cohort Studies %K Comorbidity %K Female %K Humans %K Male %K Medicare %K Randomized Controlled Trials as Topic %K Reproducibility of Results %K Socioeconomic Factors %K United States %X

BACKGROUND: The Cardiovascular Health Study (CHS), a population-based prospective cohort study, has been used to identify major risk factors associated with cardiovascular disease and stroke in the elderly.

OBJECTIVE: To assess the external validity of the CHS.

RESEARCH DESIGN: Comparison of the CHS cohort to a national cohort of Medicare beneficiaries and to Medicare beneficiaries residing in the CHS geographic regions.

SUBJECTS: CHS participants and a 5% sample of Medicare beneficiaries.

MEASURES: Demographic and administrative characteristics, comorbid conditions, resource use, and mortality.

RESULTS: Compared with both Medicare cohorts, the CHS cohort was older and included more men and African American participants. CHS participants were more likely to be enrolled in Medicare managed care than beneficiaries in the national Medicare cohort. Compared with the Medicare cohorts, mortality in the CHS was more than 40% lower at 1 year, approximately 25% lower at 5 years, and approximately 15% lower at 10 years. There were minimal differences in comorbid conditions and health care resource use.

CONCLUSION: The CHS cohort is comparable with the Medicare population, particularly with regard to comorbid conditions and resource use, but had lower mortality. The difference in mortality may reflect the CHS recruitment strategy or volunteer bias. These findings suggest it may not be appropriate to project absolute rates of disease and outcomes based on CHS data to the entire Medicare population. However, there is no reason to expect that the relative risks associated with physiologic processes identified by CHS data would differ for nonparticipants.

%B Med Care %V 47 %P 916-23 %8 2009 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/19597373?dopt=Abstract %R 10.1097/MLR.0b013e318197b104 %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 N Engl J Med %D 2009 %T Genomewide association studies of stroke. %A Ikram, M Arfan %A Seshadri, Sudha %A Bis, Joshua C %A Fornage, Myriam %A DeStefano, Anita L %A Aulchenko, Yurii S %A Debette, Stephanie %A Lumley, Thomas %A Folsom, Aaron R %A van den Herik, Evita G %A Bos, Michiel J %A Beiser, Alexa %A Cushman, Mary %A Launer, Lenore J %A Shahar, Eyal %A Struchalin, Maksim %A Du, Yangchun %A Glazer, Nicole L %A Rosamond, Wayne D %A Rivadeneira, Fernando %A Kelly-Hayes, Margaret %A Lopez, Oscar L %A Coresh, Josef %A Hofman, Albert %A DeCarli, Charles %A Heckbert, Susan R %A Koudstaal, Peter J %A Yang, Qiong %A Smith, Nicholas L %A Kase, Carlos S %A Rice, Kenneth %A Haritunians, Talin %A Roks, Gerwin %A de Kort, Paul L M %A Taylor, Kent D %A de Lau, Lonneke M %A Oostra, Ben A %A Uitterlinden, André G %A Rotter, Jerome I %A Boerwinkle, Eric %A Psaty, Bruce M %A Mosley, Thomas H %A van Duijn, Cornelia M %A Breteler, Monique M B %A Longstreth, W T %A Wolf, Philip A %K African Continental Ancestry Group %K Aged %K Chromosomes, Human, Pair 12 %K Cohort Studies %K European Continental Ancestry Group %K Female %K Genetic Markers %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Proportional Hazards Models %K Risk Factors %K Stroke %X

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

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

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

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

%B N Engl J Med %V 360 %P 1718-28 %8 2009 Apr 23 %G eng %N 17 %1 https://www.ncbi.nlm.nih.gov/pubmed/19369658?dopt=Abstract %R 10.1056/NEJMoa0900094 %0 Journal Article %J Nat Genet %D 2009 %T Genome-wide association study of blood pressure and hypertension. %A Levy, Daniel %A Ehret, Georg B %A Rice, Kenneth %A Verwoert, Germaine C %A Launer, Lenore J %A Dehghan, Abbas %A Glazer, Nicole L %A Morrison, Alanna C %A Johnson, Andrew D %A Aspelund, Thor %A Aulchenko, Yurii %A Lumley, Thomas %A Köttgen, Anna %A Vasan, Ramachandran S %A Rivadeneira, Fernando %A Eiriksdottir, Gudny %A Guo, Xiuqing %A Arking, Dan E %A Mitchell, Gary F %A Mattace-Raso, Francesco U S %A Smith, Albert V %A Taylor, Kent %A Scharpf, Robert B %A Hwang, Shih-Jen %A Sijbrands, Eric J G %A Bis, Joshua %A Harris, Tamara B %A Ganesh, Santhi K %A O'Donnell, Christopher J %A Hofman, Albert %A Rotter, Jerome I %A Coresh, Josef %A Benjamin, Emelia J %A Uitterlinden, André G %A Heiss, Gerardo %A Fox, Caroline S %A Witteman, Jacqueline C M %A Boerwinkle, Eric %A Wang, Thomas J %A Gudnason, Vilmundur %A Larson, Martin G %A Chakravarti, Aravinda %A Psaty, Bruce M %A van Duijn, Cornelia M %K Blood Pressure %K Cell Line %K Chromosome Mapping %K Chromosomes, Human %K Diastole %K Gene Expression Regulation %K Genetic Association Studies %K Genome-Wide Association Study %K Humans %K Hypertension %K Liver %K Lymphocytes %K Meta-Analysis as Topic %K Odds Ratio %K Phenotype %K Prevalence %K Risk Assessment %K Systole %X

Blood pressure is a major cardiovascular disease risk factor. To date, few variants associated with interindividual blood pressure variation have been identified and replicated. Here we report results of a genome-wide association study of systolic (SBP) and diastolic (DBP) blood pressure and hypertension in the CHARGE Consortium (n = 29,136), identifying 13 SNPs for SBP, 20 for DBP and 10 for hypertension at P < 4 × 10(-7). The top ten loci for SBP and DBP were incorporated into a risk score; mean BP and prevalence of hypertension increased in relation to the number of risk alleles carried. When ten CHARGE SNPs for each trait were included in a joint meta-analysis with the Global BPgen Consortium (n = 34,433), four CHARGE loci attained genome-wide significance (P < 5 × 10(-8)) for SBP (ATP2B1, CYP17A1, PLEKHA7, SH2B3), six for DBP (ATP2B1, CACNB2, CSK-ULK3, SH2B3, TBX3-TBX5, ULK4) and one for hypertension (ATP2B1). Identifying genes associated with blood pressure advances our understanding of blood pressure regulation and highlights potential drug targets for the prevention or treatment of hypertension.

%B Nat Genet %V 41 %P 677-87 %8 2009 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/19430479?dopt=Abstract %R 10.1038/ng.384 %0 Journal Article %J Age Ageing %D 2009 %T Heart rate variability and its changes over 5 years in older adults. %A Stein, Phyllis K %A Barzilay, Joshua I %A Chaves, Paulo H M %A Domitrovich, Peter P %A Gottdiener, John S %K Age Distribution %K Aged %K Aging %K Atrial Premature Complexes %K Autonomic Nervous System %K Cardiovascular Diseases %K Cross-Sectional Studies %K Electrocardiography, Ambulatory %K Female %K Heart Rate %K Humans %K Hypertension %K Male %K Nonlinear Dynamics %K Prevalence %K Prospective Studies %K Risk Factors %K Ventricular Premature Complexes %X

PURPOSE: to characterise the association between age, ageing and heart rate variability (HRV) in older individuals, 585 adults age >65 years with two 24-h Holter recordings in the Cardiovascular Health Study were studied.

METHODS: heart rate (HR), ventricular premature contractions (VPCs), atrial premature contractions (APCs), frequency-domain, ratio-based and non-linear HRV and heart rate turbulence (HRT) were examined cross-sectionally by 5-year age groups and prospectively over 5 years. Analyses adjusted for gender, lower versus elevated cardiovascular (CV) risk and for the change in CV risk.

RESULTS: HR declined, and VPCs and APCs increased per 5-year increase in age. Frequency-domain HRV decreased more at 65-69, less at 70-74 and minimally at > or =75 years, independent of CVD risk or change in CVD risk. Ratio and non-linear HRV continued to decline to > or =75 years old. Ratio HRV and HRT slope were more strongly related to CVD risk than frequency-domain HRV.

CONCLUSIONS: cardiac autonomic function, assessed by frequency-domain HRV, declines most at 65-70 and levels off at age >75. The decline is independent of CVD risk or change in CVD risk. Ratio-based and non-linear HRV and HRT slope continued to change with increasing age and were more closely related to CVD risk than frequency-domain HRV.

%B Age Ageing %V 38 %P 212-8 %8 2009 Mar %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/19147739?dopt=Abstract %R 10.1093/ageing/afn292 %0 Journal Article %J J Clin Endocrinol Metab %D 2009 %T High frequency of and factors associated with thyroid hormone over-replacement and under-replacement in men and women aged 65 and over. %A Somwaru, Lily L %A Arnold, Alice M %A Joshi, Neha %A Fried, Linda P %A Cappola, Anne R %K Aged %K Body Mass Index %K Body Weight %K Diabetes Mellitus %K Dose-Response Relationship, Drug %K Drug Therapy, Combination %K Female %K Hormone Replacement Therapy %K Humans %K Male %K Multivariate Analysis %K Renal Insufficiency %K Risk Factors %K Thyroid Diseases %K Thyroid Hormones %K Thyrotropin %K Thyroxine %K Triiodothyronine %X

CONTEXT: Thyroid hormone use is common in older populations, but the frequency of over- or under-replacement is debated.

OBJECTIVE: We sought to describe the frequency of and factors associated with thyroid hormone over- or under-replacement in a population of older men and women.

DESIGN: Participants were 3678 U.S. community dwelling individuals aged 65 yr or older enrolled in the Cardiovascular Health Study who had thyroid function tests in 1989-1990. Thyroid hormone users (n = 339) were identified and classified into low TSH (<0.45 mU/liter), euthyroid (0.45-4.5 mU/liter), and high TSH (>4.5 mU/liter).

RESULTS: Of the 339 thyroid hormone users, 41% had a low TSH, 16% had a high TSH, and 43% were in the euthyroid range. In multivariable analyses, lower weight (P < 0.001) was independently associated with low TSH status. For every 10 kg lower weight, the likelihood of having low TSH increased by 65% [odd ratio (OR) 1.65; 95% confidence interval (CI) 1.31-2.07]. Those with renal insufficiency were less likely to have low TSH levels (P = 0.02). The presence of diabetes was independently associated with having low (OR 3.35; 95% CI 1.46-7.65) and high TSH levels (OR 2.66; 95% CI 1.14-6.21).

CONCLUSIONS: There is a very high prevalence of thyroid function testing abnormalities in older people taking thyroid hormone preparations, particularly in those of low weight or with diabetes. Because of potential adverse cardiovascular and skeletal effects from over-replacement, older people represent a key population for increased TSH monitoring on therapy.

%B J Clin Endocrinol Metab %V 94 %P 1342-5 %8 2009 Apr %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/19126628?dopt=Abstract %R 10.1210/jc.2008-1696 %0 Journal Article %J J Clin Endocrinol Metab %D 2009 %T Higher serum testosterone concentration in older women is associated with insulin resistance, metabolic syndrome, and cardiovascular disease. %A Patel, Shrita M %A Ratcliffe, Sarah J %A Reilly, Muredach P %A Weinstein, Rachel %A Bhasin, Shalender %A Blackman, Marc R %A Cauley, Jane A %A Sutton-Tyrrell, Kim %A Robbins, John %A Fried, Linda P %A Cappola, Anne R %K Aged %K Aged, 80 and over %K Blood Glucose %K Cardiovascular Diseases %K Coronary Disease %K Female %K Humans %K Insulin %K Insulin Resistance %K Metabolic Syndrome %K Odds Ratio %K Radioimmunoassay %K Socioeconomic Factors %K Testosterone %K Treatment Outcome %X

CONTEXT: Early postmenopausal women with higher testosterone (T) levels have increased insulin resistance (IR) and cardiovascular risk factors, but whether this translates into increased cardiovascular disease later in life is unknown.

OBJECTIVE: The objective of the study was to determine whether higher T levels are associated with IR, the metabolic syndrome (MetSyn), and coronary heart disease (CHD) in elderly women.

DESIGN: Total T and free T by equilibrium dialysis were measured using ultrasensitive assays in 344 women aged 65-98 yr enrolled in the Cardiovascular Health Study. Cross-sectional analyses were performed to examine the associations between total and free T and IR, MetSyn, and CHD.

RESULTS: There was a stepwise increase in the homeostasis model assessment of insulin resistance with increasing total (P = 0.0.003) and free T (P = 0.02) level and a corresponding decrease in Quantitative Insulin Sensitivity Check Index (P < 0.001 and P = 0.002, respectively). In adjusted models, higher levels of both total and free T were strongly associated with abdominal obesity and high fasting glucose, the two MetSyn components most strongly linked to IR. After adjustment, women in the top quartile of total T levels had a 3-fold greater odds of MetSyn (odds ratio 3.15, 95% confidence interval 1.57-6.35) than those in the bottom quartile and a 3-fold greater odds of CHD (odds ratio 2.95, 95% confidence interval 1.2-7.3) than those in second quartile, whereas free T was not significantly associated with MetSyn or CHD.

CONCLUSIONS: Higher levels of T are associated with IR, MetSyn, and CHD in elderly women. Whether T is a marker or mediator of cardiovascular disease in this population merits further investigation.

%B J Clin Endocrinol Metab %V 94 %P 4776-84 %8 2009 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/19846742?dopt=Abstract %R 10.1210/jc.2009-0740 %0 Journal Article %J Exp Gerontol %D 2009 %T Inflammation and stress-related candidate genes, plasma interleukin-6 levels, and longevity in older adults. %A Walston, Jeremy D %A Matteini, Amy M %A Nievergelt, Caroline %A Lange, Leslie A %A Fallin, Dani M %A Barzilai, Nir %A Ziv, Elad %A Pawlikowska, Ludmila %A Kwok, Pui %A Cummings, Steve R %A Kooperberg, Charles %A LaCroix, Andrea %A Tracy, Russell P %A Atzmon, Gil %A Lange, Ethan M %A Reiner, Alex P %K Aged %K Aged, 80 and over %K Aging %K Cardiovascular Diseases %K Case-Control Studies %K Female %K Genetic Variation %K Genotype %K Humans %K Inflammation %K Interleukin-6 %K Longevity %K Male %K Phenotype %K Poly (ADP-Ribose) Polymerase-1 %K Poly(ADP-ribose) Polymerases %K Risk Factors %X

Interleukin-6 (IL-6) is an inflammatory cytokine that influences the development of inflammatory and aging-related disorders and ultimately longevity. In order to study the influence of variants in genes that regulate inflammatory response on IL-6 levels and longevity, we screened a panel of 477 tag SNPs across 87 candidate genes in >5000 older participants from the population-based Cardiovascular Health Study (CHS). Baseline plasma IL-6 concentration was first confirmed as a strong predictor of all-cause mortality. Functional alleles of the IL6R and PARP1 genes were significantly associated with 15%-20% higher baseline IL-6 concentration per copy among CHS European-American (EA) participants (all p<10(-4)). In a case/control analysis nested within this EA cohort, the minor allele of PARP1 rs1805415 was nominally associated with decreased longevity (p=0.001), but there was no evidence of association between IL6R genotype and longevity. The PARP1 rs1805415--longevity association was subsequently replicated in one of two independent case/control studies. In a pooled analysis of all three studies, the "risk" of longevity associated with the minor allele of PARP1 rs1805415 was 0.79 (95%CI 0.62-1.02; p=0.07). These findings warrant further study of the potential role of PARP1 genotype in inflammatory and aging-related phenotypes.

%B Exp Gerontol %V 44 %P 350-5 %8 2009 May %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/19249341?dopt=Abstract %R 10.1016/j.exger.2009.02.004 %0 Journal Article %J Sleep %D 2009 %T Insomnia did not predict incident hypertension in older adults in the cardiovascular health study. %A Phillips, Barbara %A Bůzková, Petra %A Enright, Paul %K African Americans %K Aged %K Cohort Studies %K Comorbidity %K European Continental Ancestry Group %K Female %K Follow-Up Studies %K Health Surveys %K Humans %K Hypertension %K Male %K Prospective Studies %K Risk Factors %K Sleep Initiation and Maintenance Disorders %K United States %X

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

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

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

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

INTERVENTIONS: none.

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

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

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

%B Sleep %V 32 %P 65-72 %8 2009 Jan %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/19189780?dopt=Abstract %0 Journal Article %J Br J Haematol %D 2009 %T Lack of association of soluble endothelial protein C receptor and PROCR 6936A/G polymorphism with the risk of venous thromboembolism in a prospective study. %A Yamagishi, Kazumasa %A Cushman, Mary %A Heckbert, Susan R %A Tsai, Michael Y %A Folsom, Aaron R %K Antigens, CD %K Case-Control Studies %K Endothelial Protein C Receptor %K Female %K Genotype %K Humans %K Logistic Models %K Male %K Middle Aged %K Odds Ratio %K Polymorphism, Genetic %K Prospective Studies %K Receptors, Cell Surface %K Risk %K Venous Thromboembolism %X

Prior case-control studies reported that levels of the soluble form of the endothelial protein C receptor (sEPCR) were strongly controlled by the PROCR 6963A/G polymorphism and higher levels were a risk factor for venous thromboembolism (VTE). We sought to prospectively examine the association of sEPCR and the 6963A/G polymorphism with the incidence of VTE. The Longitudinal Investigation of Thromboembolism Etiology (LITE) pooled data from the Cardiovascular Health Study (CHS) and the Atherosclerosis Risk in Communities (ARIC) Study on men and women aged > or =45 years. A nested case-control study of 458 incident VTE and 1038 controls was performed. sEPCR levels were distributed trimodally according to 6963A/G polymorphism. Adjusting for age, sex and race, there was no overall association between sEPCR level and VTE: odds ratio (OR) [95% confidence interval] for highest versus lowest quartile = 1.17[0.86-1.59]. However, higher sEPCR was associated with VTE in non-whites (OR = 1.84[1.05-3.22]) and women (OR = 1.51[1.01-2.26]). The 6963A/G polymorphism was not associated with VTE risk (OR = 0.93[0.70-1.25]). In conclusion, sEPCR levels and the PROCR 6963A/G polymorphism were not associated overall with increased risk of VTE.

%B Br J Haematol %V 145 %P 221-6 %8 2009 Apr %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/19222470?dopt=Abstract %R 10.1111/j.1365-2141.2009.07612.x %0 Journal Article %J Circ Cardiovasc Imaging %D 2009 %T Left atrial volume and geometry in healthy aging: the Cardiovascular Health Study. %A Aurigemma, Gerard P %A Gottdiener, John S %A Arnold, Alice M %A Chinali, Marcello %A Hill, Jeffrey C %A Kitzman, Dalane %K Age Factors %K Aged %K Aged, 80 and over %K Aging %K Atrial Function, Left %K Body Size %K Body Surface Area %K Echocardiography, Three-Dimensional %K Female %K Heart Atria %K Humans %K Linear Models %K Male %K Models, Biological %K Organ Size %K Population Surveillance %K Prospective Studies %K Reference Values %K Sex Factors %K United States %X

BACKGROUND: The left atrium is a validated marker of clinical and subclinical cardiovascular disease. Left atrial enlargement is often seen among older individuals; however, there are few population-based data regarding normal left atrial size among older persons, especially from those who are healthy, and from women. Furthermore, because the left atrium is a 3D structure, the commonly used parasternal long-axis diastolic diameter often underdiagnoses left atrial enlargement.

METHODS AND RESULTS: We evaluated left atrial size in 230 healthy participants (mean age, 76+/-5 years) free of prevalent cardiac disease, rhythm abnormality, hypertension, and diabetes selected from the Cardiovascular Health Study, a prospective community-based study of risk factors for cardiovascular disease in 5888 elderly participants. In addition to the standard long-axis measurement, we obtained left atrial superoinferior and lateral diameters and used these dimensions to estimate left atrial volume. These measurements were used to generate reference ranges for determining left atrial enlargement in older men and women, based on the 95% percentiles of the left atrial dimensions in healthy participants, both unadjusted, and after adjustment for age, height, and weight. In healthy elderly subjects, indices of left atrial size do not correlate with age or height but with weight and other measures of body build.

CONCLUSIONS: These data provide normative reference values for left atrial size in healthy older women and men. The results should be useful for refining diagnostic criteria for left atrial dilation in the older population and may be relevant for cardiovascular risk stratification.

%B Circ Cardiovasc Imaging %V 2 %P 282-9 %8 2009 Jul %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/19808608?dopt=Abstract %R 10.1161/CIRCIMAGING.108.826602 %0 Journal Article %J Arch Intern Med %D 2009 %T Lifestyle risk factors and new-onset diabetes mellitus in older adults: the cardiovascular health study. %A Mozaffarian, Dariush %A Kamineni, Aruna %A Carnethon, Mercedes %A Djoussé, Luc %A Mukamal, Kenneth J %A Siscovick, David %K Age of Onset %K Aged %K Aged, 80 and over %K Diabetes Mellitus, Type 2 %K Female %K Humans %K Incidence %K Life Style %K Male %K National Heart, Lung, and Blood Institute (U.S.) %K Prospective Studies %K Risk Factors %K United States %X

BACKGROUND: The combined impact of lifestyle factors on incidence of diabetes mellitus later in life is not well established. The objective of this study was to determine how lifestyle factors, assessed in combination, relate to new-onset diabetes in a broad and relatively unselected population of older adults.

METHODS: We prospectively examined associations of lifestyle factors, measured using repeated assessments later in life, with incident diabetes mellitus during a 10-year period (1989-1998) among 4883 men and women 65 years or older (mean [SD] age at baseline, 73 [6] years) enrolled in the Cardiovascular Health Study. Low-risk lifestyle groups were defined by physical activity level (leisure-time activity and walking pace) above the median; dietary score (higher fiber intake and polyunsaturated to saturated fat ratio, lower trans-fat intake and lower mean glycemic index) in the top 2 quintiles; never smoked or former smoker more than 20 years ago or for fewer than 5 pack-years; alcohol use (predominantly light or moderate); body mass index less than 25 (calculated as weight in kilograms divided by height in meters squared); and waist circumference of 88 cm for women or 92 cm for men. The main outcome measure was incident diabetes defined annually by new use of insulin or oral hypoglycemic medications. We also evaluated fasting and 2-hour postchallenge glucose levels.

RESULTS: During 34,539 person-years, 337 new cases of drug-treated diabetes mellitus occurred (9.8 per 1000 person-years). After adjustment for age, sex, race, educational level, and annual income, each lifestyle factor was independently associated with incident diabetes. Overall, the rate of incident diabetes was 35% lower (relative risk, 0.65; 95% confidence interval, 0.59-0.71) for each 1 additional lifestyle factor in the low-risk group. Participants whose physical activity level and dietary, smoking, and alcohol habits were all in the low-risk group had an 82% lower incidence of diabetes (relative risk, 0.18; 95% confidence interval, 0.06-0.56) compared with all other participants. When absence of adiposity (either body mass index <25 or waist circumference < or =88/92 cm for women/men) was added to the other 4 low-risk lifestyle factors, incidence of diabetes was 89% lower (relative risk, 0.11; 95% confidence interval, 0.01-0.76). Overall, 9 of 10 new cases of diabetes appeared to be attributable to these 5 lifestyle factors. Associations were slightly attenuated, but still highly significant, for incident diabetes defined by medication use or glucose level.

CONCLUSION: Even later in life, combined lifestyle factors are associated with a markedly lower incidence of new-onset diabetes mellitus.

%B Arch Intern Med %V 169 %P 798-807 %8 2009 Apr 27 %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/19398692?dopt=Abstract %R 10.1001/archinternmed.2009.21 %0 Journal Article %J JAMA %D 2009 %T Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. %A Erqou, Sebhat %A Kaptoge, Stephen %A Perry, Philip L %A Di Angelantonio, Emanuele %A Thompson, Alexander %A White, Ian R %A Marcovina, Santica M %A Collins, Rory %A Thompson, Simon G %A Danesh, John %K Cause of Death %K Coronary Disease %K Humans %K Lipoprotein(a) %K Risk Factors %K Stroke %X

CONTEXT: Circulating concentration of lipoprotein(a) (Lp[a]), a large glycoprotein attached to a low-density lipoprotein-like particle, may be associated with risk of coronary heart disease (CHD) and stroke.

OBJECTIVE: To assess the relationship of Lp(a) concentration with risk of major vascular and nonvascular outcomes.

STUDY SELECTION: Long-term prospective studies that recorded Lp(a) concentration and subsequent major vascular morbidity and/or cause-specific mortality published between January 1970 and March 2009 were identified through electronic searches of MEDLINE and other databases, manual searches of reference lists, and discussion with collaborators.

DATA EXTRACTION: Individual records were provided for each of 126,634 participants in 36 prospective studies. During 1.3 million person-years of follow-up, 22,076 first-ever fatal or nonfatal vascular disease outcomes or nonvascular deaths were recorded, including 9336 CHD outcomes, 1903 ischemic strokes, 338 hemorrhagic strokes, 751 unclassified strokes, 1091 other vascular deaths, 8114 nonvascular deaths, and 242 deaths of unknown cause. Within-study regression analyses were adjusted for within-person variation and combined using meta-analysis. Analyses excluded participants with known preexisting CHD or stroke at baseline.

DATA SYNTHESIS: Lipoprotein(a) concentration was weakly correlated with several conventional vascular risk factors and it was highly consistent within individuals over several years. Associations of Lp(a) with CHD risk were broadly continuous in shape. In the 24 cohort studies, the rates of CHD in the top and bottom thirds of baseline Lp(a) distributions, respectively, were 5.6 (95% confidence interval [CI], 5.4-5.9) per 1000 person-years and 4.4 (95% CI, 4.2-4.6) per 1000 person-years. The risk ratio for CHD, adjusted for age and sex only, was 1.16 (95% CI, 1.11-1.22) per 3.5-fold higher usual Lp(a) concentration (ie, per 1 SD), and it was 1.13 (95% CI, 1.09-1.18) following further adjustment for lipids and other conventional risk factors. The corresponding adjusted risk ratios were 1.10 (95% CI, 1.02-1.18) for ischemic stroke, 1.01 (95% CI, 0.98-1.05) for the aggregate of nonvascular mortality, 1.00 (95% CI, 0.97-1.04) for cancer deaths, and 1.00 (95% CI, 0.95-1.06) for nonvascular deaths other than cancer.

CONCLUSION: Under a wide range of circumstances, there are continuous, independent, and modest associations of Lp(a) concentration with risk of CHD and stroke that appear exclusive to vascular outcomes.

%B JAMA %V 302 %P 412-23 %8 2009 Jul 22 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/19622820?dopt=Abstract %R 10.1001/jama.2009.1063 %0 Journal Article %J Circ Heart Fail %D 2009 %T Lipoprotein-associated phospholipase A(2) and risk of congestive heart failure in older adults: the Cardiovascular Health Study. %A Suzuki, Takeki %A Solomon, Cam %A Jenny, Nancy Swords %A Tracy, Russell %A Nelson, Jeanenne J %A Psaty, Bruce M %A Furberg, Curt %A Cushman, Mary %K 1-Alkyl-2-acetylglycerophosphocholine Esterase %K Aged %K Biomarkers %K C-Reactive Protein %K Female %K Fibrinogen %K Heart Failure %K Humans %K Incidence %K Inflammation Mediators %K Interleukin-6 %K Kaplan-Meier Estimate %K Male %K Population Surveillance %K Proportional Hazards Models %K Prospective Studies %K Risk Assessment %K Risk Factors %K Time Factors %K United States %X

BACKGROUND: Inflammation may be a causative factor in congestive heart failure (CHF). Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is an inflammation marker associated with vascular risk. One previous study showed an association of Lp-PLA(2) activity with CHF risk, but there were only 94 CHF cases and Lp-PLA(2) antigen, which is available clinically in the United States, was not measured.

METHODS AND RESULTS: We measured baseline Lp-PLA(2) antigen and activity in 3991 men and women without baseline CHF or cardiovascular disease who were participating in the Cardiovascular Health Study, a prospective observational study of adults 65 years or older. Cox proportional hazards models adjusted for age, sex, clinic site, race, low-density and high-density lipoprotein cholesterol, body mass index, systolic and diastolic blood pressure, hypertension, smoking status, pack-years, and diabetes were used to calculate hazard ratios and 95% CIs for incident CHF. Further models adjusted for coronary disease events during follow-up and C-reactive protein. Eight hundred twenty-nine participants developed CHF during 12.1 years. Adjusted hazard ratios for CHF with Lp-PLA(2) in the fourth compared with the first quartile were 1.44 (95% CI, 1.16 to 1.79) for Lp-PLA(2) antigen and 1.06 (95% CI, 0.84 to 1.32) for activity. Adjustment for incident coronary disease attenuated the hazard ratio for Lp-PLA(2) antigen to 1.26 (95% CI, 1.02 to 1.57), adjustment for C-reactive protein had minimal impact.

CONCLUSIONS: Lp-PLA(2) antigen was associated with risk of future CHF in older people, independent of CHF and coronary risk factors, and partly mediated by coronary disease events. Further clinical and basic research is needed to better understand the role of Lp-PLA(2) in CHF.

%B Circ Heart Fail %V 2 %P 429-36 %8 2009 Sep %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/19808373?dopt=Abstract %R 10.1161/CIRCHEARTFAILURE.108.839613 %0 Journal Article %J J Am Geriatr Soc %D 2009 %T Long-term function in an older cohort--the cardiovascular health study all stars study. %A Newman, Anne B %A Arnold, Alice M %A Sachs, Michael C %A Ives, Diane G %A Cushman, Mary %A Strotmeyer, Elsa S %A Ding, Jingzhong %A Kritchevsky, Stephen B %A Chaves, Paulo H M %A Fried, Linda P %A Robbins, John %K Activities of Daily Living %K Age Factors %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Attention %K Cardiovascular Diseases %K Chronic Disease %K Cohort Studies %K Comorbidity %K Cross-Sectional Studies %K Female %K Follow-Up Studies %K Gait %K Geriatric Assessment %K Hand Strength %K Health Surveys %K Humans %K Male %K Memory, Short-Term %K Mental Status Schedule %K Proportional Hazards Models %K Psychometrics %K Risk Factors %K United States %X

OBJECTIVES: To evaluate shared and unique risk factors for maintaining physical and cognitive function into the ninth decade and beyond.

DESIGN: Longitudinal cohort study.

SETTING: Four U.S. communities.

PARTICIPANTS: One thousand six hundred seventy-seven participants in the Cardiovascular Health Study All Stars Study, assessed in 2005/06. Median age was 85 (range 77-102), 66.5% were women, and 16.6% were black.

MEASUREMENTS: Intact function was defined as no difficulty with any activities of daily living and a score of 80 or higher on the Modified Mini-Mental State Examination. Baseline characteristics assessed in 1992/93 included demographics, behavioral health factors, chronic disease history, subclinical disease markers, cardiovascular risk factors, and inflammatory markers. Multinomial logistic regression was used to compare risk for physical disability, cognitive impairment,and combined impairments with no functional impairment.

RESULTS: Of the 1,677 participants evaluated in both domains, 891 (53%) were functionally intact. Continuous measures of function, including the Digit Symbol Substitution Test and gait speed, showed that all groups, including the most functional, had declined over time. The functional group had less decline but also tended to have higher starting values. Functional individuals had a higher baseline health profile than those with either or cognitive impairment or both impairments combined. Women and individuals with greater weight had higher rates of physical impairment but not cognitive impairment. Risk factors common to both types of impairment included cardiovascular disease and hypertension.

CONCLUSION: Intact function was found in only approximately half of these older adults in the ninth decade and beyond. High baseline function and low vascular disease risk characterized functional aging.

%B J Am Geriatr Soc %V 57 %P 432-40 %8 2009 Mar %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/19187412?dopt=Abstract %R 10.1111/j.1532-5415.2008.02152.x %0 Journal Article %J J Thromb Haemost %D 2009 %T Metabolic syndrome and risk of venous thromboembolism: Longitudinal Investigation of Thromboembolism Etiology. %A Steffen, L M %A Cushman, M %A Peacock, J M %A Heckbert, S R %A Jacobs, D R %A Rosamond, W D %A Folsom, A R %K Blood Coagulation Factors %K Blood Glucose %K Blood Pressure %K Body Mass Index %K Cohort Studies %K Female %K Fibrinogen %K Humans %K Lipids %K Longitudinal Studies %K Male %K Metabolic Syndrome %K Proportional Hazards Models %K Risk Factors %K Venous Thromboembolism %X

SUMMARY BACKGROUND: In a recent case-control study, the odds of metabolic syndrome (MetSyn) among deep vein thrombosis cases were almost twice those among controls. We tested the hypothesis that the incidence of non-cancer-related venous thromboembolism (VTE) is higher among adults with MetSyn and further, that associations are stronger for idiopathic than secondary VTE.

METHODS: A total of 20 374 middle-aged and elderly adults were followed for over 12 years for incident VTE in the Longitudinal Investigation of Thromboembolism Etiology (LITE). All hospitalizations were identified and VTEs validated by chart review. Baseline MetSyn was defined using ATP III guidelines, including >or=3 of the following components: abdominal obesity, elevated blood pressure, low HDL-cholesterol, high triglycerides and high glucose. Because sex modified the relation between MetSyn and VTE (p(interaction) = 0.001), proportional hazards regression analyses were stratified by sex to assess the associations of MetSyn and its components with risk of incident non-cancer-related VTE, adjusting for potential confounders.

RESULTS: Incident VTE (n = 358) included 196 idiopathic events. Baseline MetSyn was associated with risk of total VTE (hazard ratio (HR) = 1.84, 95% CI = 1.30, 2.59) and idiopathic VTE (HR = 1.59, 95% CI = 1.02, 2.47) among men, but not women. The association was largely attributable to abdominal obesity (HR of VTE = 2.10, 95% CI = 1.51, 2.93, in men; HR of VTE = 1.70, 95% CI = 1.24, 2.34, in women), with no additional contribution by the other MetSyn components.

CONCLUSION: Although abdominal obesity was associated with increased risk of VTE in both men and women, MetSyn and its other components do not seem important in VTE etiology.

%B J Thromb Haemost %V 7 %P 746-51 %8 2009 May %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/19175496?dopt=Abstract %R 10.1111/j.1538-7836.2009.03295.x %0 Journal Article %J Radiology %D 2009 %T Mild cognitive impairment and alzheimer disease: patterns of altered cerebral blood flow at MR imaging. %A Dai, Weiying %A Lopez, Oscar L %A Carmichael, Owen T %A Becker, James T %A Kuller, Lewis H %A Gach, H Michael %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Brain %K Cerebrovascular Circulation %K Cognition Disorders %K Female %K Humans %K Magnetic Resonance Imaging %K Male %X

PURPOSE: To examine regional cerebral blood flow (rCBF) in incident mild cognitive impairment (MCI) and Alzheimer disease (AD) by using continuous arterial spin-labeling (CASL) magnetic resonance (MR) imaging.

MATERIALS AND METHODS: This study was approved by the local institutional review board and was compliant with HIPAA regulations. Informed consent was obtained. rCBF was measured in 38 control subjects, 29 MCI patients, and 37 AD patients who were participating in a longitudinal epidemiologic study. Multisection CASL MR imaging with alternating single and double adiabatic inversion pulses and ramp-sampled echo-planar imaging were performed to acquire 19 contiguous axial sections. Voxel-level rCBF was compared among groups by using an analysis of variance design; clusters of voxels with significant group differences were identified. Multiple regression models controlled for age, sex, and presence of hypertension and related the mean rCBF in those clusters to the presence of MCI and AD.

RESULTS: MCI and AD patients had decreased rCBF in the posterior cingulate gyrus (P = .01) with extension to the medial precuneus compared with that in control subjects. MCI patients had increased rCBF in the left hippocampus (P < .001), right amygdala (P = .007), and rostral head of the right caudate nucleus and ventral putamen and globus pallidus (P = .003) compared with that in control subjects. AD patients had decreased rCBF relative to that in control subjects and MCI patients in the left inferior parietal (P = .005), left lateral frontal (P < .001), left superior temporal (P = .001), and left orbitofrontal (P = .003) cortices. AD patients had increased rCBF in the right anterior cingulate gyrus (P = .02) compared with that in control subjects.

CONCLUSION: The transition from normal cognition to AD is associated with dynamic pathologic processes in the brain, and this is reflected by both decreases and increases in rCBF. Increases in rCBF suggest a cellular and vascular compensatory process associated with incipient AD.

SUPPLEMENTAL MATERIAL: http://radiology.rsnajnls.org/cgi/content/full/2503080751/DC1.

%B Radiology %V 250 %P 856-66 %8 2009 Mar %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/19164119?dopt=Abstract %R 10.1148/radiol.2503080751 %0 Journal Article %J PLoS One %D 2009 %T Multiple independent genetic factors at NOS1AP modulate the QT interval in a multi-ethnic population. %A Arking, Dan E %A Khera, Amit %A Xing, Chao %A Kao, W H Linda %A Post, Wendy %A Boerwinkle, Eric %A Chakravarti, Aravinda %K Adaptor Proteins, Signal Transducing %K Adolescent %K Adult %K African Americans %K Aged %K Death, Sudden, Cardiac %K Electrocardiography %K Ethnic Groups %K European Continental Ancestry Group %K Female %K Genome-Wide Association Study %K Heart Diseases %K Heart Rate %K Hispanic Americans %K Humans %K Linear Models %K Linkage Disequilibrium %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Sex Factors %K Young Adult %X

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

%B PLoS One %V 4 %P e4333 %8 2009 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/19180230?dopt=Abstract %R 10.1371/journal.pone.0004333 %0 Journal Article %J Nat Genet %D 2009 %T Multiple loci associated with indices of renal function and chronic kidney disease. %A Köttgen, Anna %A Glazer, Nicole L %A Dehghan, Abbas %A Hwang, Shih-Jen %A Katz, Ronit %A Li, Man %A Yang, Qiong %A Gudnason, Vilmundur %A Launer, Lenore J %A Harris, Tamara B %A Smith, Albert V %A Arking, Dan E %A Astor, Brad C %A Boerwinkle, Eric %A Ehret, Georg B %A Ruczinski, Ingo %A Scharpf, Robert B %A Chen, Yii-Der Ida %A de Boer, Ian H %A Haritunians, Talin %A Lumley, Thomas %A Sarnak, Mark %A Siscovick, David %A Benjamin, Emelia J %A Levy, Daniel %A Upadhyay, Ashish %A Aulchenko, Yurii S %A Hofman, Albert %A Rivadeneira, Fernando %A Uitterlinden, André G %A van Duijn, Cornelia M %A Chasman, Daniel I %A Paré, Guillaume %A Ridker, Paul M %A Kao, W H Linda %A Witteman, Jacqueline C %A Coresh, Josef %A Shlipak, Michael G %A Fox, Caroline S %K Chromosome Mapping %K Cohort Studies %K Genetic Variation %K Genome-Wide Association Study %K Glomerular Filtration Rate %K Humans %K Kidney %K Kidney Failure, Chronic %K Meta-Analysis as Topic %K Mucoproteins %K Netherlands %K Polymorphism, Single Nucleotide %K Prevalence %K Uromodulin %X

Chronic kidney disease (CKD) has a heritable component and is an important global public health problem because of its high prevalence and morbidity. We conducted genome-wide association studies (GWAS) to identify susceptibility loci for glomerular filtration rate, estimated by serum creatinine (eGFRcrea) and cystatin C (eGFRcys), and CKD (eGFRcrea < 60 ml/min/1.73 m(2)) in European-ancestry participants of four population-based cohorts (ARIC, CHS, FHS, RS; n = 19,877; 2,388 CKD cases), and tested for replication in 21,466 participants (1,932 CKD cases). We identified significant SNP associations (P < 5 × 10(-8)) with CKD at the UMOD locus, with eGFRcrea at UMOD, SHROOM3 and GATM-SPATA5L1, and with eGFRcys at CST and STC1. UMOD encodes the most common protein in human urine, Tamm-Horsfall protein, and rare mutations in UMOD cause mendelian forms of kidney disease. Our findings provide new insights into CKD pathogenesis and underscore the importance of common genetic variants influencing renal function and disease.

%B Nat Genet %V 41 %P 712-7 %8 2009 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/19430482?dopt=Abstract %R 10.1038/ng.377 %0 Journal Article %J Nat Genet %D 2009 %T Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium. %A Ganesh, Santhi K %A Zakai, Neil A %A van Rooij, Frank J A %A Soranzo, Nicole %A Smith, Albert V %A Nalls, Michael A %A Chen, Ming-Huei %A Köttgen, Anna %A Glazer, Nicole L %A Dehghan, Abbas %A Kuhnel, Brigitte %A Aspelund, Thor %A Yang, Qiong %A Tanaka, Toshiko %A Jaffe, Andrew %A Bis, Joshua C M %A Verwoert, Germaine C %A Teumer, Alexander %A Fox, Caroline S %A Guralnik, Jack M %A Ehret, Georg B %A Rice, Kenneth %A Felix, Janine F %A Rendon, Augusto %A Eiriksdottir, Gudny %A Levy, Daniel %A Patel, Kushang V %A Boerwinkle, Eric %A Rotter, Jerome I %A Hofman, Albert %A Sambrook, Jennifer G %A Hernandez, Dena G %A Zheng, Gang %A Bandinelli, Stefania %A Singleton, Andrew B %A Coresh, Josef %A Lumley, Thomas %A Uitterlinden, André G %A Vangils, Janine M %A Launer, Lenore J %A Cupples, L Adrienne %A Oostra, Ben A %A Zwaginga, Jaap-Jan %A Ouwehand, Willem H %A Thein, Swee-Lay %A Meisinger, Christa %A Deloukas, Panos %A Nauck, Matthias %A Spector, Tim D %A Gieger, Christian %A Gudnason, Vilmundur %A van Duijn, Cornelia M %A Psaty, Bruce M %A Ferrucci, Luigi %A Chakravarti, Aravinda %A Greinacher, Andreas %A O'Donnell, Christopher J %A Witteman, Jacqueline C M %A Furth, Susan %A Cushman, Mary %A Harris, Tamara B %A Lin, Jing-Ping %K Blood Pressure %K Cell Line %K Cohort Studies %K Endothelial Cells %K Erythrocytes %K Gene Expression %K Genome, Human %K Genome-Wide Association Study %K Humans %K Hypertension %K Phenotype %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %X

Measurements of erythrocytes within the blood are important clinical traits and can indicate various hematological disorders. We report here genome-wide association studies (GWAS) for six erythrocyte traits, including hemoglobin concentration (Hb), hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC) and red blood cell count (RBC). We performed an initial GWAS in cohorts of the CHARGE Consortium totaling 24,167 individuals of European ancestry and replication in additional independent cohorts of the HaemGen Consortium totaling 9,456 individuals. We identified 23 loci significantly associated with these traits in a meta-analysis of the discovery and replication cohorts (combined P values ranging from 5 x 10(-8) to 7 x 10(-86)). Our findings include loci previously associated with these traits (HBS1L-MYB, HFE, TMPRSS6, TFR2, SPTA1) as well as new associations (EPO, TFRC, SH2B3 and 15 other loci). This study has identified new determinants of erythrocyte traits, offering insight into common variants underlying variation in erythrocyte measures.

%B Nat Genet %V 41 %P 1191-8 %8 2009 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/19862010?dopt=Abstract %R 10.1038/ng.466 %0 Journal Article %J PLoS Genet %D 2009 %T NRXN3 is a novel locus for waist circumference: a genome-wide association study from the CHARGE Consortium. %A Heard-Costa, Nancy L %A Zillikens, M Carola %A Monda, Keri L %A Johansson, Asa %A Harris, Tamara B %A Fu, Mao %A Haritunians, Talin %A Feitosa, Mary F %A Aspelund, Thor %A Eiriksdottir, Gudny %A Garcia, Melissa %A Launer, Lenore J %A Smith, Albert V %A Mitchell, Braxton D %A McArdle, Patrick F %A Shuldiner, Alan R %A Bielinski, Suzette J %A Boerwinkle, Eric %A Brancati, Fred %A Demerath, Ellen W %A Pankow, James S %A Arnold, Alice M %A Chen, Yii-Der Ida %A Glazer, Nicole L %A McKnight, Barbara %A Psaty, Bruce M %A Rotter, Jerome I %A Amin, Najaf %A Campbell, Harry %A Gyllensten, Ulf %A Pattaro, Cristian %A Pramstaller, Peter P %A Rudan, Igor %A Struchalin, Maksim %A Vitart, Veronique %A Gao, Xiaoyi %A Kraja, Aldi %A Province, Michael A %A Zhang, Qunyuan %A Atwood, Larry D %A Dupuis, Josée %A Hirschhorn, Joel N %A Jaquish, Cashell E %A O'Donnell, Christopher J %A Vasan, Ramachandran S %A White, Charles C %A Aulchenko, Yurii S %A Estrada, Karol %A Hofman, Albert %A Rivadeneira, Fernando %A Uitterlinden, André G %A Witteman, Jacqueline C M %A Oostra, Ben A %A Kaplan, Robert C %A Gudnason, Vilmundur %A O'Connell, Jeffrey R %A Borecki, Ingrid B %A van Duijn, Cornelia M %A Cupples, L Adrienne %A Fox, Caroline S %A North, Kari E %K Aged %K Body Mass Index %K Cohort Studies %K European Continental Ancestry Group %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Nerve Tissue Proteins %K Obesity %K Polymorphism, Single Nucleotide %K Waist Circumference %X

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

%B PLoS Genet %V 5 %P e1000539 %8 2009 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/19557197?dopt=Abstract %R 10.1371/journal.pgen.1000539 %0 Journal Article %J Circulation %D 2009 %T N-terminal pro-B-type natriuretic peptide is a major predictor of the development of atrial fibrillation: the Cardiovascular Health Study. %A Patton, Kristen K %A Ellinor, Patrick T %A Heckbert, Susan R %A Christenson, Robert H %A DeFilippi, Christopher %A Gottdiener, John S %A Kronmal, Richard A %K Aged %K Aged, 80 and over %K Atrial Fibrillation %K Female %K Humans %K Immunoassay %K Longitudinal Studies %K Male %K Natriuretic Peptide, Brain %K Peptide Fragments %K Predictive Value of Tests %K Prevalence %K Proportional Hazards Models %K Risk Factors %X

BACKGROUND: Atrial fibrillation (AF), the most common cardiac rhythm abnormality, is associated with significant morbidity, mortality, and healthcare expenditures. Elevated B-type natriuretic peptide levels have been associated with the risk of heart failure, AF, and mortality.

METHODS AND RESULTS: The relation between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and AF was studied in 5445 Cardiovascular Health Study participants with the use of relative risk regression for predicting prevalent AF and Cox proportional hazards for predicting incident AF. NT-proBNP levels were strongly associated with prevalent AF, with an unadjusted prevalence ratio of 128 for the highest quintile (95% confidence interval, 17.9 to 913.3; P<0.001) and adjusted prevalence ratio of 147 for the highest quintile (95% confidence interval, 20.4 to 1064.3; P<0.001) compared with the lowest. After a median follow-up of 10 years (maximum of 16 years), there were 1126 cases of incident AF (a rate of 2.2 per 100 person-years). NT-proBNP was highly predictive of incident AF, with an unadjusted hazard ratio of 5.2 (95% confidence interval, 4.3 to 6.4; P<0.001) for the development of AF for the highest quintile compared with the lowest; for the same contrast, NT-proBNP remained the strongest predictor of incident AF after adjustment for an extensive number of covariates, including age, sex, medication use, blood pressure, echocardiographic parameters, diabetes mellitus, and heart failure, with an adjusted hazard ratio of 4.0 (95% confidence interval, 3.2 to 5.0; P<0.001).

CONCLUSIONS: In a community-based population of older adults, NT-proBNP was a remarkable predictor of incident AF, independent of any other previously described risk factor.

%B Circulation %V 120 %P 1768-74 %8 2009 Nov 03 %G eng %N 18 %1 http://www.ncbi.nlm.nih.gov/pubmed/19841297?dopt=Abstract %R 10.1161/CIRCULATIONAHA.109.873265 %0 Journal Article %J J Thromb Haemost %D 2009 %T Peak thrombin generation and subsequent venous thromboembolism: the Longitudinal Investigation of Thromboembolism Etiology (LITE) study. %A Lutsey, P L %A Folsom, A R %A Heckbert, S R %A Cushman, M %K Adult %K Aged %K Biomarkers %K Blood Coagulation Factors %K Case-Control Studies %K Ethnic Groups %K Factor VIII %K Female %K Fibrin Fibrinogen Degradation Products %K Humans %K Male %K Middle Aged %K Partial Thromboplastin Time %K Prospective Studies %K Risk Factors %K Thrombin %K United States %K Venous Thromboembolism %X

BACKGROUND: Thrombin is an enzyme that is essential for the acceleration of the coagulation cascade and the conversion of fibrinogen to clottable fibrin.

OBJECTIVES: We evaluated the relationship of basal peak thrombin generation with the risk of future venous thromboembolism (VTE), and determined whether associations were independent of other coagulation markers.

METHODS: The Longitudinal Investigation of Thromboembolism Etiology (LITE) study investigated VTE in two prospective population-based cohorts: the Atherosclerosis Risk in Communities (ARIC) study and the Cardiovascular Health Study (CHS). Peak thrombin generation was measured on stored plasma in a nested case-control sample (434 cases and 1004 controls). Logistic regression was used to estimate the relationship of peak thrombin generation with VTE, adjusted for age, sex, race, center, and body mass index. Mediation was evaluated by additionally adjusting for factor VIII and D-dimer.

RESULTS: Relative to the first quartile of peak thrombin generation, the odds ratio (OR) of VTE for those above the median was 1.74 [95% confidence interval (CI) 1.28-2.37]. The association was modestly attenuated by adjustment for FVIII and D-dimer (OR 1.47, 95% CI 1.05-2.05). Associations appeared to be stronger for idiopathic than for secondary VTE. Elevated peak thrombin generation more than added to the VTE risk associated with FV Leiden or low activated partial thromboplastin time.

CONCLUSIONS: In this prospective study of two independent cohorts, elevated basal peak thrombin generation was associated with subsequent risk of VTE, independently of established VTE risk factors.

%B J Thromb Haemost %V 7 %P 1639-48 %8 2009 Oct %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/19656279?dopt=Abstract %R 10.1111/j.1538-7836.2009.03561.x %0 Journal Article %J J Thromb Haemost %D 2009 %T Platelet count and the risk for thrombosis and death in the elderly. %A van der Bom, J G %A Heckbert, S R %A Lumley, T %A Holmes, C E %A Cushman, M %A Folsom, A R %A Rosendaal, F R %A Psaty, B M %K Aged %K Aged, 80 and over %K Cause of Death %K Cerebral Hemorrhage %K Female %K Humans %K Male %K Myocardial Infarction %K Platelet Count %K Risk %K Stroke %K Survival Analysis %K Thrombosis %K Venous Thrombosis %X

AIM: Our aim was to examine the association between platelet count and the incidence of myocardial infarction, ischemic stroke, hemorrhagic stroke, venous thrombosis, and mortality.

METHODS AND RESULTS: Platelet count was measured at baseline in 1989-1990 and at 3 years follow-up, or at baseline (for a newly recruited group) in 1992-1993 in 5766 community-dwelling individuals aged 65 years and older (mean age at baseline, 73 years). During 12-15 years of follow-up, there were 821 incident myocardial infarctions, 807 ischemic strokes, 161 hemorrhagic strokes, 159 venous thrombotic events, and 3413 participants died. Platelet count was not associated with the occurrence of myocardial infarction, ischemic or hemorrhagic stroke, venous thrombosis, or cardiovascular mortality. Non-cardiovascular mortality was higher among both participants with low and with high platelet count. Adjusted non-cardiovascular mortality rates for platelet counts below 100, 100-199, 300-399, and above 400 x 10(9) L(-1) relative to the reference mortality rate in participants with platelet count values between 200 and 299 x 10(9) L(-1) were 1.89 (1.21-2.96), 1.08 (0.98-1.20), 1.20 (1.06-1.37), and 1.47 (1.14-1.90), respectively.

CONCLUSION: Platelet counts were not associated with vascular outcomes but low and high platelet counts were associated with non-cardiovascular mortality, including cancer mortality.

%B J Thromb Haemost %V 7 %P 399-405 %8 2009 Mar %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/19143922?dopt=Abstract %R 10.1111/j.1538-7836.2008.03267.x %0 Journal Article %J Neurology %D 2009 %T Predicting risk of dementia in older adults: The late-life dementia risk index. %A Barnes, D E %A Covinsky, K E %A Whitmer, R A %A Kuller, L H %A Lopez, O L %A Yaffe, K %K Age Factors %K Aged %K Aged, 80 and over %K Alcohol Drinking %K Apolipoprotein E4 %K Body Mass Index %K Carotid Stenosis %K Cerebrum %K Cognition Disorders %K Cohort Studies %K Coronary Artery Bypass %K Dementia %K Female %K Genetic Markers %K Health Status Indicators %K Humans %K Logistic Models %K Male %K Predictive Value of Tests %K Risk Assessment %K Risk Factors %K Risk Reduction Behavior %X

OBJECTIVE: To develop a late-life dementia risk index that can accurately stratify older adults into those with a low, moderate, or high risk of developing dementia within 6 years.

METHODS: Subjects were 3,375 participants in the Cardiovascular Health Cognition Study without evidence of dementia at baseline. We used logistic regression to identify those factors most predictive of developing incident dementia within 6 years and developed a point system based on the logistic regression coefficients.

RESULTS: Subjects had a mean age of 76 years at baseline; 59% were women and 15% were African American. Fourteen percent (n = 480) developed dementia within 6 years. The final late-life dementia risk index included older age (1-2 points), poor cognitive test performance (2-4 points), body mass index <18.5 (2 points), > or =1 apolipoprotein E epsilon4 alleles (1 point), cerebral MRI findings of white matter disease (1 point) or ventricular enlargement (1 point), internal carotid artery thickening on ultrasound (1 point), history of bypass surgery (1 point), slow physical performance (1 point), and lack of alcohol consumption (1 point) (c statistic, 0.81; 95% confidence interval, 0.79-0.83). Four percent of subjects with low scores developed dementia over 6 years compared with 23% of subjects with moderate scores and 56% of subjects with high scores.

CONCLUSIONS: The late-life dementia risk index accurately stratified older adults into those with low, moderate, and high risk of developing dementia. This tool could be used in clinical or research settings to target prevention and intervention strategies toward high-risk individuals.

%B Neurology %V 73 %P 173-9 %8 2009 Jul 21 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/19439724?dopt=Abstract %R 10.1212/WNL.0b013e3181a81636 %0 Journal Article %J Am J Respir Crit Care Med %D 2009 %T Prospective study of sleep-disordered breathing and hypertension: the Sleep Heart Health Study. %A O'Connor, George T %A Caffo, Brian %A Newman, Anne B %A Quan, Stuart F %A Rapoport, David M %A Redline, Susan %A Resnick, Helaine E %A Samet, Jonathan %A Shahar, Eyal %K Adult %K Blood Pressure %K Confidence Intervals %K Cross-Sectional Studies %K Female %K Follow-Up Studies %K Humans %K Hypertension %K Incidence %K Male %K Middle Aged %K Odds Ratio %K Polysomnography %K Prognosis %K Prospective Studies %K Risk Factors %K Sleep Apnea Syndromes %K Time Factors %K United States %X

RATIONALE: Cross-sectional epidemiologic studies show an association between sleep-disordered breathing and hypertension, but only one cohort study has examined sleep-disordered breathing as a risk factor for incident hypertension.

OBJECTIVES: To examine whether sleep-disordered breathing increases the risk of incident hypertension among persons 40 years of age and older.

METHODS: In a prospective cohort study, we analyzed data from 2,470 participants who at baseline did not have hypertension, defined as blood pressure of at least 140/90 mm Hg or taking antihypertensive medication. The apnea-hypopnea index (AHI), the number of apneas plus hypopneas per hour of sleep, was measured by overnight in-home polysomnography. We estimated odds ratios for developing hypertension during 5 years of follow-up according to baseline AHI.

MEASUREMENTS AND MAIN RESULTS: The odds ratios for incident hypertension increased with increasing baseline AHI; however, this relationship was attenuated and not statistically significant after adjustment for baseline body-mass index. Although not statistically significant, the observed association between a baseline AHI greater than 30 and future hypertension (odds ratio, 1.51; 95% confidence interval, 0.93-2.47) does not exclude the possibility of a modest association.

CONCLUSIONS: Among middle-aged and older persons without hypertension, much of the relationship between AHI and risk of incident hypertension was accounted for by obesity. After adjustment for body mass index, the AHI was not a significant predictor of future hypertension, although a modest influence of an AHI greater than 30 on hypertension could not be excluded.

%B Am J Respir Crit Care Med %V 179 %P 1159-64 %8 2009 Jun 15 %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/19264976?dopt=Abstract %R 10.1164/rccm.200712-1809OC %0 Journal Article %J J Thromb Haemost %D 2009 %T Replication of findings on the association of genetic variation in 24 hemostasis genes and risk of incident venous thrombosis. %A Smith, N L %A Wiggins, K L %A Reiner, A P %A Lange, L A %A Cushman, M %A Heckbert, S R %A Lumley, T %A Rice, K M %A Folsom, A R %A Psaty, B M %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Case-Control Studies %K Cohort Studies %K Female %K Genetic Association Studies %K Genetic Predisposition to Disease %K Genetic Variation %K Haplotypes %K Hemostasis %K Humans %K Incidence %K Male %K Menopause %K Middle Aged %K Polymorphism, Single Nucleotide %K Reproducibility of Results %K Risk %K Thrombophilia %K Venous Thrombosis %K Young Adult %B J Thromb Haemost %V 7 %P 1743-6 %8 2009 Oct %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/19682239?dopt=Abstract %R 10.1111/j.1538-7836.2009.03567.x %0 Journal Article %J Ann Epidemiol %D 2009 %T Sibling history of myocardial infarction or stroke and risk of cardiovascular disease in the elderly: the Cardiovascular Health Study. %A Yanez, N David %A Burke, Gregory L %A Manolio, Teri %A Gardin, Julius M %A Polak, Joseph %K Aged %K Atherosclerosis %K Female %K Genetic Predisposition to Disease %K Humans %K Incidence %K Male %K Myocardial Infarction %K Odds Ratio %K Prevalence %K Prospective Studies %K Risk Factors %K Siblings %K Stroke %K United States %X

PURPOSE: To assess the relationship between sibling history of myocardial infarction (MI) or stroke with cardiovascular disease (CVD) and risk factors in older adults.

METHODS: Prospective cohort study of 5,888 older adults participating in the Cardiovascular Health Study (CHS). History of MI and stroke in siblings was obtained by self-report. Participants with positive sibling histories were compared to those with negative histories to determine if prevalent or incident disease (coronary heart disease [CHD], MI, stroke, angina), subclinical CVD (carotid wall thickness, left ventricular mass, hypertension, diabetes, ankle-brachial index), CVD risk factors differed between groups.

RESULTS: More than 91% (n = 5,383) of CHS participants reported at least one sibling. Sibling history of MI was associated with increased disease prevalence (CHD, MI, angina) and incidence (CHD, angina). Sibling history of stroke was associated with increased disease prevalence (CHD, angina). Sibling history of either MI or stroke was associated with increased disease prevalence and incidence for CHD, MI and angina, more subclinical disease, and a higher CVD risk profile.

CONCLUSIONS: Sibling history of MI and stroke were markers of higher CVD risk status even in older adults. Of clinical importance, participants with positive sibling history have numerous risk factors amenable to intervention.

%B Ann Epidemiol %V 19 %P 858-66 %8 2009 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/19944349?dopt=Abstract %R 10.1016/j.annepidem.2009.07.095 %0 Journal Article %J PLoS Med %D 2009 %T Sleep-disordered breathing and mortality: a prospective cohort study. %A Punjabi, Naresh M %A Caffo, Brian S %A Goodwin, James L %A Gottlieb, Daniel J %A Newman, Anne B %A O'Connor, George T %A Rapoport, David M %A Redline, Susan %A Resnick, Helaine E %A Robbins, John A %A Shahar, Eyal %A Unruh, Mark L %A Samet, Jonathan M %K Aged %K Coronary Artery Disease %K Female %K Humans %K Hypoxia %K Male %K Middle Aged %K Odds Ratio %K Proportional Hazards Models %K Prospective Studies %K Risk Factors %K Sex Factors %K Sleep Apnea Syndromes %K Survival Analysis %X

BACKGROUND: Sleep-disordered breathing is a common condition associated with adverse health outcomes including hypertension and cardiovascular disease. The overall objective of this study was to determine whether sleep-disordered breathing and its sequelae of intermittent hypoxemia and recurrent arousals are associated with mortality in a community sample of adults aged 40 years or older.

METHODS AND FINDINGS: We prospectively examined whether sleep-disordered breathing was associated with an increased risk of death from any cause in 6,441 men and women participating in the Sleep Heart Health Study. Sleep-disordered breathing was assessed with the apnea-hypopnea index (AHI) based on an in-home polysomnogram. Survival analysis and proportional hazards regression models were used to calculate hazard ratios for mortality after adjusting for age, sex, race, smoking status, body mass index, and prevalent medical conditions. The average follow-up period for the cohort was 8.2 y during which 1,047 participants (587 men and 460 women) died. Compared to those without sleep-disordered breathing (AHI: <5 events/h), the fully adjusted hazard ratios for all-cause mortality in those with mild (AHI: 5.0-14.9 events/h), moderate (AHI: 15.0-29.9 events/h), and severe (AHI: >or=30.0 events/h) sleep-disordered breathing were 0.93 (95% CI: 0.80-1.08), 1.17 (95% CI: 0.97-1.42), and 1.46 (95% CI: 1.14-1.86), respectively. Stratified analyses by sex and age showed that the increased risk of death associated with severe sleep-disordered breathing was statistically significant in men aged 40-70 y (hazard ratio: 2.09; 95% CI: 1.31-3.33). Measures of sleep-related intermittent hypoxemia, but not sleep fragmentation, were independently associated with all-cause mortality. Coronary artery disease-related mortality associated with sleep-disordered breathing showed a pattern of association similar to all-cause mortality.

CONCLUSIONS: Sleep-disordered breathing is associated with all-cause mortality and specifically that due to coronary artery disease, particularly in men aged 40-70 y with severe sleep-disordered breathing. Please see later in the article for the Editors' Summary.

%B PLoS Med %V 6 %P e1000132 %8 2009 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/19688045?dopt=Abstract %R 10.1371/journal.pmed.1000132 %0 Journal Article %J Stat Med %D 2009 %T Systematically missing confounders in individual participant data meta-analysis of observational cohort studies. %A Jackson, Dan %A White, Ian %A Kostis, J B %A Wilson, A C %A Folsom, A R %A Wu, K %A Chambless, L %A Benderly, M %A Goldbourt, U %A Willeit, J %A Kiechl, S %A Yarnell, J W G %A Sweetnam, P M %A Elwood, P C %A Cushman, M %A Psaty, B M %A Tracy, R P %A Tybjaerg-Hansen, A %A Haverkate, F %A de Maat, M P M %A Thompson, S G %A Fowkes, F G R %A Lee, A J %A Smith, F B %A Salomaa, V %A Harald, K %A Rasi, V %A Vahtera, E %A Jousilahti, P %A D'Agostino, R %A Kannel, W B %A Wilson, P W F %A Tofler, G %A Levy, D %A Marchioli, R %A Valagussa, F %A Rosengren, A %A Wilhelmsen, L %A Lappas, G %A Eriksson, H %A Cremer, P %A Nagel, D %A Curb, J D %A Rodriguez, B %A Yano, K %A Salonen, J T %A Nyyssönen, K %A Tuomainen, T-P %A Hedblad, B %A Engstrom, G %A Berglund, G %A Loewel, H %A Koenig, W %A Hense, H W %A Meade, T W %A Cooper, J A %A De Stavola, B %A Knottenbelt, C %A Miller, G J %A Cooper, J A %A Bauer, K A %A Rosenberg, R D %A Sato, S %A Kitamura, A %A Naito, Y %A Iso, H %A Salomaa, V %A Harald, K %A Rasi, V %A Vahtera, E %A Jousilahti, P %A Palosuo, T %A Ducimetiere, P %A Amouyel, P %A Arveiler, D %A Evans, A E %A Ferrieres, J %A Juhan-Vague, I %A Bingham, A %A Schulte, H %A Assmann, G %A Cantin, B %A Lamarche, B %A Després, J-P %A Dagenais, G R %A Tunstall-Pedoe, H %A Lowe, G D O %A Woodward, M %A Ben-Shlomo, Y %A Davey Smith, G %A Palmieri, V %A Yeh, J L %A Meade, T W %A Rudnicka, A %A Brennan, P %A Knottenbelt, C %A Cooper, J A %A Ridker, P %A Rodeghiero, F %A Tosetto, A %A Shepherd, J %A Lowe, G D O %A Ford, I %A Robertson, M %A Brunner, E %A Shipley, M %A Feskens, E J M %A Di Angelantonio, E %A Kaptoge, S %A Lewington, S %A Lowe, G D O %A Sarwar, N %A Thompson, S G %A Walker, M %A Watson, S %A White, I R %A Wood, A M %A Danesh, J %K Cohort Studies %K Computer Simulation %K Coronary Disease %K Data Interpretation, Statistical %K Female %K Fibrinogen %K Humans %K Male %K Meta-Analysis as Topic %K Models, Statistical %X

One difficulty in performing meta-analyses of observational cohort studies is that the availability of confounders may vary between cohorts, so that some cohorts provide fully adjusted analyses while others only provide partially adjusted analyses. Commonly, analyses of the association between an exposure and disease either are restricted to cohorts with full confounder information, or use all cohorts but do not fully adjust for confounding. We propose using a bivariate random-effects meta-analysis model to use information from all available cohorts while still adjusting for all the potential confounders. Our method uses both the fully adjusted and the partially adjusted estimated effects in the cohorts with full confounder information, together with an estimate of their within-cohort correlation. The method is applied to estimate the association between fibrinogen level and coronary heart disease incidence using data from 154,012 participants in 31 cohorts

%B Stat Med %V 28 %P 1218-37 %8 2009 Apr 15 %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/19222087?dopt=Abstract %R 10.1002/sim.3540 %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2009 %T Total and cause-specific mortality in the cardiovascular health study. %A Newman, Anne B %A Sachs, Michael C %A Arnold, Alice M %A Fried, Linda P %A Kronmal, Richard %A Cushman, Mary %A Psaty, Bruce M %A Harris, Tamara B %A Robbins, John A %A Burke, Gregory L %A Kuller, Lewis H %A Lumley, Thomas %K Age Factors %K Aged %K Aged, 80 and over %K Aging %K Cardiovascular Diseases %K Cause of Death %K Chronic Disease %K Cohort Studies %K Female %K Geriatric Assessment %K Health Surveys %K Humans %K Kaplan-Meier Estimate %K Male %K Probability %K Proportional Hazards Models %K Retrospective Studies %K Risk Assessment %K Severity of Illness Index %K Sex Factors %K Survival Analysis %K United States %X

BACKGROUND: Few cohort studies have adequate numbers of carefully reviewed deaths to allow an analysis of unique and shared risk factors for cause-specific mortality. Shared risk factors could be targeted for prevention of premature death and the study of longevity.

METHODS: A total of 5,888 community-dwelling persons aged 65 years or older living in four communities in the United States participated in the Cardiovascular Health Study cohort. Participants were initially recruited from 1989 to 1990; an additional 687 black participants were recruited in 1992-1993. The average length of follow-up was 16 years. Total and cause-specific mortality, including cardiovascular disease, stroke, cancer, dementia, pulmonary disease, infection, and other cause, were examined as outcomes. Variables previously associated with total mortality were examined for each cause of death using Cox proportional hazard models.

RESULTS: Multiple risk factors were related to total mortality. When examining specific causes, many factors were related to cardiovascular death, whereas fewer were related to other causes. For most causes, risk factors were specific for that cause. For example, apolipoprotein E epsilon4 was strongly associated for dementia death and forced vital capacity with pulmonary death. Age, male sex, markers of inflammation, and cognitive function were related to multiple causes of death.

CONCLUSIONS: In these older adults, associations of risk factors with a given cause of death were related to specific deficits in that same organ system. Inflammation may represent a common pathway to all causes of death.

%B J Gerontol A Biol Sci Med Sci %V 64 %P 1251-61 %8 2009 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/19723772?dopt=Abstract %R 10.1093/gerona/glp127 %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2009 %T Trajectories of dehydroepiandrosterone sulfate predict mortality in older adults: the cardiovascular health study. %A Cappola, Anne R %A O'Meara, Ellen S %A Guo, Wensheng %A Bartz, Traci M %A Fried, Linda P %A Newman, Anne B %K Age Factors %K Aged %K Aged, 80 and over %K Aging %K Biomarkers %K Cardiovascular Diseases %K Cause of Death %K Cohort Studies %K Dehydroepiandrosterone Sulfate %K Female %K Geriatric Assessment %K Humans %K Longitudinal Studies %K Male %K Predictive Value of Tests %K Proportional Hazards Models %K Risk Assessment %K Severity of Illness Index %K Sex Factors %K Survival Analysis %K United States %X

BACKGROUND: Dehydroepiandrosterone sulfate (DHEAS) has been proposed as an antiaging hormone, but its importance is unclear. Assessment of an individual's ability to maintain a DHEAS set point, through examination of multiple DHEAS levels over time, may provide insight into biologic aging.

METHODS: Using Cox proportional hazard models, we examined the relationship between DHEAS trajectory patterns and all-cause death in 950 individuals aged >or=65 years who were enrolled in the Cardiovascular Health Study and had DHEAS levels measured at three to six time points.

RESULTS: Overall, there was a slight decline in DHEAS levels over time (-0.013 microg/mL/y). Three trajectory components were examined: slope, variability, and baseline DHEAS. When examined individually, a steep decline or extreme variability in DHEAS levels was associated with higher mortality (p < .001 for each), whereas baseline DHEAS level was not. In adjusted models including all three components, steep decline (hazard ratio [HR] 1.75, confidence interval [CI] 1.32-2.33) and extreme variability (HR 1.89, CI 1.47-2.43) remained significant predictors of mortality, whereas baseline DHEAS level remained unpredictive of mortality (HR 0.97 per standard deviation, CI 0.88-1.07). The effect of trajectory pattern was more pronounced in men than in women. Individuals with both a steep decline and extreme variability in DHEAS levels had a significantly higher death rate than those with neither pattern (141 vs 48 deaths per 1,000 person-years, p < .001).

CONCLUSIONS: Our data show significant heterogeneity in the individual trajectories of DHEAS levels and suggest that these trajectories provide important biologic information about the rate of aging, whereas the DHEAS level itself does not.

%B J Gerontol A Biol Sci Med Sci %V 64 %P 1268-74 %8 2009 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/19713299?dopt=Abstract %R 10.1093/gerona/glp129 %0 Journal Article %J Nat Genet %D 2009 %T Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry. %A Benjamin, Emelia J %A Rice, Kenneth M %A Arking, Dan E %A Pfeufer, Arne %A van Noord, Charlotte %A Smith, Albert V %A Schnabel, Renate B %A Bis, Joshua C %A Boerwinkle, Eric %A Sinner, Moritz F %A Dehghan, Abbas %A Lubitz, Steven A %A D'Agostino, Ralph B %A Lumley, Thomas %A Ehret, Georg B %A Heeringa, Jan %A Aspelund, Thor %A Newton-Cheh, Christopher %A Larson, Martin G %A Marciante, Kristin D %A Soliman, Elsayed Z %A Rivadeneira, Fernando %A Wang, Thomas J %A Eiriksdottir, Gudny %A Levy, Daniel %A Psaty, Bruce M %A Li, Man %A Chamberlain, Alanna M %A Hofman, Albert %A Vasan, Ramachandran S %A Harris, Tamara B %A Rotter, Jerome I %A Kao, W H Linda %A Agarwal, Sunil K %A Stricker, Bruno H Ch %A Wang, Ke %A Launer, Lenore J %A Smith, Nicholas L %A Chakravarti, Aravinda %A Uitterlinden, André G %A Wolf, Philip A %A Sotoodehnia, Nona %A Köttgen, Anna %A van Duijn, Cornelia M %A Meitinger, Thomas %A Mueller, Martina %A Perz, Siegfried %A Steinbeck, Gerhard %A Wichmann, H-Erich %A Lunetta, Kathryn L %A Heckbert, Susan R %A Gudnason, Vilmundur %A Alonso, Alvaro %A Kääb, Stefan %A Ellinor, Patrick T %A Witteman, Jacqueline C M %K Atrial Fibrillation %K Chromosomes, Human, Pair 16 %K European Continental Ancestry Group %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Homeodomain Proteins %K Humans %K Meta-Analysis as Topic %K Mutation %K Polymorphism, Single Nucleotide %K Reproducibility of Results %X

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

%B Nat Genet %V 41 %P 879-81 %8 2009 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/19597492?dopt=Abstract %R 10.1038/ng.416 %0 Journal Article %J Nephrol Dial Transplant %D 2010 %T Age and cystatin C in healthy adults: a collaborative study. %A Odden, Michelle C %A Tager, Ira B %A Gansevoort, Ron T %A Bakker, Stephan J L %A Katz, Ronit %A Fried, Linda F %A Newman, Anne B %A Canada, Robert B %A Harris, Tamara %A Sarnak, Mark J %A Siscovick, David %A Shlipak, Michael G %K Adult %K Aged %K Aged, 80 and over %K Cross-Sectional Studies %K Cystatin C %K Humans %K Kidney %K Middle Aged %K Reference Values %X

BACKGROUND: Kidney function declines with age, but a substantial portion of this decline has been attributed to the higher prevalence of risk factors for kidney disease at older ages. The effect of age on kidney function has not been well described in a healthy population across a wide age spectrum.

METHODS: The authors pooled individual-level cross-sectional data from 18 253 persons aged 28-100 years in four studies: the Cardiovascular Health Study; the Health, Aging and Body Composition Study; the Multi-Ethnic Study of Atherosclerosis and the Prevention of Renal and Vascular End-Stage Disease cohort. Kidney function was measured by cystatin C. Clinical risk factors for kidney disease included diabetes, hypertension, obesity, smoking, coronary heart disease, cerebrovascular disease, peripheral arterial disease and heart failure.

RESULTS: Across the age range, there was a strong, non-linear association of age with cystatin C concentration. This association was substantial, even among participants free of clinical risk factors for kidney disease; mean cystatin C levels were 46% higher in participants 80 and older compared with those <40 years (1.06 versus 0.72 mg/L, P < 0.001). Participants with one or more risk factors had higher cystatin C concentrations for a given age, and the age association was slightly stronger (P < 0.001 for age and risk factor interaction).

CONCLUSIONS: There is a strong, non-linear association of age with kidney function, even in healthy individuals. An important area for research will be to investigate the mechanisms that lead to deterioration of kidney function in apparently healthy persons.

%B Nephrol Dial Transplant %V 25 %P 463-9 %8 2010 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/19749145?dopt=Abstract %R 10.1093/ndt/gfp474 %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 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 Circ Cardiovasc Genet %D 2010 %T Association of genome-wide variation with the risk of incident heart failure in adults of European and African ancestry: a prospective meta-analysis from the cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium. %A Smith, Nicholas L %A Felix, Janine F %A Morrison, Alanna C %A Demissie, Serkalem %A Glazer, Nicole L %A Loehr, Laura R %A Cupples, L Adrienne %A Dehghan, Abbas %A Lumley, Thomas %A Rosamond, Wayne D %A Lieb, Wolfgang %A Rivadeneira, Fernando %A Bis, Joshua C %A Folsom, Aaron R %A Benjamin, Emelia %A Aulchenko, Yurii S %A Haritunians, Talin %A Couper, David %A Murabito, Joanne %A Wang, Ying A %A Stricker, Bruno H %A Gottdiener, John S %A Chang, Patricia P %A Wang, Thomas J %A Rice, Kenneth M %A Hofman, Albert %A Heckbert, Susan R %A Fox, Ervin R %A O'Donnell, Christopher J %A Uitterlinden, André G %A Rotter, Jerome I %A Willerson, James T %A Levy, Daniel %A van Duijn, Cornelia M %A Psaty, Bruce M %A Witteman, Jacqueline C M %A Boerwinkle, Eric %A Vasan, Ramachandran S %K African Americans %K Aged %K Aged, 80 and over %K Cohort Studies %K Endopeptidases %K European Continental Ancestry Group %K Female %K Genome-Wide Association Study %K Heart Failure %K Humans %K Incidence %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Risk %K Ubiquitin-Specific Proteases %X

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

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

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

%B Circ Cardiovasc Genet %V 3 %P 256-66 %8 2010 Jun %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/20445134?dopt=Abstract %R 10.1161/CIRCGENETICS.109.895763 %0 Journal Article %J JAMA %D 2010 %T Association of serial measures of cardiac troponin T using a sensitive assay with incident heart failure and cardiovascular mortality in older adults. %A deFilippi, Christopher R %A de Lemos, James A %A Christenson, Robert H %A Gottdiener, John S %A Kop, Willem J %A Zhan, Min %A Seliger, Stephen L %K Aged %K Biomarkers %K Cardiovascular Diseases %K Cohort Studies %K Female %K Heart Failure %K Humans %K Incidence %K Male %K Predictive Value of Tests %K Risk %K Sensitivity and Specificity %K Troponin T %K United States %X

CONTEXT: Older adults comprise the majority of new-onset heart failure (HF) diagnoses, but traditional risk-factor prediction models have limited accuracy in this population to identify those at highest risk for hospitalization or death.

OBJECTIVES: To determine if cardiac troponin T (cTnT) measured by a highly sensitive assay would be detectable in the majority of community-dwelling older adults, and if serial measures were associated with risk of HF hospitalization and cardiovascular death.

DESIGN, SETTING, AND PARTICIPANTS: A longitudinal nationwide cohort study (Cardiovascular Health Study) of 4221 community-dwelling adults aged 65 years or older without prior HF who had cTnT measured using a highly sensitive assay at baseline (1989-1990) and repeated after 2 to 3 years (n = 2918).

MAIN OUTCOME MEASURES: New-onset HF and cardiovascular death were examined through June 2008 with respect to cTnT concentrations, accounting for clinical risk predictors.

RESULTS: Cardiac troponin T was detectable (≥3.00 pg/mL) in 2794 participants (66.2%). During a median follow-up of 11.8 years, 1279 participants experienced new-onset HF and 1103 cardiovascular deaths occurred, with a greater risk of both end points associated with higher cTnT concentrations. Among those participants with the highest cTnT concentrations (>12.94 pg/mL), there was an incidence rate per 100 person-years of 6.4 (95% confidence interval [CI], 5.8-7.2; adjusted hazard ratio [aHR], 2.48; 95% CI, 2.04-3.00) for HF and an incidence rate of 4.8 (95% CI, 4.3-5.4; aHR, 2.91; 95% CI, 2.37-3.58) for cardiovascular death compared with participants with undetectable cTnT levels (incidence rate, 1.6; 95% CI, 1.4-1.8 and 1.1; 95% CI, 0.9-1.2 for HF and cardiovascular death, respectively). Among individuals with initially detectable cTnT, a subsequent increase of more than 50% (n = 393, 22%) was associated with a greater risk for HF (aHR, 1.61; 95% CI, 1.32-1.97) and cardiovascular death (aHR, 1.65; 95% CI, 1.35-2.03) and a decrease of more than 50% (n = 247, 14%) was associated with a lower risk for HF (aHR, 0.73; 95% CI, 0.54-0.97) and cardiovascular death (aHR, 0.71; 95% CI, 0.52-0.97) compared with participants with 50% or less change. Addition of baseline cTnT measurements to clinical risk factors was associated with only modest improvement in discrimination, with change in C statistic of 0.015 for HF and 0.013 for cardiovascular death.

CONCLUSION: In this cohort of older adults without known HF, baseline cTnT levels and changes in cTnT levels measured with a highly sensitive assay were significantly associated with incident HF and cardiovascular death.

%B JAMA %V 304 %P 2494-502 %8 2010 Dec 08 %G eng %N 22 %1 http://www.ncbi.nlm.nih.gov/pubmed/21078811?dopt=Abstract %R 10.1001/jama.2010.1708 %0 Journal Article %J Am J Kidney Dis %D 2010 %T Associations between renal duplex parameters and adverse cardiovascular events in the elderly: a prospective cohort study. %A Pearce, Jeffrey D %A Craven, Timothy E %A Edwards, Matthew S %A Corriere, Matthew A %A Crutchley, Teresa A %A Fleming, Shawn H %A Hansen, Kimberley J %K Aged %K Cardiovascular Diseases %K Cohort Studies %K Female %K Humans %K Kidney Diseases %K Male %K Renal Artery %K Risk Factors %K Ultrasonography, Doppler, Duplex %X

BACKGROUND: Atherosclerotic renovascular disease is associated with an increased risk of cardiovascular disease (CVD) events. This study examines associations between Doppler-derived parameters from the renal artery and renal parenchyma and all-cause mortality and fatal and nonfatal CVD events in a cohort of elderly Americans.

STUDY DESIGN: Cohort study.

SETTING: A subset of participants from the Cardiovascular Health Study (CHS). Through an ancillary study, 870 (70% recruitment) Forsyth County, NC, CHS participants consented to undergo renal duplex sonography to define the prevalence of renovascular disease in the elderly, resulting in 726 (36% men; mean age, 77 years) technically adequate complete studies included in this investigation.

PREDICTOR: Renal duplex sonography-derived Doppler signals from the main renal arteries and renal parenchyma. Spectral analysis from Doppler-shifted frequencies and angle of insonation were used to estimate renal artery peak systolic and end diastolic velocity (both in meters per second). Color Doppler was used to identify the corticomedullary junction. Using a 3-mm Doppler sample, the parenchymal peak systolic and end diastolic frequency shift (both in kilohertz) were obtained. Resistive index was calculated as (1 - [end diastolic frequency shift/peak systolic frequency shift]) using Doppler samples from the hilar arteries of the left or right kidney with the higher main renal artery peak systolic velocity.

OUTCOMES & MEASUREMENTS: Proportional hazard regression analysis was used to determine associations between renal duplex sonography-derived Doppler signals and CVD events and all-cause mortality adjusted for accepted cardiovascular risk factors. Index CVD outcomes were defined as coronary events (angina, myocardial infarction, and coronary artery bypass grafting/percutaneous coronary intervention), cerebrovascular events (stroke or transient ischemic attack), and any CVD event (angina, congestive heart failure, myocardial infarction, stroke, transient ischemic attack, and coronary artery bypass grafting [CABG]/percutaneous transluminal coronary intervention [PTCI]).

RESULTS: During follow-up, 221 deaths (31%), 229 CVD events (32%), 122 coronary events (17%), and 92 cerebrovascular events (13%) were observed. Renal duplex sonography-derived Doppler signals from the renal parenchyma were associated independently with all-cause mortality and CVD outcomes. In particular, increased parenchymal end diastolic frequency shift was associated significantly with any CVD event (HR, 0.73; 95% CI, 0.62-0.87; P < 0.001). Marginally significant associations were observed between increases in parenchymal end diastolic frequency shift and decreased risk of death (HR, 0.86; 95% CI, 0.73-1.00; P = 0.06) and decreased risk of cerebrovascular events (HR, 0.78; 95% CI, 0.61-1.01; P = 0.06). Parenchymal end diastolic frequency shift was not significantly predictive of coronary events (HR, 0.84; 95% CI, 0.67-1.06; P = 0.1).

LIMITATIONS: CHS participants showed a "healthy cohort" effect that may underestimate the rate of CVD events in the general population.

CONCLUSION: Renal duplex sonographic Doppler signals from the renal parenchyma showed significant associations with subsequent CVD events after controlling for other significant risk factors. In particular, a standard deviation increase in parenchymal end diastolic frequency shift was associated with 27% risk reduction in any CVD event.

%B Am J Kidney Dis %V 55 %P 281-90 %8 2010 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/20116688?dopt=Abstract %R 10.1053/j.ajkd.2009.10.044 %0 Journal Article %J Am J Respir Crit Care Med %D 2010 %T Associations of PM10 with sleep and sleep-disordered breathing in adults from seven U.S. urban areas. %A Zanobetti, Antonella %A Redline, Susan %A Schwartz, Joel %A Rosen, Dennis %A Patel, Sanjay %A O'Connor, George T %A Lebowitz, Michael %A Coull, Brent A %A Gold, Diane R %K Adult %K Aged %K Aged, 80 and over %K Air Pollutants %K Air Pollution %K Cities %K Cohort Studies %K Female %K Humans %K Male %K Middle Aged %K Multicenter Studies as Topic %K Particle Size %K Particulate Matter %K Polysomnography %K Seasons %K Severity of Illness Index %K Sleep %K Sleep Apnea Syndromes %K Temperature %K United States %K Urban Health %X

RATIONALE: Sleep-disordered breathing (SDB), the recurrent episodic disruption of normal breathing during sleep, affects as much as 17% of U.S. adults, and may be more prevalent in poor urban environments. SDB and air pollution have been linked to increased cardiovascular diseases and mortality, but the association between pollution and SDB is poorly understood.

OBJECTIVES: We used data from the Sleep Heart Health Study (SHHS), a U.S. multicenter cohort study assessing cardiovascular and other consequences of SDB, to examine whether particulate air matter less than 10 μm in aerodynamic diameter (PM(10)) was associated with SDB among persons 39 years of age and older.

METHODS: Using baseline data from SHHS urban sites, outcomes included the following: the respiratory disturbance index (RDI); percentage of sleep time at less than 90% O(2) saturation; and sleep efficiency, measured by overnight in-home polysomnography. We applied a fixed-effect model containing a city effect, controlling for potential predictors. In all models we included both the 365-day moving averages of PM(10) and temperature (long-term effects) and the differences between the daily measures of these two predictors and their 365-day average (short-term effects).

MEASUREMENTS AND MAIN RESULTS: In summer, increases in RDI or percentage of sleep time at less than 90% O(2) saturation, and decreases in sleep efficiency, were all associated with increases in short-term variation in PM(10). Over all seasons, we found that increased RDI was associated with an 11.5% (95% confidence interval: 1.96, 22.01) increase per interquartile range increase (25.5°F) in temperature.

CONCLUSIONS: Reduction in air pollution exposure may decrease the severity of SDB and nocturnal hypoxemia and may improve cardiac risk.

%B Am J Respir Crit Care Med %V 182 %P 819-25 %8 2010 Sep 15 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/20508218?dopt=Abstract %R 10.1164/rccm.200912-1797OC %0 Journal Article %J Stat Med %D 2010 %T Bayesian methods for meta-analysis of causal relationships estimated using genetic instrumental variables. %A Burgess, Stephen %A Thompson, Simon G %A Burgess, S %A Thompson, S G %A Andrews, G %A Samani, N J %A Hall, A %A Whincup, P %A Morris, R %A Lawlor, D A %A Davey Smith, G %A Timpson, N %A Ebrahim, S %A Ben-Shlomo, Y %A Davey Smith, G %A Timpson, N %A Brown, M %A Ricketts, S %A Sandhu, M %A Reiner, A %A Psaty, B %A Lange, L %A Cushman, M %A Hung, J %A Thompson, P %A Beilby, J %A Warrington, N %A Palmer, L J %A Nordestgaard, B G %A Tybjaerg-Hansen, A %A Zacho, J %A Wu, C %A Lowe, G %A Tzoulaki, I %A Kumari, M %A Sandhu, M %A Yamamoto, J F %A Chiodini, B %A Franzosi, M %A Hankey, G J %A Jamrozik, K %A Palmer, L %A Rimm, E %A Pai, J %A Psaty, B %A Heckbert, S %A Bis, J %A Anand, S %A Engert, J %A Collins, R %A Clarke, R %A Melander, O %A Berglund, G %A Ladenvall, P %A Johansson, L %A Jansson, J-H %A Hallmans, G %A Hingorani, A %A Humphries, S %A Rimm, E %A Manson, J %A Pai, J %A Watkins, H %A Clarke, R %A Hopewell, J %A Saleheen, D %A Frossard, R %A Danesh, J %A Sattar, N %A Robertson, M %A Shepherd, J %A Schaefer, E %A Hofman, A %A Witteman, J C M %A Kardys, I %A Ben-Shlomo, Y %A Davey Smith, G %A Timpson, N %A de Faire, U %A Bennet, A %A Sattar, N %A Ford, I %A Packard, C %A Kumari, M %A Manson, J %A Lawlor, Debbie A %A Davey Smith, George %A Anand, S %A Collins, R %A Casas, J P %A Danesh, J %A Davey Smith, G %A Franzosi, M %A Hingorani, A %A Lawlor, D A %A Manson, J %A Nordestgaard, B G %A Samani, N J %A Sandhu, M %A Smeeth, L %A Wensley, F %A Anand, S %A Bowden, J %A Burgess, S %A Casas, J P %A Di Angelantonio, E %A Engert, J %A Gao, P %A Shah, T %A Smeeth, L %A Thompson, S G %A Verzilli, C %A Walker, M %A Whittaker, J %A Hingorani, A %A Danesh, J %K Bayes Theorem %K Biostatistics %K C-Reactive Protein %K Fibrinogen %K Genetic Markers %K Humans %K Meta-Analysis as Topic %K Models, Statistical %K Phenotype %K Polymorphism, Single Nucleotide %X

Genetic markers can be used as instrumental variables, in an analogous way to randomization in a clinical trial, to estimate the causal relationship between a phenotype and an outcome variable. Our purpose is to extend the existing methods for such Mendelian randomization studies to the context of multiple genetic markers measured in multiple studies, based on the analysis of individual participant data. First, for a single genetic marker in one study, we show that the usual ratio of coefficients approach can be reformulated as a regression with heterogeneous error in the explanatory variable. This can be implemented using a Bayesian approach, which is next extended to include multiple genetic markers. We then propose a hierarchical model for undertaking a meta-analysis of multiple studies, in which it is not necessary that the same genetic markers are measured in each study. This provides an overall estimate of the causal relationship between the phenotype and the outcome, and an assessment of its heterogeneity across studies. As an example, we estimate the causal relationship of blood concentrations of C-reactive protein on fibrinogen levels using data from 11 studies. These methods provide a flexible framework for efficient estimation of causal relationships derived from multiple studies. Issues discussed include weak instrument bias, analysis of binary outcome data such as disease risk, missing genetic data, and the use of haplotypes.

%B Stat Med %V 29 %P 1298-311 %8 2010 May 30 %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/20209660?dopt=Abstract %R 10.1002/sim.3843 %0 Journal Article %J Nature %D 2010 %T Biological, clinical and population relevance of 95 loci for blood lipids. %A Teslovich, Tanya M %A Musunuru, Kiran %A Smith, Albert V %A Edmondson, Andrew C %A Stylianou, Ioannis M %A Koseki, Masahiro %A Pirruccello, James P %A Ripatti, Samuli %A Chasman, Daniel I %A Willer, Cristen J %A Johansen, Christopher T %A Fouchier, Sigrid W %A Isaacs, Aaron %A Peloso, Gina M %A Barbalic, Maja %A Ricketts, Sally L %A Bis, Joshua C %A Aulchenko, Yurii S %A Thorleifsson, Gudmar %A Feitosa, Mary F %A Chambers, John %A Orho-Melander, Marju %A Melander, Olle %A Johnson, Toby %A Li, Xiaohui %A Guo, Xiuqing %A Li, Mingyao %A Shin Cho, Yoon %A Jin Go, Min %A Jin Kim, Young %A Lee, Jong-Young %A Park, Taesung %A Kim, Kyunga %A Sim, Xueling %A Twee-Hee Ong, Rick %A Croteau-Chonka, Damien C %A Lange, Leslie A %A Smith, Joshua D %A Song, Kijoung %A Hua Zhao, Jing %A Yuan, Xin %A Luan, Jian'an %A Lamina, Claudia %A Ziegler, Andreas %A Zhang, Weihua %A Zee, Robert Y L %A Wright, Alan F %A Witteman, Jacqueline C M %A Wilson, James F %A Willemsen, Gonneke %A Wichmann, H-Erich %A Whitfield, John B %A Waterworth, Dawn M %A Wareham, Nicholas J %A Waeber, Gérard %A Vollenweider, Peter %A Voight, Benjamin F %A Vitart, Veronique %A Uitterlinden, André G %A Uda, Manuela %A Tuomilehto, Jaakko %A Thompson, John R %A Tanaka, Toshiko %A Surakka, Ida %A Stringham, Heather M %A Spector, Tim D %A Soranzo, Nicole %A Smit, Johannes H %A Sinisalo, Juha %A Silander, Kaisa %A Sijbrands, Eric J G %A Scuteri, Angelo %A Scott, James %A Schlessinger, David %A Sanna, Serena %A Salomaa, Veikko %A Saharinen, Juha %A Sabatti, Chiara %A Ruokonen, Aimo %A Rudan, Igor %A Rose, Lynda M %A Roberts, Robert %A Rieder, Mark %A Psaty, Bruce M %A Pramstaller, Peter P %A Pichler, Irene %A Perola, Markus %A Penninx, Brenda W J H %A Pedersen, Nancy L %A Pattaro, Cristian %A Parker, Alex N %A Paré, Guillaume %A Oostra, Ben A %A O'Donnell, Christopher J %A Nieminen, Markku S %A Nickerson, Deborah A %A Montgomery, Grant W %A Meitinger, Thomas %A McPherson, Ruth %A McCarthy, Mark I %A McArdle, Wendy %A Masson, David %A Martin, Nicholas G %A Marroni, Fabio %A Mangino, Massimo %A Magnusson, Patrik K E %A Lucas, Gavin %A Luben, Robert %A Loos, Ruth J F %A Lokki, Marja-Liisa %A Lettre, Guillaume %A Langenberg, Claudia %A Launer, Lenore J %A Lakatta, Edward G %A Laaksonen, Reijo %A Kyvik, Kirsten O %A Kronenberg, Florian %A König, Inke R %A Khaw, Kay-Tee %A Kaprio, Jaakko %A Kaplan, Lee M %A Johansson, Asa %A Jarvelin, Marjo-Riitta %A Janssens, A Cecile J W %A Ingelsson, Erik %A Igl, Wilmar %A Kees Hovingh, G %A Hottenga, Jouke-Jan %A Hofman, Albert %A Hicks, Andrew A %A Hengstenberg, Christian %A Heid, Iris M %A Hayward, Caroline %A Havulinna, Aki S %A Hastie, Nicholas D %A Harris, Tamara B %A Haritunians, Talin %A Hall, Alistair S %A Gyllensten, Ulf %A Guiducci, Candace %A Groop, Leif C %A Gonzalez, Elena %A Gieger, Christian %A Freimer, Nelson B %A Ferrucci, Luigi %A Erdmann, Jeanette %A Elliott, Paul %A Ejebe, Kenechi G %A Döring, Angela %A Dominiczak, Anna F %A Demissie, Serkalem %A Deloukas, Panagiotis %A de Geus, Eco J C %A de Faire, Ulf %A Crawford, Gabriel %A Collins, Francis S %A Chen, Yii-der I %A Caulfield, Mark J %A Campbell, Harry %A Burtt, Noel P %A Bonnycastle, Lori L %A Boomsma, Dorret I %A Boekholdt, S Matthijs %A Bergman, Richard N %A Barroso, Inês %A Bandinelli, Stefania %A Ballantyne, Christie M %A Assimes, Themistocles L %A Quertermous, Thomas %A Altshuler, David %A Seielstad, Mark %A Wong, Tien Y %A Tai, E-Shyong %A Feranil, Alan B %A Kuzawa, Christopher W %A Adair, Linda S %A Taylor, Herman A %A Borecki, Ingrid B %A Gabriel, Stacey B %A Wilson, James G %A Holm, Hilma %A Thorsteinsdottir, Unnur %A Gudnason, Vilmundur %A Krauss, Ronald M %A Mohlke, Karen L %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 Rotter, Jerome I %A Boerwinkle, Eric %A Strachan, David P %A Mooser, Vincent %A Stefansson, Kari %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 van Duijn, Cornelia M %A Peltonen, Leena %A Abecasis, Goncalo R %A Boehnke, Michael %A Kathiresan, Sekar %K African Americans %K Animals %K Asian Continental Ancestry Group %K Cholesterol, HDL %K Cholesterol, LDL %K Coronary Artery Disease %K Europe %K European Continental Ancestry Group %K Female %K Genetic Loci %K Genome-Wide Association Study %K Genotype %K Humans %K Lipid Metabolism %K Lipids %K Liver %K Male %K Mice %K N-Acetylgalactosaminyltransferases %K Phenotype %K Polymorphism, Single Nucleotide %K Protein Phosphatase 1 %K Reproducibility of Results %K Triglycerides %X

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

%B Nature %V 466 %P 707-13 %8 2010 Aug 05 %G eng %N 7307 %1 http://www.ncbi.nlm.nih.gov/pubmed/20686565?dopt=Abstract %R 10.1038/nature09270 %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2010 %T Body weight dynamics and their association with physical function and mortality in older adults: the Cardiovascular Health Study. %A Arnold, Alice M %A Newman, Anne B %A Cushman, Mary %A Ding, Jingzhong %A Kritchevsky, Stephen %K Activities of Daily Living %K Age Factors %K Aged, 80 and over %K Body Weight %K Cardiovascular Diseases %K Female %K Follow-Up Studies %K Health Status %K Humans %K Longevity %K Male %K Prospective Studies %K Risk Factors %K Survival Rate %K United States %X

BACKGROUND: To estimate the associations of weight dynamics with physical functioning and mortality in older adults.

METHODS: Longitudinal cohort study using prospectively collected data on weight, physical function, and health status in four U.S. Communities in the Cardiovascular Health Study. Included were 3,278 participants (2,013 women and 541 African Americans), aged 65 or older at enrollment, who had at least five weight measurements. Weight was measured at annual clinic visits between 1992 and 1999, and summary measures of mean weight, coefficient of variation, average annual weight change, and episodes of loss and gain (cycling) were calculated. Participants were followed from 1999 to 2006 for activities of daily living (ADL) difficulty, incident mobility limitations, and mortality.

RESULTS: Higher mean weight, weight variability, and weight cycling increased the risk of new onset of ADL difficulties and mobility limitations. After adjustment for risk factors, the hazard ratio (95% confidence interval) for weight cycling for incident ADL impairment was 1.28 (1.12, 1.47), similar to that for several comorbidities in our model, including cancer and diabetes. Lower weight, weight loss, higher variability, and weight cycling were all risk factors for mortality, after adjustment for demographic risk factors, height, self-report health status, and comorbidities.

CONCLUSIONS: Variations in weight are important indicators of future physical limitations and mortality in the elderly and may reflect difficulties in maintaining homeostasis throughout older ages. Monitoring the weight of an older person for fluctuations or episodes of both loss and gain is an important aspect of geriatric care.

%B J Gerontol A Biol Sci Med Sci %V 65 %P 63-70 %8 2010 Jan %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/19386574?dopt=Abstract %R 10.1093/gerona/glp050 %0 Journal Article %J Circ Cardiovasc Genet %D 2010 %T Candidate gene association resource (CARe): design, methods, and proof of concept. %A Musunuru, Kiran %A Lettre, Guillaume %A Young, Taylor %A Farlow, Deborah N %A Pirruccello, James P %A Ejebe, Kenechi G %A Keating, Brendan J %A Yang, Qiong %A Chen, Ming-Huei %A Lapchyk, Nina %A Crenshaw, Andrew %A Ziaugra, Liuda %A Rachupka, Anthony %A Benjamin, Emelia J %A Cupples, L Adrienne %A Fornage, Myriam %A Fox, Ervin R %A Heckbert, Susan R %A Hirschhorn, Joel N %A Newton-Cheh, Christopher %A Nizzari, Marcia M %A Paltoo, Dina N %A Papanicolaou, George J %A Patel, Sanjay R %A Psaty, Bruce M %A Rader, Daniel J %A Redline, Susan %A Rich, Stephen S %A Rotter, Jerome I %A Taylor, Herman A %A Tracy, Russell P %A Vasan, Ramachandran S %A Wilson, James G %A Kathiresan, Sekar %A Fabsitz, Richard R %A Boerwinkle, Eric %A Gabriel, Stacey B %K African Americans %K Cholesterol, HDL %K Cholesterol, LDL %K Cohort Studies %K Databases, Genetic %K European Continental Ancestry Group %K Genetic Association Studies %K Genotype %K Humans %K Phenotype %K Pilot Projects %K Polymorphism, Single Nucleotide %K Research Design %K Triglycerides %X

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

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

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

%B Circ Cardiovasc Genet %V 3 %P 267-75 %8 2010 Jun %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/20400780?dopt=Abstract %R 10.1161/CIRCGENETICS.109.882696 %0 Journal Article %J J Am Geriatr Soc %D 2010 %T Cardiovascular disease is associated with greater incident dehydroepiandrosterone sulfate decline in the oldest old: the cardiovascular health study all stars study. %A Sanders, Jason L %A Boudreau, Robert M %A Cappola, Anne R %A Arnold, Alice M %A Robbins, John %A Cushman, Mary %A Newman, Anne B %K Age Distribution %K Aged %K Aged, 80 and over %K Biomarkers %K Cardiovascular Diseases %K Cross-Sectional Studies %K Dehydroepiandrosterone Sulfate %K Female %K Humans %K Longitudinal Studies %K Male %K Multivariate Analysis %K Regression Analysis %K Sex Distribution %K United States %X

OBJECTIVES: To describe cross-sectional and longitudinal associations with dehydroepiandrosterone sulfate (DHEAS) and change in DHEAS with age.

DESIGN: Longitudinal cohort study.

SETTING: Pittsburgh, Pennsylvania.

PARTICIPANTS: Cardiovascular Health Study All Stars study participants assessed in 2005/06 (N=989, mean age 85.2, 63.5% women, 16.5% African American).

MEASUREMENTS: Health characteristics were assessed in 2005/06 according to DHEAS level, mean DHEAS and DHEAS change across age categories were tested, and linear and logistic regression was used to identify factors present in 1996/97 associated with continuous and categorical DHEAS change.

RESULTS: Mean +/- standard deviation DHEAS was 0.555 +/- 0.414 microg/mL in 1996/97 and 0.482 +/- 0.449 microg/mL in 2005/06 for women and 0.845 +/- 0.520 microg/mL in 1996/97 and 0.658 +/- 0.516 microg/mL in 2005/06 for men. In 2005/06, DHEAS was lower in women and subjects with cardiovascular disease (CVD) and chronic pulmonary disease and higher for African Americans and subjects with hypertension and high cholesterol. Mean DHEAS change was greater in men (-0.200 microg/mL) than in women (-0.078 microg/mL) (P<.001). Each 1-year increase in age attenuated the effect of male sex by 0.01 microg/mL (P=.009), abolishing the sex difference in DHEAS change by age 79. Presence of CVD before the study period was associated with greater absolute DHEAS change (beta=-0.04 microg/mL, P=.04) and with the fourth quartile of DHEAS change versus the first to third quartiles (odds ratio=1.46, 95% confidence interval=1.03-2.05).

CONCLUSION: DHEAS change continues into very old age, is not homogenous, is affected by sex, and is associated with prevalent CVD. Future studies should investigate factors that might accelerate DHEAS decline.

%B J Am Geriatr Soc %V 58 %P 421-6 %8 2010 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/20163485?dopt=Abstract %R 10.1111/j.1532-5415.2010.02724.x %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2010 %T Change in circulating adiponectin in advanced old age: determinants and impact on physical function and mortality. The Cardiovascular Health Study All Stars Study. %A Kizer, Jorge R %A Arnold, Alice M %A Strotmeyer, Elsa S %A Ives, Diane G %A Cushman, Mary %A Ding, Jingzhong %A Kritchevsky, Stephen B %A Chaves, Paulo H M %A Hirsch, Calvin H %A Newman, Anne B %K Adiponectin %K Age Factors %K Aged %K Aging %K Analysis of Variance %K Cardiovascular Diseases %K Cause of Death %K Chi-Square Distribution %K Cohort Studies %K Cross-Sectional Studies %K Female %K Health Status %K Humans %K Linear Models %K Male %K Physical Fitness %K Proportional Hazards Models %K Risk Factors %K Sex Factors %K Time Factors %K United States %X

BACKGROUND: Cross-sectional studies show that adiponectin is higher in older than in younger adults but long-term change in adiponectin, its determinants, and its relationship to functional decline or survival in the elderly population have not been evaluated.

METHODS: We investigated predictors of longitudinal change in adiponectin, and the association of this adipokine or its antecedent change with physical deterioration and all-cause mortality in 988 participants in a population-based study who completed examinations in 1996-1997 and 2005-2006, had serial adiponectin measurements and underwent follow-up through June 2009.

RESULTS: Adiponectin level rose significantly during follow-up, but the increase was smaller in blacks, was associated with declining weight or fasting glucose and, in men, lower albumin, and was affected by medications. Adiponectin was independently associated with greater physical decline, but the relationship for adiponectin change was driven by concomitant weight decrease. Both adiponectin and its change independently predicted mortality, even after adjustment for weight change. The association for adiponectin and mortality was observed in whites but not in blacks and only for levels in the upper range (hazard ratio = 1.85, 95% confidence interval = 1.36-2.52 per SD ≥ 20 mg/L), whereas that for adiponectin change was linear throughout in both racial groups (hazard ratio = 1.30, 95% confidence interval = 1.10-1.52 per SD).

CONCLUSIONS: Adiponectin levels increase over time in long-lived adults and are associated with greater physical disability and mortality. Such increases may occur in response to age-related homeostatic dysregulation. Additional investigation is required to define the underlying mechanisms and whether this represents a marker or causal factor for mortality in this age group.

%B J Gerontol A Biol Sci Med Sci %V 65 %P 1208-14 %8 2010 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/20616148?dopt=Abstract %R 10.1093/gerona/glq122 %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2010 %T Chronic medical conditions and the sex-based disparity in disability: the Cardiovascular Health Study. %A Whitson, Heather E %A Landerman, Lawrence R %A Newman, Anne B %A Fried, Linda P %A Pieper, Carl F %A Cohen, Harvey Jay %K Aged %K Arthritis %K Cardiovascular Diseases %K Chronic Disease %K Cohort Studies %K Comorbidity %K Cross-Sectional Studies %K Disabled Persons %K Emphysema %K Female %K Hearing Disorders %K Humans %K Male %K Obesity %K Prevalence %K Sex Distribution %X

BACKGROUND: Older women experience disability more commonly than their male peers. This disparity may be due, in part, to sex-based differences in the prevalence or the disabling effects of common medical conditions. The objectives of this analysis were to (a) quantify the extent to which excess disability in women is explained by higher prevalence of selected medical conditions and (b) evaluate whether the same conditions have differing effects on disability in men and women.

METHODS: We analyzed cross-sectional data from 5,888 community-dwelling older men and women. Disability was defined as difficulty with greater than or equal to one activity of daily living. Thirteen medical conditions were assessed by self-report, testing, or record review.

RESULTS: Controlling for age, race, education, and marital status, women were more likely to experience disability (odds ratio = 1.70, 95% confidence interval = 1.36-2.11). Higher prevalence of arthritis and obesity in women explained 30.2% and 12.9%, respectively, of the sex-based difference in disability rates, whereas male prevalent diseases like vascular conditions and emphysema narrowed the disability gap. Women with arthritis, hearing problems, coronary artery disease, congestive heart failure, stroke, and claudication were more likely to exhibit disability compared with men with the same conditions (p < .001).

CONCLUSIONS: Efforts to lessen sex-based inequality in disability should focus on reducing the prevalence of arthritis and obesity. Future generations may see greater functional disparity if rates of vascular disease and emphysema rise among women. Several conditions were more often associated with disability in women, suggesting additional sex-based differences in the disablement process.

%B J Gerontol A Biol Sci Med Sci %V 65 %P 1325-31 %8 2010 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/20675619?dopt=Abstract %R 10.1093/gerona/glq139 %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 Alzheimers Dement %D 2010 %T Commentary on "Developing a national strategy to prevent dementia: Leon Thal Symposium 2009." Dementia risk indices: A framework for identifying individuals with a high dementia risk. %A Barnes, Deborah E %A Covinsky, Kenneth E %A Whitmer, Rachel A %A Kuller, Lewis H %A Lopez, Oscar L %A Yaffe, Kristine %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Dementia %K Diagnosis, Differential %K Disability Evaluation %K Early Diagnosis %K Humans %K National Health Programs %K Predictive Value of Tests %K Prognosis %K Risk Assessment %K Risk Factors %K United States %B Alzheimers Dement %V 6 %P 138-41 %8 2010 Mar %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/20298975?dopt=Abstract %R 10.1016/j.jalz.2010.01.005 %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 Nat Genet %D 2010 %T Common variants in KCNN3 are associated with lone atrial fibrillation. %A Ellinor, Patrick T %A Lunetta, Kathryn L %A Glazer, Nicole L %A Pfeufer, Arne %A Alonso, Alvaro %A Chung, Mina K %A Sinner, Moritz F %A de Bakker, Paul I W %A Mueller, Martina %A Lubitz, Steven A %A Fox, Ervin %A Darbar, Dawood %A Smith, Nicholas L %A Smith, Jonathan D %A Schnabel, Renate B %A Soliman, Elsayed Z %A Rice, Kenneth M %A Van Wagoner, David R %A Beckmann, Britt-M %A van Noord, Charlotte %A Wang, Ke %A Ehret, Georg B %A Rotter, Jerome I %A Hazen, Stanley L %A Steinbeck, Gerhard %A Smith, Albert V %A Launer, Lenore J %A Harris, Tamara B %A Makino, Seiko %A Nelis, Mari %A Milan, David J %A Perz, Siegfried %A Esko, Tõnu %A Köttgen, Anna %A Moebus, Susanne %A Newton-Cheh, Christopher %A Li, Man %A Möhlenkamp, Stefan %A Wang, Thomas J %A Kao, W H Linda %A Vasan, Ramachandran S %A Nöthen, Markus M %A MacRae, Calum A %A Stricker, Bruno H Ch %A Hofman, Albert %A Uitterlinden, André G %A Levy, Daniel %A Boerwinkle, Eric %A Metspalu, Andres %A Topol, Eric J %A Chakravarti, Aravinda %A Gudnason, Vilmundur %A Psaty, Bruce M %A Roden, Dan M %A Meitinger, Thomas %A Wichmann, H-Erich %A Witteman, Jacqueline C M %A Barnard, John %A Arking, Dan E %A Benjamin, Emelia J %A Heckbert, Susan R %A Kääb, Stefan %K Adolescent %K Adult %K Aged %K Atrial Fibrillation %K Case-Control Studies %K Cohort Studies %K Female %K Genome-Wide Association Study %K Humans %K Introns %K Male %K Meta-Analysis as Topic %K Middle Aged %K Polymorphism, Single Nucleotide %K Small-Conductance Calcium-Activated Potassium Channels %K Young Adult %X

Atrial fibrillation (AF) is the most common sustained arrhythmia. Previous studies have identified several genetic loci associated with typical AF. We sought to identify common genetic variants underlying lone AF. This condition affects a subset of individuals without overt heart disease and with an increased heritability of AF. We report a meta-analysis of genome-wide association studies conducted using 1,335 individuals with lone AF (cases) and 12,844 unaffected individuals (referents). Cases were obtained from the German AF Network, Heart and Vascular Health Study, the Atherosclerosis Risk in Communities Study, the Cleveland Clinic and Massachusetts General Hospital. We identified an association on chromosome 1q21 to lone AF (rs13376333, adjusted odds ratio = 1.56; P = 6.3 x 10(-12)), and we replicated this association in two independent cohorts with lone AF (overall combined odds ratio = 1.52, 95% CI 1.40-1.64; P = 1.83 x 10(-21)). rs13376333 is intronic to KCNN3, which encodes a potassium channel protein involved in atrial repolarization.

%B Nat Genet %V 42 %P 240-4 %8 2010 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/20173747?dopt=Abstract %R 10.1038/ng.537 %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 J Gerontol A Biol Sci Med Sci %D 2010 %T Concurrent change in dehydroepiandrosterone sulfate and functional performance in the oldest old: results from the Cardiovascular Health Study All Stars study. %A Sanders, J L %A Cappola, A R %A Arnold, A M %A Boudreau, R M %A Chaves, P H %A Robbins, J %A Cushman, M %A Newman, A B %K Aged, 80 and over %K Biomarkers %K Cognition %K Cohort Studies %K Dehydroepiandrosterone Sulfate %K Female %K Gait %K Geriatric Assessment %K Hand Strength %K Health Surveys %K Humans %K Longitudinal Studies %K Male %K Neuropsychological Tests %K Sex Factors %K United States %X

INTRODUCTION: The correlation between dehydroepiandrosterone sulfate (DHEAS) decline and age led to the hypothesis that DHEAS might be a marker of primary aging, though conflicting data from observational studies of mortality do not support this. We evaluated concurrent DHEAS and functional decline in a very old cohort to test if DHEAS change tracks with functional change during aging.

METHODS: DHEAS and functional performance (gait speed, grip strength, Modified Mini-Mental State Examination [3MSE] score, and digit symbol substitution test [DSST] score) were measured in 1996-1997 and 2005-2006 in 989 participants in the Cardiovascular Health Study All Stars study (mean age 85.2 years in 2005-2006, 63.5% women and 16.5% African American). We used multivariable linear regression to test the association of DHEAS decline with functional decline.

RESULTS: After adjustment, each standard deviation decrease in DHEAS was associated with greater declines in gait speed (0.12 m/s, p = .01), grip strength (0.09 kg, p = .03), 3MSE score (0.13 points, p < .001), and DSST score (0.14 points, p = .001) in women only. Additional adjustment for baseline DHEAS attenuated the association with grip strength but did not alter other estimates appreciably, and baseline DHEAS was unassociated with functional decline.

CONCLUSIONS: In this cohort of very old individuals, DHEAS decline tracked with declines in gait speed, 3MSE score, and DSST score, but not grip strength, in women independent of baseline DHEAS level. DHEAS decline might be a marker for age-associated performance decline, but its relevance is specific to women.

%B J Gerontol A Biol Sci Med Sci %V 65 %P 976-81 %8 2010 Sep %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/20466773?dopt=Abstract %R 10.1093/gerona/glq072 %0 Journal Article %J Lancet %D 2010 %T C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. %A Kaptoge, Stephen %A Di Angelantonio, Emanuele %A Lowe, Gordon %A Pepys, Mark B %A Thompson, Simon G %A Collins, Rory %A Danesh, John %K Alcohol Drinking %K Biomarkers %K Blood Pressure %K Body Mass Index %K C-Reactive Protein %K Cholesterol %K Coronary Disease %K Databases, Factual %K Diabetes Mellitus %K Female %K Fibrinogen %K Humans %K Interleukin-6 %K Leukocyte Count %K Lung Diseases %K Male %K Middle Aged %K Motor Activity %K Neoplasms %K Regression Analysis %K Risk Assessment %K Risk Factors %K Serum Albumin %K Sex Factors %K Smoking %K Stroke %K Triglycerides %X

BACKGROUND: Associations of C-reactive protein (CRP) concentration with risk of major diseases can best be assessed by long-term prospective follow-up of large numbers of people. We assessed the associations of CRP concentration with risk of vascular and non-vascular outcomes under different circumstances.

METHODS: We meta-analysed individual records of 160 309 people without a history of vascular disease (ie, 1.31 million person-years at risk, 27 769 fatal or non-fatal disease outcomes) from 54 long-term prospective studies. Within-study regression analyses were adjusted for within-person variation in risk factor levels.

RESULTS: Log(e) CRP concentration was linearly associated with several conventional risk factors and inflammatory markers, and nearly log-linearly with the risk of ischaemic vascular disease and non-vascular mortality. Risk ratios (RRs) for coronary heart disease per 1-SD higher log(e) CRP concentration (three-fold higher) were 1.63 (95% CI 1.51-1.76) when initially adjusted for age and sex only, and 1.37 (1.27-1.48) when adjusted further for conventional risk factors; 1.44 (1.32-1.57) and 1.27 (1.15-1.40) for ischaemic stroke; 1.71 (1.53-1.91) and 1.55 (1.37-1.76) for vascular mortality; and 1.55 (1.41-1.69) and 1.54 (1.40-1.68) for non-vascular mortality. RRs were largely unchanged after exclusion of smokers or initial follow-up. After further adjustment for fibrinogen, the corresponding RRs were 1.23 (1.07-1.42) for coronary heart disease; 1.32 (1.18-1.49) for ischaemic stroke; 1.34 (1.18-1.52) for vascular mortality; and 1.34 (1.20-1.50) for non-vascular mortality.

INTERPRETATION: CRP concentration has continuous associations with the risk of coronary heart disease, ischaemic stroke, vascular mortality, and death from several cancers and lung disease that are each of broadly similar size. The relevance of CRP to such a range of disorders is unclear. Associations with ischaemic vascular disease depend considerably on conventional risk factors and other markers of inflammation.

FUNDING: British Heart Foundation, UK Medical Research Council, BUPA Foundation, and GlaxoSmithKline.

%B Lancet %V 375 %P 132-40 %8 2010 Jan 09 %G eng %N 9709 %1 http://www.ncbi.nlm.nih.gov/pubmed/20031199?dopt=Abstract %R 10.1016/S0140-6736(09)61717-7 %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 Am J Med %D 2010 %T Diabetes and coronary heart disease as risk factors for mortality in older adults. %A Carnethon, Mercedes R %A Biggs, Mary L %A Barzilay, Joshua %A Kuller, Lewis H %A Mozaffarian, Dariush %A Mukamal, Kenneth %A Smith, Nicholas L %A Siscovick, David %K Aged %K Coronary Disease %K Diabetes Mellitus, Type 2 %K Female %K Follow-Up Studies %K Humans %K Male %K Prevalence %K Risk Factors %K Sex Distribution %K Survival Rate %K Time Factors %K United States %X

BACKGROUND: Type 2 diabetes has been described as a coronary heart disease (CHD) "risk equivalent." We tested whether cardiovascular and all-cause mortality rates were similar between participants with prevalent CHD vs diabetes in an older adult population in whom both glucose disorders and preexisting atherosclerosis are common.

METHODS: The Cardiovascular Health Study is a longitudinal study of men and women (n=5784) aged > or =65 years at baseline who were followed from baseline (1989/1992-1993) through 2005 for mortality. Diabetes was defined by fasting plasma glucose > or =7.0 mmol/L or use of diabetes control medications. Prevalent CHD was determined by confirmed history of myocardial infarction, angina, or coronary revascularization.

RESULTS: Following multivariable adjustment for other cardiovascular disease risk factors and subclinical atherosclerosis, CHD mortality risk was similar between participants with CHD alone vs diabetes alone (hazard ratio [HR] 1.04, 95% confidence interval [CI], 0.83-1.30). The proportion of mortality attributable to prevalent diabetes (population-attributable risk percent=8.4%) and prevalent CHD (6.7%) was similar in women, but the proportion of mortality attributable to CHD (16.5%) as compared with diabetes (6.4%) was markedly higher in men. Patterns were similar for cardiovascular disease mortality. By contrast, the adjusted relative hazard of total mortality was lower among participants with CHD alone (HR 0.85, 95% CI, 0.75-0.96) as compared with those who had diabetes alone.

CONCLUSIONS: Among older adults, diabetes alone confers a risk for cardiovascular mortality similar to that from established clinical CHD. The public health burden of both diabetes and CHD is substantial, particularly among women.

%B Am J Med %V 123 %P 556.e1-9 %8 2010 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/20569763?dopt=Abstract %R 10.1016/j.amjmed.2009.11.023 %0 Journal Article %J PLoS One %D 2010 %T Differential white blood cell count and type 2 diabetes: systematic review and meta-analysis of cross-sectional and prospective studies. %A Gkrania-Klotsas, Effrossyni %A Ye, Zheng %A Cooper, Andrew J %A Sharp, Stephen J %A Luben, Robert %A Biggs, Mary L %A Chen, Liang-Kung %A Gokulakrishnan, Kuppan %A Hanefeld, Markolf %A Ingelsson, Erik %A Lai, Wen-An %A Lin, Shih-Yi %A Lind, Lars %A Lohsoonthorn, Vitool %A Mohan, Viswanathan %A Muscari, Antonio %A Nilsson, Goran %A Ohrvik, John %A Chao Qiang, Jiang %A Jenny, Nancy Swords %A Tamakoshi, Koji %A Temelkova-Kurktschiev, Theodora %A Wang, Ya-Yu %A Yajnik, Chittaranjan Sakerlal %A Zoli, Marco %A Khaw, Kay-Tee %A Forouhi, Nita G %A Wareham, Nicholas J %A Langenberg, Claudia %K Adult %K Aged %K Cross-Sectional Studies %K Diabetes Mellitus, Type 2 %K Female %K Humans %K Leukocyte Count %K Male %K Middle Aged %K Prospective Studies %X

OBJECTIVE: Biological evidence suggests that inflammation might induce type 2 diabetes (T2D), and epidemiological studies have shown an association between higher white blood cell count (WBC) and T2D. However, the association has not been systematically investigated.

RESEARCH DESIGN AND METHODS: Studies were identified through computer-based and manual searches. Previously unreported studies were sought through correspondence. 20 studies were identified (8,647 T2D cases and 85,040 non-cases). Estimates of the association of WBC with T2D were combined using random effects meta-analysis; sources of heterogeneity as well as presence of publication bias were explored.

RESULTS: The combined relative risk (RR) comparing the top to bottom tertile of the WBC count was 1.61 (95% CI: 1.45; 1.79, p = 1.5*10(-18)). Substantial heterogeneity was present (I(2) = 83%). For granulocytes the RR was 1.38 (95% CI: 1.17; 1.64, p = 1.5*10(-4)), for lymphocytes 1.26 (95% CI: 1.02; 1.56, p = 0.029), and for monocytes 0.93 (95% CI: 0.68; 1.28, p = 0.67) comparing top to bottom tertile. In cross-sectional studies, RR was 1.74 (95% CI: 1.49; 2.02, p = 7.7*10(-13)), while in cohort studies it was 1.48 (95% CI: 1.22; 1.79, p = 7.7*10(-5)). We assessed the impact of confounding in EPIC-Norfolk study and found that the age and sex adjusted HR of 2.19 (95% CI: 1.74; 2.75) was attenuated to 1.82 (95% CI: 1.45; 2.29) after further accounting for smoking, T2D family history, physical activity, education, BMI and waist circumference.

CONCLUSIONS: A raised WBC is associated with higher risk of T2D. The presence of publication bias and failure to control for all potential confounders in all studies means the observed association is likely an overestimate.

%B PLoS One %V 5 %P e13405 %8 2010 Oct 18 %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/20976133?dopt=Abstract %R 10.1371/journal.pone.0013405 %0 Journal Article %J J Am Coll Cardiol %D 2010 %T Dynamic cardiovascular risk assessment in elderly people. The role of repeated N-terminal pro-B-type natriuretic peptide testing. %A deFilippi, Christopher R %A Christenson, Robert H %A Gottdiener, John S %A Kop, Willem J %A Seliger, Stephen L %K Aged %K Biomarkers %K Female %K Heart Failure %K Humans %K Male %K Natriuretic Peptide, Brain %K Peptide Fragments %K Prognosis %K Prospective Studies %K Risk Assessment %K Risk Factors %K United States %X

OBJECTIVES: This study sought to determine whether serial measurement of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in community-dwelling elderly people would provide additional prognostic information to that from traditional risk factors.

BACKGROUND: Accurate cardiovascular risk stratification is challenging in elderly people.

METHODS: NT-proBNP was measured at baseline and 2 to 3 years later in 2,975 community-dwelling older adults free of heart failure in the longitudinal CHS (Cardiovascular Health Study). This investigation examined the risk of new-onset heart failure (HF) and death from cardiovascular causes associated with baseline NT-proBNP and changes in NT-proBNP levels, adjusting for potential confounders.

RESULTS: NT-proBNP levels in the highest quintile (>267.7 pg/ml) were independently associated with greater risks of HF (hazard ratio [HR]: 3.05; 95% confidence interval [CI]: 2.46 to 3.78) and cardiovascular death (HR: 3.02; 95% CI: 2.36 to 3.86) compared with the lowest quintile (<47.5 pg/ml). The inflection point for elevated risk occurred at NT-proBNP 190 pg/ml. Among participants with initially low NT-proBNP (<190 pg/ml), those who developed a >25% increase on follow-up to >190 pg/ml (21%) were at greater adjusted risk of HF (HR: 2.13; 95% CI: 1.68 to 2.71) and cardiovascular death (HR: 1.91; 95% CI: 1.43 to 2.53) compared with those with sustained low levels. Among participants with initially high NT-proBNP, those who developed a >25% increase (40%) were at higher risk of HF (HR: 2.06; 95% CI: 1.56 to 2.72) and cardiovascular death (HR: 1.88; 95% CI: 1.37 to 2.57), whereas those who developed a >25% decrease to

CONCLUSIONS: NT-proBNP levels independently predict heart failure and cardiovascular death in older adults. NT-proBNP levels frequently change over time, and these fluctuations reflect dynamic changes in cardiovascular risk.

%B J Am Coll Cardiol %V 55 %P 441-50 %8 2010 Feb 02 %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/20117457?dopt=Abstract %R 10.1016/j.jacc.2009.07.069 %0 Journal Article %J Am J Clin Nutr %D 2010 %T Egg consumption and risk of type 2 diabetes in older adults. %A Djoussé, Luc %A Kamineni, Aruna %A Nelson, Tracy L %A Carnethon, Mercedes %A Mozaffarian, Dariush %A Siscovick, David %A Mukamal, Kenneth J %K Aged %K Blood Glucose %K Cholesterol, Dietary %K Diabetes Mellitus, Type 2 %K Diet %K Diet Surveys %K Eggs %K Feeding Behavior %K Female %K Humans %K Insulin %K Insulin Resistance %K Male %K Proportional Hazards Models %K Prospective Studies %K Risk Factors %K Surveys and Questionnaires %X

BACKGROUND: Type 2 diabetes (T2D) remains an important public health issue in the United States. There are limited and inconsistent data on the association between egg consumption and fasting glucose or incident diabetes.

OBJECTIVES: We assessed the association between egg intake and incident diabetes in older adults.

DESIGN: In this prospective study of 3898 men and women from the Cardiovascular Health Study (1989-2007), we assessed egg consumption by using a picture-sorted food questionnaire and ascertained incident T2D annually by using information on hypoglycemic agents and plasma glucose. We used Cox proportional hazards models to estimate adjusted relative risks.

RESULTS: During a mean follow-up of 11.3 y, 313 new cases of T2D occurred. Crude incidence rates of T2D were 7.39, 6.83, 7.00, 6.72, and 12.20 per 1000 person-years in people who reported egg consumption of never, <1 egg/mo, 1-3 eggs/mo, 1-4 eggs/wk, and almost daily, respectively. In multivariable-adjusted models, there was no association between egg consumption and increased risk of T2D in either sex and overall. In a secondary analysis, dietary cholesterol was not associated with incident diabetes (P for trend = 0.47). In addition, egg consumption was not associated with clinically meaningful differences in fasting glucose, fasting insulin, or measures of insulin resistance despite small absolute analytic differences that were significant.

CONCLUSION: In this cohort of older adults with limited egg intake, there was no association between egg consumption or dietary cholesterol and increased risk of incident T2D.

%B Am J Clin Nutr %V 92 %P 422-7 %8 2010 Aug %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/20534749?dopt=Abstract %R 10.3945/ajcn.2010.29406 %0 Journal Article %J Circulation %D 2010 %T European ancestry as a risk factor for atrial fibrillation in African Americans. %A Marcus, Gregory M %A Alonso, Alvaro %A Peralta, Carmen A %A Lettre, Guillaume %A Vittinghoff, Eric %A Lubitz, Steven A %A Fox, Ervin R %A Levitzky, Yamini S %A Mehra, Reena %A Kerr, Kathleen F %A Deo, Rajat %A Sotoodehnia, Nona %A Akylbekova, Meggie %A Ellinor, Patrick T %A Paltoo, Dina N %A Soliman, Elsayed Z %A Benjamin, Emelia J %A Heckbert, Susan R %K African Americans %K Aged %K Atrial Fibrillation %K European Continental Ancestry Group %K Female %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Risk Factors %X

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

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

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

%B Circulation %V 122 %P 2009-15 %8 2010 Nov 16 %G eng %N 20 %1 http://www.ncbi.nlm.nih.gov/pubmed/21098467?dopt=Abstract %R 10.1161/CIRCULATIONAHA.110.958306 %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 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 N Engl J Med %D 2010 %T Genetic ancestry in lung-function predictions. %A Kumar, Rajesh %A Seibold, Max A %A Aldrich, Melinda C %A Williams, L Keoki %A Reiner, Alex P %A Colangelo, Laura %A Galanter, Joshua %A Gignoux, Christopher %A Hu, Donglei %A Sen, Saunak %A Choudhry, Shweta %A Peterson, Edward L %A Rodriguez-Santana, Jose %A Rodriguez-Cintron, William %A Nalls, Michael A %A Leak, Tennille S %A O'Meara, Ellen %A Meibohm, Bernd %A Kritchevsky, Stephen B %A Li, Rongling %A Harris, Tamara B %A Nickerson, Deborah A %A Fornage, Myriam %A Enright, Paul %A Ziv, Elad %A Smith, Lewis J %A Liu, Kiang %A Burchard, Esteban González %K Adolescent %K Adult %K African Americans %K Aged %K Aged, 80 and over %K Female %K Forced Expiratory Volume %K Genetic Markers %K Genotype %K Humans %K Linear Models %K Male %K Middle Aged %K Oligonucleotide Array Sequence Analysis %K Reference Values %K Respiratory Function Tests %K Vital Capacity %K Young Adult %X

BACKGROUND: Self-identified race or ethnic group is used to determine normal reference standards in the prediction of pulmonary function. We conducted a study to determine whether the genetically determined percentage of African ancestry is associated with lung function and whether its use could improve predictions of lung function among persons who identified themselves as African American.

METHODS: We assessed the ancestry of 777 participants self-identified as African American in the Coronary Artery Risk Development in Young Adults (CARDIA) study and evaluated the relation between pulmonary function and ancestry by means of linear regression. We performed similar analyses of data for two independent cohorts of subjects identifying themselves as African American: 813 participants in the Health, Aging, and Body Composition (HABC) study and 579 participants in the Cardiovascular Health Study (CHS). We compared the fit of two types of models to lung-function measurements: models based on the covariates used in standard prediction equations and models incorporating ancestry. We also evaluated the effect of the ancestry-based models on the classification of disease severity in two asthma-study populations.

RESULTS: African ancestry was inversely related to forced expiratory volume in 1 second (FEV(1)) and forced vital capacity in the CARDIA cohort. These relations were also seen in the HABC and CHS cohorts. In predicting lung function, the ancestry-based model fit the data better than standard models. Ancestry-based models resulted in the reclassification of asthma severity (based on the percentage of the predicted FEV(1)) in 4 to 5% of participants.

CONCLUSIONS: Current predictive equations, which rely on self-identified race alone, may misestimate lung function among subjects who identify themselves as African American. Incorporating ancestry into normative equations may improve lung-function estimates and more accurately categorize disease severity. (Funded by the National Institutes of Health and others.)

%B N Engl J Med %V 363 %P 321-30 %8 2010 Jul 22 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/20647190?dopt=Abstract %R 10.1056/NEJMoa0907897 %0 Journal Article %J JAMA %D 2010 %T Genome-wide analysis of genetic loci associated with Alzheimer disease. %A Seshadri, Sudha %A Fitzpatrick, Annette L %A Ikram, M Arfan %A DeStefano, Anita L %A Gudnason, Vilmundur %A Boada, Merce %A Bis, Joshua C %A Smith, Albert V %A Carassquillo, Minerva M %A Lambert, Jean Charles %A Harold, Denise %A Schrijvers, Elisabeth M C %A Ramirez-Lorca, Reposo %A Debette, Stephanie %A Longstreth, W T %A Janssens, A Cecile J W %A Pankratz, V Shane %A Dartigues, Jean François %A Hollingworth, Paul %A Aspelund, Thor %A Hernandez, Isabel %A Beiser, Alexa %A Kuller, Lewis H %A Koudstaal, Peter J %A Dickson, Dennis W %A Tzourio, Christophe %A Abraham, Richard %A Antunez, Carmen %A Du, Yangchun %A Rotter, Jerome I %A Aulchenko, Yurii S %A Harris, Tamara B %A Petersen, Ronald C %A Berr, Claudine %A Owen, Michael J %A Lopez-Arrieta, Jesus %A Varadarajan, Badri N %A Becker, James T %A Rivadeneira, Fernando %A Nalls, Michael A %A Graff-Radford, Neill R %A Campion, Dominique %A Auerbach, Sanford %A Rice, Kenneth %A Hofman, Albert %A Jonsson, Palmi V %A Schmidt, Helena %A Lathrop, Mark %A Mosley, Thomas H %A Au, Rhoda %A Psaty, Bruce M %A Uitterlinden, André G %A Farrer, Lindsay A %A Lumley, Thomas %A Ruiz, Agustin %A Williams, Julie %A Amouyel, Philippe %A Younkin, Steve G %A Wolf, Philip A %A Launer, Lenore J %A Lopez, Oscar L %A van Duijn, Cornelia M %A Breteler, Monique M B %K Age of Onset %K Aged %K Alzheimer Disease %K Case-Control Studies %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Odds Ratio %K Polymorphism, Single Nucleotide %X

CONTEXT: Genome-wide association studies (GWAS) have recently identified CLU, PICALM, and CR1 as novel genes for late-onset Alzheimer disease (AD).

OBJECTIVES: To identify and strengthen additional loci associated with AD and confirm these in an independent sample and to examine the contribution of recently identified genes to AD risk prediction in a 3-stage analysis of new and previously published GWAS on more than 35,000 persons (8371 AD cases).

DESIGN, SETTING, AND PARTICIPANTS: In stage 1, we identified strong genetic associations (P < 10(-3)) in a sample of 3006 AD cases and 14,642 controls by combining new data from the population-based Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (1367 AD cases [973 incident]) with previously reported results from the Translational Genomics Research Institute and the Mayo AD GWAS. We identified 2708 single-nucleotide polymorphisms (SNPs) with P < 10(-3). In stage 2, we pooled results for these SNPs with the European AD Initiative (2032 cases and 5328 controls) to identify 38 SNPs (10 loci) with P < 10(-5). In stage 3, we combined data for these 10 loci with data from the Genetic and Environmental Risk in AD consortium (3333 cases and 6995 controls) to identify 4 SNPs with P < 1.7x10(-8). These 4 SNPs were replicated in an independent Spanish sample (1140 AD cases and 1209 controls). Genome-wide association analyses were completed in 2007-2008 and the meta-analyses and replication in 2009.

MAIN OUTCOME MEASURE: Presence of Alzheimer disease.

RESULTS: Two loci were identified to have genome-wide significance for the first time: rs744373 near BIN1 (odds ratio [OR],1.13; 95% confidence interval [CI],1.06-1.21 per copy of the minor allele; P = 1.59x10(-11)) and rs597668 near EXOC3L2/BLOC1S3/MARK4 (OR, 1.18; 95% CI, 1.07-1.29; P = 6.45x10(-9)). Associations of these 2 loci plus the previously identified loci CLU and PICALM with AD were confirmed in the Spanish sample (P < .05). However, although CLU and PICALM were confirmed to be associated with AD in this independent sample, they did not improve the ability of a model that included age, sex, and APOE to predict incident AD (improvement in area under the receiver operating characteristic curve from 0.847 to 0.849 in the Rotterdam Study and 0.702 to 0.705 in the Cardiovascular Health Study).

CONCLUSIONS: Two genetic loci for AD were found for the first time to reach genome-wide statistical significance. These findings were replicated in an independent population. Two recently reported associations were also confirmed. These loci did not improve AD risk prediction. While not clinically useful, they may implicate biological pathways useful for future research.

%B JAMA %V 303 %P 1832-40 %8 2010 May 12 %G eng %N 18 %1 http://www.ncbi.nlm.nih.gov/pubmed/20460622?dopt=Abstract %R 10.1001/jama.2010.574 %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 Proc Natl Acad Sci U S A %D 2010 %T Genome-wide association identifies OBFC1 as a locus involved in human leukocyte telomere biology. %A Levy, Daniel %A Neuhausen, Susan L %A Hunt, Steven C %A Kimura, Masayuki %A Hwang, Shih-Jen %A Chen, Wei %A Bis, Joshua C %A Fitzpatrick, Annette L %A Smith, Erin %A Johnson, Andrew D %A Gardner, Jeffrey P %A Srinivasan, Sathanur R %A Schork, Nicholas %A Rotter, Jerome I %A Herbig, Utz %A Psaty, Bruce M %A Sastrasinh, Malinee %A Murray, Sarah S %A Vasan, Ramachandran S %A Province, Michael A %A Glazer, Nicole L %A Lu, Xiaobin %A Cao, Xiaojian %A Kronmal, Richard %A Mangino, Massimo %A Soranzo, Nicole %A Spector, Tim D %A Berenson, Gerald S %A Aviv, Abraham %K Cohort Studies %K Genome-Wide Association Study %K Genotype %K Humans %K Leukocytes %K Polymorphism, Single Nucleotide %K Receptors, CXCR4 %K Telomere %K Telomere-Binding Proteins %X

Telomeres are engaged in a host of cellular functions, and their length is regulated by multiple genes. Telomere shortening, in the course of somatic cell replication, ultimately leads to replicative senescence. In humans, rare mutations in genes that regulate telomere length have been identified in monogenic diseases such as dyskeratosis congenita and idiopathic pulmonary fibrosis, which are associated with shortened leukocyte telomere length (LTL) and increased risk for aplastic anemia. Shortened LTL is observed in a host of aging-related complex genetic diseases and is associated with diminished survival in the elderly. We report results of a genome-wide association study of LTL in a consortium of four observational studies (n = 3,417 participants with LTL and genome-wide genotyping). SNPs in the regions of the oligonucleotide/oligosaccharide-binding folds containing one gene (OBFC1; rs4387287; P = 3.9 x 10(-9)) and chemokine (C-X-C motif) receptor 4 gene (CXCR4; rs4452212; P = 2.9 x 10(-8)) were associated with LTL at a genome-wide significance level (P < 5 x 10(-8)). We attempted replication of the top SNPs at these loci through de novo genotyping of 1,893 additional individuals and in silico lookup in another observational study (n = 2,876), and we confirmed the association findings for OBFC1 but not CXCR4. In addition, we confirmed the telomerase RNA component (TERC) as a gene associated with LTL (P = 1.1 x 10(-5)). The identification of OBFC1 through genome-wide association as a locus for interindividual variation in LTL in the general population advances the understanding of telomere biology in humans and may provide insights into aging-related disorders linked to altered LTL dynamics.

%B Proc Natl Acad Sci U S A %V 107 %P 9293-8 %8 2010 May 18 %G eng %N 20 %1 http://www.ncbi.nlm.nih.gov/pubmed/20421499?dopt=Abstract %R 10.1073/pnas.0911494107 %0 Journal Article %J Stroke %D 2010 %T Genome-wide association studies of MRI-defined brain infarcts: meta-analysis from the CHARGE Consortium. %A Debette, Stephanie %A Bis, Joshua C %A Fornage, Myriam %A Schmidt, Helena %A Ikram, M Arfan %A Sigurdsson, Sigurdur %A Heiss, Gerardo %A Struchalin, Maksim %A Smith, Albert V %A van der Lugt, Aad %A DeCarli, Charles %A Lumley, Thomas %A Knopman, David S %A Enzinger, Christian %A Eiriksdottir, Gudny %A Koudstaal, Peter J %A DeStefano, Anita L %A Psaty, Bruce M %A Dufouil, Carole %A Catellier, Diane J %A Fazekas, Franz %A Aspelund, Thor %A Aulchenko, Yurii S %A Beiser, Alexa %A Rotter, Jerome I %A Tzourio, Christophe %A Shibata, Dean K %A Tscherner, Maria %A Harris, Tamara B %A Rivadeneira, Fernando %A Atwood, Larry D %A Rice, Kenneth %A Gottesman, Rebecca F %A van Buchem, Mark A %A Uitterlinden, André G %A Kelly-Hayes, Margaret %A Cushman, Mary %A Zhu, Yicheng %A Boerwinkle, Eric %A Gudnason, Vilmundur %A Hofman, Albert %A Romero, Jose R %A Lopez, Oscar %A van Duijn, Cornelia M %A Au, Rhoda %A Heckbert, Susan R %A Wolf, Philip A %A Mosley, Thomas H %A Seshadri, Sudha %A Breteler, Monique M B %A Schmidt, Reinhold %A Launer, Lenore J %A Longstreth, W T %K African Americans %K Aged %K Brain %K Brain Infarction %K Cohort Studies %K DNA Mutational Analysis %K Female %K Gene Frequency %K Genetic Markers %K Genetic Predisposition to Disease %K Genetic Testing %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Linkage Disequilibrium %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Prospective Studies %X

BACKGROUND AND PURPOSE: Previous studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI infarct in persons without histories of transient ischemic attack or stroke. We performed meta-analysis of genome-wide association studies of white participants in 6 studies comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.

METHODS: Using 2.2 million genotyped and imputed single nucleotide polymorphisms, each study performed cross-sectional genome-wide association analysis of MRI infarct using age- and sex-adjusted logistic regression models. Study-specific findings were combined in an inverse-variance-weighted meta-analysis, including 9401 participants with mean age 69.7 (19.4% of whom had >or=1 MRI infarct).

RESULTS: The most significant association was found with rs2208454 (minor allele frequency, 20%), located in intron 3 of MACRO domain containing 2 gene and in the downstream region of fibronectin leucine-rich transmembrane protein 3 gene. Each copy of the minor allele was associated with lower risk of MRI infarcts (odds ratio, 0.76; 95% confidence interval, 0.68-0.84; P=4.64x10(-7)). Highly suggestive associations (P<1.0x10(-5)) were also found for 22 other single nucleotide polymorphisms in linkage disequilibrium (r(2)>0.64) with rs2208454. The association with rs2208454 did not replicate in independent samples of 1822 white and 644 black participants, although 4 single nucleotide polymorphisms within 200 kb from rs2208454 were associated with MRI infarcts in the black population sample.

CONCLUSIONS: This first community-based, genome-wide association study on covert MRI infarcts uncovered novel associations. Although replication of the association with top single nucleotide polymorphisms failed, possibly because of insufficient power, results in the black population sample are encouraging, and further efforts at replication are needed.

%B Stroke %V 41 %P 210-7 %8 2010 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/20044523?dopt=Abstract %R 10.1161/STROKEAHA.109.569194 %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 Nat Genet %D 2010 %T Genome-wide association study of PR interval. %A Pfeufer, Arne %A van Noord, Charlotte %A Marciante, Kristin D %A Arking, Dan E %A Larson, Martin G %A Smith, Albert Vernon %A Tarasov, Kirill V %A Müller, Martina %A Sotoodehnia, Nona %A Sinner, Moritz F %A Verwoert, Germaine C %A Li, Man %A Kao, W H Linda %A Köttgen, Anna %A Coresh, Josef %A Bis, Joshua C %A Psaty, Bruce M %A Rice, Kenneth %A Rotter, Jerome I %A Rivadeneira, Fernando %A Hofman, Albert %A Kors, Jan A %A Stricker, Bruno H C %A Uitterlinden, André G %A van Duijn, Cornelia M %A Beckmann, Britt M %A Sauter, Wiebke %A Gieger, Christian %A Lubitz, Steven A %A Newton-Cheh, Christopher %A Wang, Thomas J %A Magnani, Jared W %A Schnabel, Renate B %A Chung, Mina K %A Barnard, John %A Smith, Jonathan D %A Van Wagoner, David R %A Vasan, Ramachandran S %A Aspelund, Thor %A Eiriksdottir, Gudny %A Harris, Tamara B %A Launer, Lenore J %A Najjar, Samer S %A Lakatta, Edward %A Schlessinger, David %A Uda, Manuela %A Abecasis, Goncalo R %A Müller-Myhsok, Bertram %A Ehret, Georg B %A Boerwinkle, Eric %A Chakravarti, Aravinda %A Soliman, Elsayed Z %A Lunetta, Kathryn L %A Perz, Siegfried %A Wichmann, H-Erich %A Meitinger, Thomas %A Levy, Daniel %A Gudnason, Vilmundur %A Ellinor, Patrick T %A Sanna, Serena %A Kääb, Stefan %A Witteman, Jacqueline C M %A Alonso, Alvaro %A Benjamin, Emelia J %A Heckbert, Susan R %K Aged %K Atrial Fibrillation %K Cohort Studies %K Electrocardiography %K Female %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Heart Conduction System %K Humans %K Male %K Meta-Analysis as Topic %X

The electrocardiographic PR interval (or PQ interval) reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation. We report a meta-analysis of genome-wide association studies for PR interval from seven population-based European studies in the CHARGE Consortium: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study, and SardiNIA (N = 28,517). We identified nine loci associated with PR interval at P < 5 x 10(-8). At the 3p22.2 locus, we observed two independent associations in voltage-gated sodium channel genes, SCN10A and SCN5A. Six of the loci were near cardiac developmental genes, including CAV1-CAV2, NKX2-5 (CSX1), SOX5, WNT11, MEIS1, and TBX5-TBX3, providing pathophysiologically interesting candidate genes. Five of the loci, SCN5A, SCN10A, NKX2-5, CAV1-CAV2, and SOX5, were also associated with atrial fibrillation (N = 5,741 cases, P < 0.0056). This suggests a role for common variation in ion channel and developmental genes in atrial and atrioventricular conduction as well as in susceptibility to atrial fibrillation.

%B Nat Genet %V 42 %P 153-9 %8 2010 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/20062060?dopt=Abstract %R 10.1038/ng.517 %0 Journal Article %J Nat Genet %D 2010 %T Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. %A Franke, Andre %A McGovern, Dermot P B %A Barrett, Jeffrey C %A Wang, Kai %A Radford-Smith, Graham L %A Ahmad, Tariq %A Lees, Charlie W %A Balschun, Tobias %A Lee, James %A Roberts, Rebecca %A Anderson, Carl A %A Bis, Joshua C %A Bumpstead, Suzanne %A Ellinghaus, David %A Festen, Eleonora M %A Georges, Michel %A Green, Todd %A Haritunians, Talin %A Jostins, Luke %A Latiano, Anna %A Mathew, Christopher G %A Montgomery, Grant W %A Prescott, Natalie J %A Raychaudhuri, Soumya %A Rotter, Jerome I %A Schumm, Philip %A Sharma, Yashoda %A Simms, Lisa A %A Taylor, Kent D %A Whiteman, David %A Wijmenga, Cisca %A Baldassano, Robert N %A Barclay, Murray %A Bayless, Theodore M %A Brand, Stephan %A Büning, Carsten %A Cohen, Albert %A Colombel, Jean-Frederick %A Cottone, Mario %A Stronati, Laura %A Denson, Ted %A De Vos, Martine %A D'Inca, Renata %A Dubinsky, Marla %A Edwards, Cathryn %A Florin, Tim %A Franchimont, Denis %A Gearry, Richard %A Glas, Jürgen %A Van Gossum, Andre %A Guthery, Stephen L %A Halfvarson, Jonas %A Verspaget, Hein W %A Hugot, Jean-Pierre %A Karban, Amir %A Laukens, Debby %A Lawrance, Ian %A Lemann, Marc %A Levine, Arie %A Libioulle, Cecile %A Louis, Edouard %A Mowat, Craig %A Newman, William %A Panés, Julián %A Phillips, Anne %A Proctor, Deborah D %A Regueiro, Miguel %A Russell, Richard %A Rutgeerts, Paul %A Sanderson, Jeremy %A Sans, Miquel %A Seibold, Frank %A Steinhart, A Hillary %A Stokkers, Pieter C F %A Törkvist, Leif %A Kullak-Ublick, Gerd %A Wilson, David %A Walters, Thomas %A Targan, Stephan R %A Brant, Steven R %A Rioux, John D %A D'Amato, Mauro %A Weersma, Rinse K %A Kugathasan, Subra %A Griffiths, Anne M %A Mansfield, John C %A Vermeire, Severine %A Duerr, Richard H %A Silverberg, Mark S %A Satsangi, Jack %A Schreiber, Stefan %A Cho, Judy H %A Annese, Vito %A Hakonarson, Hakon %A Daly, Mark J %A Parkes, Miles %K Computational Biology %K Crohn Disease %K Genetic Linkage %K Genetic Loci %K Genetic Predisposition to Disease %K Genetic Variation %K Genome, Human %K Genome-Wide Association Study %K Humans %K Reproducibility of Results %X

We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10⁻⁸). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease.

%B Nat Genet %V 42 %P 1118-25 %8 2010 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/21102463?dopt=Abstract %R 10.1038/ng.717 %0 Journal Article %J Circ Cardiovasc Genet %D 2010 %T Genomic variation associated with mortality among adults of European and African ancestry with heart failure: the cohorts for heart and aging research in genomic epidemiology consortium. %A Morrison, Alanna C %A Felix, Janine F %A Cupples, L Adrienne %A Glazer, Nicole L %A Loehr, Laura R %A Dehghan, Abbas %A Demissie, Serkalem %A Bis, Joshua C %A Rosamond, Wayne D %A Aulchenko, Yurii S %A Wang, Ying A %A Haritunians, Talin %A Folsom, Aaron R %A Rivadeneira, Fernando %A Benjamin, Emelia J %A Lumley, Thomas %A Couper, David %A Stricker, Bruno H %A O'Donnell, Christopher J %A Rice, Kenneth M %A Chang, Patricia P %A Hofman, Albert %A Levy, Daniel %A Rotter, Jerome I %A Fox, Ervin R %A Uitterlinden, André G %A Wang, Thomas J %A Psaty, Bruce M %A Willerson, James T %A van Duijn, Cornelia M %A Boerwinkle, Eric %A Witteman, Jacqueline C M %A Vasan, Ramachandran S %A Smith, Nicholas L %K African Americans %K Aged %K Aged, 80 and over %K Chemokines %K Cohort Studies %K European Continental Ancestry Group %K Female %K Genome-Wide Association Study %K Genotype %K Heart Failure %K Humans %K Introns %K Male %K MARVEL Domain-Containing Proteins %K Membrane Proteins %K Middle Aged %K Polymorphism, Single Nucleotide %K Risk Factors %X

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

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

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

%B Circ Cardiovasc Genet %V 3 %P 248-55 %8 2010 Jun %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/20400778?dopt=Abstract %R 10.1161/CIRCGENETICS.109.895995 %0 Journal Article %J J Am Geriatr Soc %D 2010 %T Geriatric impairments and disability: the cardiovascular health study. %A Chaudhry, Sarwat I %A McAvay, Gail %A Ning, Yuming %A Allore, Heather G %A Newman, Anne B %A Gill, Thomas M %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Cardiac Rehabilitation %K Cardiovascular Diseases %K Disabled Persons %K Female %K Follow-Up Studies %K Geriatric Assessment %K Health Status %K Humans %K Male %K Morbidity %K Retrospective Studies %K Risk Factors %K Time Factors %K United States %X

OBJECTIVES: To determine the relative importance of geriatric impairments (in muscle strength, physical capacity, cognition, vision, hearing, and psychological status) and chronic diseases in predicting subsequent functional disability in longitudinal analyses.

DESIGN: Longitudinal data from the Cardiovascular Health Study were analyzed. Multivariable Cox hazards regression modeling was used to analyze associations between time-dependent predictors and onset of disability in activities of daily living (ADLs) and mobility.

SETTING: Four communities across the United States (Sacramento County, CA; Washington County, MD; Forsyth County, NC; and Allegheny County, PA).

PARTICIPANTS: Five thousand eight hundred eighty-eight elderly persons.

MEASUREMENTS: Data were collected annually through in-person examinations.

RESULTS: ADL disability developed in 15% of participants and mobility disability in 30%. A single multivariable model was developed that included demographics, marital status, body mass index, and number of impairments and diseases. The hazard ratios (HRs) of having one, two, and three or more geriatric impairments (vs none) for the outcome of ADL disability were 2.12 (95% confidence interval (CI)=1.63-2.75), 4.25 (95% CI=3.30-5.48), and 7.87 (95% CI=6.10-10.17), respectively, and for having one, two, and three or more chronic diseases were 1.75 (95% CI=1.41-2.19), 2.45 (95% CI=1.95-3.07), and 3.26 (95% CI=2.53-4.19), respectively. Similarly, the HRs of having one, two, and three or more impairments for the outcome of mobility disability were 1.48 (95% CI=1.27-1.73), 2.08 (95% CI=1.77-2.45), and 3.70 (95% CI=3.09-4.42), respectively, and for having one, two, and three or more diseases were 2.06 (95% CI=1.76-2.40), 2.80 (95% CI=2.36-3.31), and 4.20 (95% CI=3.44-5.14), respectively.

CONCLUSION: Number of geriatric impairments was more strongly associated than number of chronic diseases with subsequent ADL disability and nearly as strongly associated with the subsequent mobility disability.

%B J Am Geriatr Soc %V 58 %P 1686-92 %8 2010 Sep %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/20863328?dopt=Abstract %R 10.1111/j.1532-5415.2010.03022.x %0 Journal Article %J Nutr Metab Cardiovasc Dis %D 2010 %T Glycosylated hemoglobin and the risk of death and cardiovascular mortality in the elderly. %A Chonchol, M %A Katz, R %A Fried, L F %A Sarnak, M J %A Siscovick, D S %A Newman, A B %A Strotmeyer, E S %A Bertoni, A %A Shlipak, M G %K Aged %K Aged, 80 and over %K Body Mass Index %K Cardiovascular Diseases %K Cohort Studies %K Disease Progression %K Female %K Glycated Hemoglobin A %K Health Surveys %K Heart Failure %K Humans %K Incidence %K Male %K Myocardial Infarction %K Risk Factors %K Statistics as Topic %K Stroke %K United States %X

BACKGROUND AND AIMS: Glycosylated hemoglobin (HbA(1c)) has been associated with incident cardiovascular disease (CVD), but the findings are inconsistent. We tested the hypothesis that HbA(1c) may be associated with an increased risk of death and cardiovascular mortality in older adults.

METHODS AND RESULTS: We evaluated the association between HbA(1c) with all-cause and cardiovascular mortality in 810 participants without a history of diabetes in a sub-study of the Cardiovascular Health Study (CHS), a community cohort study of individuals > or =65 years of age. Glycosylated hemoglobin was measured at baseline and all-cause and cardiovascular mortality was assessed during the follow-up period. The relation between baseline HbA(1c) and death was evaluated with multivariate Cox proportional hazards regression models. After a median follow-up of 14.2 years, 416 deaths were observed. The crude incidence rates of all-cause mortality across HbA(1c) groups were: 4.4% per year, 4.3% per year and 4.6% per year for tertile 1 (< or =5.6%), tertile 2 (5.61-6.20%) and tertile 3 (> or =6.21%), respectively. In unadjusted and fully adjusted analyses, baseline HbA(1c) was not associated with all-cause mortality and cardiovascular mortality (hazard ratio: 1.16 [95% confidence interval 0.91-1.47] and hazard ratio: 1.31 [95% confidence interval 0.90-1.93], respectively for the highest HbA(1c) tertile compared with the lowest).

CONCLUSION: These results suggest that HbA(1c) does not significantly predict all-cause and cardiovascular mortality in non-diabetic community-dwelling older adults.

%B Nutr Metab Cardiovasc Dis %V 20 %P 15-21 %8 2010 Jan %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/19364638?dopt=Abstract %R 10.1016/j.numecd.2009.02.007 %0 Journal Article %J Eur Heart J %D 2010 %T Hip fractures and heart failure: findings from the Cardiovascular Health Study. %A Carbone, Laura %A Bůzková, Petra %A Fink, Howard A %A Lee, Jennifer S %A Chen, Zhao %A Ahmed, Ali %A Parashar, Susmita %A Robbins, John R %K Aged %K Female %K Heart Failure %K Hip Fractures %K Humans %K Incidence %K Male %K Risk Factors %K United States %X

AIMS: The aim of the study was to find the epidemiology of hip fractures in heart failure. The increasing survival rate for patients with heart failure places them at risk for other diseases of ageing, including osteoporosis.

METHODS AND RESULTS: We included 5613 persons from the Cardiovascular Health Study (CHS) with an average of 11.5 year follow-up. We determined incidence rates and hazard ratios (HRs) in persons with heart failure compared with persons without heart failure and mortality hazards following these fractures. Annualized incidence rates for hip fractures were 14 per 1000 person-years in heart failure and 6.8 per 1000 person-years without heart failure. Unadjusted and multivariable adjusted HRs for hip fracture associated with heart failure in men were 1.87 (95% CI 1.2-2.93) and 1.59 (95% CI 0.93-2.72), respectively. Respective HRs for women were 1.75 (95% CI 1.27-2.4) and 1.41 (95% CI 0.98-2.03). Mortality hazard was approximately 2-fold greater in patients with heart failure and hip fracture compared with those having heart failure alone.

CONCLUSION: Persons with heart failure are at high risk for hip fractures. However, much of the association between hip fractures and heart failure is explained by shared risk factors. Hip fractures are a substantial contributor to mortality in men and women with heart failure.

%B Eur Heart J %V 31 %P 77-84 %8 2010 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/19892715?dopt=Abstract %R 10.1093/eurheartj/ehp483 %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 Circulation %D 2010 %T Independent susceptibility markers for atrial fibrillation on chromosome 4q25. %A Lubitz, Steven A %A Sinner, Moritz F %A Lunetta, Kathryn L %A Makino, Seiko %A Pfeufer, Arne %A Rahman, Rosanna %A Veltman, Caroline E %A Barnard, John %A Bis, Joshua C %A Danik, Stephan P %A Sonni, Akshata %A Shea, Marisa A %A Del Monte, Federica %A Perz, Siegfried %A Müller, Martina %A Peters, Annette %A Greenberg, Steven M %A Furie, Karen L %A van Noord, Charlotte %A Boerwinkle, Eric %A Stricker, Bruno H C %A Witteman, Jacqueline %A Smith, Jonathan D %A Chung, Mina K %A Heckbert, Susan R %A Benjamin, Emelia J %A Rosand, Jonathan %A Arking, Dan E %A Alonso, Alvaro %A Kääb, Stefan %A Ellinor, Patrick T %K Aged %K Aged, 80 and over %K Atrial Fibrillation %K Chromosome Mapping %K Chromosomes, Human, Pair 4 %K European Continental Ancestry Group %K Female %K Genetic Markers %K Genetic Predisposition to Disease %K Haplotypes %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Risk Factors %X

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

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

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

%B Circulation %V 122 %P 976-84 %8 2010 Sep 07 %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/20733104?dopt=Abstract %R 10.1161/CIRCULATIONAHA.109.886440 %0 Journal Article %J Nephrol Dial Transplant %D 2010 %T Inflammatory biomarkers and decline in kidney function in the elderly: the Cardiovascular Health Study. %A Keller, Christopher %A Katz, Ronit %A Sarnak, Mark J %A Fried, Linda F %A Kestenbaum, Bryan %A Cushman, Mary %A Shlipak, Michael G %K Aged %K Biomarkers %K C-Reactive Protein %K Cohort Studies %K Cystatin C %K Female %K Glomerular Filtration Rate %K Humans %K Inflammation %K Intercellular Adhesion Molecule-1 %K Interleukin-6 %K Kidney %K Logistic Models %K Longitudinal Studies %K Male %K Prospective Studies %K Serum Albumin %X

BACKGROUND: Cross-sectional studies have demonstrated a consistent and linear association between circulating inflammatory markers and kidney function. The objective of this study was to determine whether elevated markers of inflammation are independently associated with longitudinal kidney function decline.

METHODS: This study included 4128 subjects from the Cardiovascular Health Study. Cystatin C was measured at baseline, 3 years later and 7 years later; eligible subjects had at least two measures. Cystatin C-based estimated glomerular filtration rate (eGFR(cysC)) was estimated, and rapid kidney function decline was defined as an annual loss of eGFR(cysC) >3 mL/min/1.73 m(2). Predictors included ten inflammatory and procoagulant biomarkers: C-reactive protein, interleukin-6, intercellular adhesion molecule-1, white blood cell count, fibrinogen, factor VII, factor VIII, D-dimer, plasmin-antiplasmin complex and serum albumin.

RESULTS: During the study, 1059 subjects (26%) had a rapid decline in kidney function. In contrast to the other nine inflammatory or procoagulant biomarkers, serum albumin had a consistent and inverse association with rapid kidney function decline [final adjusted logistic regression model: 1.14-fold increased odds (95% CI 1.06-1.23) of rapid decline per standard deviation lower albumin]. The lowest quartile of albumin had an odds ratio of 1.55 (95% CI 1.23-1.96) for rapid decline compared with the highest quartile. These associations persisted after adjusting the albumin models for CRP, IL-6 and fibrinogen.

CONCLUSIONS: In contrast to nine other inflammatory and procoagulant markers, only lower baseline levels of serum albumin were consistently associated with a rapid decline in kidney function, as measured by cystatin C-based eGFR.

%B Nephrol Dial Transplant %V 25 %P 119-24 %8 2010 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/19734138?dopt=Abstract %R 10.1093/ndt/gfp429 %0 Journal Article %J Ann Hum Genet %D 2010 %T Interaction between fibrinogen and IL-6 genetic variants and associations with cardiovascular disease risk in the Cardiovascular Health Study. %A Carty, Cara L %A Heagerty, Patrick %A Heckbert, Susan R %A Jarvik, Gail P %A Lange, Leslie A %A Cushman, Mary %A Tracy, Russell P %A Reiner, Alexander P %K Aged %K Cardiovascular Diseases %K Carotid Arteries %K Female %K Fibrinogen %K Genetic Predisposition to Disease %K Genetic Variation %K Humans %K Interleukin-6 %K Male %K Models, Biological %K Myocardial Infarction %K Polymorphism, Single Nucleotide %K Risk %K Stroke %X

The inflammatory cytokine interleukin-6 (IL-6) is a main regulator of fibrinogen synthesis, though its interaction with fibrinogen genes (FGA, FGB, FGG) and subsequent impact on cardiovascular disease (CVD) risk is not well-studied. We investigated joint associations of fibrinogen and IL6 tagSNPs with fibrinogen concentrations, carotid intima-media thickness, and myocardial infarction or ischemic stroke in 3900 European-American Cardiovascular Health Study participants. To identify combinations of genetic main effects and interactions associated with outcomes, we used logic regression. We also evaluated whether the relationship between fibrinogen SNPs and fibrinogen level varied by IL-6 level using linear regression models with multiplicative interaction terms. Combinations of fibrinogen and IL6 SNPs were significantly associated with fibrinogen level (p < 0.005), but not with other outcomes. Fibrinogen levels were higher in individuals having FGB1437 (rs1800790) and lacking FGA6534 (rs6050) minor alleles; these SNPs interacted with IL6 rs1800796 to influence fibrinogen level. Marginally significant (p= 0.03) interactions between IL-6 level and FGA and FGG promoter SNPs associated with fibrinogen levels were detected. We identified potential gene-gene interactions influencing fibrinogen levels. Although IL-6 responsive binding sites are present in fibrinogen gene promoter regions, we did not find strong evidence of interaction between fibrinogen SNPs and IL6 SNPs or levels influencing CVD.

%B Ann Hum Genet %V 74 %P 1-10 %8 2010 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/20059469?dopt=Abstract %R 10.1111/j.1469-1809.2009.00551.x %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 Am J Emerg Med %D 2010 %T Intravenous tissue plasminogen activator and stroke in the elderly. %A Longstreth, W T %A Katz, Ronit %A Tirschwell, David L %A Cushman, Mary %A Psaty, Bruce M %K Aged, 80 and over %K Female %K Fibrinolytic Agents %K Humans %K Longitudinal Studies %K Male %K Placebos %K Randomized Controlled Trials as Topic %K Stroke %K Tissue Plasminogen Activator %K Treatment Outcome %K United States %X

OBJECTIVE: Since publication in 1995 of the National Institute of Neurological Disorders and Stroke (NINDS) trial of intravenous tissue plasminogen activator (IV tPA) for acute ischemic stroke, the benefit and frequency of use of IV tPA in the elderly have remained uncertain.

METHODS: We obtained data from the NINDS trial to summarize outcomes for randomized subjects older than 80 years. We used data from the Cardiovascular Health Study, a cohort study of 5888 elderly participants from 4 US communities followed longitudinally for stroke since 1989 to estimate the use of and hospital outcome after IV tPA in older adults following publication of the trial in 1995.

RESULTS: In the NINDS trial, 44 subjects older than 80 years were randomized, and their 3-month functional outcomes were not significantly improved with IV tPA. Of 25 randomized to IV tPA, 4 experienced symptomatic intracranial hemorrhages within 36 hours of treatment. Compared with younger patients, older patients were 2.87 times more likely to experience a symptomatic intracranial hemorrhage within 36 hours of IV tPA (95% confidence interval, 1.04-7.93). Of 227 Cardiovascular Health Study participants hospitalized for ischemic stroke between 1995 and 2002, seven, whose mean age was 84 years, were treated with IV tPA (3.1%; 95% confidence interval 1.2-6.2). Two had symptomatic intracranial hemorrhages, 3 failed to improve, and 2 of the 7 had good outcomes.

CONCLUSIONS: These data highlight the need to clarify the risk-benefit profile of IV tPA in ischemic stroke victims who are older than 80 years.

%B Am J Emerg Med %V 28 %P 359-63 %8 2010 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/20223397?dopt=Abstract %R 10.1016/j.ajem.2009.01.025 %0 Journal Article %J Lancet %D 2010 %T Lipoprotein-associated phospholipase A(2) and risk of coronary disease, stroke, and mortality: collaborative analysis of 32 prospective studies. %A Thompson, Alexander %A Gao, Pei %A Orfei, Lia %A Watson, Sarah %A Di Angelantonio, Emanuele %A Kaptoge, Stephen %A Ballantyne, Christie %A Cannon, Christopher P %A Criqui, Michael %A Cushman, Mary %A Hofman, Albert %A Packard, Chris %A Thompson, Simon G %A Collins, Rory %A Danesh, John %K 1-Alkyl-2-acetylglycerophosphocholine Esterase %K Blood Pressure %K Coronary Disease %K Female %K Humans %K Linear Models %K Lipids %K Male %K Middle Aged %K Prospective Studies %K Risk Assessment %K Risk Factors %K Stroke %K Systole %X

BACKGROUND: Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), an inflammatory enzyme expressed in atherosclerotic plaques, is a therapeutic target being assessed in trials of vascular disease prevention. We investigated associations of circulating Lp-PLA(2) mass and activity with risk of coronary heart disease, stroke, and mortality under different circumstances.

METHODS: With use of individual records from 79 036 participants in 32 prospective studies (yielding 17 722 incident fatal or non-fatal outcomes during 474 976 person-years at risk), we did a meta-analysis of within-study regressions to calculate risk ratios (RRs) per 1 SD higher value of Lp-PLA(2) or other risk factor. The primary outcome was coronary heart disease.

FINDINGS: Lp-PLA(2) activity and mass were associated with each other (r=0.51, 95% CI 0.47-0.56) and proatherogenic lipids. We noted roughly log-linear associations of Lp-PLA(2) activity and mass with risk of coronary heart disease and vascular death. RRs, adjusted for conventional risk factors, were: 1.10 (95% CI 1.05-1.16) with Lp-PLA(2) activity and 1.11 (1.07-1.16) with Lp-PLA(2) mass for coronary heart disease; 1.08 (0.97-1.20) and 1.14 (1.02-1.27) for ischaemic stroke; 1.16 (1.09-1.24) and 1.13 (1.05-1.22) for vascular mortality; and 1.10 (1.04-1.17) and 1.10 (1.03-1.18) for non-vascular mortality, respectively. RRs with Lp-PLA(2) did not differ significantly in people with and without initial stable vascular disease, apart from for vascular death with Lp-PLA(2) mass. Adjusted RRs for coronary heart disease were 1.10 (1.02-1.18) with non-HDL cholesterol and 1.10 (1.00-1.21) with systolic blood pressure.

INTERPRETATION: Lp-PLA(2) activity and mass each show continuous associations with risk of coronary heart disease, similar in magnitude to that with non-HDL cholesterol or systolic blood pressure in this population. Associations of Lp-PLA(2) mass and activity are not exclusive to vascular outcomes, and the vascular associations depend at least partly on lipids.

FUNDING: UK Medical Research Council, GlaxoSmithKline, and British Heart Foundation.

%B Lancet %V 375 %P 1536-44 %8 2010 May 01 %G eng %N 9725 %1 https://www.ncbi.nlm.nih.gov/pubmed/20435228?dopt=Abstract %R 10.1016/S0140-6736(10)60319-4 %0 Journal Article %J Atherosclerosis %D 2010 %T Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) and risk of cardiovascular disease in older adults: results from the Cardiovascular Health Study. %A Jenny, Nancy Swords %A Solomon, Cam %A Cushman, Mary %A Tracy, Russell P %A Nelson, Jeanenne J %A Psaty, Bruce M %A Furberg, Curt D %K 1-Alkyl-2-acetylglycerophosphocholine Esterase %K Aged %K C-Reactive Protein %K Cardiovascular Diseases %K Female %K Humans %K Myocardial Infarction %K Population Surveillance %K Prospective Studies %K Risk %K Stroke %X

OBJECTIVE: To examine associations between lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) antigen level (mass) and enzymatic activity (activity) and cardiovascular disease (CVD) in older adults.

METHODS: We examined associations of Lp-PLA(2) mass and activity with incident myocardial infarction (MI; n=508), stroke (n=565) and CVD death (n=665) using Cox regressions adjusted for age, sex, ethnicity and CVD risk factors in 3949 older adults, aged > or =65 years at baseline, from the Cardiovascular Health Study (CHS).

RESULTS: Lp-PLA(2) was associated with incident CVD events in these older adults. Hazard ratios (95% confidence intervals) for highest versus lowest tertiles of Lp-PLA(2) mass were 1.49 (1.19-1.85) for MI, 1.21 (0.98-1.49) for stroke and 1.11 (0.92-1.33) for CVD death. The highest tertile of Lp-PLA(2) activity was associated with MI (1.36; 1.09-1.70) and CVD death (1.23; 1.02-1.50). Combined Lp-PLA(2) tertile 3 and CRP>3mg/l, compared to Lp-PLA(2) tertile 1 and CRP<1mg/l, was associated with MI (2.29; 1.49-3.52) for Lp-PLA(2) mass and MI (1.66; 1.10-2.51) and CVD death (1.57; 1.08-2.26) for activity. For MI, both mass and activity added excess risk to elevated CRP alone ( approximately 20% excess risk) and activity added excess risk for CVD death ( approximately 12%).

CONCLUSION: Lp-PLA(2) mass and activity were associated with incident CVD events in older adults in CHS. Lp-PLA(2) and CRP were independent and additive in prediction of events. While associations were modest, these results support further exploration of Lp-PLA(2) to identify older individuals at risk for CVD.

%B Atherosclerosis %V 209 %P 528-32 %8 2010 Apr %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/19804884?dopt=Abstract %R 10.1016/j.atherosclerosis.2009.09.021 %0 Journal Article %J J Am Geriatr Soc %D 2010 %T Long-term retention of older adults in the Cardiovascular Health Study: implications for studies of the oldest old. %A Strotmeyer, Elsa S %A Arnold, Alice M %A Boudreau, Robert M %A Ives, Diane G %A Cushman, Mary %A Robbins, John A %A Harris, Tamara B %A Newman, Anne B %K Age Factors %K Aged %K Aged, 80 and over %K Ambulatory Care Facilities %K Analysis of Variance %K Cardiovascular Diseases %K Chi-Square Distribution %K Epidemiologic Studies %K Female %K Geriatric Assessment %K House Calls %K Humans %K Logistic Models %K Longitudinal Studies %K Male %K Multivariate Analysis %K Patient Dropouts %K Patient Selection %K Research Subjects %K Telephone %K United States %X

OBJECTIVES: To describe retention according to age and visit type (clinic, home, telephone) and to determine characteristics associated with visit types for a longitudinal epidemiological study in older adults.

DESIGN: Longitudinal cohort study.

SETTING: Four U.S. clinical sites.

PARTICIPANTS: Five thousand eight hundred eighty-eight Cardiovascular Health Study (CHS) participants aged 65 to 100 at 1989/90 or 1992/93 enrollment (58.6% female; 15.7% black). CHS participants were contacted every 6 months, with annual assessments through 1999 and in 2005/06 for the All Stars Study visit of the CHS cohort (aged 77-102; 66.5% female; 16.6% black).

MEASUREMENTS: All annual contacts through 1999 (n=43,772) and for the 2005/06 visit (n=1,942).

RESULTS: CHS had 43,772 total participant contacts from 1989 to 1999: 34,582 clinic visits (79.0%), 2,238 refusals (5.1%), 4,401 telephone visits (10.1%), 1,811 home visits (4.1%), and 740 other types (1.7%). In 2005/06, the All Stars participants of the CHS cohort had 36.6% clinic, 22.3% home, and 41.1% telephone visits. Compared with participants aged 65 to 69, odds ratios of not attending a CHS clinic visit were 1.82 (95% confidence interval (CI)=1.54-2.13), 2.94 (95% CI=2.45-3.57), 4.55 (95% CI=3.70-5.56), and 9.09 (95% CI=7.69-11.11) for those aged 70 to 74, 75 to 79, 80 to 84, and 85 and older, respectively, in sex-adjusted regression. In multivariable regression, participants with a 2005/06 clinic visit were younger, more likely to be male and in good health, and had had better cognitive and physical function 7 years earlier than participants with other visit types. Participants with home, telephone, and missing visits were similar on characteristics measured 7 years earlier.

CONCLUSION: Offering home, telephone, and proxy visits are essential to optimizing follow-up of aging cohorts. Home visits increased in-person retention from 36.5% to 58.8% and diversified the cohort with respect to age, health, and physical functioning.

%B J Am Geriatr Soc %V 58 %P 696-701 %8 2010 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/20398149?dopt=Abstract %R 10.1111/j.1532-5415.2010.02770.x %0 Journal Article %J Nat Genet %D 2010 %T Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function. %A Hancock, Dana B %A Eijgelsheim, Mark %A Wilk, Jemma B %A Gharib, Sina A %A Loehr, Laura R %A Marciante, Kristin D %A Franceschini, Nora %A van Durme, Yannick M T A %A Chen, Ting-Hsu %A Barr, R Graham %A Schabath, Matthew B %A Couper, David J %A Brusselle, Guy G %A Psaty, Bruce M %A van Duijn, Cornelia M %A Rotter, Jerome I %A Uitterlinden, André G %A Hofman, Albert %A Punjabi, Naresh M %A Rivadeneira, Fernando %A Morrison, Alanna C %A Enright, Paul L %A North, Kari E %A Heckbert, Susan R %A Lumley, Thomas %A Stricker, Bruno H C %A O'Connor, George T %A London, Stephanie J %K Databases, Genetic %K Female %K Forced Expiratory Volume %K Genetic Predisposition to Disease %K Genome, Human %K Genome-Wide Association Study %K Humans %K Lung %K Lung Diseases %K Male %K Meta-Analysis as Topic %K Polymorphism, Single Nucleotide %K Spirometry %K Vital Capacity %X

Spirometric measures of lung function are heritable traits that reflect respiratory health and predict morbidity and mortality. We meta-analyzed genome-wide association studies for two clinically important lung-function measures: forced expiratory volume in the first second (FEV(1)) and its ratio to forced vital capacity (FEV(1)/FVC), an indicator of airflow obstruction. This meta-analysis included 20,890 participants of European ancestry from four CHARGE Consortium studies: Atherosclerosis Risk in Communities, Cardiovascular Health Study, Framingham Heart Study and Rotterdam Study. We identified eight loci associated with FEV(1)/FVC (HHIP, GPR126, ADAM19, AGER-PPT2, FAM13A, PTCH1, PID1 and HTR4) and one locus associated with FEV(1) (INTS12-GSTCD-NPNT) at or near genome-wide significance (P < 5 x 10(-8)) in the CHARGE Consortium dataset. Our findings may offer insights into pulmonary function and pathogenesis of chronic lung disease.

%B Nat Genet %V 42 %P 45-52 %8 2010 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/20010835?dopt=Abstract %R 10.1038/ng.500 %0 Journal Article %J Nat Genet %D 2010 %T Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. %A Heid, Iris M %A Jackson, Anne U %A Randall, Joshua C %A Winkler, Thomas W %A Qi, Lu %A Steinthorsdottir, Valgerdur %A Thorleifsson, Gudmar %A Zillikens, M Carola %A Speliotes, Elizabeth K %A Mägi, Reedik %A Workalemahu, Tsegaselassie %A White, Charles C %A Bouatia-Naji, Nabila %A Harris, Tamara B %A Berndt, Sonja I %A Ingelsson, Erik %A Willer, Cristen J %A Weedon, Michael N %A Luan, Jian'an %A Vedantam, Sailaja %A Esko, Tõnu %A Kilpeläinen, Tuomas O %A Kutalik, Zoltán %A Li, Shengxu %A Monda, Keri L %A Dixon, Anna L %A Holmes, Christopher C %A Kaplan, Lee M %A Liang, Liming %A Min, Josine L %A Moffatt, Miriam F %A Molony, Cliona %A Nicholson, George %A Schadt, Eric E %A Zondervan, Krina T %A Feitosa, Mary F %A Ferreira, Teresa %A Lango Allen, Hana %A Weyant, Robert J %A Wheeler, Eleanor %A Wood, Andrew R %A Estrada, Karol %A Goddard, Michael E %A Lettre, Guillaume %A Mangino, Massimo %A Nyholt, Dale R %A Purcell, Shaun %A Smith, Albert Vernon %A Visscher, Peter M %A Yang, Jian %A McCarroll, Steven A %A Nemesh, James %A Voight, Benjamin F %A Absher, Devin %A Amin, Najaf %A Aspelund, Thor %A Coin, Lachlan %A Glazer, Nicole L %A Hayward, Caroline %A Heard-Costa, Nancy L %A Hottenga, Jouke-Jan %A Johansson, Asa %A Johnson, Toby %A Kaakinen, Marika %A Kapur, Karen %A Ketkar, Shamika %A Knowles, Joshua W %A Kraft, Peter %A Kraja, Aldi T %A Lamina, Claudia %A Leitzmann, Michael F %A McKnight, Barbara %A Morris, Andrew P %A Ong, Ken K %A Perry, John R B %A Peters, Marjolein J %A Polasek, Ozren %A Prokopenko, Inga %A Rayner, Nigel W %A Ripatti, Samuli %A Rivadeneira, Fernando %A Robertson, Neil R %A Sanna, Serena %A Sovio, Ulla %A Surakka, Ida %A Teumer, Alexander %A van Wingerden, Sophie %A Vitart, Veronique %A Zhao, Jing Hua %A Cavalcanti-Proença, Christine %A Chines, Peter S %A Fisher, Eva %A Kulzer, Jennifer R %A Lecoeur, Cécile %A Narisu, Narisu %A Sandholt, Camilla %A Scott, Laura J %A Silander, Kaisa %A Stark, Klaus %A Tammesoo, Mari-Liis %A Teslovich, Tanya M %A Timpson, Nicholas John %A Watanabe, Richard M %A Welch, Ryan %A Chasman, Daniel I %A Cooper, Matthew N %A Jansson, John-Olov %A Kettunen, Johannes %A Lawrence, Robert W %A Pellikka, Niina %A Perola, Markus %A Vandenput, Liesbeth %A Alavere, Helene %A Almgren, Peter %A Atwood, Larry D %A Bennett, Amanda J %A Biffar, Reiner %A Bonnycastle, Lori L %A Bornstein, Stefan R %A Buchanan, Thomas A %A Campbell, Harry %A Day, Ian N M %A Dei, Mariano %A Dörr, Marcus %A Elliott, Paul %A Erdos, Michael R %A Eriksson, Johan G %A Freimer, Nelson B %A Fu, Mao %A Gaget, Stefan %A Geus, Eco J C %A Gjesing, Anette P %A Grallert, Harald %A Grässler, Jürgen %A Groves, Christopher J %A Guiducci, Candace %A Hartikainen, Anna-Liisa %A Hassanali, Neelam %A Havulinna, Aki S %A Herzig, Karl-Heinz %A Hicks, Andrew A %A Hui, Jennie %A Igl, Wilmar %A Jousilahti, Pekka %A Jula, Antti %A Kajantie, Eero %A Kinnunen, Leena %A Kolcic, Ivana %A Koskinen, Seppo %A Kovacs, Peter %A Kroemer, Heyo K %A Krzelj, Vjekoslav %A Kuusisto, Johanna %A Kvaloy, Kirsti %A Laitinen, Jaana %A Lantieri, Olivier %A Lathrop, G Mark %A Lokki, Marja-Liisa %A Luben, Robert N %A Ludwig, Barbara %A McArdle, Wendy L %A McCarthy, Anne %A Morken, Mario A %A Nelis, Mari %A Neville, Matt J %A Paré, Guillaume %A Parker, Alex N %A Peden, John F %A Pichler, Irene %A Pietiläinen, Kirsi H %A Platou, Carl G P %A Pouta, Anneli %A Ridderstråle, Martin %A Samani, Nilesh J %A Saramies, Jouko %A Sinisalo, Juha %A Smit, Jan H %A Strawbridge, Rona J %A Stringham, Heather M %A Swift, Amy J %A Teder-Laving, Maris %A Thomson, Brian %A Usala, Gianluca %A van Meurs, Joyce B J %A van Ommen, Gert-Jan %A Vatin, Vincent %A Volpato, Claudia B %A Wallaschofski, Henri %A Walters, G Bragi %A Widen, Elisabeth %A Wild, Sarah H %A Willemsen, Gonneke %A Witte, Daniel R %A Zgaga, Lina %A Zitting, Paavo %A Beilby, John P %A James, Alan L %A Kähönen, Mika %A Lehtimäki, Terho %A Nieminen, Markku S %A Ohlsson, Claes %A Palmer, Lyle J %A Raitakari, Olli %A Ridker, Paul M %A Stumvoll, Michael %A Tönjes, Anke %A Viikari, Jorma %A Balkau, Beverley %A Ben-Shlomo, Yoav %A Bergman, Richard N %A Boeing, Heiner %A Smith, George Davey %A Ebrahim, Shah %A Froguel, Philippe %A Hansen, Torben %A Hengstenberg, Christian %A Hveem, Kristian %A Isomaa, Bo %A Jørgensen, Torben %A Karpe, Fredrik %A Khaw, Kay-Tee %A Laakso, Markku %A Lawlor, Debbie A %A Marre, Michel %A Meitinger, Thomas %A Metspalu, Andres %A Midthjell, Kristian %A Pedersen, Oluf %A Salomaa, Veikko %A Schwarz, Peter E H %A Tuomi, Tiinamaija %A Tuomilehto, Jaakko %A Valle, Timo T %A Wareham, Nicholas J %A Arnold, Alice M %A Beckmann, Jacques S %A Bergmann, Sven %A Boerwinkle, Eric %A Boomsma, Dorret I %A Caulfield, Mark J %A Collins, Francis S %A Eiriksdottir, Gudny %A Gudnason, Vilmundur %A Gyllensten, Ulf %A Hamsten, Anders %A Hattersley, Andrew T %A Hofman, Albert %A Hu, Frank B %A Illig, Thomas %A Iribarren, Carlos %A Jarvelin, Marjo-Riitta %A Kao, W H Linda %A Kaprio, Jaakko %A Launer, Lenore J %A Munroe, Patricia B %A Oostra, Ben %A Penninx, Brenda W %A Pramstaller, Peter P %A Psaty, Bruce M %A Quertermous, Thomas %A Rissanen, Aila %A Rudan, Igor %A Shuldiner, Alan R %A Soranzo, Nicole %A Spector, Timothy D %A Syvänen, Ann-Christine %A Uda, Manuela %A Uitterlinden, Andre %A Völzke, Henry %A Vollenweider, Peter %A Wilson, James F %A Witteman, Jacqueline C %A Wright, Alan F %A Abecasis, Goncalo R %A Boehnke, Michael %A Borecki, Ingrid B %A Deloukas, Panos %A Frayling, Timothy M %A Groop, Leif C %A Haritunians, Talin %A Hunter, David J %A Kaplan, Robert C %A North, Kari E %A O'Connell, Jeffrey R %A Peltonen, Leena %A Schlessinger, David %A Strachan, David P %A Hirschhorn, Joel N %A Assimes, Themistocles L %A Wichmann, H-Erich %A Thorsteinsdottir, Unnur %A van Duijn, Cornelia M %A Stefansson, Kari %A Cupples, L Adrienne %A Loos, Ruth J F %A Barroso, Inês %A McCarthy, Mark I %A Fox, Caroline S %A Mohlke, Karen L %A Lindgren, Cecilia M %K Adipose Tissue %K Age Factors %K Chromosome Mapping %K Female %K Genome, Human %K Genome-Wide Association Study %K Humans %K Male %K Meta-Analysis as Topic %K Polymorphism, Single Nucleotide %K Sex Characteristics %K Waist-Hip Ratio %X

Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.

%B Nat Genet %V 42 %P 949-60 %8 2010 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/20935629?dopt=Abstract %R 10.1038/ng.685 %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2010 %T A meta-analysis of four genome-wide association studies of survival to age 90 years or older: the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. %A Newman, Anne B %A Walter, Stefan %A Lunetta, Kathryn L %A Garcia, Melissa E %A Slagboom, P Eline %A Christensen, Kaare %A Arnold, Alice M %A Aspelund, Thor %A Aulchenko, Yurii S %A Benjamin, Emelia J %A Christiansen, Lene %A D'Agostino, Ralph B %A Fitzpatrick, Annette L %A Franceschini, Nora %A Glazer, Nicole L %A Gudnason, Vilmundur %A Hofman, Albert %A Kaplan, Robert %A Karasik, David %A Kelly-Hayes, Margaret %A Kiel, Douglas P %A Launer, Lenore J %A Marciante, Kristin D %A Massaro, Joseph M %A Miljkovic, Iva %A Nalls, Michael A %A Hernandez, Dena %A Psaty, Bruce M %A Rivadeneira, Fernando %A Rotter, Jerome %A Seshadri, Sudha %A Smith, Albert V %A Taylor, Kent D %A Tiemeier, Henning %A Uh, Hae-Won %A Uitterlinden, André G %A Vaupel, James W %A Walston, Jeremy %A Westendorp, Rudi G J %A Harris, Tamara B %A Lumley, Thomas %A van Duijn, Cornelia M %A Murabito, Joanne M %K Adult %K Age Factors %K Aged %K Aged, 80 and over %K Alleles %K Cohort Studies %K Confidence Intervals %K Female %K Genome-Wide Association Study %K Genotype %K Humans %K Longevity %K Male %K Middle Aged %K Odds Ratio %K Polymorphism, Single Nucleotide %X

BACKGROUND: Genome-wide association studies (GWAS) may yield insights into longevity.

METHODS: We performed a meta-analysis of GWAS in Caucasians from four prospective cohort studies: the Age, Gene/Environment Susceptibility-Reykjavik Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Longevity was defined as survival to age 90 years or older (n = 1,836); the comparison group comprised cohort members who died between the ages of 55 and 80 years (n = 1,955). In a second discovery stage, additional genotyping was conducted in the Leiden Longevity Study cohort and the Danish 1905 cohort.

RESULTS: There were 273 single-nucleotide polymorphism (SNP) associations with p < .0001, but none reached the prespecified significance level of 5 x 10(-8). Of the most significant SNPs, 24 were independent signals, and 16 of these SNPs were successfully genotyped in the second discovery stage, with one association for rs9664222, reaching 6.77 x 10(-7) for the combined meta-analysis of CHARGE and the stage 2 cohorts. The SNP lies in a region near MINPP1 (chromosome 10), a well-conserved gene involved in regulation of cellular proliferation. The minor allele was associated with lower odds of survival past age 90 (odds ratio = 0.82). Associations of interest in a homologue of the longevity assurance gene (LASS3) and PAPPA2 were not strengthened in the second stage.

CONCLUSION: Survival studies of larger size or more extreme or specific phenotypes may support or refine these initial findings.

%B J Gerontol A Biol Sci Med Sci %V 65 %P 478-87 %8 2010 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/20304771?dopt=Abstract %R 10.1093/gerona/glq028 %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 Nat Genet %D 2010 %T New loci associated with kidney function and chronic kidney disease. %A Köttgen, Anna %A Pattaro, Cristian %A Böger, Carsten A %A Fuchsberger, Christian %A Olden, Matthias %A Glazer, Nicole L %A Parsa, Afshin %A Gao, Xiaoyi %A Yang, Qiong %A Smith, Albert V %A O'Connell, Jeffrey R %A Li, Man %A Schmidt, Helena %A Tanaka, Toshiko %A Isaacs, Aaron %A Ketkar, Shamika %A Hwang, Shih-Jen %A Johnson, Andrew D %A Dehghan, Abbas %A Teumer, Alexander %A Paré, Guillaume %A Atkinson, Elizabeth J %A Zeller, Tanja %A Lohman, Kurt %A Cornelis, Marilyn C %A Probst-Hensch, Nicole M %A Kronenberg, Florian %A Tönjes, Anke %A Hayward, Caroline %A Aspelund, Thor %A Eiriksdottir, Gudny %A Launer, Lenore J %A Harris, Tamara B %A Rampersaud, Evadnie %A Mitchell, Braxton D %A Arking, Dan E %A Boerwinkle, Eric %A Struchalin, Maksim %A Cavalieri, Margherita %A Singleton, Andrew %A Giallauria, Francesco %A Metter, Jeffrey %A de Boer, Ian H %A Haritunians, Talin %A Lumley, Thomas %A Siscovick, David %A Psaty, Bruce M %A Zillikens, M Carola %A Oostra, Ben A %A Feitosa, Mary %A Province, Michael %A de Andrade, Mariza %A Turner, Stephen T %A Schillert, Arne %A Ziegler, Andreas %A Wild, Philipp S %A Schnabel, Renate B %A Wilde, Sandra %A Munzel, Thomas F %A Leak, Tennille S %A Illig, Thomas %A Klopp, Norman %A Meisinger, Christa %A Wichmann, H-Erich %A Koenig, Wolfgang %A Zgaga, Lina %A Zemunik, Tatijana %A Kolcic, Ivana %A Minelli, Cosetta %A Hu, Frank B %A Johansson, Asa %A Igl, Wilmar %A Zaboli, Ghazal %A Wild, Sarah H %A Wright, Alan F %A Campbell, Harry %A Ellinghaus, David %A Schreiber, Stefan %A Aulchenko, Yurii S %A Felix, Janine F %A Rivadeneira, Fernando %A Uitterlinden, André G %A Hofman, Albert %A Imboden, Medea %A Nitsch, Dorothea %A Brandstätter, Anita %A Kollerits, Barbara %A Kedenko, Lyudmyla %A Mägi, Reedik %A Stumvoll, Michael %A Kovacs, Peter %A Boban, Mladen %A Campbell, Susan %A Endlich, Karlhans %A Völzke, Henry %A Kroemer, Heyo K %A Nauck, Matthias %A Völker, Uwe %A Polasek, Ozren %A Vitart, Veronique %A Badola, Sunita %A Parker, Alexander N %A Ridker, Paul M %A Kardia, Sharon L R %A Blankenberg, Stefan %A Liu, Yongmei %A Curhan, Gary C %A Franke, Andre %A Rochat, Thierry %A Paulweber, Bernhard %A Prokopenko, Inga %A Wang, Wei %A Gudnason, Vilmundur %A Shuldiner, Alan R %A Coresh, Josef %A Schmidt, Reinhold %A Ferrucci, Luigi %A Shlipak, Michael G %A van Duijn, Cornelia M %A Borecki, Ingrid %A Krämer, Bernhard K %A Rudan, Igor %A Gyllensten, Ulf %A Wilson, James F %A Witteman, Jacqueline C %A Pramstaller, Peter P %A Rettig, Rainer %A Hastie, Nick %A Chasman, Daniel I %A Kao, W H %A Heid, Iris M %A Fox, Caroline S %K Cohort Studies %K Creatinine %K Cystatin C %K Diet %K Europe %K Genetic Markers %K Genome-Wide Association Study %K Glomerular Filtration Rate %K Humans %K Kidney %K Kidney Failure, Chronic %K Models, Genetic %K Risk Factors %X

Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m(2); n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide-significant loci (P < 5 x 10(-8)) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney.

%B Nat Genet %V 42 %P 376-84 %8 2010 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/20383146?dopt=Abstract %R 10.1038/ng.568 %0 Journal Article %J Sleep %D 2010 %T A novel approach to prediction of mild obstructive sleep disordered breathing in a population-based sample: the Sleep Heart Health Study. %A Caffo, Brian %A Diener-West, Marie %A Punjabi, Naresh M %A Samet, Jonathan %K Age Factors %K Aged %K Algorithms %K Body Mass Index %K Cohort Studies %K Female %K Humans %K Male %K Middle Aged %K Predictive Value of Tests %K Risk Factors %K ROC Curve %K Sleep Apnea Syndromes %K Snoring %K Waist Circumference %X

This manuscript considers a data-mining approach for the prediction of mild obstructive sleep disordered breathing, defined as an elevated respiratory disturbance index (RDI), in 5,530 participants in a community-based study, the Sleep Heart Health Study. The prediction algorithm was built using modern ensemble learning algorithms, boosting in specific, which allowed for assessing potential high-dimensional interactions between predictor variables or classifiers. To evaluate the performance of the algorithm, the data were split into training and validation sets for varying thresholds for predicting the probability of a high RDI (≥7 events per hour in the given results). Based on a moderate classification threshold from the boosting algorithm, the estimated post-test odds of a high RDI were 2.20 times higher than the pre-test odds given a positive test, while the corresponding post-test odds were decreased by 52% given a negative test (sensitivity and specificity of 0.66 and 0.70, respectively). In rank order, the following variables had the largest impact on prediction performance: neck circumference, body mass index, age, snoring frequency, waist circumference, and snoring loudness.

%B Sleep %V 33 %P 1641-8 %8 2010 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/21120126?dopt=Abstract %0 Journal Article %J Circulation %D 2010 %T Novel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: The CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium. %A Smith, Nicholas L %A Chen, Ming-Huei %A Dehghan, Abbas %A Strachan, David P %A Basu, Saonli %A Soranzo, Nicole %A Hayward, Caroline %A Rudan, Igor %A Sabater-Lleal, Maria %A Bis, Joshua C %A de Maat, Moniek P M %A Rumley, Ann %A Kong, Xiaoxiao %A Yang, Qiong %A Williams, Frances M K %A Vitart, Veronique %A Campbell, Harry %A Mälarstig, Anders %A Wiggins, Kerri L %A van Duijn, Cornelia M %A McArdle, Wendy L %A Pankow, James S %A Johnson, Andrew D %A Silveira, Angela %A McKnight, Barbara %A Uitterlinden, André G %A Aleksic, Nena %A Meigs, James B %A Peters, Annette %A Koenig, Wolfgang %A Cushman, Mary %A Kathiresan, Sekar %A Rotter, Jerome I %A Bovill, Edwin G %A Hofman, Albert %A Boerwinkle, Eric %A Tofler, Geoffrey H %A Peden, John F %A Psaty, Bruce M %A Leebeek, Frank %A Folsom, Aaron R %A Larson, Martin G %A Spector, Timothy D %A Wright, Alan F %A Wilson, James F %A Hamsten, Anders %A Lumley, Thomas %A Witteman, Jacqueline C M %A Tang, Weihong %A O'Donnell, Christopher J %K Adult %K Factor VII %K Factor VIII %K Female %K Genome-Wide Association Study %K Hemostasis %K Humans %K Male %K Middle Aged %K Phenotype %K Polymorphism, Single Nucleotide %K Thrombosis %K von Willebrand Factor %X

BACKGROUND: Plasma levels of coagulation factors VII (FVII), VIII (FVIII), and von Willebrand factor (vWF) influence risk of hemorrhage and thrombosis. We conducted genome-wide association studies to identify new loci associated with plasma levels.

METHODS AND RESULTS: The setting of the study included 5 community-based studies for discovery comprising 23 608 European-ancestry participants: Atherosclerosis Risk In Communities Study, Cardiovascular Health Study, British 1958 Birth Cohort, Framingham Heart Study, and Rotterdam Study. All subjects had genome-wide single-nucleotide polymorphism (SNP) scans and at least 1 phenotype measured: FVII activity/antigen, FVIII activity, and vWF antigen. Each study used its genotype data to impute to HapMap SNPs and independently conducted association analyses of hemostasis measures using an additive genetic model. Study findings were combined by meta-analysis. Replication was conducted in 7604 participants not in the discovery cohort. For FVII, 305 SNPs exceeded the genome-wide significance threshold of 5.0x10(-8) and comprised 5 loci on 5 chromosomes: 2p23 (smallest P value 6.2x10(-24)), 4q25 (3.6x10(-12)), 11q12 (2.0x10(-10)), 13q34 (9.0x10(-259)), and 20q11.2 (5.7x10(-37)). Loci were within or near genes, including 4 new candidate genes and F7 (13q34). For vWF, 400 SNPs exceeded the threshold and marked 8 loci on 6 chromosomes: 6q24 (1.2x10(-22)), 8p21 (1.3x10(-16)), 9q34 (<5.0x10(-324)), 12p13 (1.7x10(-32)), 12q23 (7.3x10(-10)), 12q24.3 (3.8x10(-11)), 14q32 (2.3x10(-10)), and 19p13.2 (1.3x10(-9)). All loci were within genes, including 6 new candidate genes, as well as ABO (9q34) and VWF (12p13). For FVIII, 5 loci were identified and overlapped vWF findings. Nine of the 10 new findings were replicated.

CONCLUSIONS: New genetic associations were discovered outside previously known biological pathways and may point to novel prevention and treatment targets of hemostasis disorders.

%B Circulation %V 121 %P 1382-92 %8 2010 Mar 30 %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/20231535?dopt=Abstract %R 10.1161/CIRCULATIONAHA.109.869156 %0 Journal Article %J Neurobiol Aging %D 2010 %T Obesity is linked with lower brain volume in 700 AD and MCI patients. %A Ho, April J %A Raji, Cyrus A %A Becker, James T %A Lopez, Oscar L %A Kuller, Lewis H %A Hua, Xue %A Lee, Suh %A Hibar, Derrek %A Dinov, Ivo D %A Stein, Jason L %A Jack, Clifford R %A Weiner, Michael W %A Toga, Arthur W %A Thompson, Paul M %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Atrophy %K Body Mass Index %K Brain %K Cognition Disorders %K Cohort Studies %K Female %K Humans %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Obesity %K Organ Size %K Prospective Studies %K Risk Factors %X

Obesity is associated with lower brain volumes in cognitively normal elderly subjects, but no study has yet investigated the effects of obesity on brain structure in patients with mild cognitive impairment (MCI) or Alzheimer's disease (AD). To determine if higher body mass index (BMI) is associated with brain volume deficits in cognitively impaired elderly subjects, we analyzed brain magnetic resonance imaging (MRI) scans of 700 MCI or AD patients from 2 different cohorts: the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Cardiovascular Health Study-Cognition Study (CHS-CS). Tensor-based morphometry (TBM) was used to create 3-dimensional maps of regional tissue excess or deficits in subjects with MCI (ADNI, n = 399; CHS-CS, n = 77) and AD (ADNI, n = 188; CHS, n = 36). In both AD and MCI groups, higher body mass index was associated with brain volume deficits in frontal, temporal, parietal, and occipital lobes; the atrophic pattern was consistent in both ADNI and CHS populations. Cardiovascular risk factors, especially obesity, should be considered as influencing brain structure in those already afflicted by cognitive impairment and dementia.

%B Neurobiol Aging %V 31 %P 1326-39 %8 2010 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/20570405?dopt=Abstract %R 10.1016/j.neurobiolaging.2010.04.006 %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 PLoS One %D 2010 %T Polymorphisms in the mitochondrial DNA control region and frailty in older adults. %A Moore, Ann Z %A Biggs, Mary L %A Matteini, Amy %A O'Connor, Ashley %A McGuire, Sarah %A Beamer, Brock A %A Fallin, M Danielle %A Fried, Linda P %A Walston, Jeremy %A Chakravarti, Aravinda %A Arking, Dan E %K Aged %K Aged, 80 and over %K DNA, Mitochondrial %K Female %K Frail Elderly %K Genotype %K Humans %K Male %K Polymorphism, Genetic %X

BACKGROUND: Mitochondria contribute to the dynamics of cellular metabolism, the production of reactive oxygen species, and apoptotic pathways. Consequently, mitochondrial function has been hypothesized to influence functional decline and vulnerability to disease in later life. Mitochondrial genetic variation may contribute to altered susceptibility to the frailty syndrome in older adults.

METHODOLOGY/PRINCIPAL FINDINGS: To assess potential mitochondrial genetic contributions to the likelihood of frailty, mitochondrial DNA (mtDNA) variation was compared in frail and non-frail older adults. Associations of selected SNPs with a muscle strength phenotype were also explored. Participants were selected from the Cardiovascular Health Study (CHS), a population-based observational study (1989-1990, 1992-1993). At baseline, frailty was identified as the presence of three or more of five indicators (weakness, slowness, shrinking, low physical activity, and exhaustion). mtDNA variation was assessed in a pilot study, including 315 individuals selected as extremes of the frailty phenotype, using an oligonucleotide sequencing microarray based on the Revised Cambridge Reference Sequence. Three mtDNA SNPs were statistically significantly associated with frailty across all pilot participants or in sex-stratified comparisons: mt146, mt204, and mt228. In addition to pilot participants, 4,459 additional men and women with frailty classifications, and an overlapping subset of 4,453 individuals with grip strength measurements, were included in the study population genotyped at mt204 and mt228. In the study population, the mt204 C allele was associated with greater likelihood of frailty (adjusted odds ratio = 2.04, 95% CI = 1.07-3.60, p = 0.020) and lower grip strength (adjusted coefficient = -2.04, 95% CI = -3.33- -0.74, p = 0.002).

CONCLUSIONS: This study supports a role for mitochondrial genetic variation in the frailty syndrome and later life muscle strength, demonstrating the importance of the mitochondrial genome in complex geriatric phenotypes.

%B PLoS One %V 5 %P e11069 %8 2010 Jun 10 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/20548781?dopt=Abstract %R 10.1371/journal.pone.0011069 %0 Journal Article %J Neuroepidemiology %D 2010 %T Post hoc Parkinson's disease: identifying an uncommon disease in the Cardiovascular Health Study. %A Ton, T G %A Jain, S %A Boudreau, R %A Thacker, E L %A Strotmeyer, E S %A Newman, A B %A Longstreth, W T %A Checkoway, H %K Aged %K Aged, 80 and over %K Cardiovascular System %K Cohort Studies %K Female %K Health Status %K Humans %K Incidence %K Male %K Odds Ratio %K Parkinson Disease %K Prevalence %K Prospective Studies %K Risk Factors %K Smoking %K Surveys and Questionnaires %K United States %X

BACKGROUND: Although ongoing cohort studies offer a unique opportunity to apply existing information collected prospectively to further the scientific understanding of Parkinson's disease (PD), they typically have limited information for clinical diagnosis.

METHODS: We used combinations of self-report, International Classification of Diseases - 9th edition codes and antiparkinsonian medications to identify PD in the Cardiovascular Health Study. To determine whether the expected inverse association between smoking and PD is evident using our outcome definitions, we assessed baseline smoking characteristics for various definitions of PD.

RESULTS: We identified 60 cases with prevalent PD (1.0%; 95% confidence interval, CI = 0.8-1.3%) and 154 with incident PD by year 14. Clear associations were observed for current smokers (odds ratio, OR = 0.50; 95% CI = 0.26-0.95) and for those who smoked ≥50 pack-years (OR = 0.53; 95% CI = 0.29-0.96). Estimates for smoking were similar when ≥2 data sources were required. Estimates for self-report alone were attenuated towards null.

CONCLUSIONS: Using multiple data sources to identify PD represents an alternative method of outcome identification in a cohort that would otherwise not be possible for PD research. Ongoing cohort studies can provide settings in which rapid replication and explorations of new hypotheses for PD are possible.

%B Neuroepidemiology %V 35 %P 241-9 %8 2010 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/20881426?dopt=Abstract %R 10.1159/000319895 %0 Journal Article %J Br J Haematol %D 2010 %T Reproductive history, hormone replacement, and incidence of venous thromboembolism: the Longitudinal Investigation of Thromboembolism Etiology. %A Ohira, Tetsuya %A Folsom, Aaron R %A Cushman, Mary %A White, Richard H %A Hannan, Peter J %A Rosamond, Wayne D %A Heckbert, Susan R %K Age Factors %K Aged %K Epidemiologic Methods %K Estrogen Replacement Therapy %K Female %K Humans %K Male %K Middle Aged %K Parity %K Pregnancy %K Reproductive History %K United States %K Venous Thromboembolism %X

Numerous studies have established that hormone replacement therapy increases the risk of venous thromboembolism (VTE), but an association of endogenous oestrogen exposure with the incidence of VTE is not fully established. Using a prospective design combining the Atherosclerosis Risk in Communities and the Cardiovascular Health Study cohort, we studied the 12-year risk of VTE in relation to hormone replacement therapy use, age at menopause, parity number, and type of menopause in 8236 post-menopausal women. There were no significant associations of age at menopause, parity number, or type of menopause with incidence of VTE. Women currently using hormone replacement had a 1.6-times higher multivariate-adjusted rate ratio (RR) of VTE compared with those without hormone use in the time-dependent model (RR=1.60, 95% confidence interval [CI], 1.06-2.36; Population attributable fraction=6.7%, 95%CI, 1.0-10.3). When we excluded women with 1-year or more duration of hormone therapy at baseline, the association was stronger (RR=2.02, 95%CI, 1.31-3.12). The multivariate-adjusted RRs of VTE for current users tended to be higher in those with idiopathic VTE (RR=2.40, 95%CI, 1.40-4.12) than those with secondary VTE (RR=1.08, 95%CI, 0.63-1.85). Hormone replacement therapy is associated with increased risk of VTE, but reproductive history markers of endogenous oestrogen exposure were not associated with VTE.

%B Br J Haematol %V 149 %P 606-12 %8 2010 May %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/20230397?dopt=Abstract %R 10.1111/j.1365-2141.2010.08128.x %0 Journal Article %J Am J Epidemiol %D 2010 %T Secondhand smoke, vascular disease, and dementia incidence: findings from the cardiovascular health cognition study. %A Barnes, Deborah E %A Haight, Thaddeus J %A Mehta, Kala M %A Carlson, Michelle C %A Kuller, Lewis H %A Tager, Ira B %K Aged %K Dementia %K Female %K Humans %K Incidence %K Male %K Risk Factors %K Tobacco Smoke Pollution %K Vascular Diseases %X

Recent studies have found that smoking is associated with an increased risk of dementia, but the effects of secondhand smoke (SHS) on dementia risk are not known to have previously been studied. The authors used Cox proportional hazards marginal structural models to examine the association between self-reported lifetime household SHS exposure and risk of incident dementia over 6 years among 970 US participants in the Cardiovascular Health Cognition Study (performed from 1991 to 1999) who were never smokers and were free of clinical cardiovascular disease (CVD), dementia, and mild cognitive impairment at baseline. In addition, because prior studies have found that SHS is associated with increased risk of CVD and that CVD is associated with increased risk of dementia, the authors tested for interactions between SHS and measures of clinical and subclinical CVD on dementia risk. Moderate (16-25 years) and high (>25 years) SHS exposure levels were not independently associated with dementia risk; however, subjects with >25 years of SHS exposure and >25% carotid artery stenosis had a 3-fold increase (hazard ratio = 3.00, 95% confidence interval: 1.03, 9.72) in dementia risk compared with subjects with no/low (0-15 years) SHS exposure and < or =25% carotid artery stenosis. High lifetime SHS exposure may increase the risk of dementia in elderly with undiagnosed CVD.

%B Am J Epidemiol %V 171 %P 292-302 %8 2010 Feb 01 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/20051462?dopt=Abstract %R 10.1093/aje/kwp376 %0 Journal Article %J Thromb Haemost %D 2010 %T Serum albumin and risk of venous thromboembolism. %A Folsom, Aaron R %A Lutsey, Pamela L %A Heckbert, Susan R %A Cushman, Mary %K Aged %K Biomarkers %K Female %K Follow-Up Studies %K Humans %K Incidence %K Male %K Middle Aged %K Risk Factors %K Serum Albumin %K United States %K Venous Thromboembolism %X

The incidence of venous thromboembolism (VTE) is increased in patients with albuminuria. However, whether a low serum albumin concentration is associated with increased risk of VTE has been a matter of controversy. We determined the association of serum albumin with VTE incidence in two large, prospective, population-based cohorts: the Atherosclerosis Risk in Communities (ARIC) Study (n = 15,300) and the Cardiovascular Health Study (CHS) (n = 5,400). Validated VTE occurrence (n = 462 in ARIC and n = 174 in CHS) was ascertained during follow-up. In both studies, after adjustment for age, sex, race, use of hormone replacement therapy, estimated glomerular filtration rate, history of cancer, and diabetes, serum albumin tended to be associated inversely with VTE. The adjusted hazard ratio per standard deviation lower albumin was 1.18 (95% confidence interval [CI] = 1.08, 1.31) in ARIC and 1.10 (95% CI = 0.94, 1.29) in CHS. The hazard ratio for albumin below (vs. above) the fifth percentile was 1.28 (95% CI = 0.90, 1.84) in ARIC and 1.80 (95% CI = 1.11, 2.93) in CHS. In conclusion, low serum albumin was a modest marker of increased VTE risk. The observed association likely does not reflect cause and effect, but rather that low serum albumin reflects a hyperinflammatory or hypercoagulable state. Whether this association has clinical relevance warrants further study.

%B Thromb Haemost %V 104 %P 100-4 %8 2010 Jul %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/20390234?dopt=Abstract %R 10.1160/TH09-12-0856 %0 Journal Article %J Am J Respir Crit Care Med %D 2010 %T Sleepiness, quality of life, and sleep maintenance in REM versus non-REM sleep-disordered breathing. %A Chami, Hassan A %A Baldwin, Carol M %A Silverman, Angela %A Zhang, Ying %A Rapoport, David %A Punjabi, Naresh M %A Gottlieb, Daniel J %K Aged %K Disorders of Excessive Somnolence %K Female %K Humans %K Male %K Middle Aged %K Polysomnography %K Quality of Life %K Sleep %K Sleep Apnea Syndromes %K Sleep, REM %X

RATIONALE: The impact of REM-predominant sleep-disordered breathing (SDB) on sleepiness, quality of life (QOL), and sleep maintenance is uncertain.

OBJECTIVE: To evaluate the association of SDB during REM sleep with daytime sleepiness, health-related QOL, and difficulty maintaining sleep, in comparison to their association with SDB during non-REM sleep in a community-based cohort.

METHODS: Cross-sectional analysis of 5,649 Sleep Heart Health Study participants (mean age 62.5 [SD = 10.9], 52.6% women, 22.6% ethnic minorities). SDB during REM and non-REM sleep was quantified using polysomnographically derived apnea-hypopnea index in REM (AHI(REM)) and non-REM (AHI(NREM)) sleep. Sleepiness, sleep maintenance, and QOL were respectively quantified using the Epworth Sleepiness Scale (ESS), the Sleep Heart Health Study Sleep Habit Questionnaire, and the physical and mental composites scales of the Medical Outcomes Study Short Form (SF)-36.

MEASUREMENTS AND MAIN RESULTS: AHI(REM) was not associated with the ESS scores or the physical and mental components scales scores of the SF-36 after adjusting for demographics, body mass index, and AHI(NREM) x AHI(REM) was not associated with frequent difficulty maintaining sleep or early awakening from sleep. AHI(NREM) was associated with the ESS score (beta = 0.25; 95% confidence interval [CI], 0.16 to 0.34) and the physical (beta = -0.12; 95% CI, -0.42 to -0.01) and mental (beta = -0.20; 95% CI, -0.20 to -0.01) components scores of the SF-36 adjusting for demographics, body mass index, and AHI(REM).

CONCLUSIONS: In a community-based sample of middle-aged and older adults, REM-predominant SDB is not independently associated with daytime sleepiness, impaired health-related QOL, or self-reported sleep disruption.

%B Am J Respir Crit Care Med %V 181 %P 997-1002 %8 2010 May 01 %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/20093641?dopt=Abstract %R 10.1164/rccm.200908-1304OC %0 Journal Article %J JAMA %D 2010 %T Subclinical hypothyroidism and the risk of coronary heart disease and mortality. %A Rodondi, Nicolas %A den Elzen, Wendy P J %A Bauer, Douglas C %A Cappola, Anne R %A Razvi, Salman %A Walsh, John P %A Asvold, Bjørn O %A Iervasi, Giorgio %A Imaizumi, Misa %A Collet, Tinh-Hai %A Bremner, Alexandra %A Maisonneuve, Patrick %A Sgarbi, José A %A Khaw, Kay-Tee %A Vanderpump, Mark P J %A Newman, Anne B %A Cornuz, Jacques %A Franklyn, Jayne A %A Westendorp, Rudi G J %A Vittinghoff, Eric %A Gussekloo, Jacobijn %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Coronary Disease %K Female %K Humans %K Hypothyroidism %K Male %K Middle Aged %K Mortality %K Prospective Studies %K Risk %K Thyrotropin %K Young Adult %X

CONTEXT: Data regarding the association between subclinical hypothyroidism and cardiovascular disease outcomes are conflicting among large prospective cohort studies. This might reflect differences in participants' age, sex, thyroid-stimulating hormone (TSH) levels, or preexisting cardiovascular disease.

OBJECTIVE: To assess the risks of coronary heart disease (CHD) and total mortality for adults with subclinical hypothyroidism.

DATA SOURCES AND STUDY SELECTION: The databases of MEDLINE and EMBASE (1950 to May 31, 2010) were searched without language restrictions for prospective cohort studies with baseline thyroid function and subsequent CHD events, CHD mortality, and total mortality. The reference lists of retrieved articles also were searched.

DATA EXTRACTION: Individual data on 55,287 participants with 542,494 person-years of follow-up between 1972 and 2007 were supplied from 11 prospective cohorts in the United States, Europe, Australia, Brazil, and Japan. The risk of CHD events was examined in 25,977 participants from 7 cohorts with available data. Euthyroidism was defined as a TSH level of 0.50 to 4.49 mIU/L. Subclinical hypothyroidism was defined as a TSH level of 4.5 to 19.9 mIU/L with normal thyroxine concentrations.

RESULTS: Among 55,287 adults, 3450 had subclinical hypothyroidism (6.2%) and 51,837 had euthyroidism. During follow-up, 9664 participants died (2168 of CHD), and 4470 participants had CHD events (among 7 studies). The risk of CHD events and CHD mortality increased with higher TSH concentrations. In age- and sex-adjusted analyses, the hazard ratio (HR) for CHD events was 1.00 (95% confidence interval [CI], 0.86-1.18) for a TSH level of 4.5 to 6.9 mIU/L (20.3 vs 20.3/1000 person-years for participants with euthyroidism), 1.17 (95% CI, 0.96-1.43) for a TSH level of 7.0 to 9.9 mIU/L (23.8/1000 person-years), and 1.89 (95% CI, 1.28-2.80) for a TSH level of 10 to 19.9 mIU/L (n = 70 events/235; 38.4/1000 person-years; P <.001 for trend). The corresponding HRs for CHD mortality were 1.09 (95% CI, 0.91-1.30; 5.3 vs 4.9/1000 person-years for participants with euthyroidism), 1.42 (95% CI, 1.03-1.95; 6.9/1000 person-years), and 1.58 (95% CI, 1.10-2.27, n = 28 deaths/333; 7.7/1000 person-years; P = .005 for trend). Total mortality was not increased among participants with subclinical hypothyroidism. Results were similar after further adjustment for traditional cardiovascular risk factors. Risks did not significantly differ by age, sex, or preexisting cardiovascular disease.

CONCLUSIONS: Subclinical hypothyroidism is associated with an increased risk of CHD events and CHD mortality in those with higher TSH levels, particularly in those with a TSH concentration of 10 mIU/L or greater.

%B JAMA %V 304 %P 1365-74 %8 2010 Sep 22 %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/20858880?dopt=Abstract %R 10.1001/jama.2010.1361 %0 Journal Article %J Arch Intern Med %D 2010 %T Subclinical thyroid dysfunction and incident hip fracture in older adults. %A Lee, Jennifer S %A Bůzková, Petra %A Fink, Howard A %A Vu, Joseph %A Carbone, Laura %A Chen, Zhao %A Cauley, Jane %A Bauer, Doug C %A Cappola, Anne R %A Robbins, John %K Aged %K Female %K Follow-Up Studies %K Hip Fractures %K Humans %K Hyperthyroidism %K Hypothyroidism %K Incidence %K Male %K Multivariate Analysis %K Proportional Hazards Models %K Prospective Studies %K Risk Factors %K Sex Distribution %K Thyrotropin %K United States %X

BACKGROUND: Subclinical thyroid dysfunction is common in older adults and affects bone metabolism, but its effects on fracture risk have not been reported. We sought to determine prospectively whether older men and women with subclinical hyperthyroidism or hypothyroidism have an increased risk of hip fracture.

METHODS: Prospective cohort of 3567 US community-dwelling adults, 65 years or older, with biochemically defined subclinical thyroid dysfunction or euthyroidism was enrolled from June 10, 1989, through May 30, 1990, and followed up through 2004. Main outcome measures included incidence and hazard ratios (HRs), with 95% confidence intervals (CIs), of confirmed incident hip fractures for groups with subclinical hypothyroidism, subclinical hyperthyroidism, and euthyroidism as defined at baseline.

RESULTS: During 39 952 person-years (median follow-up, 13 years), hip fracture incidence (per 1000 men-years) was 13.65 in men with subclinical hyperthyroidism (n = 29) and 10.27 in men with subclinical hypothyroidism (n = 184), both greater than 5.0 in men with euthyroidism (n = 1159). Men with subclinical hypothyroidism had a multivariable-adjusted HR of 2.31 (95% CI, 1.25-4.27); those with subclinical hyperthyroidism, 3.27 (0.99-11.30). After excluding those with baseline use of thyroid-altering medications, men with endogenous subclinical hyperthyroidism had a higher HR of 4.91 (95% CI, 1.13-21.27), as did men with endogenous subclinical hypothyroidism (2.45, 1.27-4.73). Hip fracture incidence (per 1000 women-years) was 8.93 in women with subclinical hypothyroidism (n = 359) and 10.90 in women with subclinical hyperthyroidism (n = 142) compared with 10.18 in women with euthyroidism (n = 1694). No clear association between subclinical dysfunction and fracture was observed in women.

CONCLUSIONS: Older men with subclinical hyperthyroidism or hypothyroidism are at increased risk for hip fracture. Whether treatment of the subclinical syndrome reduces this risk is unknown.

%B Arch Intern Med %V 170 %P 1876-83 %8 2010 Nov 22 %G eng %N 21 %1 http://www.ncbi.nlm.nih.gov/pubmed/21098345?dopt=Abstract %R 10.1001/archinternmed.2010.424 %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 Sleep %D 2010 %T Utility of sleep stage transitions in assessing sleep continuity. %A Laffan, Alison %A Caffo, Brian %A Swihart, Bruce J %A Punjabi, Naresh M %K Age Factors %K Aged %K Arousal %K Body Mass Index %K Cohort Studies %K Female %K Humans %K Male %K Middle Aged %K Polysomnography %K Predictive Value of Tests %K Risk Factors %K Sex Factors %K Sleep Stages %K Sleep Wake Disorders %X

STUDY OBJECTIVES: Sleep continuity is commonly assessed with polysomnographic measures such as sleep efficiency, sleep stage percentages, and the arousal index. The aim of this study was to examine whether the transition rate between different sleep stages could be used as an index of sleep continuity to predict self-reported sleep quality independent of other commonly used metrics.

DESIGN AND SETTING: Analysis of the Sleep Heart Health Study polysomnographic data.

PARTICIPANTS: A community cohort.

MEASUREMENTS AND RESULTS: Sleep recordings on 5,684 participants were deemed to be of sufficient quality to allow visual scoring of NREM and REM sleep. For each participant, we tabulated the frequency of transitions between wake, NREM sleep, and REM sleep. An overall transition rate was determined as the number of all transitions per hour sleep. Stage-specific transition rates between wake, NREM sleep, and REM sleep were also determined. A 5-point Likert scale was used to assess the subjective experience of restless and light sleep the morning after the sleep study. Multivariable regression models showed that a high overall sleep stage transition rate was associated with restless and light sleep independent of several covariates including total sleep time, percentages of sleep stages, wake time after sleep onset, and the arousal index. Compared to the lowest quartile of the overall transition rate (<7.76 events/h), the odds ratios for restless sleep were 1.27, 1.42, and 1.38, for the second (7.77-10.10 events/h), third (10.11-13.34 events/h), and fourth (≥13.35 events/h) quartiles, respectively. Analysis of stage-specific transition rates showed that transitions between wake and NREM sleep were also independently associated with restless and light sleep.

CONCLUSIONS: Assessing overall and stage-specific transition rates provides a complementary approach for assessing sleep continuity. Incorporating such measures, along with conventional metrics, could yield useful insights into the significance of sleep continuity for clinical outcomes.

%B Sleep %V 33 %P 1681-6 %8 2010 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/21120130?dopt=Abstract %0 Journal Article %J Circ Heart Fail %D 2010 %T Validation of the health ABC heart failure model for incident heart failure risk prediction: the Cardiovascular Health Study. %A Kalogeropoulos, Andreas %A Psaty, Bruce M %A Vasan, Ramachandran S %A Georgiopoulou, Vasiliki %A Smith, Andrew L %A Smith, Nicholas L %A Kritchevsky, Stephen B %A Wilson, Peter W F %A Newman, Anne B %A Harris, Tamara B %A Butler, Javed %K Age Distribution %K Aged %K Aged, 80 and over %K Cause of Death %K Cohort Studies %K Confidence Intervals %K Disease Progression %K Echocardiography, Doppler %K Female %K Heart Failure %K Humans %K Incidence %K Male %K Models, Statistical %K Predictive Value of Tests %K Prognosis %K Severity of Illness Index %K Sex Distribution %K Survival Analysis %K United States %X

BACKGROUND: The recently developed and internally validated Health ABC HF model uses 9 routinely available clinical variables to determine incident heart failure risk. In this study, we sought to externally validate the Health ABC HF model.

METHODS AND RESULTS: Observed 5-year incidence of heart failure, defined as first hospitalization for new-onset heart failure, was compared with 5-year risk estimates derived from the Health ABC HF model among participants without heart failure at baseline in the Cardiovascular Health Study. During follow-up, 400 of 5335 (7.5%) participants developed heart failure over 5 years versus 364 (6.8%) predicted by the Health ABC HF model (predicted-to-observed ratio, 0.90). Observed versus predicted 5-year heart failure probabilities were 3.2% versus 2.8%, 9.0% versus 7.0%, 15.9% versus 13.7%, and 24.6% versus 30.8% for the <5%, 5% to 10%, 10% to 20%, and >20% 5-year risk categories, respectively. The Hosmer-Lemeshow chi(2) was 14.72 (degrees of freedom, 10; P=0.14), and the C index was 0.74 (95% CI, 0.72 to 0.76). Calibration and discrimination demonstrated adequate performance across sex and race overall; however, risk was underestimated in white men, especially in the 5% to 10% risk category. Model performance was optimal when participants with normal left ventricular function at baseline were assessed separately. Performance was consistent across age groups. Analyses with death as a competing risk yielded similar results.

CONCLUSIONS: The Health ABC HF model adequately predicted 5-year heart failure risk in a large community-based study, providing support for the external validity of the model. This tool may be used to identify individuals to whom to target heart failure prevention efforts.

%B Circ Heart Fail %V 3 %P 495-502 %8 2010 Jul %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/20427700?dopt=Abstract %R 10.1161/CIRCHEARTFAILURE.109.904300 %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 Thromb Haemost %D 2011 %T Association of coagulation-related and inflammation-related genes and factor VIIc levels with stroke: the Cardiovascular Health Study. %A Zakai, N A %A Lange, L %A Longstreth, W T %A O'Meara, E S %A Kelley, J L %A Fornage, M %A Nikerson, D %A Cushman, M %A Reiner, A P %K Blood Coagulation Factors %K Cardiovascular Diseases %K Cohort Studies %K Factor VII %K Female %K Humans %K Inflammation %K Male %K Polymorphism, Single Nucleotide %K Prospective Studies %K Risk Factors %K Stroke %X

BACKGROUND: Thrombosis and inflammation are critical in stroke etiology, but associations of coagulation and inflammation gene variants with stroke, and particularly factor VII levels, are inconclusive.

OBJECTIVES: To test the associations between 736 single-nucleotide polymorphisms (SNPs) between tagging haplotype patterns of 130 coagulation and inflammation genes, and stroke events, in the 5888 participants aged ≥ 65 years of the observational Cardiovascular Health Study cohort.

PATIENTS/METHODS: With 16 years of follow-up, age-adjusted and sex-adjusted Cox models were used to estimate associations of SNPs and FVIIc levels with future stroke.

RESULTS: Eight hundred and fifteen strokes occurred in 5255 genotyped participants without baseline stroke (748 ischemic strokes; 586 among whites). Among whites, six SNPs were associated with stroke, with a nominal P-value of < 0.01: rs6046 and rs3093261 (F7); rs4918851 and rs3781387 (HABP2); and rs3138055 (NFKB1A) and rs4648004 (NFKB1). Two of these SNPs were associated with FVIIc levels (units of percentage activity): rs6046 (β = -18.5, P = 2.38 × 10(-83)) and rs3093261 (β = 2.99, P = 3.93 × 10(-6)). After adjustment for age, sex, race, and cardiovascular risk factors, the association of FVIIc quintiles (Q) with stroke were as follows (hazard ratio; 95% confidence interval): Q1, reference; Q2, 1.4, 1.1-1.9); Q3, 1.1, 0.8-1.5); Q4, 1.5, 1.1-2.0); and Q5, 1.6, 1.2-2.2). Associations between SNPs and stroke were independent of FVIIc levels.

CONCLUSIONS: Variations in FVII-related genes and FVIIc levels were associated with risk of incident ischemic stroke in this elderly cohort, suggesting a potential causal role for FVII in stroke etiology.

%B J Thromb Haemost %V 9 %P 267-74 %8 2011 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/21114618?dopt=Abstract %R 10.1111/j.1538-7836.2010.04149.x %0 Journal Article %J PLoS Genet %D 2011 %T Association of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD. %A Böger, Carsten A %A Gorski, Mathias %A Li, Man %A Hoffmann, Michael M %A Huang, Chunmei %A Yang, Qiong %A Teumer, Alexander %A Krane, Vera %A O'Seaghdha, Conall M %A Kutalik, Zoltán %A Wichmann, H-Erich %A Haak, Thomas %A Boes, Eva %A Coassin, Stefan %A Coresh, Josef %A Kollerits, Barbara %A Haun, Margot %A Paulweber, Bernhard %A Köttgen, Anna %A Li, Guo %A Shlipak, Michael G %A Powe, Neil %A Hwang, Shih-Jen %A Dehghan, Abbas %A Rivadeneira, Fernando %A Uitterlinden, Andre %A Hofman, Albert %A Beckmann, Jacques S %A Krämer, Bernhard K %A Witteman, Jacqueline %A Bochud, Murielle %A Siscovick, David %A Rettig, Rainer %A Kronenberg, Florian %A Wanner, Christoph %A Thadhani, Ravi I %A Heid, Iris M %A Fox, Caroline S %A Kao, W H %K Adaptor Proteins, Signal Transducing %K Adult %K Aged %K Chronic Disease %K Creatinine %K European Continental Ancestry Group %K Female %K Follow-Up Studies %K Genetic Association Studies %K Humans %K Kidney Diseases %K Kidney Failure, Chronic %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Receptor, Epidermal Growth Factor %K Uromodulin %X

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

%B PLoS Genet %V 7 %P e1002292 %8 2011 Sep %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/21980298?dopt=Abstract %R 10.1371/journal.pgen.1002292 %0 Journal Article %J Circ Cardiovasc Genet %D 2011 %T Association of genetic variants and incident coronary heart disease in multiethnic cohorts: the PAGE study. %A Franceschini, Nora %A Carty, Cara %A Bůzková, Petra %A Reiner, Alex P %A Garrett, Tiana %A Lin, Yi %A Vöckler, Jens-S %A Hindorff, Lucia A %A Cole, Shelley A %A Boerwinkle, Eric %A Lin, Dan-Yu %A Bookman, Ebony %A Best, Lyle G %A Bella, Jonathan N %A Eaton, Charles %A Greenland, Philip %A Jenny, Nancy %A North, Kari E %A Taverna, Darin %A Young, Alicia M %A Deelman, Ewa %A Kooperberg, Charles %A Psaty, Bruce %A Heiss, Gerardo %K Aged %K Aged, 80 and over %K Continental Population Groups %K Coronary Disease %K Female %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Prospective Studies %X

BACKGROUND: Genome-wide association studies identified several single nucleotide polymorphisms (SNP) associated with prevalent coronary heart disease (CHD), but less is known of associations with incident CHD. The association of 13 published CHD SNPs was examined in 5 ancestry groups of 4 large US prospective cohorts.

METHODS AND RESULTS: The analyses included incident coronary events over an average 9.1 to 15.7 follow-up person-years in up to 26 617 white individuals (6626 events), 8018 black individuals (914 events), 1903 Hispanic individuals (113 events), 3669 American Indian individuals (595 events), and 885 Asian/Pacific Islander individuals (66 events). We used Cox proportional hazards models (with additive mode of inheritance) adjusted for age, sex, and ancestry (as needed). Nine loci were statistically associated with incident CHD events in white participants: 9p21 (rs10757278; P=4.7 × 10(-41)), 16q23.1 (rs2549513; P=0.0004), 6p24.1 (rs499818; P=0.0002), 2q36.3 (rs2943634; P=6.7 × 10(-6)), MTHFD1L (rs6922269, P=5.1 × 10(-10)), APOE (rs429358; P=2.7×10(-18)), ZNF627 (rs4804611; P=5.0 × 10(-8)), CXCL12 (rs501120; P=1.4 × 10(-6)) and LPL (rs268; P=2.7 × 10(-17)). The 9p21 region showed significant between-study heterogeneity, with larger effects in individuals age 55 years or younger and in women. Inclusion of coronary revascularization procedures among the incident CHD events introduced heterogeneity. The SNPs were not associated with CHD in black participants, and associations varied in other US minorities.

CONCLUSIONS: Prospective analyses of white participants replicated several reported cross-sectional CHD-SNP associations.

%B Circ Cardiovasc Genet %V 4 %P 661-72 %8 2011 Dec %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/22042884?dopt=Abstract %R 10.1161/CIRCGENETICS.111.960096 %0 Journal Article %J Exp Gerontol %D 2011 %T The association of genetic variants in interleukin-1 genes with cognition: findings from the cardiovascular health study. %A Benke, K S %A Carlson, M C %A Doan, B Q %A Walston, J D %A Xue, Q L %A Reiner, A P %A Fried, L P %A Arking, D E %A Chakravarti, A %A Fallin, M D %K African Americans %K Aged %K Aged, 80 and over %K Cognition %K Cognition Disorders %K Dementia %K Educational Status %K European Continental Ancestry Group %K Female %K Genetic Predisposition to Disease %K Genetic Variation %K Genotype %K Humans %K Interleukin 1 Receptor Antagonist Protein %K Interleukin-1alpha %K Interleukin-1beta %K Linkage Disequilibrium %K Longitudinal Studies %K Male %K Polymorphism, Single Nucleotide %K Prospective Studies %K Risk Factors %K United States %X

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

%B Exp Gerontol %V 46 %P 1010-9 %8 2011 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/21968104?dopt=Abstract %R 10.1016/j.exger.2011.09.005 %0 Journal Article %J Hum Mol Genet %D 2011 %T Association of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study. %A Fox, Ervin R %A Young, J Hunter %A Li, Yali %A Dreisbach, Albert W %A Keating, Brendan J %A Musani, Solomon K %A Liu, Kiang %A Morrison, Alanna C %A Ganesh, Santhi %A Kutlar, Abdullah %A Ramachandran, Vasan S %A Polak, Josef F %A Fabsitz, Richard R %A Dries, Daniel L %A Farlow, Deborah N %A Redline, Susan %A Adeyemo, Adebowale %A Hirschorn, Joel N %A Sun, Yan V %A Wyatt, Sharon B %A Penman, Alan D %A Palmas, Walter %A Rotter, Jerome I %A Townsend, Raymond R %A Doumatey, Ayo P %A Tayo, Bamidele O %A Mosley, Thomas H %A Lyon, Helen N %A Kang, Sun J %A Rotimi, Charles N %A Cooper, Richard S %A Franceschini, Nora %A Curb, J David %A Martin, Lisa W %A Eaton, Charles B %A Kardia, Sharon L R %A Taylor, Herman A %A Caulfield, Mark J %A Ehret, Georg B %A Johnson, Toby %A Chakravarti, Aravinda %A Zhu, Xiaofeng %A Levy, Daniel %K Adult %K African Americans %K Aged %K Blood Pressure %K Cohort Studies %K Diastole %K European Continental Ancestry Group %K Female %K Genetic Loci %K Genome-Wide Association Study %K Genotype %K Humans %K Hypertension %K Male %K Middle Aged %K Phenotype %K Polymorphism, Single Nucleotide %K Systole %X

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

%B Hum Mol Genet %V 20 %P 2273-84 %8 2011 Jun 01 %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/21378095?dopt=Abstract %R 10.1093/hmg/ddr092 %0 Journal Article %J Hypertension %D 2011 %T Association of hypertension drug target genes with blood pressure and hypertension in 86,588 individuals. %A Johnson, Andrew D %A Newton-Cheh, Christopher %A Chasman, Daniel I %A Ehret, Georg B %A Johnson, Toby %A Rose, Lynda %A Rice, Kenneth %A Verwoert, Germaine C %A Launer, Lenore J %A Gudnason, Vilmundur %A Larson, Martin G %A Chakravarti, Aravinda %A Psaty, Bruce M %A Caulfield, Mark %A van Duijn, Cornelia M %A Ridker, Paul M %A Munroe, Patricia B %A Levy, Daniel %K Alleles %K Angiotensinogen %K Antihypertensive Agents %K Blood Pressure %K Female %K Genetic Predisposition to Disease %K Genotype %K Humans %K Hypertension %K Male %K Pharmacogenetics %K Polymorphism, Single Nucleotide %K Receptors, Adrenergic, beta-1 %X

We previously conducted genome-wide association meta-analysis of systolic blood pressure, diastolic blood pressure, and hypertension in 29,136 people from 6 cohort studies in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Here we examine associations of these traits with 30 gene regions encoding known antihypertensive drug targets. We find nominal evidence of association of ADRB1, ADRB2, AGT, CACNA1A, CACNA1C, and SLC12A3 polymorphisms with 1 or more BP traits in the Cohorts for Heart and Aging Research in Genomic Epidemiology genome-wide association meta-analysis. We attempted replication of the top meta-analysis single nucleotide polymorphisms for these genes in the Global BPgen Consortium (n=34,433) and the Women's Genome Health Study (n=23,019) and found significant results for rs1801253 in ADRB1 (Arg389Gly), with the Gly allele associated with a lower mean systolic blood pressure (β: 0.57 mm Hg; SE: 0.09 mm Hg; meta-analysis: P=4.7×10(-10)), diastolic blood pressure (β: 0.36 mm Hg; SE: 0.06 mm Hg; meta-analysis: P=9.5×10(-10)), and prevalence of hypertension (β: 0.06 mm Hg; SE: 0.02 mm Hg; meta-analysis: P=3.3×10(-4)). Variation in AGT (rs2004776) was associated with systolic blood pressure (β: 0.42 mm Hg; SE: 0.09 mm Hg; meta-analysis: P=3.8×10(-6)), as well as diastolic blood pressure (P=5.0×10(-8)) and hypertension (P=3.7×10(-7)). A polymorphism in ACE (rs4305) showed modest replication of association with increased hypertension (β: 0.06 mm Hg; SE: 0.01 mm Hg; meta-analysis: P=3.0×10(-5)). Two loci, ADRB1 and AGT, contain single nucleotide polymorphisms that reached a genome-wide significance threshold in meta-analysis for the first time. Our findings suggest that these genes warrant further studies of their genetic effects on blood pressure, including pharmacogenetic interactions.

%B Hypertension %V 57 %P 903-10 %8 2011 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/21444836?dopt=Abstract %R 10.1161/HYPERTENSIONAHA.110.158667 %0 Journal Article %J Circulation %D 2011 %T Association of incident cardiovascular disease with progression of sleep-disordered breathing. %A Chami, Hassan A %A Resnick, Helaine E %A Quan, Stuart F %A Gottlieb, Daniel J %K Aged %K Cardiovascular Diseases %K Disease Progression %K Female %K Follow-Up Studies %K Humans %K Incidence %K Male %K Middle Aged %K Polysomnography %K Risk Factors %K Sleep Apnea Syndromes %X

BACKGROUND: Prospective data suggest that sleep-disordered breathing enhances risk for incident and recurrent cardiovascular disease (CVD). However, a reverse causal pathway whereby incident CVD causes or worsens sleep-disordered breathing has not been studied.

METHODS AND RESULTS: A total of 2721 Sleep Heart Health Study participants (mean age 62, standard deviation=10 years; 57% women; 23% minority) without CVD at baseline underwent 2 polysomnograms 5 years apart. Incident CVD events, including myocardial infarction, congestive heart failure, and stroke, were ascertained and adjudicated. The relation of incident CVD to change in apnea-hypopnea index between the 2 polysomnograms was tested with general linear models, with adjustment for age, sex, race, study center, history of diabetes mellitus, change in body mass index, change in neck circumference, percent sleep time spent in supine sleep, and time between the 2 polysomnograms. Incident CVD occurred in 95 participants between the first and second polysomnograms. Compared with participants without incident CVD, those with incident CVD experienced larger increases in apnea-hypopnea index between polysomnograms. The difference in adjusted mean apnea-hypopnea index change between subjects with and without incident CVD was 2.75 events per hour (95% confidence interval, 0.26 to 5.24; P=0.032). This association persisted after subjects with central sleep apnea were excluded. Compared with participants without incident CVD, participants with incident CVD had greater increases in both mean obstructive and central apnea indices, by 1.75 events per hour (95% confidence interval, 0.10 to 1.75; P=0.04) and by 1.07 events per hour (95% confidence interval, 0.40 to 1.74; P=0.001), respectively.

CONCLUSIONS: In a diverse, community-based sample of middle-aged and older adults, incident CVD was associated with worsening sleep-disordered breathing over 5 years.

%B Circulation %V 123 %P 1280-6 %8 2011 Mar 29 %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/21403097?dopt=Abstract %R 10.1161/CIRCULATIONAHA.110.974022 %0 Journal Article %J Invest Ophthalmol Vis Sci %D 2011 %T Association of polymorphisms in the hepatocyte growth factor gene promoter with keratoconus. %A Burdon, Kathryn P %A Macgregor, Stuart %A Bykhovskaya, Yelena %A Javadiyan, Sharhbanou %A Li, Xiaohui %A Laurie, Kate J %A Muszynska, Dorota %A Lindsay, Richard %A Lechner, Judith %A Haritunians, Talin %A Henders, Anjali K %A Dash, Durga %A Siscovick, David %A Anand, Seema %A Aldave, Anthony %A Coster, Douglas J %A Szczotka-Flynn, Loretta %A Mills, Richard A %A Iyengar, Sudha K %A Taylor, Kent D %A Phillips, Tony %A Montgomery, Grant W %A Rotter, Jerome I %A Hewitt, Alex W %A Sharma, Shiwani %A Rabinowitz, Yaron S %A Willoughby, Colin %A Craig, Jamie E %K Adult %K Aged %K Chromosomes, Human, Pair 7 %K Corneal Topography %K Enzyme-Linked Immunosorbent Assay %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Hepatocyte Growth Factor %K Humans %K Keratoconus %K Middle Aged %K Nucleic Acid Hybridization %K Polymorphism, Single Nucleotide %K Promoter Regions, Genetic %K Sequence Tagged Sites %X

PURPOSE: Keratoconus is a progressive disorder of the cornea that can lead to severe visual impairment or blindness. Although several genomic regions have been linked to rare familial forms of keratoconus, no genes have yet been definitively identified for common forms of the disease.

METHODS: Two genome-wide association scans were undertaken in parallel. The first used pooled DNA from an Australian cohort, followed by typing of top-ranked single-nucleotide polymorphisms (SNPs) in individual DNA samples. The second was conducted in individually genotyped patients, and controls from the USA. Tag SNPs around the hepatocyte growth factor (HGF) gene were typed in three additional replication cohorts. Serum levels of HGF protein in normal individuals were assessed with ELISA and correlated with genotype.

RESULTS: The only SNP observed to be associated in both the pooled discovery and primary replication cohort was rs1014091, located upstream of the HGF gene. The nearby SNP rs3735520 was found to be associated in the individually typed discovery cohort (P = 6.1 × 10(-7)). Genotyping of tag SNPs around HGF revealed association at rs3735520 and rs17501108/rs1014091 in four of the five cohorts. Meta-analysis of all five datasets together yielded suggestive P values for rs3735520 (P = 9.9 × 10(-7)) and rs17501108 (P = 9.9 × 10(-5)). In addition, SNP rs3735520 was found to be associated with serum HGF level in normal individuals (P = 0.036).

CONCLUSIONS: Taken together, these results implicate genetic variation at the HGF locus with keratoconus susceptibility.

%B Invest Ophthalmol Vis Sci %V 52 %P 8514-9 %8 2011 Oct 31 %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/22003120?dopt=Abstract %R 10.1167/iovs.11-8261 %0 Journal Article %J Diabetes %D 2011 %T A bivariate genome-wide approach to metabolic syndrome: STAMPEED consortium. %A Kraja, Aldi T %A Vaidya, Dhananjay %A Pankow, James S %A Goodarzi, Mark O %A Assimes, Themistocles L %A Kullo, Iftikhar J %A Sovio, Ulla %A Mathias, Rasika A %A Sun, Yan V %A Franceschini, Nora %A Absher, Devin %A Li, Guo %A Zhang, Qunyuan %A Feitosa, Mary F %A Glazer, Nicole L %A Haritunians, Talin %A Hartikainen, Anna-Liisa %A Knowles, Joshua W %A North, Kari E %A Iribarren, Carlos %A Kral, Brian %A Yanek, Lisa %A O'Reilly, Paul F %A McCarthy, Mark I %A Jaquish, Cashell %A Couper, David J %A Chakravarti, Aravinda %A Psaty, Bruce M %A Becker, Lewis C %A Province, Michael A %A Boerwinkle, Eric %A Quertermous, Thomas %A Palotie, Leena %A Jarvelin, Marjo-Riitta %A Becker, Diane M %A Kardia, Sharon L R %A Rotter, Jerome I %A Chen, Yii-Der Ida %A Borecki, Ingrid B %K Adult %K Aged %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Male %K Meta-Analysis as Topic %K Metabolic Syndrome %K Middle Aged %K Phenotype %K Polymorphism, Single Nucleotide %X

OBJECTIVE The metabolic syndrome (MetS) is defined as concomitant disorders of lipid and glucose metabolism, central obesity, and high blood pressure, with an increased risk of type 2 diabetes and cardiovascular disease. This study tests whether common genetic variants with pleiotropic effects account for some of the correlated architecture among five metabolic phenotypes that define MetS. RESEARCH DESIGN AND METHODS Seven studies of the STAMPEED consortium, comprising 22,161 participants of European ancestry, underwent genome-wide association analyses of metabolic traits using a panel of ∼2.5 million imputed single nucleotide polymorphisms (SNPs). Phenotypes were defined by the National Cholesterol Education Program (NCEP) criteria for MetS in pairwise combinations. Individuals exceeding the NCEP thresholds for both traits of a pair were considered affected. RESULTS Twenty-nine common variants were associated with MetS or a pair of traits. Variants in the genes LPL, CETP, APOA5 (and its cluster), GCKR (and its cluster), LIPC, TRIB1, LOC100128354/MTNR1B, ABCB11, and LOC100129150 were further tested for their association with individual qualitative and quantitative traits. None of the 16 top SNPs (one per gene) associated simultaneously with more than two individual traits. Of them 11 variants showed nominal associations with MetS per se. The effects of 16 top SNPs on the quantitative traits were relatively small, together explaining from ∼9% of the variance in triglycerides, 5.8% of high-density lipoprotein cholesterol, 3.6% of fasting glucose, and 1.4% of systolic blood pressure. CONCLUSIONS Qualitative and quantitative pleiotropic tests on pairs of traits indicate that a small portion of the covariation in these traits can be explained by the reported common genetic variants.

%B Diabetes %V 60 %P 1329-39 %8 2011 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/21386085?dopt=Abstract %R 10.2337/db10-1011 %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 Biostatistics %D 2011 %T Comparing costs associated with risk stratification rules for t-year survival. %A Cai, Tianxi %A Tian, Lu %A Lloyd-Jones, Donald M %K Biostatistics %K Coronary Disease %K Cost-Benefit Analysis %K Costs and Cost Analysis %K Humans %K Models, Statistical %K Risk Assessment %K Risk Factors %K Time Factors %X

Accurate risk prediction is an important step in developing optimal strategies for disease prevention and treatment. Based on the predicted risks, patients can be stratified to different risk categories where each category corresponds to a particular clinical intervention. Incorrect or suboptimal interventions are likely to result in unnecessary financial and medical consequences. It is thus essential to account for the costs associated with the clinical interventions when developing and evaluating risk stratification (RS) rules for clinical use. In this article, we propose to quantify the value of an RS rule based on the total expected cost attributed to incorrect assignment of risk groups due to the rule. We have established the relationship between cost parameters and optimal threshold values used in the stratification rule that minimizes the total expected cost over the entire population of interest. Statistical inference procedures are developed for evaluating and comparing given RS rules and examined through simulation studies. The proposed procedures are illustrated with an example from the Cardiovascular Health Study.

%B Biostatistics %V 12 %P 597-609 %8 2011 Oct %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/21415016?dopt=Abstract %R 10.1093/biostatistics/kxr001 %0 Journal Article %J BMC Cardiovasc Disord %D 2011 %T The contribution of a 9p21.3 variant, a KIF6 variant, and C-reactive protein to predicting risk of myocardial infarction in a prospective study. %A Shiffman, Dov %A O'Meara, Ellen S %A Rowland, Charles M %A Louie, Judy Z %A Cushman, Mary %A Tracy, Russell P %A Devlin, James J %A Psaty, Bruce M %K African Continental Ancestry Group %K Aged %K Aged, 80 and over %K C-Reactive Protein %K Case-Control Studies %K European Continental Ancestry Group %K Female %K Follow-Up Studies %K Genetic Variation %K Humans %K Kinesin %K Male %K Myocardial Infarction %K Predictive Value of Tests %K Prospective Studies %K Risk Factors %X

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

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

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

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

%B BMC Cardiovasc Disord %V 11 %P 10 %8 2011 Mar 15 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/21406102?dopt=Abstract %R 10.1186/1471-2261-11-10 %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 N Engl J Med %D 2011 %T Diabetes mellitus, fasting glucose, and risk of cause-specific death. %A Rao Kondapally Seshasai, Sreenivasa %A Kaptoge, Stephen %A Thompson, Alexander %A Di Angelantonio, Emanuele %A Gao, Pei %A Sarwar, Nadeem %A Whincup, Peter H %A Mukamal, Kenneth J %A Gillum, Richard F %A Holme, Ingar %A Njølstad, Inger %A Fletcher, Astrid %A Nilsson, Peter %A Lewington, Sarah %A Collins, Rory %A Gudnason, Vilmundur %A Thompson, Simon G %A Sattar, Naveed %A Selvin, Elizabeth %A Hu, Frank B %A Danesh, John %K Blood Glucose %K Cause of Death %K Diabetes Mellitus %K Female %K Humans %K Hyperglycemia %K Life Expectancy %K Male %K Middle Aged %K Risk %K Survival Analysis %X

BACKGROUND: The extent to which diabetes mellitus or hyperglycemia is related to risk of death from cancer or other nonvascular conditions is uncertain.

METHODS: We calculated hazard ratios for cause-specific death, according to baseline diabetes status or fasting glucose level, from individual-participant data on 123,205 deaths among 820,900 people in 97 prospective studies.

RESULTS: After adjustment for age, sex, smoking status, and body-mass index, hazard ratios among persons with diabetes as compared with persons without diabetes were as follows: 1.80 (95% confidence interval [CI], 1.71 to 1.90) for death from any cause, 1.25 (95% CI, 1.19 to 1.31) for death from cancer, 2.32 (95% CI, 2.11 to 2.56) for death from vascular causes, and 1.73 (95% CI, 1.62 to 1.85) for death from other causes. Diabetes (vs. no diabetes) was moderately associated with death from cancers of the liver, pancreas, ovary, colorectum, lung, bladder, and breast. Aside from cancer and vascular disease, diabetes (vs. no diabetes) was also associated with death from renal disease, liver disease, pneumonia and other infectious diseases, mental disorders, nonhepatic digestive diseases, external causes, intentional self-harm, nervous-system disorders, and chronic obstructive pulmonary disease. Hazard ratios were appreciably reduced after further adjustment for glycemia measures, but not after adjustment for systolic blood pressure, lipid levels, inflammation or renal markers. Fasting glucose levels exceeding 100 mg per deciliter (5.6 mmol per liter), but not levels of 70 to 100 mg per deciliter (3.9 to 5.6 mmol per liter), were associated with death. A 50-year-old with diabetes died, on average, 6 years earlier than a counterpart without diabetes, with about 40% of the difference in survival attributable to excess nonvascular deaths.

CONCLUSIONS: In addition to vascular disease, diabetes is associated with substantial premature death from several cancers, infectious diseases, external causes, intentional self-harm, and degenerative disorders, independent of several major risk factors. (Funded by the British Heart Foundation and others.).

%B N Engl J Med %V 364 %P 829-841 %8 2011 Mar 03 %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/21366474?dopt=Abstract %R 10.1056/NEJMoa1008862 %0 Journal Article %J Heart %D 2011 %T Electrocardiographic and clinical predictors separating atherosclerotic sudden cardiac death from incident coronary heart disease. %A Soliman, Elsayed Z %A Prineas, Ronald J %A Case, L Douglas %A Russell, Gregory %A Rosamond, Wayne %A Rea, Thomas %A Sotoodehnia, Nona %A Post, Wendy S %A Siscovick, David %A Psaty, Bruce M %A Burke, Gregory L %K Adult %K Aged %K Aged, 80 and over %K Body Mass Index %K Continental Population Groups %K Coronary Disease %K Death, Sudden, Cardiac %K Electrocardiography %K Ethnic Groups %K Female %K Heart Rate %K Humans %K Hypertension %K Male %K Middle Aged %K Predictive Value of Tests %K Prognosis %K Proportional Hazards Models %K Risk Adjustment %K Risk Factors %K Time Factors %K United States %X

OBJECTIVE: To identify specific ECG and clinical predictors that separate atherosclerotic sudden cardiac death (SCD) from incident coronary heart disease (CHD) (non-fatal events and non-sudden death) in the combined cohorts of the Atherosclerosis Risk in Communities study and the Cardiovascular Health Study.

METHODS: This analysis included 18,497 participants (58% females, 24% black individuals, mean age 58 years) who were initially free of clinical CHD. A competing risk analysis was conducted to examine the prognostic significance of baseline clinical characteristics and an extensive electronic database of ECG measurements for prediction of 229 cases of SCD as a first event versus 2297 incident CHD cases (2122 non-fatal events and 175 non-sudden death) that occurred during a median follow-up time of 13 years in the Cardiovascular Health Study and 14 years in the Atherosclerosis Risk in Communities study.

RESULTS: After adjusting for common CHD risk factors, a number of clinical characteristics and ECG measurements were independently predictive of SCD and CHD. However, the risk of SCD versus incident CHD was significantly different for race/ethnicity, hypertension, body mass index (BMI), heart rate, QTc, abnormally inverted T wave in any ECG lead group and level of ST elevation in V2. Black race/ethnicity (compared to non-black) was predictive of high SCD risk but less risk of incident CHD (p value for differences in the risk (HR) for SCD versus CHD <0.0001). Hypertension, increased heart rate, prolongation of QTc and abnormally inverted T wave were stronger predictors of high SCD risk compared to CHD (p value=0.0460, 0.0398, 0.0158 and 0.0265, respectively). BMI was not predictive of incident CHD but was predictive of high SCD risk in a quadratic fashion (p value=0.0220). On the other hand, elevated ST height as measured at the J point and that measured at 60 ms after the J point in V2 were not predictive of SCD but were predictive of high incident CHD risk (p value=0.0251 and 0.0155, respectively).

CONCLUSIONS: SCD and CHD have many risk factors in common. Hypertension, race/ethnicity, BMI, heart rate, QTc, abnormally inverted T wave in any ECG lead group and level of ST elevation in V2 have the potential to separate between the risks of SCD and CHD. These results need to be validated in another cohort.

%B Heart %V 97 %P 1597-601 %8 2011 Oct %G eng %N 19 %1 http://www.ncbi.nlm.nih.gov/pubmed/21775508?dopt=Abstract %R 10.1136/hrt.2010.215871 %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 JAMA %D 2011 %T Gait speed and survival in older adults. %A Studenski, Stephanie %A Perera, Subashan %A Patel, Kushang %A Rosano, Caterina %A Faulkner, Kimberly %A Inzitari, Marco %A Brach, Jennifer %A Chandler, Julie %A Cawthon, Peggy %A Connor, Elizabeth Barrett %A Nevitt, Michael %A Visser, Marjolein %A Kritchevsky, Stephen %A Badinelli, Stefania %A Harris, Tamara %A Newman, Anne B %A Cauley, Jane %A Ferrucci, Luigi %A Guralnik, Jack %K Aged %K Cohort Studies %K Female %K Gait %K Geriatric Assessment %K Humans %K Life Expectancy %K Male %K Survival Analysis %K United States %X

CONTEXT: Survival estimates help individualize goals of care for geriatric patients, but life tables fail to account for the great variability in survival. Physical performance measures, such as gait speed, might help account for variability, allowing clinicians to make more individualized estimates.

OBJECTIVE: To evaluate the relationship between gait speed and survival.

DESIGN, SETTING, AND PARTICIPANTS: Pooled analysis of 9 cohort studies (collected between 1986 and 2000), using individual data from 34,485 community-dwelling older adults aged 65 years or older with baseline gait speed data, followed up for 6 to 21 years. Participants were a mean (SD) age of 73.5 (5.9) years; 59.6%, women; and 79.8%, white; and had a mean (SD) gait speed of 0.92 (0.27) m/s.

MAIN OUTCOME MEASURES: Survival rates and life expectancy.

RESULTS: There were 17,528 deaths; the overall 5-year survival rate was 84.8% (confidence interval [CI], 79.6%-88.8%) and 10-year survival rate was 59.7% (95% CI, 46.5%-70.6%). Gait speed was associated with survival in all studies (pooled hazard ratio per 0.1 m/s, 0.88; 95% CI, 0.87-0.90; P < .001). Survival increased across the full range of gait speeds, with significant increments per 0.1 m/s. At age 75, predicted 10-year survival across the range of gait speeds ranged from 19% to 87% in men and from 35% to 91% in women. Predicted survival based on age, sex, and gait speed was as accurate as predicted based on age, sex, use of mobility aids, and self-reported function or as age, sex, chronic conditions, smoking history, blood pressure, body mass index, and hospitalization.

CONCLUSION: In this pooled analysis of individual data from 9 selected cohorts, gait speed was associated with survival in older adults.

%B JAMA %V 305 %P 50-8 %8 2011 Jan 05 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/21205966?dopt=Abstract %R 10.1001/jama.2010.1923 %0 Journal Article %J Am J Cardiol %D 2011 %T Gender differences between the Minnesota code and Novacode electrocardiographic prognostication of coronary heart disease in the cardiovascular health study. %A Zhang, Zhu-Ming %A Prineas, Ronald J %A Case, Doug %A Psaty, Bruce M %A Suzuki, Takeki %A Burke, Gregory L %K Aged %K Coronary Disease %K Electrocardiography %K Female %K Humans %K Incidence %K Male %K Predictive Value of Tests %K Prognosis %K Proportional Hazards Models %K Prospective Studies %K Risk Assessment %K Risk Factors %K Sex Factors %K United States %X

The Minnesota Code (MC) and Novacode (Nova) are the most widely used electrocardiographic (ECG) classification systems. The comparative strengths of their classifications for Q- and ST-T-wave abnormalities in predicting coronary heart disease (CHD) events and total mortality have not been evaluated separately by gender. We studied standard 12-lead electrocardiograms at rest from 4,988 participants in the Cardiovascular Health Study. Average age at baseline was 73 years, 60% of participants were women 85% were white, and 22% had a history of cardiovascular disease or presence of ECG myocardial infarction by MC or Nova. Starting in 1989 with an average 17-year follow-up, 65% of participants died and 33% had incident CHD in a cohort free of cardiovascular disease at baseline. Of these, electrocardiograms with major Q-wave or major ST-T abnormalities by MC or Nova predicted increased risk for CHD events and total mortality with no significant differences in predictability between men and women. The study also found that women had fewer major Q-wave changes but more major ST-T abnormalities than men. However, there were no gender differences in predicting CHD events and total mortality. In conclusion, ECG classification systems for myocardial infarction/ischemia abnormalities by MC or Nova are valuable and useful for men and women in clinical trials and epidemiologic studies.

%B Am J Cardiol %V 107 %P 817-820.e1 %8 2011 Mar 15 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/21247534?dopt=Abstract %R 10.1016/j.amjcard.2010.11.004 %0 Journal Article %J J Alzheimers Dis %D 2011 %T Gender differences in tea, coffee, and cognitive decline in the elderly: the Cardiovascular Health Study. %A Arab, Lenore %A Biggs, Mary L %A O'Meara, Ellen S %A Longstreth, W T %A Crane, Paul K %A Fitzpatrick, Annette L %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Coffee %K Cognition Disorders %K Cohort Studies %K Female %K Follow-Up Studies %K Humans %K Longitudinal Studies %K Male %K Prospective Studies %K Sex Characteristics %K Tea %X

Although caffeine can enhance cognitive function acutely, long-term effects of consumption of caffeine-containing beverages such as tea and coffee are uncertain. Data on 4,809 participants aged 65 and older from the Cardiovascular Health Study (CHS) were used to examine the relationship of consumption of tea and coffee, assessed by food frequency questionnaire, on change in cognitive function by gender. Cognitive performance was assessed using serial Modified Mini-Mental State (3MS) examinations, which were administered annually up to 9 times. Linear mixed models were used to estimate rates of change in standard 3MS scores and scores modeled using item response theory (IRT). Models were adjusted for age, education, smoking status, clinic site, diabetes, hypertension, stroke, coronary heart disease, depression score, and APOE genotype. Over the median 7.9 years of follow-up, participants who did not consume tea or coffee declined annually an average of 1.30 points (women) and 1.11 points (men) on standard 3MS scores. In fully adjusted models using either standard or IRT 3MS scores, we found modestly reduced rates of cognitive decline for some, but not all, levels of coffee and tea consumption for women, with no consistent effect for men. Caffeine consumption was also associated with attenuation in cognitive decline in women. Dose-response relationships were not linear. These longitudinal analyses suggest a somewhat attenuated rate of cognitive decline among tea and coffee consumers compared to non-consumers in women but not in men. Whether this association is causal or due to unmeasured confounding requires further study.

%B J Alzheimers Dis %V 27 %P 553-66 %8 2011 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/21841254?dopt=Abstract %R 10.3233/JAD-2011-110431 %0 Journal Article %J PLoS Genet %D 2011 %T Genetic association for renal traits among participants of African ancestry reveals new loci for renal function. %A Liu, Ching-Ti %A Garnaas, Maija K %A Tin, Adrienne %A Köttgen, Anna %A Franceschini, Nora %A Peralta, Carmen A %A de Boer, Ian H %A Lu, Xiaoning %A Atkinson, Elizabeth %A Ding, Jingzhong %A Nalls, Michael %A Shriner, Daniel %A Coresh, Josef %A Kutlar, Abdullah %A Bibbins-Domingo, Kirsten %A Siscovick, David %A Akylbekova, Ermeg %A Wyatt, Sharon %A Astor, Brad %A Mychaleckjy, Josef %A Li, Man %A Reilly, Muredach P %A Townsend, Raymond R %A Adeyemo, Adebowale %A Zonderman, Alan B %A de Andrade, Mariza %A Turner, Stephen T %A Mosley, Thomas H %A Harris, Tamara B %A Rotimi, Charles N %A Liu, Yongmei %A Kardia, Sharon L R %A Evans, Michele K %A Shlipak, Michael G %A Kramer, Holly %A Flessner, Michael F %A Dreisbach, Albert W %A Goessling, Wolfram %A Cupples, L Adrienne %A Kao, W Linda %A Fox, Caroline S %K Adaptor Proteins, Vesicular Transport %K Adult %K African Continental Ancestry Group %K Aged %K Animals %K Female %K Gene Knockdown Techniques %K Genetic Association Studies %K Genetic Loci %K Genome-Wide Association Study %K Glomerular Filtration Rate %K Humans %K KCNQ1 Potassium Channel %K Kidney %K Kidney Failure, Chronic %K Male %K Middle Aged %K Neoplasm Proteins %K Phenotype %K Polymorphism, Single Nucleotide %K Zebrafish %X

Chronic kidney disease (CKD) is an increasing global public health concern, particularly among populations of African ancestry. We performed an interrogation of known renal loci, genome-wide association (GWA), and IBC candidate-gene SNP association analyses in African Americans from the CARe Renal Consortium. In up to 8,110 participants, we performed meta-analyses of GWA and IBC array data for estimated glomerular filtration rate (eGFR), CKD (eGFR <60 mL/min/1.73 m(2)), urinary albumin-to-creatinine ratio (UACR), and microalbuminuria (UACR >30 mg/g) and interrogated the 250 kb flanking region around 24 SNPs previously identified in European Ancestry renal GWAS analyses. Findings were replicated in up to 4,358 African Americans. To assess function, individually identified genes were knocked down in zebrafish embryos by morpholino antisense oligonucleotides. Expression of kidney-specific genes was assessed by in situ hybridization, and glomerular filtration was evaluated by dextran clearance. Overall, 23 of 24 previously identified SNPs had direction-consistent associations with eGFR in African Americans, 2 of which achieved nominal significance (UMOD, PIP5K1B). Interrogation of the flanking regions uncovered 24 new index SNPs in African Americans, 12 of which were replicated (UMOD, ANXA9, GCKR, TFDP2, DAB2, VEGFA, ATXN2, GATM, SLC22A2, TMEM60, SLC6A13, and BCAS3). In addition, we identified 3 suggestive loci at DOK6 (p-value = 5.3×10(-7)) and FNDC1 (p-value = 3.0×10(-7)) for UACR, and KCNQ1 with eGFR (p = 3.6×10(-6)). Morpholino knockdown of kcnq1 in the zebrafish resulted in abnormal kidney development and filtration capacity. We identified several SNPs in association with eGFR in African Ancestry individuals, as well as 3 suggestive loci for UACR and eGFR. Functional genetic studies support a role for kcnq1 in glomerular development in zebrafish.

%B PLoS Genet %V 7 %P e1002264 %8 2011 Sep %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/21931561?dopt=Abstract %R 10.1371/journal.pgen.1002264 %0 Journal Article %J PLoS Genet %D 2011 %T Genetic determinants of lipid traits in diverse populations from the population architecture using genomics and epidemiology (PAGE) study. %A Dumitrescu, Logan %A Carty, Cara L %A Taylor, Kira %A Schumacher, Fredrick R %A Hindorff, Lucia A %A Ambite, José L %A Anderson, Garnet %A Best, Lyle G %A Brown-Gentry, Kristin %A Bůzková, Petra %A Carlson, Christopher S %A Cochran, Barbara %A Cole, Shelley A %A Devereux, Richard B %A Duggan, Dave %A Eaton, Charles B %A Fornage, Myriam %A Franceschini, Nora %A Haessler, Jeff %A Howard, Barbara V %A Johnson, Karen C %A Laston, Sandra %A Kolonel, Laurence N %A Lee, Elisa T %A MacCluer, Jean W %A Manolio, Teri A %A Pendergrass, Sarah A %A Quibrera, Miguel %A Shohet, Ralph V %A Wilkens, Lynne R %A Haiman, Christopher A %A Le Marchand, Loïc %A Buyske, Steven %A Kooperberg, Charles %A North, Kari E %A Crawford, Dana C %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Continental Population Groups %K Female %K Gene Frequency %K Genetics, Population %K Genome-Wide Association Study %K Humans %K Linkage Disequilibrium %K Lipid Metabolism %K Lipoproteins, HDL %K Lipoproteins, LDL %K Male %K Middle Aged %K Molecular Epidemiology %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Risk Factors %K Triglycerides %K Young Adult %X

For the past five years, genome-wide association studies (GWAS) have identified hundreds of common variants associated with human diseases and traits, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels. Approximately 95 loci associated with lipid levels have been identified primarily among populations of European ancestry. The Population Architecture using Genomics and Epidemiology (PAGE) study was established in 2008 to characterize GWAS-identified variants in diverse population-based studies. We genotyped 49 GWAS-identified SNPs associated with one or more lipid traits in at least two PAGE studies and across six racial/ethnic groups. We performed a meta-analysis testing for SNP associations with fasting HDL-C, LDL-C, and ln(TG) levels in self-identified European American (~20,000), African American (~9,000), American Indian (~6,000), Mexican American/Hispanic (~2,500), Japanese/East Asian (~690), and Pacific Islander/Native Hawaiian (~175) adults, regardless of lipid-lowering medication use. We replicated 55 of 60 (92%) SNP associations tested in European Americans at p<0.05. Despite sufficient power, we were unable to replicate ABCA1 rs4149268 and rs1883025, CETP rs1864163, and TTC39B rs471364 previously associated with HDL-C and MAFB rs6102059 previously associated with LDL-C. Based on significance (p<0.05) and consistent direction of effect, a majority of replicated genotype-phentoype associations for HDL-C, LDL-C, and ln(TG) in European Americans generalized to African Americans (48%, 61%, and 57%), American Indians (45%, 64%, and 77%), and Mexican Americans/Hispanics (57%, 56%, and 86%). Overall, 16 associations generalized across all three populations. For the associations that did not generalize, differences in effect sizes, allele frequencies, and linkage disequilibrium offer clues to the next generation of association studies for these traits.

%B PLoS Genet %V 7 %P e1002138 %8 2011 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/21738485?dopt=Abstract %R 10.1371/journal.pgen.1002138 %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 Circulation %D 2011 %T Genetic predictors of fibrin D-dimer levels in healthy adults. %A Smith, Nicholas L %A Huffman, Jennifer E %A Strachan, David P %A Huang, Jie %A Dehghan, Abbas %A Trompet, Stella %A Lopez, Lorna M %A Shin, So-Youn %A Baumert, Jens %A Vitart, Veronique %A Bis, Joshua C %A Wild, Sarah H %A Rumley, Ann %A Yang, Qiong %A Uitterlinden, André G %A Stott, David J %A Davies, Gail %A Carter, Angela M %A Thorand, Barbara %A Polasek, Ozren %A McKnight, Barbara %A Campbell, Harry %A Rudnicka, Alicja R %A Chen, Ming-Huei %A Buckley, Brendan M %A Harris, Sarah E %A Peters, Annette %A Pulanic, Drazen %A Lumley, Thomas %A de Craen, Anton J M %A Liewald, David C %A Gieger, Christian %A Campbell, Susan %A Ford, Ian %A Gow, Alan J %A Luciano, Michelle %A Porteous, David J %A Guo, Xiuqing %A Sattar, Naveed %A Tenesa, Albert %A Cushman, Mary %A Slagboom, P Eline %A Visscher, Peter M %A Spector, Tim D %A Illig, Thomas %A Rudan, Igor %A Bovill, Edwin G %A Wright, Alan F %A McArdle, Wendy L %A Tofler, Geoffrey %A Hofman, Albert %A Westendorp, Rudi G J %A Starr, John M %A Grant, Peter J %A Karakas, Mahir %A Hastie, Nicholas D %A Psaty, Bruce M %A Wilson, James F %A Lowe, Gordon D O %A O'Donnell, Christopher J %A Witteman, Jacqueline C M %A Jukema, J Wouter %A Deary, Ian J %A Soranzo, Nicole %A Koenig, Wolfgang %A Hayward, Caroline %K Adult %K Aged %K Blood Coagulation %K European Continental Ancestry Group %K Factor V %K Female %K Fibrin Fibrinogen Degradation Products %K Fibrinogen %K Genetic Testing %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Reference Values %K Thromboplastin %X

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

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

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

%B Circulation %V 123 %P 1864-72 %8 2011 May 03 %G eng %N 17 %1 http://www.ncbi.nlm.nih.gov/pubmed/21502573?dopt=Abstract %R 10.1161/CIRCULATIONAHA.110.009480 %0 Journal Article %J Nature %D 2011 %T Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. %A Ehret, Georg B %A Munroe, Patricia B %A Rice, Kenneth M %A Bochud, Murielle %A Johnson, Andrew D %A Chasman, Daniel I %A Smith, Albert V %A Tobin, Martin D %A Verwoert, Germaine C %A Hwang, Shih-Jen %A Pihur, Vasyl %A Vollenweider, Peter %A O'Reilly, Paul F %A Amin, Najaf %A Bragg-Gresham, Jennifer L %A Teumer, Alexander %A Glazer, Nicole L %A Launer, Lenore %A Zhao, Jing Hua %A Aulchenko, Yurii %A Heath, Simon %A Sõber, Siim %A Parsa, Afshin %A Luan, Jian'an %A Arora, Pankaj %A Dehghan, Abbas %A Zhang, Feng %A Lucas, Gavin %A Hicks, Andrew A %A Jackson, Anne U %A Peden, John F %A Tanaka, Toshiko %A Wild, Sarah H %A Rudan, Igor %A Igl, Wilmar %A Milaneschi, Yuri %A Parker, Alex N %A Fava, Cristiano %A Chambers, John C %A Fox, Ervin R %A Kumari, Meena %A Go, Min Jin %A van der Harst, Pim %A Kao, Wen Hong Linda %A Sjögren, Marketa %A Vinay, D G %A Alexander, Myriam %A Tabara, Yasuharu %A Shaw-Hawkins, Sue %A Whincup, Peter H %A Liu, Yongmei %A Shi, Gang %A Kuusisto, Johanna %A Tayo, Bamidele %A Seielstad, Mark %A Sim, Xueling %A Nguyen, Khanh-Dung Hoang %A Lehtimäki, Terho %A Matullo, Giuseppe %A Wu, Ying %A Gaunt, Tom R %A Onland-Moret, N Charlotte %A Cooper, Matthew N %A Platou, Carl G P %A Org, Elin %A Hardy, Rebecca %A Dahgam, Santosh %A Palmen, Jutta %A Vitart, Veronique %A Braund, Peter S %A Kuznetsova, Tatiana %A Uiterwaal, Cuno S P M %A Adeyemo, Adebowale %A Palmas, Walter %A Campbell, Harry %A Ludwig, Barbara %A Tomaszewski, Maciej %A Tzoulaki, Ioanna %A Palmer, Nicholette D %A Aspelund, Thor %A Garcia, Melissa %A Chang, Yen-Pei C %A O'Connell, Jeffrey R %A Steinle, Nanette I %A Grobbee, Diederick E %A Arking, Dan E %A Kardia, Sharon L %A Morrison, Alanna C %A Hernandez, Dena %A Najjar, Samer %A McArdle, Wendy L %A Hadley, David %A Brown, Morris J %A Connell, John M %A Hingorani, Aroon D %A Day, Ian N M %A Lawlor, Debbie A %A Beilby, John P %A Lawrence, Robert W %A Clarke, Robert %A Hopewell, Jemma C %A Ongen, Halit %A Dreisbach, Albert W %A Li, Yali %A Young, J Hunter %A Bis, Joshua C %A Kähönen, Mika %A Viikari, Jorma %A Adair, Linda S %A Lee, Nanette R %A Chen, Ming-Huei %A Olden, Matthias %A Pattaro, Cristian %A Bolton, Judith A Hoffman %A Köttgen, Anna %A Bergmann, Sven %A Mooser, Vincent %A Chaturvedi, Nish %A Frayling, Timothy M %A Islam, Muhammad %A Jafar, Tazeen H %A Erdmann, Jeanette %A Kulkarni, Smita R %A Bornstein, Stefan R %A Grässler, Jürgen %A Groop, Leif %A Voight, Benjamin F %A Kettunen, Johannes %A Howard, Philip %A Taylor, Andrew %A Guarrera, Simonetta %A Ricceri, Fulvio %A Emilsson, Valur %A Plump, Andrew %A Barroso, Inês %A Khaw, Kay-Tee %A Weder, Alan B %A Hunt, Steven C %A Sun, Yan V %A Bergman, Richard N %A Collins, Francis S %A Bonnycastle, Lori L %A Scott, Laura J %A Stringham, Heather M %A Peltonen, Leena %A Perola, Markus %A Vartiainen, Erkki %A Brand, Stefan-Martin %A Staessen, Jan A %A Wang, Thomas J %A Burton, Paul R %A Soler Artigas, Maria %A Dong, Yanbin %A Snieder, Harold %A Wang, Xiaoling %A Zhu, Haidong %A Lohman, Kurt K %A Rudock, Megan E %A Heckbert, Susan R %A Smith, Nicholas L %A Wiggins, Kerri L %A Doumatey, Ayo %A Shriner, Daniel %A Veldre, Gudrun %A Viigimaa, Margus %A Kinra, Sanjay %A Prabhakaran, Dorairaj %A Tripathy, Vikal %A Langefeld, Carl D %A Rosengren, Annika %A Thelle, Dag S %A Corsi, Anna Maria %A Singleton, Andrew %A Forrester, Terrence %A Hilton, Gina %A McKenzie, Colin A %A Salako, Tunde %A Iwai, Naoharu %A Kita, Yoshikuni %A Ogihara, Toshio %A Ohkubo, Takayoshi %A Okamura, Tomonori %A Ueshima, Hirotsugu %A Umemura, Satoshi %A Eyheramendy, Susana %A Meitinger, Thomas %A Wichmann, H-Erich %A Cho, Yoon Shin %A Kim, Hyung-Lae %A Lee, Jong-Young %A Scott, James %A Sehmi, Joban S %A Zhang, Weihua %A Hedblad, Bo %A Nilsson, Peter %A Smith, George Davey %A Wong, Andrew %A Narisu, Narisu %A Stančáková, Alena %A Raffel, Leslie J %A Yao, Jie %A Kathiresan, Sekar %A O'Donnell, Christopher J %A Schwartz, Stephen M %A Ikram, M Arfan %A Longstreth, W T %A Mosley, Thomas H %A Seshadri, Sudha %A Shrine, Nick R G %A Wain, Louise V %A Morken, Mario A %A Swift, Amy J %A Laitinen, Jaana %A Prokopenko, Inga %A Zitting, Paavo %A Cooper, Jackie A %A Humphries, Steve E %A Danesh, John %A Rasheed, Asif %A Goel, Anuj %A Hamsten, Anders %A Watkins, Hugh %A Bakker, Stephan J L %A van Gilst, Wiek H %A Janipalli, Charles S %A Mani, K Radha %A Yajnik, Chittaranjan S %A Hofman, Albert %A Mattace-Raso, Francesco U S %A Oostra, Ben A %A Demirkan, Ayse %A Isaacs, Aaron %A Rivadeneira, Fernando %A Lakatta, Edward G %A Orrù, Marco %A Scuteri, Angelo %A Ala-Korpela, Mika %A Kangas, Antti J %A Lyytikäinen, Leo-Pekka %A Soininen, Pasi %A Tukiainen, Taru %A Würtz, Peter %A Ong, Rick Twee-Hee %A Dörr, Marcus %A Kroemer, Heyo K %A Völker, Uwe %A Völzke, Henry %A Galan, Pilar %A Hercberg, Serge %A Lathrop, Mark %A Zelenika, Diana %A Deloukas, Panos %A Mangino, Massimo %A Spector, Tim D %A Zhai, Guangju %A Meschia, James F %A Nalls, Michael A %A Sharma, Pankaj %A Terzic, Janos %A Kumar, M V Kranthi %A Denniff, Matthew %A Zukowska-Szczechowska, Ewa %A Wagenknecht, Lynne E %A Fowkes, F Gerald R %A Charchar, Fadi J %A Schwarz, Peter E H %A Hayward, Caroline %A Guo, Xiuqing %A Rotimi, Charles %A Bots, Michiel L %A Brand, Eva %A Samani, Nilesh J %A Polasek, Ozren %A Talmud, Philippa J %A Nyberg, Fredrik %A Kuh, Diana %A Laan, Maris %A Hveem, Kristian %A Palmer, Lyle J %A van der Schouw, Yvonne T %A Casas, Juan P %A Mohlke, Karen L %A Vineis, Paolo %A Raitakari, Olli %A Ganesh, Santhi K %A Wong, Tien Y %A Tai, E Shyong %A Cooper, Richard S %A Laakso, Markku %A Rao, Dabeeru C %A Harris, Tamara B %A Morris, Richard W %A Dominiczak, Anna F %A Kivimaki, Mika %A Marmot, Michael G %A Miki, Tetsuro %A Saleheen, Danish %A Chandak, Giriraj R %A Coresh, Josef %A Navis, Gerjan %A Salomaa, Veikko %A Han, Bok-Ghee %A Zhu, Xiaofeng %A Kooner, Jaspal S %A Melander, Olle %A Ridker, Paul M %A Bandinelli, Stefania %A Gyllensten, Ulf B %A Wright, Alan F %A Wilson, James F %A Ferrucci, Luigi %A Farrall, Martin %A Tuomilehto, Jaakko %A Pramstaller, Peter P %A Elosua, Roberto %A Soranzo, Nicole %A Sijbrands, Eric J G %A Altshuler, David %A Loos, Ruth J F %A Shuldiner, Alan R %A Gieger, Christian %A Meneton, Pierre %A Uitterlinden, André G %A Wareham, Nicholas J %A Gudnason, Vilmundur %A Rotter, Jerome I %A Rettig, Rainer %A Uda, Manuela %A Strachan, David P %A Witteman, Jacqueline C M %A Hartikainen, Anna-Liisa %A Beckmann, Jacques S %A Boerwinkle, Eric %A Vasan, Ramachandran S %A Boehnke, Michael %A Larson, Martin G %A Jarvelin, Marjo-Riitta %A Psaty, Bruce M %A Abecasis, Goncalo R %A Chakravarti, Aravinda %A Elliott, Paul %A van Duijn, Cornelia M %A Newton-Cheh, Christopher %A Levy, Daniel %A Caulfield, Mark J %A Johnson, Toby %K Africa %K Asia %K Blood Pressure %K Cardiovascular Diseases %K Coronary Artery Disease %K Europe %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Hypertension %K Kidney Diseases %K Polymorphism, Single Nucleotide %K Stroke %X

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

%B Nature %V 478 %P 103-9 %8 2011 Sep 11 %G eng %N 7367 %1 http://www.ncbi.nlm.nih.gov/pubmed/21909115?dopt=Abstract %R 10.1038/nature10405 %0 Journal Article %J Brain %D 2011 %T Genetic variants of the NOTCH3 gene in the elderly and magnetic resonance imaging correlates of age-related cerebral small vessel disease. %A Schmidt, Helena %A Zeginigg, Marion %A Wiltgen, Marco %A Freudenberger, Paul %A Petrovic, Katja %A Cavalieri, Margherita %A Gider, Pierre %A Enzinger, Christian %A Fornage, Myriam %A Debette, Stephanie %A Rotter, Jerome I %A Ikram, Mohammad A %A Launer, Lenore J %A Schmidt, Reinhold %K Aged %K Aged, 80 and over %K Alleles %K Brain %K Cerebral Small Vessel Diseases %K Exons %K Female %K Follow-Up Studies %K Genetic Association Studies %K Genotype %K Humans %K Hypertension %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Phenotype %K Promoter Regions, Genetic %K Prospective Studies %K Receptor, Notch3 %K Receptors, Notch %X

Cerebral small vessel disease-related brain lesions such as white matter lesions and lacunes are common findings of magnetic resonance imaging in the elderly. These lesions are thought to be major contributors to disability in old age, and risk factors that include age and hypertension have been established. The radiological, histopathologic and clinical phenotypes of age-related cerebral small vessel disease remarkably resemble autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy, which is caused by mutations in NOTCH3. We hypothesized that genetic variations in NOTCH3 also play a role in age-related cerebral small vessel disease. We directly sequenced all 33 exons, the promoter and 3'-untranslated region of NOTCH3 in 195 participants with either coalescent white matter lesions or lacunes and compared the results to 82 randomly selected participants with no focal changes on magnetic resonance images in the Austrian Stroke Prevention Study. We detected nine common and 33 rare single nucleotide polymorphisms, of which 20 were novel. All common single nucleotide polymorphisms were genotyped in the entire cohort (n = 888), and four of them, rs1043994, rs10404382, rs10423702 and rs1043997, were associated significantly with both the presence and progression of white matter lesions. The association was confined to hypertensives, a result which we replicated in the Cohorts for Heart and Ageing Research in Genomic Epidemiology Consortium on an independent sample of 4773 stroke-free hypertensive elderly individuals of European descent (P = 0.04). The 33 rare single nucleotide polymorphisms were scattered over the NOTCH3 gene with three being located in the promoter region, 24 in exons (18 non-synonymous), three in introns and three in the 3'-untranslated region. None of the single nucleotide polymorphisms affected a cysteine residue. Sorting Intolerant From Tolerant, PolyPhen2 analyses and protein structure simulation consistently predicted six of the non-synonymous single nucleotide polymorphisms (H170R, P496L, V1183M, L1518M, D1823N and V1952M) to be functional, with four being exclusively or mainly detected in subjects with severe white matter lesions. In four individuals with rare non-synonymous single nucleotide polymorphisms, we noted anterior temporal lobe hyperintensity, hyperintensity in the external capsule, lacunar infarcts or subcortical lacunar lesions. None of the observed abnormalities were specific to cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy. This is the first comprehensive study investigating (i) the frequency of NOTCH3 variations in community-dwelling elderly and (ii) their effect on cerebral small vessel disease related magnetic resonance imaging phenotypes. We show that the NOTCH3 gene is highly variable with both common and rare single nucleotide polymorphisms spreading across the gene, and that common variants at the NOTCH3 gene increase the risk of age-related white matter lesions in hypertensives. Additional investigations are required to explore the biological mechanisms underlying the observed association.

%B Brain %V 134 %P 3384-97 %8 2011 Nov %G eng %N Pt 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/22006983?dopt=Abstract %R 10.1093/brain/awr252 %0 Journal Article %J Nat Genet %D 2011 %T Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile. %A Kilpeläinen, Tuomas O %A Zillikens, M Carola %A Stančáková, Alena %A Finucane, Francis M %A Ried, Janina S %A Langenberg, Claudia %A Zhang, Weihua %A Beckmann, Jacques S %A Luan, Jian'an %A Vandenput, Liesbeth %A Styrkarsdottir, Unnur %A Zhou, Yanhua %A Smith, Albert Vernon %A Zhao, Jing-Hua %A Amin, Najaf %A Vedantam, Sailaja %A Shin, So-Youn %A Haritunians, Talin %A Fu, Mao %A Feitosa, Mary F %A Kumari, Meena %A Halldorsson, Bjarni V %A Tikkanen, Emmi %A Mangino, Massimo %A Hayward, Caroline %A Song, Ci %A Arnold, Alice M %A Aulchenko, Yurii S %A Oostra, Ben A %A Campbell, Harry %A Cupples, L Adrienne %A Davis, Kathryn E %A Döring, Angela %A Eiriksdottir, Gudny %A Estrada, Karol %A Fernández-Real, José Manuel %A Garcia, Melissa %A Gieger, Christian %A Glazer, Nicole L %A Guiducci, Candace %A Hofman, Albert %A Humphries, Steve E %A Isomaa, Bo %A Jacobs, Leonie C %A Jula, Antti %A Karasik, David %A Karlsson, Magnus K %A Khaw, Kay-Tee %A Kim, Lauren J %A Kivimaki, Mika %A Klopp, Norman %A Kuhnel, Brigitte %A Kuusisto, Johanna %A Liu, Yongmei %A Ljunggren, Osten %A Lorentzon, Mattias %A Luben, Robert N %A McKnight, Barbara %A Mellström, Dan %A Mitchell, Braxton D %A Mooser, Vincent %A Moreno, José Maria %A Männistö, Satu %A O'Connell, Jeffery R %A Pascoe, Laura %A Peltonen, Leena %A Peral, Belén %A Perola, Markus %A Psaty, Bruce M %A Salomaa, Veikko %A Savage, David B %A Semple, Robert K %A Skaric-Juric, Tatjana %A Sigurdsson, Gunnar %A Song, Kijoung S %A Spector, Timothy D %A Syvänen, Ann-Christine %A Talmud, Philippa J %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Uitterlinden, André G %A van Duijn, Cornelia M %A Vidal-Puig, Antonio %A Wild, Sarah H %A Wright, Alan F %A Clegg, Deborah J %A Schadt, Eric %A Wilson, James F %A Rudan, Igor %A Ripatti, Samuli %A Borecki, Ingrid B %A Shuldiner, Alan R %A Ingelsson, Erik %A Jansson, John-Olov %A Kaplan, Robert C %A Gudnason, Vilmundur %A Harris, Tamara B %A Groop, Leif %A Kiel, Douglas P %A Rivadeneira, Fernando %A Walker, Mark %A Barroso, Inês %A Vollenweider, Peter %A Waeber, Gérard %A Chambers, John C %A Kooner, Jaspal S %A Soranzo, Nicole %A Hirschhorn, Joel N %A Stefansson, Kari %A Wichmann, H-Erich %A Ohlsson, Claes %A O'Rahilly, Stephen %A Wareham, Nicholas J %A Speliotes, Elizabeth K %A Fox, Caroline S %A Laakso, Markku %A Loos, Ruth J F %K Adiponectin %K Adiposity %K Alleles %K Body Fat Distribution %K Body Mass Index %K Body Weight %K Female %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Insulin Receptor Substrate Proteins %K Intracellular Signaling Peptides and Proteins %K Male %K Membrane Proteins %K Meta-Analysis as Topic %K Metabolome %K Obesity %K Polymorphism, Single Nucleotide %K Subcutaneous Fat %X

Genome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between ∼2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10(-6)) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 × 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 × 10(-11)) and one near SPRY2 (P = 3 × 10(-8)). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance.

%B Nat Genet %V 43 %P 753-60 %8 2011 Jun 26 %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/21706003?dopt=Abstract %R 10.1038/ng.866 %0 Journal Article %J PLoS Genet %D 2011 %T Genome-wide association analysis of soluble ICAM-1 concentration reveals novel associations at the NFKBIK, PNPLA3, RELA, and SH2B3 loci. %A Paré, Guillaume %A Ridker, Paul M %A Rose, Lynda %A Barbalic, Maja %A Dupuis, Josée %A Dehghan, Abbas %A Bis, Joshua C %A Benjamin, Emelia J %A Shiffman, Dov %A Parker, Alexander N %A Chasman, Daniel I %K ABO Blood-Group System %K Cohort Studies %K Female %K Gene Frequency %K Genetic Loci %K Genome, Human %K Genome-Wide Association Study %K Genotype %K Humans %K I-kappa B Kinase %K Intercellular Adhesion Molecule-1 %K Lipase %K Membrane Proteins %K Models, Genetic %K Multifactorial Inheritance %K Polymorphism, Single Nucleotide %K Proteins %K Transcription Factor RelA %X

Soluble ICAM-1 (sICAM-1) is an endothelium-derived inflammatory marker that has been associated with diverse conditions such as myocardial infarction, diabetes, stroke, and malaria. Despite evidence for a heritable component to sICAM-1 levels, few genetic loci have been identified so far. To comprehensively address this issue, we performed a genome-wide association analysis of sICAM-1 concentration in 22,435 apparently healthy women from the Women's Genome Health Study. While our results confirm the previously reported associations at the ABO and ICAM1 loci, four novel associations were identified in the vicinity of NFKBIK (rs3136642, P = 5.4 × 10(-9)), PNPLA3 (rs738409, P  =  5.8 × 10(-9)), RELA (rs1049728, P =  2.7 × 10(-16)), and SH2B3 (rs3184504, P =  2.9 × 10(-17)). Two loci, NFKBIB and RELA, are involved in NFKB signaling pathway; PNPLA3 is known for its association with fatty liver disease; and SH3B2 has been associated with a multitude of traits and disease including myocardial infarction. These associations provide insights into the genetic regulation of sICAM-1 levels and implicate these loci in the regulation of endothelial function.

%B PLoS Genet %V 7 %P e1001374 %8 2011 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/21533024?dopt=Abstract %R 10.1371/journal.pgen.1001374 %0 Journal Article %J Nat Genet %D 2011 %T Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function. %A Soler Artigas, Maria %A Loth, Daan W %A Wain, Louise V %A Gharib, Sina A %A Obeidat, Ma'en %A Tang, Wenbo %A Zhai, Guangju %A Zhao, Jing Hua %A Smith, Albert Vernon %A Huffman, Jennifer E %A Albrecht, Eva %A Jackson, Catherine M %A Evans, David M %A Cadby, Gemma %A Fornage, Myriam %A Manichaikul, Ani %A Lopez, Lorna M %A Johnson, Toby %A Aldrich, Melinda C %A Aspelund, Thor %A Barroso, Inês %A Campbell, Harry %A Cassano, Patricia A %A Couper, David J %A Eiriksdottir, Gudny %A Franceschini, Nora %A Garcia, Melissa %A Gieger, Christian %A Gislason, Gauti Kjartan %A Grkovic, Ivica %A Hammond, Christopher J %A Hancock, Dana B %A Harris, Tamara B %A Ramasamy, Adaikalavan %A Heckbert, Susan R %A Heliövaara, Markku %A Homuth, Georg %A Hysi, Pirro G %A James, Alan L %A Jankovic, Stipan %A Joubert, Bonnie R %A Karrasch, Stefan %A Klopp, Norman %A Koch, Beate %A Kritchevsky, Stephen B %A Launer, Lenore J %A Liu, Yongmei %A Loehr, Laura R %A Lohman, Kurt %A Loos, Ruth J F %A Lumley, Thomas %A Al Balushi, Khalid A %A Ang, Wei Q %A Barr, R Graham %A Beilby, John %A Blakey, John D %A Boban, Mladen %A Boraska, Vesna %A Brisman, Jonas %A Britton, John R %A Brusselle, Guy G %A Cooper, Cyrus %A Curjuric, Ivan %A Dahgam, Santosh %A Deary, Ian J %A Ebrahim, Shah %A Eijgelsheim, Mark %A Francks, Clyde %A Gaysina, Darya %A Granell, Raquel %A Gu, Xiangjun %A Hankinson, John L %A Hardy, Rebecca %A Harris, Sarah E %A Henderson, John %A Henry, Amanda %A Hingorani, Aroon D %A Hofman, Albert %A Holt, Patrick G %A Hui, Jennie %A Hunter, Michael L %A Imboden, Medea %A Jameson, Karen A %A Kerr, Shona M %A Kolcic, Ivana %A Kronenberg, Florian %A Liu, Jason Z %A Marchini, Jonathan %A McKeever, Tricia %A Morris, Andrew D %A Olin, Anna-Carin %A Porteous, David J %A Postma, Dirkje S %A Rich, Stephen S %A Ring, Susan M %A Rivadeneira, Fernando %A Rochat, Thierry %A Sayer, Avan Aihie %A Sayers, Ian %A Sly, Peter D %A Smith, George Davey %A Sood, Akshay %A Starr, John M %A Uitterlinden, André G %A Vonk, Judith M %A Wannamethee, S Goya %A Whincup, Peter H %A Wijmenga, Cisca %A Williams, O Dale %A Wong, Andrew %A Mangino, Massimo %A Marciante, Kristin D %A McArdle, Wendy L %A Meibohm, Bernd %A Morrison, Alanna C %A North, Kari E %A Omenaas, Ernst %A Palmer, Lyle J %A Pietiläinen, Kirsi H %A Pin, Isabelle %A Pola Sbreve Ek, Ozren %A Pouta, Anneli %A Psaty, Bruce M %A Hartikainen, Anna-Liisa %A Rantanen, Taina %A Ripatti, Samuli %A Rotter, Jerome I %A Rudan, Igor %A Rudnicka, Alicja R %A Schulz, Holger %A Shin, So-Youn %A Spector, Tim D %A Surakka, Ida %A Vitart, Veronique %A Völzke, Henry %A Wareham, Nicholas J %A Warrington, Nicole M %A Wichmann, H-Erich %A Wild, Sarah H %A Wilk, Jemma B %A Wjst, Matthias %A Wright, Alan F %A Zgaga, Lina %A Zemunik, Tatijana %A Pennell, Craig E %A Nyberg, Fredrik %A Kuh, Diana %A Holloway, John W %A Boezen, H Marike %A Lawlor, Debbie A %A Morris, Richard W %A Probst-Hensch, Nicole %A Kaprio, Jaakko %A Wilson, James F %A Hayward, Caroline %A Kähönen, Mika %A Heinrich, Joachim %A Musk, Arthur W %A Jarvis, Deborah L %A Gläser, Sven %A Jarvelin, Marjo-Riitta %A Ch Stricker, Bruno H %A Elliott, Paul %A O'Connor, George T %A Strachan, David P %A London, Stephanie J %A Hall, Ian P %A Gudnason, Vilmundur %A Tobin, Martin D %K Child %K European Continental Ancestry Group %K Genome-Wide Association Study %K Humans %K Pulmonary Disease, Chronic Obstructive %K Respiratory Function Tests %X

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

%B Nat Genet %V 43 %P 1082-90 %8 2011 Sep 25 %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/21946350?dopt=Abstract %R 10.1038/ng.941 %0 Journal Article %J Ann Neurol %D 2011 %T Genome-wide association studies of cerebral white matter lesion burden: the CHARGE consortium. %A Fornage, Myriam %A Debette, Stephanie %A Bis, Joshua C %A Schmidt, Helena %A Ikram, M Arfan %A Dufouil, Carole %A Sigurdsson, Sigurdur %A Lumley, Thomas %A DeStefano, Anita L %A Fazekas, Franz %A Vrooman, Henri A %A Shibata, Dean K %A Maillard, Pauline %A Zijdenbos, Alex %A Smith, Albert V %A Gudnason, Haukur %A de Boer, Renske %A Cushman, Mary %A Mazoyer, Bernard %A Heiss, Gerardo %A Vernooij, Meike W %A Enzinger, Christian %A Glazer, Nicole L %A Beiser, Alexa %A Knopman, David S %A Cavalieri, Margherita %A Niessen, Wiro J %A Harris, Tamara B %A Petrovic, Katja %A Lopez, Oscar L %A Au, Rhoda %A Lambert, Jean-Charles %A Hofman, Albert %A Gottesman, Rebecca F %A Garcia, Melissa %A Heckbert, Susan R %A Atwood, Larry D %A Catellier, Diane J %A Uitterlinden, André G %A Yang, Qiong %A Smith, Nicholas L %A Aspelund, Thor %A Romero, Jose R %A Rice, Kenneth %A Taylor, Kent D %A Nalls, Michael A %A Rotter, Jerome I %A Sharrett, Richey %A van Duijn, Cornelia M %A Amouyel, Philippe %A Wolf, Philip A %A Gudnason, Vilmundur %A van der Lugt, Aad %A Boerwinkle, Eric %A Psaty, Bruce M %A Seshadri, Sudha %A Tzourio, Christophe %A Breteler, Monique M B %A Mosley, Thomas H %A Schmidt, Reinhold %A Longstreth, W T %A DeCarli, Charles %A Launer, Lenore J %K Aged %K Aged, 80 and over %K Cerebral Cortex %K Chromosomes, Human, Pair 17 %K Cognition Disorders %K Cohort Studies %K European Continental Ancestry Group %K Female %K Gene Frequency %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Leukoencephalopathies %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Movement Disorders %K Nerve Fibers, Myelinated %K Polymorphism, Single Nucleotide %K Residence Characteristics %K RNA, Messenger %X

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

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

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

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

%B Ann Neurol %V 69 %P 928-39 %8 2011 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/21681796?dopt=Abstract %R 10.1002/ana.22403 %0 Journal Article %J Hum Mol Genet %D 2011 %T Genome-wide association study for serum urate concentrations and gout among African Americans identifies genomic risk loci and a novel URAT1 loss-of-function allele. %A Tin, Adrienne %A Woodward, Owen M %A Kao, Wen Hong Linda %A Liu, Ching-Ti %A Lu, Xiaoning %A Nalls, Michael A %A Shriner, Daniel %A Semmo, Mariam %A Akylbekova, Ermeg L %A Wyatt, Sharon B %A Hwang, Shih-Jen %A Yang, Qiong %A Zonderman, Alan B %A Adeyemo, Adebowale A %A Palmer, Cameron %A Meng, Yan %A Reilly, Muredach %A Shlipak, Michael G %A Siscovick, David %A Evans, Michele K %A Rotimi, Charles N %A Flessner, Michael F %A Köttgen, Michael %A Cupples, L Adrienne %A Fox, Caroline S %A Köttgen, Anna %K Adult %K African Americans %K Aged %K Animals %K CHO Cells %K Cricetinae %K European Continental Ancestry Group %K Female %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Gout %K Humans %K Loss of Heterozygosity %K Male %K Middle Aged %K Organic Anion Transporters %K Organic Cation Transport Proteins %K Polymorphism, Single Nucleotide %K Uric Acid %K Young Adult %X

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

%B Hum Mol Genet %V 20 %P 4056-68 %8 2011 Oct 15 %G eng %N 20 %1 http://www.ncbi.nlm.nih.gov/pubmed/21768215?dopt=Abstract %R 10.1093/hmg/ddr307 %0 Journal Article %J Hum Mol Genet %D 2011 %T A genome-wide association study identifies novel loci associated with circulating IGF-I and IGFBP-3. %A Kaplan, Robert C %A Petersen, Ann-Kristin %A Chen, Ming-Huei %A Teumer, Alexander %A Glazer, Nicole L %A Döring, Angela %A Lam, Carolyn S P %A Friedrich, Nele %A Newman, Anne %A Müller, Martina %A Yang, Qiong %A Homuth, Georg %A Cappola, Anne %A Klopp, Norman %A Smith, Holly %A Ernst, Florian %A Psaty, Bruce M %A Wichmann, H-Erich %A Sawyer, Douglas B %A Biffar, Reiner %A Rotter, Jerome I %A Gieger, Christian %A Sullivan, Lisa S %A Völzke, Henry %A Rice, Kenneth %A Spyroglou, Ariadni %A Kroemer, Heyo K %A Ida Chen, Y-D %A Manolopoulou, Jenny %A Nauck, Matthias %A Strickler, Howard D %A Goodarzi, Mark O %A Reincke, Martin %A Pollak, Michael N %A Bidlingmaier, Martin %A Vasan, Ramachandran S %A Wallaschofski, Henri %K Aged %K Chromosomes, Human, Pair 7 %K Cohort Studies %K European Continental Ancestry Group %K Female %K Genome-Wide Association Study %K Humans %K Insulin-Like Growth Factor Binding Protein 3 %K Insulin-Like Growth Factor I %K Male %K Polymorphism, Single Nucleotide %X

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

%B Hum Mol Genet %V 20 %P 1241-51 %8 2011 Mar 15 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/21216879?dopt=Abstract %R 10.1093/hmg/ddq560 %0 Journal Article %J Nat Genet %D 2011 %T Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure. %A Wain, Louise V %A Verwoert, Germaine C %A O'Reilly, Paul F %A Shi, Gang %A Johnson, Toby %A Johnson, Andrew D %A Bochud, Murielle %A Rice, Kenneth M %A Henneman, Peter %A Smith, Albert V %A Ehret, Georg B %A Amin, Najaf %A Larson, Martin G %A Mooser, Vincent %A Hadley, David %A Dörr, Marcus %A Bis, Joshua C %A Aspelund, Thor %A Esko, Tõnu %A Janssens, A Cecile J W %A Zhao, Jing Hua %A Heath, Simon %A Laan, Maris %A Fu, Jingyuan %A Pistis, Giorgio %A Luan, Jian'an %A Arora, Pankaj %A Lucas, Gavin %A Pirastu, Nicola %A Pichler, Irene %A Jackson, Anne U %A Webster, Rebecca J %A Zhang, Feng %A Peden, John F %A Schmidt, Helena %A Tanaka, Toshiko %A Campbell, Harry %A Igl, Wilmar %A Milaneschi, Yuri %A Hottenga, Jouke-Jan %A Vitart, Veronique %A Chasman, Daniel I %A Trompet, Stella %A Bragg-Gresham, Jennifer L %A Alizadeh, Behrooz Z %A Chambers, John C %A Guo, Xiuqing %A Lehtimäki, Terho %A Kuhnel, Brigitte %A Lopez, Lorna M %A Polasek, Ozren %A Boban, Mladen %A Nelson, Christopher P %A Morrison, Alanna C %A Pihur, Vasyl %A Ganesh, Santhi K %A Hofman, Albert %A Kundu, Suman %A Mattace-Raso, Francesco U S %A Rivadeneira, Fernando %A Sijbrands, Eric J G %A Uitterlinden, André G %A Hwang, Shih-Jen %A Vasan, Ramachandran S %A Wang, Thomas J %A Bergmann, Sven %A Vollenweider, Peter %A Waeber, Gérard %A Laitinen, Jaana %A Pouta, Anneli %A Zitting, Paavo %A McArdle, Wendy L %A Kroemer, Heyo K %A Völker, Uwe %A Völzke, Henry %A Glazer, Nicole L %A Taylor, Kent D %A Harris, Tamara B %A Alavere, Helene %A Haller, Toomas %A Keis, Aime %A Tammesoo, Mari-Liis %A Aulchenko, Yurii %A Barroso, Inês %A Khaw, Kay-Tee %A Galan, Pilar %A Hercberg, Serge %A Lathrop, Mark %A Eyheramendy, Susana %A Org, Elin %A Sõber, Siim %A Lu, Xiaowen %A Nolte, Ilja M %A Penninx, Brenda W %A Corre, Tanguy %A Masciullo, Corrado %A Sala, Cinzia %A Groop, Leif %A Voight, Benjamin F %A Melander, Olle %A O'Donnell, Christopher J %A Salomaa, Veikko %A d'Adamo, Adamo Pio %A Fabretto, Antonella %A Faletra, Flavio %A Ulivi, Sheila %A Del Greco, Fabiola M %A Facheris, Maurizio %A Collins, Francis S %A Bergman, Richard N %A Beilby, John P %A Hung, Joseph %A Musk, A William %A Mangino, Massimo %A Shin, So-Youn %A Soranzo, Nicole %A Watkins, Hugh %A Goel, Anuj %A Hamsten, Anders %A Gider, Pierre %A Loitfelder, Marisa %A Zeginigg, Marion %A Hernandez, Dena %A Najjar, Samer S %A Navarro, Pau %A Wild, Sarah H %A Corsi, Anna Maria %A Singleton, Andrew %A de Geus, Eco J C %A Willemsen, Gonneke %A Parker, Alex N %A Rose, Lynda M %A Buckley, Brendan %A Stott, David %A Orrù, Marco %A Uda, Manuela %A van der Klauw, Melanie M %A Zhang, Weihua %A Li, Xinzhong %A Scott, James %A Chen, Yii-Der Ida %A Burke, Gregory L %A Kähönen, Mika %A Viikari, Jorma %A Döring, Angela %A Meitinger, Thomas %A Davies, Gail %A Starr, John M %A Emilsson, Valur %A Plump, Andrew %A Lindeman, Jan H %A Hoen, Peter A C 't %A König, Inke R %A Felix, Janine F %A Clarke, Robert %A Hopewell, Jemma C %A Ongen, Halit %A Breteler, Monique %A Debette, Stephanie %A DeStefano, Anita L %A Fornage, Myriam %A Mitchell, Gary F %A Smith, Nicholas L %A Holm, Hilma %A Stefansson, Kari %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Samani, Nilesh J %A Preuss, Michael %A Rudan, Igor %A Hayward, Caroline %A Deary, Ian J %A Wichmann, H-Erich %A Raitakari, Olli T %A Palmas, Walter %A Kooner, Jaspal S %A Stolk, Ronald P %A Jukema, J Wouter %A Wright, Alan F %A Boomsma, Dorret I %A Bandinelli, Stefania %A Gyllensten, Ulf B %A Wilson, James F %A Ferrucci, Luigi %A Schmidt, Reinhold %A Farrall, Martin %A Spector, Tim D %A Palmer, Lyle J %A Tuomilehto, Jaakko %A Pfeufer, Arne %A Gasparini, Paolo %A Siscovick, David %A Altshuler, David %A Loos, Ruth J F %A Toniolo, Daniela %A Snieder, Harold %A Gieger, Christian %A Meneton, Pierre %A Wareham, Nicholas J %A Oostra, Ben A %A Metspalu, Andres %A Launer, Lenore %A Rettig, Rainer %A Strachan, David P %A Beckmann, Jacques S %A Witteman, Jacqueline C M %A Erdmann, Jeanette %A van Dijk, Ko Willems %A Boerwinkle, Eric %A Boehnke, Michael %A Ridker, Paul M %A Jarvelin, Marjo-Riitta %A Chakravarti, Aravinda %A Abecasis, Goncalo R %A Gudnason, Vilmundur %A Newton-Cheh, Christopher %A Levy, Daniel %A Munroe, Patricia B %A Psaty, Bruce M %A Caulfield, Mark J %A Rao, Dabeeru C %A Tobin, Martin D %A Elliott, Paul %A van Duijn, Cornelia M %K Arteries %K Blood Pressure %K Case-Control Studies %K Follow-Up Studies %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Hypertension %K Linkage Disequilibrium %K Polymorphism, Single Nucleotide %X

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.

%B Nat Genet %V 43 %P 1005-11 %8 2011 Sep 11 %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/21909110?dopt=Abstract %R 10.1038/ng.922 %0 Journal Article %J Neurobiol Aging %D 2011 %T A genome-wide association study of aging. %A Walter, Stefan %A Atzmon, Gil %A Demerath, Ellen W %A Garcia, Melissa E %A Kaplan, Robert C %A Kumari, Meena %A Lunetta, Kathryn L %A Milaneschi, Yuri %A Tanaka, Toshiko %A Tranah, Gregory J %A Völker, Uwe %A Yu, Lei %A Arnold, Alice %A Benjamin, Emelia J %A Biffar, Reiner %A Buchman, Aron S %A Boerwinkle, Eric %A Couper, David %A De Jager, Philip L %A Evans, Denis A %A Harris, Tamara B %A Hoffmann, Wolfgang %A Hofman, Albert %A Karasik, David %A Kiel, Douglas P %A Kocher, Thomas %A Kuningas, Maris %A Launer, Lenore J %A Lohman, Kurt K %A Lutsey, Pamela L %A Mackenbach, Johan %A Marciante, Kristin %A Psaty, Bruce M %A Reiman, Eric M %A Rotter, Jerome I %A Seshadri, Sudha %A Shardell, Michelle D %A Smith, Albert V %A van Duijn, Cornelia %A Walston, Jeremy %A Zillikens, M Carola %A Bandinelli, Stefania %A Baumeister, Sebastian E %A Bennett, David A %A Ferrucci, Luigi %A Gudnason, Vilmundur %A Kivimaki, Mika %A Liu, Yongmei %A Murabito, Joanne M %A Newman, Anne B %A Tiemeier, Henning %A Franceschini, Nora %K Aging %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Longevity %X

Human longevity and healthy aging show moderate heritability (20%-50%). We conducted a meta-analysis of genome-wide association studies from 9 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium for 2 outcomes: (1) all-cause mortality, and (2) survival free of major disease or death. No single nucleotide polymorphism (SNP) was a genome-wide significant predictor of either outcome (p < 5 × 10(-8)). We found 14 independent SNPs that predicted risk of death, and 8 SNPs that predicted event-free survival (p < 10(-5)). These SNPs are in or near genes that are highly expressed in the brain (HECW2, HIP1, BIN2, GRIA1), genes involved in neural development and function (KCNQ4, LMO4, GRIA1, NETO1) and autophagy (ATG4C), and genes that are associated with risk of various diseases including cancer and Alzheimer's disease. In addition to considerable overlap between the traits, pathway and network analysis corroborated these findings. These findings indicate that variation in genes involved in neurological processes may be an important factor in regulating aging free of major disease and achieving longevity.

%B Neurobiol Aging %V 32 %P 2109.e15-28 %8 2011 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/21782286?dopt=Abstract %R 10.1016/j.neurobiolaging.2011.05.026 %0 Journal Article %J Aging (Albany NY) %D 2011 %T Health and function of participants in the Long Life Family Study: A comparison with other cohorts. %A Newman, Anne B %A Glynn, Nancy W %A Taylor, Christopher A %A Sebastiani, Paola %A Perls, Thomas T %A Mayeux, Richard %A Christensen, Kaare %A Zmuda, Joseph M %A Barral, Sandra %A Lee, Joseph H %A Simonsick, Eleanor M %A Walston, Jeremy D %A Yashin, Anatoli I %A Hadley, Evan %K Aged %K Aged, 80 and over %K Aging %K Blood Pressure %K Cardiovascular Diseases %K Cohort Studies %K Female %K Gait %K Humans %K Longevity %K Male %K Middle Aged %K Psychomotor Performance %K Research Design %X

Individuals from families recruited for the Long Life Family Study (LLFS) (n= 4559) were examined and compared to individuals from other cohorts to determine whether the recruitment targeting longevity resulted in a cohort of individuals with better health and function. Other cohorts with similar data included the Cardiovascular Health Study, the Framingham Heart Study, and the New England Centenarian Study. Diabetes, chronic pulmonary disease and peripheral artery disease tended to be less common in LLFS probands and offspring compared to similar aged persons in the other cohorts. Pulse pressure and triglycerides were lower, high density lipids were higher, and a perceptual speed task and gait speed were better in LLFS. Age-specific comparisons showed differences that would be consistent with a higher peak, later onset of decline or slower rate of change across age in LLFS participants. These findings suggest several priority phenotypes for inclusion in future genetic analysis to identify loci contributing to exceptional survival.

%B Aging (Albany NY) %V 3 %P 63-76 %8 2011 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/21258136?dopt=Abstract %R 10.18632/aging.100242 %0 Journal Article %J J Clin Endocrinol Metab %D 2011 %T Higher serum free testosterone concentration in older women is associated with greater bone mineral density, lean body mass, and total fat mass: the cardiovascular health study. %A Rariy, Chevon M %A Ratcliffe, Sarah J %A Weinstein, Rachel %A Bhasin, Shalender %A Blackman, Marc R %A Cauley, Jane A %A Robbins, John %A Zmuda, Joseph M %A Harris, Tamara B %A Cappola, Anne R %K Adipose Tissue %K Aged %K Aged, 80 and over %K Body Mass Index %K Bone Density %K Cardiovascular Physiological Phenomena %K Cohort Studies %K Female %K Health %K Humans %K Organ Size %K Osmolar Concentration %K Osteoporosis, Postmenopausal %K Testosterone %K Thinness %K Up-Regulation %X

CONTEXT: The physiological importance of endogenous testosterone (T) in older women is poorly understood.

OBJECTIVE: The aim of the study was to determine the association of higher total and free T levels with bone mineral density (BMD), lean body mass, and fat mass in elderly women.

DESIGN: Total and free T were measured using sensitive assays in 232 community-dwelling women aged 67-94 yr who were enrolled in the Cardiovascular Health Study and had dual-energy x-ray absorptiometry scans. Cross-sectional analyses were performed to examine associations between total and free T and BMD and body composition.

RESULTS: In adjusted models, total T was directly associated with BMD at the lumbar spine (P = 0.04) and hip (P = 0.001), but not body composition outcomes, in all women, and after excluding estrogen users and adjusting for estradiol (P = 0.04 and 0.01, respectively). Free T was positively related to hip BMD, lean body mass, and body fat (all P < 0.05), with more than 10% differences in each outcome between women at the highest and lowest ends of the free T range, with attenuation after excluding estrogen users and adjusting for estradiol.

CONCLUSIONS: In the setting of the low estradiol levels found in older women, circulating T levels were associated with bone density. Women with higher free T levels had greater lean body mass, consistent with the anabolic effect of T, and, in contrast to men, greater fat mass. Mechanistic studies are required to determine whether a causal relationship exists between T, bone, and body composition in this population and the degree to which any T effects are estrogen-independent.

%B J Clin Endocrinol Metab %V 96 %P 989-96 %8 2011 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/21289255?dopt=Abstract %R 10.1210/jc.2010-0926 %0 Journal Article %J Stroke %D 2011 %T Hospitalization for infection and risk of acute ischemic stroke: the Cardiovascular Health Study. %A Elkind, Mitchell S V %A Carty, Cara L %A O'Meara, Ellen S %A Lumley, Thomas %A Lefkowitz, David %A Kronmal, Richard A %A Longstreth, W T %K Bacterial Infections %K Brain Ischemia %K Cardiology %K Cohort Studies %K Cross-Over Studies %K Female %K Follow-Up Studies %K Hospitalization %K Humans %K Male %K Odds Ratio %K Proportional Hazards Models %K Regression Analysis %K Risk %K Stroke %K Time Factors %X

BACKGROUND AND PURPOSE: Little is known about the acute precipitants of ischemic stroke, although evidence suggests infections contribute to risk. We hypothesized that acute hospitalization for infection is associated with the short-term risk of stroke.

METHODS: The case-crossover design was used to compare hospitalization for infection during case periods (90, 30, or 14 days before an incident ischemic stroke) and control periods (equivalent time periods exactly 1 or 2 years before stroke) in the Cardiovascular Health Study, a population-based cohort of 5888 elderly participants from 4 US sites. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by conditional logistic regression. Confirmatory analyses assessed hazard ratios of stroke from Cox regression models, with hospitalization for infection as a time-varying exposure.

RESULTS: During a median follow-up of 12.2 years, 669 incident ischemic strokes were observed in participants without a baseline history of stroke. Hospitalization for infection was more likely during case than control time periods; for 90 days before stroke, OR=3.4 (95% CI, 1.8 to 6.5). The point estimates of risks were higher when we examined shorter intervals: for 30 days, OR=7.3 (95% CI, 1.9 to 40.9), and for 14 days, OR=8.0 (95% CI, 1.7 to 77.3). In survival analyses, risk of stroke was associated with hospitalization for infection in the preceding 90 days, adjusted hazard ratio=2.4 (95% CI, 1.6 to 3.4).

CONCLUSIONS: Hospitalization for infection is associated with a short-term increased risk of stroke, with higher risks observed for shorter intervals preceding stroke.

%B Stroke %V 42 %P 1851-6 %8 2011 Jul %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/21546476?dopt=Abstract %R 10.1161/STROKEAHA.110.608588 %0 Journal Article %J Circulation %D 2011 %T Hypertension, white matter hyperintensities, and concurrent impairments in mobility, cognition, and mood: the Cardiovascular Health Study. %A Hajjar, Ihab %A Quach, Lien %A Yang, Frances %A Chaves, Paulo H M %A Newman, Anne B %A Mukamal, Kenneth %A Longstreth, Will %A Inzitari, Marco %A Lipsitz, Lewis A %K Aged %K Aged, 80 and over %K Brain %K Cognition Disorders %K Female %K Humans %K Hypertension %K Kaplan-Meier Estimate %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Microcirculation %K Mobility Limitation %K Mood Disorders %K Nerve Fibers, Myelinated %K Retrospective Studies %K Risk Factors %X

BACKGROUND: Our objective was to investigate the association between hypertension and concurrent impairments in mobility, cognition, and mood; the role of brain white matter hyperintensities in mediating this association; and the impact of these impairments on disability and mortality in elderly hypertensive individuals.

METHODS AND RESULTS: -Blood pressure, gait speed, digit symbol substitution test, and the Center for Epidemiological Studies Depression Scale were measured yearly (1992-1999) on 4700 participants in the Cardiovascular Health Study (age: 74.7, 58% women, 17% blacks, 68% hypertension, 3600 had brain magnetic resonance imaging in 1992-1993, survival data 1992-2005). Using latent profile analysis at baseline, we found that 498 (11%) subjects had concurrent impairments and 3086 (66%) were intact on all 3 measures. Between 1992 and 1999, 651 (21%) became impaired in all 3 domains. Hypertensive individuals were more likely to be impaired at baseline (odds ratio 1.23, 95% confidence interval 1.04 to 1.42, P=0.01) and become impaired during the follow-up (hazard ratio=1.3, 95% confidence interval 1.02 to 1.66, P=0.037). A greater degree of white matter hyperintensities was associated with impairments in the 3 domains (P=0.007) and mediated the association with hypertension (P=0.19 for hypertension after adjusting for white matter hyperintensities in the model, 21% hazard ratio change). Impairments in the 3 domains increased subsequent disability with hypertension (P<0.0001). Hypertension mortality also was increased in those impaired (compared with unimpaired hypertensive individuals: HR=1.10, 95% confidence interval 1.04 to 1.17, P=0.004).

CONCLUSIONS: Hypertension increases the risk of concurrent impairments in mobility, cognition, and mood, which increases disability and mortality. This association is mediated in part by microvascular brain injury.

%B Circulation %V 123 %P 858-65 %8 2011 Mar 01 %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/21321150?dopt=Abstract %R 10.1161/CIRCULATIONAHA.110.978114 %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 Nephrol %D 2011 %T Kidney function decline in the elderly: impact of lipoprotein-associated phospholipase A(2). %A Peralta, Carmen A %A Katz, Ronit %A Shlipak, Michael %A Dubin, Ruth %A DeBoer, Ian %A Jenny, Nancy %A Fitzpatrick, Annette %A Koro, Carol %A Kestenbaum, Bryan %A Ix, Joachim %A Sarnak, Mark %A Cushman, Mary %K Aged %K Cardiovascular Diseases %K Creatinine %K Cystatin C %K Disease Progression %K Female %K Geriatrics %K Glomerular Filtration Rate %K Humans %K Kidney %K Kidney Diseases %K Male %K Middle Aged %K Phospholipases A2 %K Risk Factors %K Treatment Outcome %X

BACKGROUND: Whether lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) levels are associated with kidney function decline has not been well studied.

METHODS: We investigated associations of Lp-PLA(2) antigen and activity with kidney function decline and rapid decline over 5.7 years in the Cardiovascular Health Study (n = 4,359). We estimated kidney function by cystatin C (eGFRcys) in repeated measures, and defined rapid decline as ≥3 ml/min/1.73 m(2) per year. We stratified by baseline preserved GFR (≥60 ml/min/1.73 m(2)).

RESULTS: Mean age was 72 ± 5 years. Average eGFRcys decline was -1.79 ml/min/1.73 m(2) (SD = 2.60) per year. Among persons with preserved GFR, compared to the lowest quartile of Lp-PLA(2) antigen, eGFRcys decline was faster among persons in the second, β -0.31 (95% CI -0.52, -0.10), third -0.19 (-0.41, 0.02) and fourth quartiles -0.26 (-0.48, -0.04) after full adjustment. Persons in the highest quartile of Lp-PLA(2) antigen had increased odds of rapid decline 1.34 (1.03, 1.75), compared to the lowest. There was no significant association between levels of Lp-PLA(2) activity and eGFRcys decline or rapid decline. Associations were not statistically significant among persons with low eGFR (<60 ml/min/1.73 m(2)) at baseline.

CONCLUSION: Higher levels of Lp-PLA(2) antigen but not activity were significantly associated with faster rates of kidney function decline. These findings may suggest a novel vascular pathway for kidney disease progression.

%B Am J Nephrol %V 34 %P 512-8 %8 2011 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/22056971?dopt=Abstract %R 10.1159/000333045 %0 Journal Article %J Circ Cardiovasc Genet %D 2011 %T Large-scale candidate gene analysis in whites and African Americans identifies IL6R polymorphism in relation to atrial fibrillation: the National Heart, Lung, and Blood Institute's Candidate Gene Association Resource (CARe) project. %A Schnabel, Renate B %A Kerr, Kathleen F %A Lubitz, Steven A %A Alkylbekova, Ermeg L %A Marcus, Gregory M %A Sinner, Moritz F %A Magnani, Jared W %A Wolf, Philip A %A Deo, Rajat %A Lloyd-Jones, Donald M %A Lunetta, Kathryn L %A Mehra, Reena %A Levy, Daniel %A Fox, Ervin R %A Arking, Dan E %A Mosley, Thomas H %A Müller-Nurasyid, Martina %A Young, Taylor R %A Wichmann, H-Erich %A Seshadri, Sudha %A Farlow, Deborah N %A Rotter, Jerome I %A Soliman, Elsayed Z %A Glazer, Nicole L %A Wilson, James G %A Breteler, Monique M B %A Sotoodehnia, Nona %A Newton-Cheh, Christopher %A Kääb, Stefan %A Ellinor, Patrick T %A Alonso, Alvaro %A Benjamin, Emelia J %A Heckbert, Susan R %K African Americans %K Aged %K Alleles %K Atrial Fibrillation %K Chromosomes, Human, Pair 4 %K Cohort Studies %K European Continental Ancestry Group %K Female %K Humans %K Male %K Middle Aged %K National Heart, Lung, and Blood Institute (U.S.) %K Polymorphism, Single Nucleotide %K Receptors, Interleukin-6 %K Risk Factors %K Stroke %K United States %X

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

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

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

%B Circ Cardiovasc Genet %V 4 %P 557-64 %8 2011 Oct %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/21846873?dopt=Abstract %R 10.1161/CIRCGENETICS.110.959197 %0 Journal Article %J J Am Coll Cardiol %D 2011 %T Left ventricular ejection fraction assessment in older adults: an adjunct to natriuretic peptide testing to identify risk of new-onset heart failure and cardiovascular death? %A deFilippi, Christopher R %A Christenson, Robert H %A Kop, Willem J %A Gottdiener, John S %A Zhan, Min %A Seliger, Stephen L %K Age Factors %K Aged %K Aged, 80 and over %K Biomarkers %K Cohort Studies %K Death %K Female %K Follow-Up Studies %K Heart Failure %K Humans %K Male %K Natriuretic Peptide, Brain %K Peptide Fragments %K Prospective Studies %K Risk Factors %K Stroke Volume %K Survival Rate %K Ventricular Function, Left %X

OBJECTIVES: The goal of this paper was to determine whether assessment of left ventricular ejection fraction (LVEF) enhances prediction of new-onset heart failure (HF) and cardiovascular mortality over and above N-terminal pro-B-type natriuretic peptide (NT-proBNP) level in older adults.

BACKGROUND: Elevated NT-proBNP levels are common in older adults and are associated with increased risk of HF.

METHODS: NT-proBNP and LVEF were measured in 4,137 older adults free of HF. Repeat measures of NT-proBNP were performed 2 to 3 years later and echocardiography was repeated 5 years later (n = 2,375), with a median follow-up of 10.7 years. The addition of an abnormal (<55%) LVEF (n = 317 [7.7%]) to initially elevated or rising NT-proBNP levels was evaluated to determine risk of HF or cardiovascular mortality. Changes in NT-proBNP levels were also assessed for estimating the risk of conversion from a normal to abnormal LVEF.

RESULTS: For participants with a low baseline NT-proBNP level (<190 pg/ml; n = 2,918), addition of an abnormal LVEF did not improve the estimation of risk of HF and identified a moderate increase in adjusted risk for cardiovascular mortality (hazard ratio: 1.69 [95% confidence interval: 1.22 to 2.31]). Among those whose NT-proBNP subsequently increased ≥25% to ≥190 pg/ml, an abnormal LVEF was likewise associated with an increased risk of cardiovascular mortality but not HF. Participants with an initially high NT-proBNP level (≥190 pg/ml) were at greater risk overall for both outcomes, and those with an abnormal LVEF were at the highest risk. However, an abnormal LVEF did not improve model classification or risk stratification for either endpoint when added to demographic factors and change in NT-proBNP. An initially elevated NT-proBNP or rising level was associated with an increased risk of developing an abnormal LVEF.

CONCLUSIONS: Assessment of LVEF in HF-free older adults based on NT-proBNP levels should be considered on an individual basis, as such assessments do not routinely improve prognostication.

%B J Am Coll Cardiol %V 58 %P 1497-506 %8 2011 Sep 27 %G eng %N 14 %1 http://www.ncbi.nlm.nih.gov/pubmed/21939835?dopt=Abstract %R 10.1016/j.jacc.2011.06.042 %0 Journal Article %J Diabetologia %D 2011 %T Lipoprotein-associated phospholipase A(2) and future risk of subclinical disease and cardiovascular events in individuals with type 2 diabetes: the Cardiovascular Health Study. %A Nelson, T L %A Kamineni, A %A Psaty, B %A Cushman, M %A Jenny, N S %A Hokanson, J %A Furberg, C %A Mukamal, K J %K 1-Alkyl-2-acetylglycerophosphocholine Esterase %K Aged %K Cardiovascular Diseases %K Cross-Sectional Studies %K Diabetes Mellitus, Type 2 %K Female %K Humans %K Male %K Proportional Hazards Models %K Prospective Studies %K Risk Factors %X

AIMS/HYPOTHESIS: Type 2 diabetes is an established risk factor for cardiovascular disease (CVD). This increased risk may be due in part to the increased levels of inflammatory factors associated with diabetes. Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is a risk marker for CVD and has pro-inflammatory effects in atherosclerotic plaques. We therefore sought to determine whether Lp-PLA(2) levels partially explain the greater prevalence of subclinical CVD and greater incidence of CVD outcomes associated with type 2 diabetes in the Cardiovascular Health Study.

METHODS: We conducted a cross-sectional and prospective study of 4,062 men and women without previous CVD from the Cardiovascular Health Study (1989 to 2007). Lp-PLA(2) mass and activity were measured in baseline plasma. Subclinical disease was determined at baseline and incident CVD was ascertained annually. We used logistic regression for cross-sectional analyses and Cox proportional hazards models for incident analyses.

RESULTS: At baseline, Lp-PLA(2) mass did not differ significantly by type 2 diabetes status; however, Lp-PLA(2) activity was significantly higher among type 2 diabetic individuals. Baseline subclinical disease was significantly associated with baseline diabetes and this association was similar in models unadjusted or adjusted for Lp-PLA(2) (OR 1.68 [95% CI 1.31-2.15] vs OR 1.67 [95% CI 1.30-2.13]). Baseline type 2 diabetes was also significantly associated with incident CVD events, including fatal CHD, fatal myocardial infarction (MI) and non-fatal MI in multivariable analyses. There were no differences in these estimates after further adjustment for Lp-PLA(2) activity.

CONCLUSIONS/INTERPRETATION: In this older cohort, differences in Lp-PLA(2) activity did not explain any of the excess risk for subclinical disease or CVD outcomes related to diabetes.

%B Diabetologia %V 54 %P 329-33 %8 2011 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/21103980?dopt=Abstract %R 10.1007/s00125-010-1969-4 %0 Journal Article %J Thromb Haemost %D 2011 %T Longer legs are associated with greater risk of incident venous thromboembolism independent of total body height. The Longitudinal Study of Thromboembolism Etiology (LITE). %A Lutsey, Pamela L %A Cushman, Mary %A Heckbert, Susan R %A Tang, Weihong %A Folsom, Aaron R %K Adult %K Aged %K Anthropometry %K Body Height %K Female %K Follow-Up Studies %K Humans %K Leg %K Male %K Middle Aged %K Population Groups %K Prospective Studies %K Risk Factors %K United States %K Venous Thromboembolism %X

Several studies have reported that taller individuals are at greater risk of venous thromboembolism (VTE). We hypothesised that longer leg length would be positively associated with incident VTE, and would explain the height association. LITE ascertained VTE in a prospective population-based sample of 21,860 individuals aged 45 and older. Leg length was measured as standing height minus torso length. Cox regression models were adjusted for age, race, sex, waist circumference, diabetes, and factor VIII. To evaluate whether leg length was associated with VTE risk independent of height, we standardised leg length and height per 1 standard deviation (SD), and then included them simultaneously in Cox regression models. A total of 641 incident VTE cases accrued over a median follow-up of 16 years. Participants in the highest quintile of leg length were at 59% (95% CI: 22%-108%) greater risk of VTE, relative to the lowest quintile. For height, risk was 45% (12%-88%) greater for those in the highest quintile, compared to the lowest. When leg length and height were modelled simultaneously leg length remained associated with VTE risk (HR per 1 SD: 1.21 (1.04-1.40) while height was unrelated (HR per 1 SD: 1.00 (0.86-1.16). To conclude, participants with longer legs were at greater risk of incident VTE, and leg length explained the relation of height to VTE. It remains to be established whether this finding is due to greater venous surface area, a larger number of venous valves, or greater hydrostatic pressure among individuals with longer legs.

%B Thromb Haemost %V 106 %P 113-20 %8 2011 Jul %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/21655679?dopt=Abstract %R 10.1160/TH11-02-0100 %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2011 %T Longitudinal changes in adiponectin and inflammatory markers and relation to survival in the oldest old: the Cardiovascular Health Study All Stars study. %A Kizer, Jorge R %A Arnold, Alice M %A Jenny, Nancy S %A Cushman, Mary %A Strotmeyer, Elsa S %A Ives, Diane G %A Ding, Jingzhong %A Kritchevsky, Stephen B %A Chaves, Paulo H M %A Hirsch, Calvin H %A Newman, Anne B %K Adiponectin %K Aged, 80 and over %K Biomarkers %K C-Reactive Protein %K Cardiovascular Diseases %K Chi-Square Distribution %K Enzyme-Linked Immunosorbent Assay %K Female %K Humans %K Inflammation %K Interleukin-6 %K Male %K Mortality %K Predictive Value of Tests %K Risk Factors %K Sensitivity and Specificity %K Survival Analysis %K United States %X

BACKGROUND: Adiponectin has anti-inflammatory properties, and its production is suppressed by inflammatory factors. Although elevated levels of adiponectin and inflammatory markers each predict mortality in older adults, the implications of their interdependent actions have not been examined.

METHODS: We investigated the joint associations of levels and interval changes in adiponectin, C-reactive protein (CRP), and interleukin 6 (IL-6) with risk of death in 840 older adults participating in a population-based study. Adiponectin, CRP, and IL-6 were measured in samples collected 8.9 (8.2-9.8) years apart, and all-cause mortality was subsequently ascertained (n = 176).

RESULTS: Interval changes and end levels of adiponectin, CRP, and IL-6 showed mostly positive, independent associations with mortality, without evidence of multiplicative interaction. Joint models, however, showed an U-shaped relationship between end level of adiponectin and outcome (hazard ratio [HR] [95% CI] = 0.72 [0.52-0.99] per standard deviation [SD] for levels <20.0 mg/L; HR = 1.91 [1.61-3.44] per SD for levels ≥20.0 mg/L). Participants with the greatest longitudinal increases (upper quartile) in both adiponectin and inflammatory markers had a higher risk of death (HR = 2.85 [1.78-4.58]) than those with large increases in adiponectin alone (HR = 1.87 [1.20-2.92]) (p = .043), but not inflammatory markers alone (HR = 2.48 [1.67-3.67]) (p = .55), as compared with smaller changes for both.

CONCLUSION: Higher levels or interval change in adiponectin and inflammatory markers predict increased mortality in older persons independent of each other, although for adiponectin, the association appears inverse below 20 mg/L. These findings suggest that inflammatory and noninflammatory mechanisms governing aging-related decline operate in parallel and provide a potential explanation for paradoxical adiponectin-outcome associations reported previously.

%B J Gerontol A Biol Sci Med Sci %V 66 %P 1100-7 %8 2011 Oct %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/21659339?dopt=Abstract %R 10.1093/gerona/glr098 %0 Journal Article %J Kidney Int %D 2011 %T Lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes. A collaborative meta-analysis of general and high-risk population cohorts. %A Gansevoort, Ron T %A Matsushita, Kunihiro %A van der Velde, Marije %A Astor, Brad C %A Woodward, Mark %A Levey, Andrew S %A de Jong, Paul E %A Coresh, Josef %K Aged %K Albuminuria %K Cohort Studies %K Creatinine %K Female %K Glomerular Filtration Rate %K Humans %K Kidney Failure, Chronic %K Male %K Middle Aged %K Prognosis %K Proportional Hazards Models %K Risk Factors %X

Both a low estimated glomerular filtration rate (eGFR) and albuminuria are known risk factors for end-stage renal disease (ESRD). To determine their joint contribution to ESRD and other kidney outcomes, we performed a meta-analysis of nine general population cohorts with 845,125 participants and an additional eight cohorts with 173,892 patients, the latter selected because of their high risk for chronic kidney disease (CKD). In the general population, the risk for ESRD was unrelated to eGFR at values between 75 and 105 ml/min per 1.73 m(2) but increased exponentially at lower levels. Hazard ratios for eGFRs averaging 60, 45, and 15 were 4, 29, and 454, respectively, compared with an eGFR of 95, after adjustment for albuminuria and cardiovascular risk factors. Log albuminuria was linearly associated with log ESRD risk without thresholds. Adjusted hazard ratios at albumin-to-creatinine ratios of 30, 300, and 1000 mg/g were 5, 13, and 28, respectively, compared with an albumin-to-creatinine ratio of 5. Albuminuria and eGFR were associated with ESRD, without evidence for multiplicative interaction. Similar associations were found for acute kidney injury and progressive CKD. In high-risk cohorts, the findings were generally comparable. Thus, lower eGFR and higher albuminuria are risk factors for ESRD, acute kidney injury and progressive CKD in both general and high-risk populations, independent of each other and of cardiovascular risk factors.

%B Kidney Int %V 80 %P 93-104 %8 2011 Jul %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/21289597?dopt=Abstract %R 10.1038/ki.2010.531 %0 Journal Article %J Genet Epidemiol %D 2011 %T Meta-analysis of gene-environment interaction: joint estimation of SNP and SNP × environment regression coefficients. %A Manning, Alisa K %A LaValley, Michael %A Liu, Ching-Ti %A Rice, Kenneth %A An, Ping %A Liu, Yongmei %A Miljkovic, Iva %A Rasmussen-Torvik, Laura %A Harris, Tamara B %A Province, Michael A %A Borecki, Ingrid B %A Florez, Jose C %A Meigs, James B %A Cupples, L Adrienne %A Dupuis, Josée %K Adult %K Aged %K Body Mass Index %K Confidence Intervals %K Diabetes Mellitus, Type 2 %K Environment %K Fasting %K Female %K Genome, Human %K Genome-Wide Association Study %K Genotype %K Humans %K Insulin %K Least-Squares Analysis %K Male %K Mathematical Computing %K Meta-Analysis as Topic %K Middle Aged %K Polymorphism, Single Nucleotide %K PPAR gamma %X

INTRODUCTION: Genetic discoveries are validated through the meta-analysis of genome-wide association scans in large international consortia. Because environmental variables may interact with genetic factors, investigation of differing genetic effects for distinct levels of an environmental exposure in these large consortia may yield additional susceptibility loci undetected by main effects analysis. We describe a method of joint meta-analysis (JMA) of SNP and SNP by Environment (SNP × E) regression coefficients for use in gene-environment interaction studies.

METHODS: In testing SNP × E interactions, one approach uses a two degree of freedom test to identify genetic variants that influence the trait of interest. This approach detects both main and interaction effects between the trait and the SNP. We propose a method to jointly meta-analyze the SNP and SNP × E coefficients using multivariate generalized least squares. This approach provides confidence intervals of the two estimates, a joint significance test for SNP and SNP × E terms, and a test of homogeneity across samples.

RESULTS: We present a simulation study comparing this method to four other methods of meta-analysis and demonstrate that the JMA performs better than the others when both main and interaction effects are present. Additionally, we implemented our methods in a meta-analysis of the association between SNPs from the type 2 diabetes-associated gene PPARG and log-transformed fasting insulin levels and interaction by body mass index in a combined sample of 19,466 individuals from five cohorts.

%B Genet Epidemiol %V 35 %P 11-8 %8 2011 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/21181894?dopt=Abstract %R 10.1002/gepi.20546 %0 Journal Article %J Nat Genet %D 2011 %T Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque. %A Bis, Joshua C %A Kavousi, Maryam %A Franceschini, Nora %A Isaacs, Aaron %A Abecasis, Goncalo R %A Schminke, Ulf %A Post, Wendy S %A Smith, Albert V %A Cupples, L Adrienne %A Markus, Hugh S %A Schmidt, Reinhold %A Huffman, Jennifer E %A Lehtimäki, Terho %A Baumert, Jens %A Münzel, Thomas %A Heckbert, Susan R %A Dehghan, Abbas %A North, Kari %A Oostra, Ben %A Bevan, Steve %A Stoegerer, Eva-Maria %A Hayward, Caroline %A Raitakari, Olli %A Meisinger, Christa %A Schillert, Arne %A Sanna, Serena %A Völzke, Henry %A Cheng, Yu-Ching %A Thorsson, Bolli %A Fox, Caroline S %A Rice, Kenneth %A Rivadeneira, Fernando %A Nambi, Vijay %A Halperin, Eran %A Petrovic, Katja E %A Peltonen, Leena %A Wichmann, H Erich %A Schnabel, Renate B %A Dörr, Marcus %A Parsa, Afshin %A Aspelund, Thor %A Demissie, Serkalem %A Kathiresan, Sekar %A Reilly, Muredach P %A Taylor, Kent %A Uitterlinden, Andre %A Couper, David J %A Sitzer, Matthias %A Kähönen, Mika %A Illig, Thomas %A Wild, Philipp S %A Orrù, Marco %A Lüdemann, Jan %A Shuldiner, Alan R %A Eiriksdottir, Gudny %A White, Charles C %A Rotter, Jerome I %A Hofman, Albert %A Seissler, Jochen %A Zeller, Tanja %A Usala, Gianluca %A Ernst, Florian %A Launer, Lenore J %A D'Agostino, Ralph B %A O'Leary, Daniel H %A Ballantyne, Christie %A Thiery, Joachim %A Ziegler, Andreas %A Lakatta, Edward G %A Chilukoti, Ravi Kumar %A Harris, Tamara B %A Wolf, Philip A %A Psaty, Bruce M %A Polak, Joseph F %A Li, Xia %A Rathmann, Wolfgang %A Uda, Manuela %A Boerwinkle, Eric %A Klopp, Norman %A Schmidt, Helena %A Wilson, James F %A Viikari, Jorma %A Koenig, Wolfgang %A Blankenberg, Stefan %A Newman, Anne B %A Witteman, Jacqueline %A Heiss, Gerardo %A Duijn, Cornelia van %A Scuteri, Angelo %A Homuth, Georg %A Mitchell, Braxton D %A Gudnason, Vilmundur %A O'Donnell, Christopher J %K Adult %K Aged %K Aging %K Atherosclerosis %K Carotid Intima-Media Thickness %K Cohort Studies %K Coronary Artery Disease %K European Continental Ancestry Group %K Genetic Loci %K Genetic Predisposition to Disease %K Genome, Human %K Genome-Wide Association Study %K Genotype %K Heart %K Humans %K Middle Aged %K Phenotype %K Plaque, Atherosclerotic %K Polymorphism, Single Nucleotide %K Risk Factors %X

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

%B Nat Genet %V 43 %P 940-7 %8 2011 Sep 11 %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/21909108?dopt=Abstract %R 10.1038/ng.920 %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 Nature %D 2011 %T New gene functions in megakaryopoiesis and platelet formation. %A Gieger, Christian %A Radhakrishnan, Aparna %A Cvejic, Ana %A Tang, Weihong %A Porcu, Eleonora %A Pistis, Giorgio %A Serbanovic-Canic, Jovana %A Elling, Ulrich %A Goodall, Alison H %A Labrune, Yann %A Lopez, Lorna M %A Mägi, Reedik %A Meacham, Stuart %A Okada, Yukinori %A Pirastu, Nicola %A Sorice, Rossella %A Teumer, Alexander %A Voss, Katrin %A Zhang, Weihua %A Ramirez-Solis, Ramiro %A Bis, Joshua C %A Ellinghaus, David %A Gögele, Martin %A Hottenga, Jouke-Jan %A Langenberg, Claudia %A Kovacs, Peter %A O'Reilly, Paul F %A Shin, So-Youn %A Esko, Tõnu %A Hartiala, Jaana %A Kanoni, Stavroula %A Murgia, Federico %A Parsa, Afshin %A Stephens, Jonathan %A van der Harst, Pim %A Ellen van der Schoot, C %A Allayee, Hooman %A Attwood, Antony %A Balkau, Beverley %A Bastardot, François %A Basu, Saonli %A Baumeister, Sebastian E %A Biino, Ginevra %A Bomba, Lorenzo %A Bonnefond, Amélie %A Cambien, Francois %A Chambers, John C %A Cucca, Francesco %A D'Adamo, Pio %A Davies, Gail %A de Boer, Rudolf A %A de Geus, Eco J C %A Döring, Angela %A Elliott, Paul %A Erdmann, Jeanette %A Evans, David M %A Falchi, Mario %A Feng, Wei %A Folsom, Aaron R %A Frazer, Ian H %A Gibson, Quince D %A Glazer, Nicole L %A Hammond, Chris %A Hartikainen, Anna-Liisa %A Heckbert, Susan R %A Hengstenberg, Christian %A Hersch, Micha %A Illig, Thomas %A Loos, Ruth J F %A Jolley, Jennifer %A Khaw, Kay Tee %A Kuhnel, Brigitte %A Kyrtsonis, Marie-Christine %A Lagou, Vasiliki %A Lloyd-Jones, Heather %A Lumley, Thomas %A Mangino, Massimo %A Maschio, Andrea %A Mateo Leach, Irene %A McKnight, Barbara %A Memari, Yasin %A Mitchell, Braxton D %A Montgomery, Grant W %A Nakamura, Yusuke %A Nauck, Matthias %A Navis, Gerjan %A Nöthlings, Ute %A Nolte, Ilja M %A Porteous, David J %A Pouta, Anneli %A Pramstaller, Peter P %A Pullat, Janne %A Ring, Susan M %A Rotter, Jerome I %A Ruggiero, Daniela %A Ruokonen, Aimo %A Sala, Cinzia %A Samani, Nilesh J %A Sambrook, Jennifer %A Schlessinger, David %A Schreiber, Stefan %A Schunkert, Heribert %A Scott, James %A Smith, Nicholas L %A Snieder, Harold %A Starr, John M %A Stumvoll, Michael %A Takahashi, Atsushi %A Tang, W H Wilson %A Taylor, Kent %A Tenesa, Albert %A Lay Thein, Swee %A Tönjes, Anke %A Uda, Manuela %A Ulivi, Sheila %A van Veldhuisen, Dirk J %A Visscher, Peter M %A Völker, Uwe %A Wichmann, H-Erich %A Wiggins, Kerri L %A Willemsen, Gonneke %A Yang, Tsun-Po %A Hua Zhao, Jing %A Zitting, Paavo %A Bradley, John R %A Dedoussis, George V %A Gasparini, Paolo %A Hazen, Stanley L %A Metspalu, Andres %A Pirastu, Mario %A Shuldiner, Alan R %A Joost van Pelt, L %A Zwaginga, Jaap-Jan %A Boomsma, Dorret I %A Deary, Ian J %A Franke, Andre %A Froguel, Philippe %A Ganesh, Santhi K %A Jarvelin, Marjo-Riitta %A Martin, Nicholas G %A Meisinger, Christa %A Psaty, Bruce M %A Spector, Timothy D %A Wareham, Nicholas J %A Akkerman, Jan-Willem N %A Ciullo, Marina %A Deloukas, Panos %A Greinacher, Andreas %A Jupe, Steve %A Kamatani, Naoyuki %A Khadake, Jyoti %A Kooner, Jaspal S %A Penninger, Josef %A Prokopenko, Inga %A Stemple, Derek %A Toniolo, Daniela %A Wernisch, Lorenz %A Sanna, Serena %A Hicks, Andrew A %A Rendon, Augusto %A Ferreira, Manuel A %A Ouwehand, Willem H %A Soranzo, Nicole %K Animals %K Blood Platelets %K Cell Size %K Drosophila melanogaster %K Drosophila Proteins %K Europe %K Gene Expression Profiling %K Gene Silencing %K Genome, Human %K Genome-Wide Association Study %K Hematopoiesis %K Humans %K Megakaryocytes %K Platelet Count %K Protein Interaction Maps %K Transcription, Genetic %K Zebrafish %K Zebrafish Proteins %X

Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function.

%B Nature %V 480 %P 201-8 %8 2011 Nov 30 %G eng %N 7376 %1 http://www.ncbi.nlm.nih.gov/pubmed/22139419?dopt=Abstract %R 10.1038/nature10659 %0 Journal Article %J Am J Epidemiol %D 2011 %T The Next PAGE in understanding complex traits: design for the analysis of Population Architecture Using Genetics and Epidemiology (PAGE) Study. %A Matise, Tara C %A Ambite, Jose Luis %A Buyske, Steven %A Carlson, Christopher S %A Cole, Shelley A %A Crawford, Dana C %A Haiman, Christopher A %A Heiss, Gerardo %A Kooperberg, Charles %A Marchand, Loic Le %A Manolio, Teri A %A North, Kari E %A Peters, Ulrike %A Ritchie, Marylyn D %A Hindorff, Lucia A %A Haines, Jonathan L %K Epidemiologic Methods %K Epidemiologic Research Design %K Ethnic Groups %K Genetic Association Studies %K Genetics, Population %K Genome-Wide Association Study %K Humans %K Interinstitutional Relations %K Multifactorial Inheritance %K National Human Genome Research Institute (U.S.) %K Phenotype %K Pilot Projects %K Research Design %K Risk Factors %K United States %X

Genetic studies have identified thousands of variants associated with complex traits. However, most association studies are limited to populations of European descent and a single phenotype. The Population Architecture using Genomics and Epidemiology (PAGE) Study was initiated in 2008 by the National Human Genome Research Institute to investigate the epidemiologic architecture of well-replicated genetic variants associated with complex diseases in several large, ethnically diverse population-based studies. Combining DNA samples and hundreds of phenotypes from multiple cohorts, PAGE is well-suited to address generalization of associations and variability of effects in diverse populations; identify genetic and environmental modifiers; evaluate disease subtypes, intermediate phenotypes, and biomarkers; and investigate associations with novel phenotypes. PAGE investigators harmonize phenotypes across studies where possible and perform coordinated cohort-specific analyses and meta-analyses. PAGE researchers are genotyping thousands of genetic variants in up to 121,000 DNA samples from African-American, white, Hispanic/Latino, Asian/Pacific Islander, and American Indian participants. Initial analyses will focus on single nucleotide polymorphisms (SNPs) associated with obesity, lipids, cardiovascular disease, type 2 diabetes, inflammation, various cancers, and related biomarkers. PAGE SNPs are also assessed for pleiotropy using the "phenome-wide association study" approach, testing each SNP for associations with hundreds of phenotypes. PAGE data will be deposited into the National Center for Biotechnology Information's Database of Genotypes and Phenotypes and made available via a custom browser.

%B Am J Epidemiol %V 174 %P 849-59 %8 2011 Oct 01 %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/21836165?dopt=Abstract %R 10.1093/aje/kwr160 %0 Journal Article %J J Am Geriatr Soc %D 2011 %T Patterns and predictors of recovery from exhaustion in older adults: the cardiovascular health study. %A Whitson, Heather E %A Thielke, Stephen %A Diehr, Paula %A O'Hare, Ann M %A Chaves, Paulo H M %A Zakai, Neil A %A Arnold, Alice %A Chaudhry, Sarwat %A Ives, Diane %A Newman, Anne B %K Aged %K Aging %K Cardiovascular Physiological Phenomena %K Exercise Test %K Exercise Tolerance %K Female %K Follow-Up Studies %K Geriatric Assessment %K Health Status %K Humans %K Male %K Predictive Value of Tests %K Recovery of Function %K Retrospective Studies %K United States %X

OBJECTIVES: To estimate the likelihood of, and factors associated with, recovery from exhaustion in older adults.

DESIGN: Secondary analysis of a cohort study.

SETTING: Six annual examinations in four U.S. communities.

PARTICIPANTS: Four thousand five hundred eighty-four men and women aged 69 and older.

MEASUREMENTS: Exhaustion was considered present when a participant responded "a moderate amount" or "most of the time" to either of two questions: "How often have you had a hard time getting going?" and "How often does everything seem an effort?"

RESULTS: Of the 964 participants who originally reported exhaustion, 634 (65.8%) were exhaustion free at least once during follow-up. When data from all time points were considered, 48% of those who reported exhaustion were exhaustion free the following year. After adjustment for age, sex, race, education, and marital status, 1-year recovery was less likely in individuals with worse self-rated health and in those who were taking six or more medications or were obese, depressed, or had musculoskeletal pain or history of stroke. In proportional hazards models, the following risk factors were associated with more persistent exhaustion over 5 years: poor self-rated health, six or more medications, obesity, and depression. Recovery was not less likely in participants with a history of cancer or heart disease.

CONCLUSION: Exhaustion is common in old age but is dynamic, even in those with a history of cancer and congestive heart failure. Recovery is especially likely in seniors who have a positive perception of their overall health, take few medications, and are not obese or depressed. These findings support the notion that resiliency is associated with physical and psychological well-being.

%B J Am Geriatr Soc %V 59 %P 207-13 %8 2011 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/21288229?dopt=Abstract %R 10.1111/j.1532-5415.2010.03238.x %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 Cardiol %D 2011 %T Predictive value of depressive symptoms and B-type natriuretic peptide for new-onset heart failure and mortality. %A van den Broek, Krista C %A deFilippi, Christopher R %A Christenson, Robert H %A Seliger, Stephen L %A Gottdiener, John S %A Kop, Willem J %K Aged %K Depression %K Disease Progression %K Female %K Follow-Up Studies %K Heart Failure %K Humans %K Incidence %K Male %K Natriuretic Peptide, Brain %K Prognosis %K Retrospective Studies %K Risk Factors %K Survival Rate %K United States %X

Depression and natriuretic peptides predict heart failure (HF) progression, but the unique contributions of depression and biomarkers associated with HF outcomes are not known. The present study determined the additive predictive value of depression and aminoterminal pro-B-type natriuretic peptide (NT-proBNP) for new-onset HF in HF-free subjects and mortality in patients with HF. The participants in the Cardiovascular Health Study were assessed for depressive symptoms using the Center for Epidemiologic Studies Depression Scale and NT-proBNP using an electrochemiluminescence immunoassay. The validated cutoff values for depression (Center for Epidemiologic Studies Depression Scale ≥8) and NT-proBNP (≥190 pg/ml) were used. The risks of incident HF and mortality (cardiovascular disease-related and all-cause) were examined during a median follow-up of 11 years, adjusting for demographics, clinical factors, and health behaviors. In patients with HF (n = 208), depression was associated with an elevated risk of cardiovascular disease mortality (hazard ratios [HR] 2.07, 95% confidence interval [CI] 1.31 to 3.27) and all-cause mortality (HR 1.49, 95% CI 1.05 to 2.11), independent of the NT-proBNP level and covariates. The combined presence of depression and elevated NT-proBNP was associated with substantially elevated covariate-adjusted risks of cardiovascular disease mortality (HR 5.42, 95% CI 2.38 to 12.36) and all-cause mortality (HR 3.72, 95% CI 2.20 to 6.37). In the 4,114 HF-free subjects, new-onset HF was independently predicted by an elevated NT-proBNP level (HR 2.27, 95% CI 1.97 to 2.62) but not depression (HR 1.08, 95% CI 0.92 to 1.26) in covariate-adjusted analysis. In conclusion, depression and NT-proBNP displayed additive predictive value for mortality in patients with HF. These associations can be explained by complementary pathophysiologic mechanisms. The presence of both elevated depression and NT-proBNP levels might improve the identification of patients with HF with a high risk of mortality.

%B Am J Cardiol %V 107 %P 723-9 %8 2011 Mar 01 %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/21316507?dopt=Abstract %R 10.1016/j.amjcard.2010.10.055 %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2011 %T Predictors of thyroid hormone initiation in older adults: results from the cardiovascular health study. %A Somwaru, Lily L %A Arnold, Alice M %A Cappola, Anne R %K Aged %K Aged, 80 and over %K Body Mass Index %K Cardiovascular Diseases %K Dose-Response Relationship, Drug %K Drug Administration Schedule %K Female %K Follow-Up Studies %K Humans %K Hypothyroidism %K Incidence %K Male %K Prevalence %K Prognosis %K Retrospective Studies %K Risk Factors %K Sex Factors %K Thyroid Hormones %K Thyroxine %K Time Factors %K United States %X

BACKGROUND: Despite widespread use, there are no data on initiation of thyroid hormone use in older people. We report the prevalence of thyroid hormone use and predictors of thyroid hormone initiation in a population of older men and women.

METHODS: Thyroid hormone medication data were collected annually from 1989 to 2006 in community-dwelling individuals aged 65 years and older enrolled in the Cardiovascular Health Study (N = 5,888). Associations of age, sex, race, body mass index, education, and coronary heart disease with initiation were evaluated using discrete-time survival analysis.

RESULTS: In 1989-1990, 8.9% (95% confidence interval 8.1%-9.7%) of participants were taking a thyroid hormone preparation, increasing to 20.0% (95% confidence interval 8.2%-21.8%) over 16 years. The average initiation rate was 1% per year. The initiation rate was nonlinear with age, and those aged 85 years and older initiated thyroid hormone more than twice as frequently as those aged 65-69 years (hazard ratio = 2.34; 95% confidence interval 1.43-3.85). White women were more likely to initiate thyroid hormone than any other race and sex group. Higher body mass index was independently associated with higher risk for initiation (p = .002) as was greater education (p = .02) and prevalent coronary heart disease (p = .03).

CONCLUSIONS: Thyroid hormone use is common in older people. The indications and benefits of thyroid hormone use in older individuals with the highest rate of thyroid hormone initiation-the oldest old, overweight and obese individuals, and those with coronary heart disease-should be investigated.

%B J Gerontol A Biol Sci Med Sci %V 66 %P 809-14 %8 2011 Jul %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/21628677?dopt=Abstract %R 10.1093/gerona/glr063 %0 Journal Article %J J Card Fail %D 2011 %T Risk factors for onset of disability among older persons newly diagnosed with heart failure: the Cardiovascular Health Study. %A Chaudhry, Sarwat I %A McAvay, Gail %A Ning, Yuming %A Allore, Heather G %A Newman, Anne B %A Gill, Thomas M %K Activities of Daily Living %K Age Factors %K Aged %K Aged, 80 and over %K Disability Evaluation %K Disabled Persons %K Female %K Health Status %K Heart Failure %K Humans %K Longitudinal Studies %K Male %K Risk Factors %X

BACKGROUND: As the heart failure population continues to age, disability is becoming an increasingly important issue. Our objective was to identify risk factors for the onset of disability in activities of daily living among older persons with heart failure.

METHODS: The study population included participants with newly diagnosed heart failure from the Cardiovascular Health Study, a longitudinal study of community-living, older persons. Data were collected through annual examinations. Cox regression modeling was used to examine associations between time-dependent predictors and onset of disability.

RESULTS: Of 461 participants newly diagnosed with heart failure (mean age 78.7 [SD 5.89]), 23% subsequently developed disability. The first year after heart failure diagnosis was the period of greatest risk for onset of disability (chi-square P value <.001). Factors that were independently associated with disability included: impaired gait speed (HR 2.29, 95% CI 1.34-3.90); impaired cognition (HR 1.87, 95% CI 1.14-3.05); and depressive symptoms (HR 1.72, 95% CI 1.04-2.83).

CONCLUSIONS: Onset of disability is a common occurrence among older persons newly diagnosed with heart failure. Risk factors for onset of disability in this population are potentially modifiable, and should be routinely assessed in an effort to reduce disability in this growing population.

%B J Card Fail %V 17 %P 764-70 %8 2011 Sep %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/21872147?dopt=Abstract %R 10.1016/j.cardfail.2011.04.015 %0 Journal Article %J Lancet %D 2011 %T Separate and combined associations of body-mass index and abdominal adiposity with cardiovascular disease: collaborative analysis of 58 prospective studies. %A Wormser, David %A Kaptoge, Stephen %A Di Angelantonio, Emanuele %A Wood, Angela M %A Pennells, Lisa %A Thompson, Alex %A Sarwar, Nadeem %A Kizer, Jorge R %A Lawlor, Debbie A %A Nordestgaard, Børge G %A Ridker, Paul %A Salomaa, Veikko %A Stevens, June %A Woodward, Mark %A Sattar, Naveed %A Collins, Rory %A Thompson, Simon G %A Whitlock, Gary %A Danesh, John %K Age Factors %K Blood Pressure %K Body Mass Index %K Cardiovascular Diseases %K Cholesterol %K Cholesterol, HDL %K Diabetes Mellitus %K Female %K Humans %K Male %K Middle Aged %K Obesity, Abdominal %K Proportional Hazards Models %K Prospective Studies %K Risk Assessment %K Sex Factors %K Smoking %K Systole %K Waist Circumference %K Waist-Hip Ratio %X

BACKGROUND: Guidelines differ about the value of assessment of adiposity measures for cardiovascular disease risk prediction when information is available for other risk factors. We studied the separate and combined associations of body-mass index (BMI), waist circumference, and waist-to-hip ratio with risk of first-onset cardiovascular disease.

METHODS: We used individual records from 58 cohorts to calculate hazard ratios (HRs) per 1 SD higher baseline values (4.56 kg/m(2) higher BMI, 12.6 cm higher waist circumference, and 0.083 higher waist-to-hip ratio) and measures of risk discrimination and reclassification. Serial adiposity assessments were used to calculate regression dilution ratios.

RESULTS: Individual records were available for 221,934 people in 17 countries (14,297 incident cardiovascular disease outcomes; 1.87 million person-years at risk). Serial adiposity assessments were made in up to 63,821 people (mean interval 5.7 years [SD 3.9]). In people with BMI of 20 kg/m(2) or higher, HRs for cardiovascular disease were 1.23 (95% CI 1.17-1.29) with BMI, 1.27 (1.20-1.33) with waist circumference, and 1.25 (1.19-1.31) with waist-to-hip ratio, after adjustment for age, sex, and smoking status. After further adjustment for baseline systolic blood pressure, history of diabetes, and total and HDL cholesterol, corresponding HRs were 1.07 (1.03-1.11) with BMI, 1.10 (1.05-1.14) with waist circumference, and 1.12 (1.08-1.15) with waist-to-hip ratio. Addition of information on BMI, waist circumference, or waist-to-hip ratio to a cardiovascular disease risk prediction model containing conventional risk factors did not importantly improve risk discrimination (C-index changes of -0.0001, -0.0001, and 0.0008, respectively), nor classification of participants to categories of predicted 10-year risk (net reclassification improvement -0.19%, -0.05%, and -0.05%, respectively). Findings were similar when adiposity measures were considered in combination. Reproducibility was greater for BMI (regression dilution ratio 0.95, 95% CI 0.93-0.97) than for waist circumference (0.86, 0.83-0.89) or waist-to-hip ratio (0.63, 0.57-0.70).

INTERPRETATION: BMI, waist circumference, and waist-to-hip ratio, whether assessed singly or in combination, do not importantly improve cardiovascular disease risk prediction in people in developed countries when additional information is available for systolic blood pressure, history of diabetes, and lipids.

FUNDING: British Heart Foundation and UK Medical Research Council.

%B Lancet %V 377 %P 1085-95 %8 2011 Mar 26 %G eng %N 9771 %1 http://www.ncbi.nlm.nih.gov/pubmed/21397319?dopt=Abstract %R 10.1016/S0140-6736(11)60105-0 %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 J Am Geriatr Soc %D 2011 %T Serum 25-hydroxyvitamin D and physical function in older adults: the Cardiovascular Health Study All Stars. %A Houston, Denise K %A Tooze, Janet A %A Davis, Cralen C %A Chaves, Paulo H M %A Hirsch, Calvin H %A Robbins, John A %A Arnold, Alice M %A Newman, Anne B %A Kritchevsky, Stephen B %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Female %K Follow-Up Studies %K Geriatric Assessment %K Health Surveys %K Humans %K Male %K Mobility Limitation %K Muscle Strength %K Physical Fitness %K Proportional Hazards Models %K Reference Values %K United States %K Vitamin D %K Vitamin D Deficiency %X

OBJECTIVES: To examine the association between 25-hydroxyvitamin D (25(OH)D) and physical function in adults of advanced age.

DESIGN: Cross-sectional and longitudinal analysis of physical function over 3 years of follow-up in the Cardiovascular Health Study All Stars.

SETTING: Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Allegheny County, Pennsylvania.

PARTICIPANTS: Community-dwelling adults aged 77 to 100 (N = 988).

MEASUREMENTS: Serum 25-hydroxyvitamin D 25(OH)D), Short Physical Performance Battery (SPPB), and grip and knee extensor strength assessed at baseline. Mobility disability (difficulty walking half a mile or up 10 steps) and activities of daily living (ADLs) disability were assessed at baseline and every 6 months over 3 years of follow-up.

RESULTS: Almost one-third (30.8%) of participants were deficient in 25(OH)D (<20 ng/mL). SPPB scores were lower in those with deficient 25(OH)D (mean (standard error) 6.53 (0.24)) than in those with sufficient 25(OH)D (≥30 ng/mL) (7.15 (0.25)) after adjusting for sociodemographic characteristics, season, health behaviors, and chronic conditions (P = .006). Grip strength adjusted for body size was also lower in those with deficient 25(OH)D than in those with sufficient 25(OH)D (24.7 (0.6) kg vs 26.0 (0.6) kg, P = .02). Participants with deficient 25(OH)D were more likely to have prevalent mobility (OR = 1.44, 95% confidence interval (CI)) = 0.96-2.14) and ADL disability (OR = 1.51, 95% CI = 1.01-2.25) at baseline than those with sufficient 25(OH)D. Furthermore, participants with deficient 25(OH)D were at greater risk of incident mobility disability over 3 years of follow-up (hazard ratio = 1.56, 95% CI = 1.06-2.30).

CONCLUSION: Vitamin D deficiency was common and was associated with poorer physical performance, lower muscle strength, and prevalent mobility and ADL disability in community-dwelling older adults. Moreover, vitamin D deficiency predicted incident mobility disability.

%B J Am Geriatr Soc %V 59 %P 1793-801 %8 2011 Oct %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/22091492?dopt=Abstract %R 10.1111/j.1532-5415.2011.03601.x %0 Journal Article %J Aging Clin Exp Res %D 2011 %T Surrogate screening models for the low physical activity criterion of frailty. %A Eckel, Sandrah P %A Bandeen-Roche, Karen %A Chaves, Paulo H M %A Fried, Linda P %A Louis, Thomas A %K Activities of Daily Living %K Aged %K Cohort Studies %K Exercise %K Female %K Follow-Up Studies %K Frail Elderly %K Geriatric Assessment %K Humans %K Leisure Activities %K Logistic Models %K Male %K Motor Activity %K Prospective Studies %K Surveys and Questionnaires %K Women's Health %X

BACKGROUND AND AIMS: Low physical activity, one of five criteria in a validated clinical phenotype of frailty, is assessed by a standardized, semiquantitative questionnaire on up to 20 leisure time activities. Because of the time demanded to collect the interview data, it has been challenging to translate to studies other than the Cardiovascular Health Study (CHS), for which it was developed. Considering subsets of activities, we identified and evaluated streamlined surrogate assessment methods and compared them to one implemented in the Women's Health and Aging Study (WHAS).

METHODS: Using data on men and women ages 65 and older from the CHS, we applied logistic regression models to rank activities by "relative influence" in predicting low physical activity.We considered subsets of the most influential activities as inputs to potential surrogate models (logistic regressions). We evaluated predictive accuracy and predictive validity using the area under receiver operating characteristic curves and assessed criterion validity using proportional hazards models relating frailty status (defined using the surrogate) to mortality.

RESULTS: Walking for exercise and moderately strenuous household chores were highly influential for both genders. Women required fewer activities than men for accurate classification. The WHAS model (8 CHS activities) was an effective surrogate, but a surrogate using 6 activities (walking, chores, gardening, general exercise, mowing and golfing) was also highly predictive.

CONCLUSIONS: We recommend a 6 activity questionnaire to assess physical activity for men and women. If efficiency is essential and the study involves only women, fewer activities can be included.

%B Aging Clin Exp Res %V 23 %P 209-16 %8 2011 Jun %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/21993168?dopt=Abstract %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 Hypertension %D 2011 %T Vitamin D, parathyroid hormone, and sudden cardiac death: results from the Cardiovascular Health Study. %A Deo, Rajat %A Katz, Ronit %A Shlipak, Michael G %A Sotoodehnia, Nona %A Psaty, Bruce M %A Sarnak, Mark J %A Fried, Linda F %A Chonchol, Michel %A de Boer, Ian H %A Enquobahrie, Daniel %A Siscovick, David %A Kestenbaum, Bryan %K Aged %K Cardiovascular Diseases %K Comorbidity %K Death, Sudden, Cardiac %K Diabetes Mellitus %K Female %K Follow-Up Studies %K Humans %K Hypertension %K Incidence %K Kidney %K Male %K Middle Aged %K Minerals %K Parathyroid Hormone %K Proportional Hazards Models %K Risk Factors %K Socioeconomic Factors %K United States %K Vitamin D %X

Recent studies have demonstrated greater risks of cardiovascular events and mortality among persons who have lower 25-hydroxyvitamin D (25-OHD) and higher parathyroid hormone (PTH) levels. We sought to evaluate the association between markers of mineral metabolism and sudden cardiac death (SCD) among the 2312 participants from the Cardiovascular Health Study who were free of clinical cardiovascular disease at baseline. We estimated associations of baseline 25-OHD and PTH concentrations individually and in combination with SCD using Cox proportional hazards models after adjustment for demographics, cardiovascular risk factors, and kidney function. During a median follow-up of 14 years, there were 73 adjudicated SCD events. The annual incidence of SCD was greater among subjects who had lower 25-OHD concentrations, 2 events per 1000 for 25-OHD ≥20 ng/mL and 4 events per 1000 for 25-OHD <20 ng/mL. Similarly, SCD incidence was greater among subjects who had higher PTH concentrations, 2 events per 1000 for PTH <65 pg/mL and 4 events per 1000 for PTH ≥65 pg/mL. Multivariate adjustment attenuated associations of 25-OHD and PTH with SCD. Finally, 267 participants (11.7% of the cohort) had high PTH and low 25-OHD concentrations. This combination was associated with a >2-fold risk of SCD after adjustment (hazard ratio: 2.19 [95% CI: 1.17-4.10]; P=0.017) compared with participants with normal levels of PTH and 25-OHD. The combination of lower 25-OHD and higher PTH concentrations appears to be associated independently with SCD risk among older adults without cardiovascular disease.

%B Hypertension %V 58 %P 1021-8 %8 2011 Dec %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/22068871?dopt=Abstract %R 10.1161/HYPERTENSIONAHA.111.179135 %0 Journal Article %J JAMA %D 2012 %T Age and association of kidney measures with mortality and end-stage renal disease. %A Hallan, Stein I %A Matsushita, Kunihiro %A Sang, Yingying %A Mahmoodi, Bakhtawar K %A Black, Corri %A Ishani, Areef %A Kleefstra, Nanne %A Naimark, David %A Roderick, Paul %A Tonelli, Marcello %A Wetzels, Jack F M %A Astor, Brad C %A Gansevoort, Ron T %A Levin, Adeera %A Wen, Chi-Pang %A Coresh, Josef %K Adolescent %K Adult %K Age Factors %K Aged %K Albuminuria %K Cohort Studies %K Female %K Glomerular Filtration Rate %K Humans %K Kidney %K Kidney Failure, Chronic %K Male %K Middle Aged %K Risk %K Young Adult %X

CONTEXT: Chronic kidney disease (CKD) is prevalent in older individuals, but the risk implications of low estimated glomerular filtration rate (eGFR) and high albuminuria across the full age range are controversial.

OBJECTIVE: To evaluate possible effect modification (interaction) by age of the association of eGFR and albuminuria with clinical risk, examining both relative and absolute risks.

DESIGN, SETTING, AND PARTICIPANTS: Individual-level meta-analysis including 2,051,244 participants from 33 general population or high-risk (of vascular disease) cohorts and 13 CKD cohorts from Asia, Australasia, Europe, and North/South America, conducted in 1972-2011 with a mean follow-up time of 5.8 years (range, 0-31 years).

MAIN OUTCOME MEASURES: Hazard ratios (HRs) of mortality and end-stage renal disease (ESRD) according to eGFR and albuminuria were meta-analyzed across age categories after adjusting for sex, race, cardiovascular disease, diabetes, systolic blood pressure, cholesterol, body mass index, and smoking. Absolute risks were estimated using HRs and average incidence rates.

RESULTS: Mortality (112,325 deaths) and ESRD (8411 events) risks were higher at lower eGFR and higher albuminuria in every age category. In general and high-risk cohorts, relative mortality risk for reduced eGFR decreased with increasing age; eg, adjusted HRs at an eGFR of 45 mL/min/1.73 m2 vs 80 mL/min/1.73 m2 were 3.50 (95% CI, 2.55-4.81), 2.21 (95% CI, 2.02-2.41), 1.59 (95% CI, 1.42-1.77), and 1.35 (95% CI, 1.23-1.48) in age categories 18-54, 55-64, 65-74, and ≥75 years, respectively (P <.05 for age interaction). Absolute risk differences for the same comparisons were higher at older age (9.0 [95% CI, 6.0-12.8], 12.2 [95% CI, 10.3-14.3], 13.3 [95% CI, 9.0-18.6], and 27.2 [95% CI, 13.5-45.5] excess deaths per 1000 person-years, respectively). For increased albuminuria, reduction of relative risk with increasing age was less evident, while differences in absolute risk were higher in older age categories (7.5 [95% CI, 4.3-11.9], 12.2 [95% CI, 7.9-17.6], 22.7 [95% CI, 15.3-31.6], and 34.3 [95% CI, 19.5-52.4] excess deaths per 1000 person-years, respectively by age category, at an albumin-creatinine ratio of 300 mg/g vs 10 mg/g). In CKD cohorts, adjusted relative hazards of mortality did not decrease with age. In all cohorts, ESRD relative risks and absolute risk differences at lower eGFR or higher albuminuria were comparable across age categories.

CONCLUSIONS: Both low eGFR and high albuminuria were independently associated with mortality and ESRD regardless of age across a wide range of populations. Mortality showed lower relative risk but higher absolute risk differences at older age.

%B JAMA %V 308 %P 2349-60 %8 2012 Dec 12 %G eng %N 22 %R 10.1001/jama.2012.16817 %0 Journal Article %J J Bone Miner Res %D 2012 %T Assessment of gene-by-sex interaction effect on bone mineral density. %A Liu, Ching-Ti %A Estrada, Karol %A Yerges-Armstrong, Laura M %A Amin, Najaf %A Evangelou, Evangelos %A Li, Guo %A Minster, Ryan L %A Carless, Melanie A %A Kammerer, Candace M %A Oei, Ling %A Zhou, Yanhua %A Alonso, Nerea %A Dailiana, Zoe %A Eriksson, Joel %A García-Giralt, Natalia %A Giroux, Sylvie %A Husted, Lise Bjerre %A Khusainova, Rita I %A Koromila, Theodora %A Kung, Annie Waichee %A Lewis, Joshua R %A Masi, Laura %A Mencej-Bedrac, Simona %A Nogues, Xavier %A Patel, Millan S %A Prezelj, Janez %A Richards, J Brent %A Sham, Pak Chung %A Spector, Timothy %A Vandenput, Liesbeth %A Xiao, Su-Mei %A Zheng, Hou-Feng %A Zhu, Kun %A Balcells, Susana %A Brandi, Maria Luisa %A Frost, Morten %A Goltzman, David %A González-Macías, Jesús %A Karlsson, Magnus %A Khusnutdinova, Elza K %A Kollia, Panagoula %A Langdahl, Bente Lomholt %A Ljunggren, Osten %A Lorentzon, Mattias %A Marc, Janja %A Mellström, Dan %A Ohlsson, Claes %A Olmos, José M %A Ralston, Stuart H %A Riancho, José A %A Rousseau, François %A Urreizti, Roser %A Van Hul, Wim %A Zarrabeitia, María T %A Castano-Betancourt, Martha %A Demissie, Serkalem %A Grundberg, Elin %A Herrera, Lizbeth %A Kwan, Tony %A Medina-Gómez, Carolina %A Pastinen, Tomi %A Sigurdsson, Gunnar %A Thorleifsson, Gudmar %A Vanmeurs, Joyce Bj %A Blangero, John %A Hofman, Albert %A Liu, Yongmei %A Mitchell, Braxton D %A O'Connell, Jeffrey R %A Oostra, Ben A %A Rotter, Jerome I %A Stefansson, Kari %A Streeten, Elizabeth A %A Styrkarsdottir, Unnur %A Thorsteinsdottir, Unnur %A Tylavsky, Frances A %A Uitterlinden, Andre %A Cauley, Jane A %A Harris, Tamara B %A Ioannidis, John Pa %A Psaty, Bruce M %A Robbins, John A %A Zillikens, M Carola %A Vanduijn, Cornelia M %A Prince, Richard L %A Karasik, David %A Rivadeneira, Fernando %A Kiel, Douglas P %A Cupples, L Adrienne %A Hsu, Yi-Hsiang %K Bone Density %K Cohort Studies %K Female %K Genes %K Genome-Wide Association Study %K Humans %K Male %K Meta-Analysis as Topic %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Reproducibility of Results %K Sex Characteristics %X

Sexual dimorphism in various bone phenotypes, including bone mineral density (BMD), is widely observed; however, the extent to which genes explain these sex differences is unclear. To identify variants with different effects by sex, we examined gene-by-sex autosomal interactions genome-wide, and performed expression quantitative trait loci (eQTL) analysis and bioinformatics network analysis. We conducted an autosomal genome-wide meta-analysis of gene-by-sex interaction on lumbar spine (LS) and femoral neck (FN) BMD in 25,353 individuals from 8 cohorts. In a second stage, we followed up the 12 top single-nucleotide polymorphisms (SNPs; p < 1 × 10(-5) ) in an additional set of 24,763 individuals. Gene-by-sex interaction and sex-specific effects were examined in these 12 SNPs. We detected one novel genome-wide significant interaction associated with LS-BMD at the Chr3p26.1-p25.1 locus, near the GRM7 gene (male effect = 0.02 and p = 3.0 × 10(-5) ; female effect = -0.007 and p = 3.3 × 10(-2) ), and 11 suggestive loci associated with either FN- or LS-BMD in discovery cohorts. However, there was no evidence for genome-wide significant (p < 5 × 10(-8) ) gene-by-sex interaction in the joint analysis of discovery and replication cohorts. Despite the large collaborative effort, no genome-wide significant evidence for gene-by-sex interaction was found to influence BMD variation in this screen of autosomal markers. If they exist, gene-by-sex interactions for BMD probably have weak effects, accounting for less than 0.08% of the variation in these traits per implicated SNP. © 2012 American Society for Bone and Mineral Research.

%B J Bone Miner Res %V 27 %P 2051-64 %8 2012 Oct %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/22692763?dopt=Abstract %R 10.1002/jbmr.1679 %0 Journal Article %J Circ Cardiovasc Genet %D 2012 %T Association between chromosome 9p21 variants and the ankle-brachial index identified by a meta-analysis of 21 genome-wide association studies. %A Murabito, Joanne M %A White, Charles C %A Kavousi, Maryam %A Sun, Yan V %A Feitosa, Mary F %A Nambi, Vijay %A Lamina, Claudia %A Schillert, Arne %A Coassin, Stefan %A Bis, Joshua C %A Broer, Linda %A Crawford, Dana C %A Franceschini, Nora %A Frikke-Schmidt, Ruth %A Haun, Margot %A Holewijn, Suzanne %A Huffman, Jennifer E %A Hwang, Shih-Jen %A Kiechl, Stefan %A Kollerits, Barbara %A Montasser, May E %A Nolte, Ilja M %A Rudock, Megan E %A Senft, Andrea %A Teumer, Alexander %A van der Harst, Pim %A Vitart, Veronique %A Waite, Lindsay L %A Wood, Andrew R %A Wassel, Christina L %A Absher, Devin M %A Allison, Matthew A %A Amin, Najaf %A Arnold, Alice %A Asselbergs, Folkert W %A Aulchenko, Yurii %A Bandinelli, Stefania %A Barbalic, Maja %A Boban, Mladen %A Brown-Gentry, Kristin %A Couper, David J %A Criqui, Michael H %A Dehghan, Abbas %A den Heijer, Martin %A Dieplinger, Benjamin %A Ding, Jingzhong %A Dörr, Marcus %A Espinola-Klein, Christine %A Felix, Stephan B %A Ferrucci, Luigi %A Folsom, Aaron R %A Fraedrich, Gustav %A Gibson, Quince %A Goodloe, Robert %A Gunjaca, Grgo %A Haltmayer, Meinhard %A Heiss, Gerardo %A Hofman, Albert %A Kieback, Arne %A Kiemeney, Lambertus A %A Kolcic, Ivana %A Kullo, Iftikhar J %A Kritchevsky, Stephen B %A Lackner, Karl J %A Li, Xiaohui %A Lieb, Wolfgang %A Lohman, Kurt %A Meisinger, Christa %A Melzer, David %A Mohler, Emile R %A Mudnic, Ivana %A Mueller, Thomas %A Navis, Gerjan %A Oberhollenzer, Friedrich %A Olin, Jeffrey W %A O'Connell, Jeff %A O'Donnell, Christopher J %A Palmas, Walter %A Penninx, Brenda W %A Petersmann, Astrid %A Polasek, Ozren %A Psaty, Bruce M %A Rantner, Barbara %A Rice, Ken %A Rivadeneira, Fernando %A Rotter, Jerome I %A Seldenrijk, Adrie %A Stadler, Marietta %A Summerer, Monika %A Tanaka, Toshiko %A Tybjaerg-Hansen, Anne %A Uitterlinden, André G %A van Gilst, Wiek H %A Vermeulen, Sita H %A Wild, Sarah H %A Wild, Philipp S %A Willeit, Johann %A Zeller, Tanja %A Zemunik, Tatijana %A Zgaga, Lina %A Assimes, Themistocles L %A Blankenberg, Stefan %A Boerwinkle, Eric %A Campbell, Harry %A Cooke, John P %A de Graaf, Jacqueline %A Herrington, David %A Kardia, Sharon L R %A Mitchell, Braxton D %A Murray, Anna %A Münzel, Thomas %A Newman, Anne B %A Oostra, Ben A %A Rudan, Igor %A Shuldiner, Alan R %A Snieder, Harold %A van Duijn, Cornelia M %A Völker, Uwe %A Wright, Alan F %A Wichmann, H-Erich %A Wilson, James F %A Witteman, Jacqueline C M %A Liu, Yongmei %A Hayward, Caroline %A Borecki, Ingrid B %A Ziegler, Andreas %A North, Kari E %A Cupples, L Adrienne %A Kronenberg, Florian %K Adult %K Age Factors %K Aged %K Aged, 80 and over %K Alleles %K Ankle Brachial Index %K Chromosomes, Human, Pair 9 %K Cohort Studies %K Cyclin-Dependent Kinase Inhibitor p15 %K Female %K Genome-Wide Association Study %K Genotype %K HapMap Project %K Humans %K Logistic Models %K Male %K Middle Aged %K Peripheral Vascular Diseases %K Phenotype %K Polymorphism, Single Nucleotide %K Risk Factors %K Sex Factors %X

BACKGROUND: Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts.

METHODS AND RESULTS: Continuous ABI and PAD (ABI ≤0.9) phenotypes adjusted for age and sex were examined. Each study conducted genotyping and imputed data to the ≈2.5 million single nucleotide polymorphisms (SNPs) in HapMap. Linear and logistic regression models were used to test each SNP for association with ABI and PAD using additive genetic models. Study-specific data were combined using fixed effects inverse variance weighted meta-analyses. There were a total of 41 692 participants of European ancestry (≈60% women, mean ABI 1.02 to 1.19), including 3409 participants with PAD and with genome-wide association study data available. In the discovery meta-analysis, rs10757269 on chromosome 9 near CDKN2B had the strongest association with ABI (β=-0.006, P=2.46×10(-8)). We sought replication of the 6 strongest SNP associations in 5 population-based studies and 3 clinical samples (n=16 717). The association for rs10757269 strengthened in the combined discovery and replication analysis (P=2.65×10(-9)). No other SNP associations for ABI or PAD achieved genome-wide significance. However, 2 previously reported candidate genes for PAD and 1 SNP associated with coronary artery disease were associated with ABI: DAB21P (rs13290547, P=3.6×10(-5)), CYBA (rs3794624, P=6.3×10(-5)), and rs1122608 (LDLR, P=0.0026).

CONCLUSIONS: Genome-wide association studies in more than 40 000 individuals identified 1 genome wide significant association on chromosome 9p21 with ABI. Two candidate genes for PAD and 1 SNP for coronary artery disease are associated with ABI.

%B Circ Cardiovasc Genet %V 5 %P 100-12 %8 2012 Feb 01 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/22199011?dopt=Abstract %R 10.1161/CIRCGENETICS.111.961292 %0 Journal Article %J PLoS One %D 2012 %T Association of genetic loci with sleep apnea in European Americans and African-Americans: the Candidate Gene Association Resource (CARe). %A Patel, Sanjay R %A Goodloe, Robert %A De, Gourab %A Kowgier, Matthew %A Weng, Jia %A Buxbaum, Sarah G %A Cade, Brian %A Fulop, Tibor %A Gharib, Sina A %A Gottlieb, Daniel J %A Hillman, David %A Larkin, Emma K %A Lauderdale, Diane S %A Li, Li %A Mukherjee, Sutapa %A Palmer, Lyle %A Zee, Phyllis %A Zhu, Xiaofeng %A Redline, Susan %K Adult %K African Americans %K Aged %K Alleles %K European Continental Ancestry Group %K Female %K Genetic Association Studies %K Genetic Loci %K Genetic Predisposition to Disease %K Genotype %K Humans %K Male %K Middle Aged %K Phenotype %K Polymorphism, Single Nucleotide %K Polysomnography %K Sleep Apnea, Obstructive %X

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

%B PLoS One %V 7 %P e48836 %8 2012 %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/23155414?dopt=Abstract %R 10.1371/journal.pone.0048836 %0 Journal Article %J Circulation %D 2012 %T Association of mild to moderate chronic kidney disease with venous thromboembolism: pooled analysis of five prospective general population cohorts. %A Mahmoodi, Bakhtawar K %A Gansevoort, Ron T %A Næss, Inger Anne %A Lutsey, Pamela L %A Brækkan, Sigrid K %A Veeger, Nic J G M %A Brodin, Ellen E %A Meijer, Karina %A Sang, Yingying %A Matsushita, Kunihiro %A Hallan, Stein I %A Hammerstrøm, Jens %A Cannegieter, Suzanne C %A Astor, Brad C %A Coresh, Josef %A Folsom, Aaron R %A Hansen, John-Bjarne %A Cushman, Mary %K Aged %K Cohort Studies %K Europe %K Female %K Humans %K Incidence %K Male %K Middle Aged %K Prevalence %K Renal Insufficiency, Chronic %K Risk Factors %K Severity of Illness Index %K Venous Thromboembolism %X

BACKGROUND: Recent findings suggest that chronic kidney disease (CKD) may be associated with an increased risk of venous thromboembolism (VTE). Given the high prevalence of mild-to-moderate CKD in the general population, in depth analysis of this association is warranted.

METHODS AND RESULTS: We pooled individual participant data from 5 community-based cohorts from Europe (second Nord-Trøndelag Health Study [HUNT2], Prevention of Renal and Vascular End-stage Disease [PREVEND], and the Tromsø study) and the United States (Atherosclerosis Risks in Communities [ARIC] and Cardiovascular Health Study [CHS]) to assess the association of estimated glomerular filtration rate (eGFR), albuminuria, and CKD with objectively verified VTE. To estimate adjusted hazard ratios for VTE, categorical and continuous spline models were fit by using Cox regression with shared-frailty or random-effect meta-analysis. A total of 1178 VTE events occurred over 599 453 person-years follow-up. Relative to eGFR 100 mL/min per 1.73 m(2), hazard ratios for VTE were 1.29 (95% confidence interval, 1.04-1.59) for eGFR 75, 1.31 (1.00-1.71) for eGFR 60, 1.82 (1.27-2.60) for eGFR 45, and 1.95 (1.26-3.01) for eGFR 30 mL/min per 1.73 m(2). In comparison with an albumin-to-creatinine ratio (ACR) of 5.0 mg/g, the hazard ratios for VTE were 1.34 (1.04-1.72) for ACR 30 mg/g, 1.60 (1.08-2.36) for ACR 300 mg/g, and 1.92 (1.19-3.09) for ACR 1000 mg/g. There was no interaction between clinical categories of eGFR and ACR (P=0.20). The adjusted hazard ratio for CKD, defined as eGFR <60 mL/min per 1.73 m(2) or albuminuria ≥30 mg/g, (versus no CKD) was 1.54 (95% confidence interval, 1.15-2.06). Associations were consistent in subgroups according to age, sex, and comorbidities, and for unprovoked versus provoked VTE, as well.

CONCLUSIONS: Both eGFR and ACR are independently associated with increased risk of VTE in the general population, even across the normal eGFR and ACR ranges.

%B Circulation %V 126 %P 1964-71 %8 2012 Oct 16 %G eng %N 16 %1 http://www.ncbi.nlm.nih.gov/pubmed/22977129?dopt=Abstract %R 10.1161/CIRCULATIONAHA.112.113944 %0 Journal Article %J JAMA %D 2012 %T Association of weight status with mortality in adults with incident diabetes. %A Carnethon, Mercedes R %A De Chavez, Peter John D %A Biggs, Mary L %A Lewis, Cora E %A Pankow, James S %A Bertoni, Alain G %A Golden, Sherita H %A Liu, Kiang %A Mukamal, Kenneth J %A Campbell-Jenkins, Brenda %A Dyer, Alan R %K Adult %K Aged %K Aged, 80 and over %K Body Mass Index %K Body Weight %K Cardiovascular Diseases %K Cause of Death %K Diabetes Mellitus, Type 2 %K Female %K Humans %K Longitudinal Studies %K Male %K Middle Aged %K Obesity %K Overweight %K United States %X

CONTEXT: Type 2 diabetes in normal-weight adults (body mass index [BMI] <25) is a representation of the metabolically obese normal-weight phenotype with unknown mortality consequences.

OBJECTIVE: To test the association of weight status with mortality in adults with new-onset diabetes in order to minimize the influence of diabetes duration and voluntary weight loss on mortality.

DESIGN, SETTING, AND PARTICIPANTS: Pooled analysis of 5 longitudinal cohort studies: Atherosclerosis Risk in Communities study, 1990-2006; Cardiovascular Health Study, 1992-2008; Coronary Artery Risk Development in Young Adults, 1987-2011; Framingham Offspring Study, 1979-2007; and Multi-Ethnic Study of Atherosclerosis, 2002-2011. A total of 2625 participants with incident diabetes contributed 27,125 person-years of follow-up. Included were men and women (age >40 years) who developed incident diabetes based on fasting glucose 126 mg/dL or greater or newly initiated diabetes medication and who had concurrent measurements of BMI. Participants were classified as normal weight if their BMI was 18.5 to 24.99 or overweight/obese if BMI was 25 or greater.

MAIN OUTCOME MEASURES: Total, cardiovascular, and noncardiovascular mortality.

RESULTS: The proportion of adults who were normal weight at the time of incident diabetes ranged from 9% to 21% (overall 12%). During follow-up, 449 participants died: 178 from cardiovascular causes and 253 from noncardiovascular causes (18 were not classified). The rates of total, cardiovascular, and noncardiovascular mortality were higher in normal-weight participants (284.8, 99.8, and 198.1 per 10,000 person-years, respectively) than in overweight/obese participants (152.1, 67.8, and 87.9 per 10,000 person-years, respectively). After adjustment for demographic characteristics and blood pressure, lipid levels, waist circumference, and smoking status, hazard ratios comparing normal-weight participants with overweight/obese participants for total, cardiovascular, and noncardiovascular mortality were 2.08 (95% CI, 1.52-2.85), 1.52 (95% CI, 0.89-2.58), and 2.32 (95% CI, 1.55-3.48), respectively.

CONCLUSION: Adults who were normal weight at the time of incident diabetes had higher mortality than adults who are overweight or obese.

%B JAMA %V 308 %P 581-90 %8 2012 Aug 08 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/22871870?dopt=Abstract %R 10.1001/jama.2012.9282 %0 Journal Article %J Circ Cardiovasc Genet %D 2012 %T Associations between incident ischemic stroke events and stroke and cardiovascular disease-related genome-wide association studies single nucleotide polymorphisms in the Population Architecture Using Genomics and Epidemiology study. %A Carty, Cara L %A Bůzková, Petra %A Fornage, Myriam %A Franceschini, Nora %A Cole, Shelley %A Heiss, Gerardo %A Hindorff, Lucia A %A Howard, Barbara V %A Mann, Sue %A Martin, Lisa W %A Zhang, Ying %A Matise, Tara C %A Prentice, Ross %A Reiner, Alexander P %A Kooperberg, Charles %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Cholesterol, HDL %K Cholesterol, LDL %K European Continental Ancestry Group %K Female %K Genetics, Population %K Genome-Wide Association Study %K Genomics %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Risk Factors %K Stroke %K Triglycerides %X

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

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

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

%B Circ Cardiovasc Genet %V 5 %P 210-6 %8 2012 Apr 01 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/22403240?dopt=Abstract %R 10.1161/CIRCGENETICS.111.962191 %0 Journal Article %J Lancet %D 2012 %T Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta-analysis. %A Fox, Caroline S %A Matsushita, Kunihiro %A Woodward, Mark %A Bilo, Henk J G %A Chalmers, John %A Heerspink, Hiddo J Lambers %A Lee, Brian J %A Perkins, Robert M %A Rossing, Peter %A Sairenchi, Toshimi %A Tonelli, Marcello %A Vassalotti, Joseph A %A Yamagishi, Kazumasa %A Coresh, Josef %A de Jong, Paul E %A Wen, Chi-Pang %A Nelson, Robert G %K Aged %K Albuminuria %K Cardiovascular Diseases %K Cause of Death %K Diabetic Nephropathies %K Female %K Glomerular Filtration Rate %K Humans %K Kidney Failure, Chronic %K Male %K Middle Aged %K Risk Factors %X

BACKGROUND: Chronic kidney disease is characterised by low estimated glomerular filtration rate (eGFR) and high albuminuria, and is associated with adverse outcomes. Whether these risks are modified by diabetes is unknown.

METHODS: We did a meta-analysis of studies selected according to Chronic Kidney Disease Prognosis Consortium criteria. Data transfer and analyses were done between March, 2011, and June, 2012. We used Cox proportional hazards models to estimate the hazard ratios (HR) of mortality and end-stage renal disease (ESRD) associated with eGFR and albuminuria in individuals with and without diabetes.

FINDINGS: We analysed data for 1,024,977 participants (128,505 with diabetes) from 30 general population and high-risk cardiovascular cohorts and 13 chronic kidney disease cohorts. In the combined general population and high-risk cohorts with data for all-cause mortality, 75,306 deaths occurred during a mean follow-up of 8·5 years (SD 5·0). In the 23 studies with data for cardiovascular mortality, 21,237 deaths occurred from cardiovascular disease during a mean follow-up of 9·2 years (SD 4·9). In the general and high-risk cohorts, mortality risks were 1·2-1·9 times higher for participants with diabetes than for those without diabetes across the ranges of eGFR and albumin-to-creatinine ratio (ACR). With fixed eGFR and ACR reference points in the diabetes and no diabetes groups, HR of mortality outcomes according to lower eGFR and higher ACR were much the same in participants with and without diabetes (eg, for all-cause mortality at eGFR 45 mL/min per 1·73 m(2) [vs 95 mL/min per 1·73 m(2)], HR 1·35; 95% CI 1·18-1·55; vs 1·33; 1·19-1·48 and at ACR 30 mg/g [vs 5 mg/g], 1·50; 1·35-1·65 vs 1·52; 1·38-1·67). The overall interactions were not significant. We identified much the same findings for ESRD in the chronic kidney disease cohorts.

INTERPRETATION: Despite higher risks for mortality and ESRD in diabetes, the relative risks of these outcomes by eGFR and ACR are much the same irrespective of the presence or absence of diabetes, emphasising the importance of kidney disease as a predictor of clinical outcomes.

FUNDING: US National Kidney Foundation.

%B Lancet %V 380 %P 1662-73 %8 2012 Nov 10 %G eng %N 9854 %1 http://www.ncbi.nlm.nih.gov/pubmed/23013602?dopt=Abstract %R 10.1016/S0140-6736(12)61350-6 %0 Journal Article %J Stat Med %D 2012 %T Bootstrap-based inference on the difference in the means of two correlated functional processes. %A Crainiceanu, Ciprian M %A Staicu, Ana-Maria %A Ray, Shubankar %A Punjabi, Naresh %K Biostatistics %K Cohort Studies %K Confidence Intervals %K Humans %K Models, Statistical %K Sleep Apnea Syndromes %K Statistics, Nonparametric %X

We propose nonparametric inference methods on the mean difference between two correlated functional processes. We compare methods that (1) incorporate different levels of smoothing of the mean and covariance; (2) preserve the sampling design; and (3) use parametric and nonparametric estimation of the mean functions. We apply our method to estimating the mean difference between average normalized δ power of sleep electroencephalograms for 51 subjects with severe sleep apnea and 51 matched controls in the first 4  h after sleep onset. We obtain data from the Sleep Heart Health Study, the largest community cohort study of sleep. Although methods are applied to a single case study, they can be applied to a large number of studies that have correlated functional data.

%B Stat Med %V 31 %P 3223-40 %8 2012 Nov 20 %G eng %N 26 %1 http://www.ncbi.nlm.nih.gov/pubmed/22855258?dopt=Abstract %R 10.1002/sim.5439 %0 Journal Article %J Circ Heart Fail %D 2012 %T Cardiac microinjury measured by troponin T predicts collagen metabolism in adults aged >=65 years with heart failure. %A Kop, Willem J %A Gottdiener, John S %A deFilippi, Christopher R %A Barasch, Eddy %A Seliger, Stephen L %A Jenny, Nancy S %A Christenson, Robert H %K Age Factors %K Aged %K Aged, 80 and over %K Biomarkers %K Case-Control Studies %K Chi-Square Distribution %K Collagen %K Collagen Type I %K Female %K Fibrosis %K Heart Failure %K Humans %K Linear Models %K Longitudinal Studies %K Male %K Multivariate Analysis %K Myocardium %K Peptide Fragments %K Peptides %K Predictive Value of Tests %K Procollagen %K Prospective Studies %K Risk Assessment %K Risk Factors %K Time Factors %K Troponin T %K Up-Regulation %X

BACKGROUND: Repeated myocardial microinjuries lead to collagen deposition and fibrosis, thereby increasing the risk of clinical heart failure. Little is known about the longitudinal association between increases in myocardial injury and the biology of collagen synthesis and deposition.

METHODS AND RESULTS: Repeated measures of highly sensitive cardiac troponin T (cTnT) were obtained in participants of the Cardiovascular Health Study (N=353; mean age, 74±6 years; 52% women) at baseline and at 3 years follow-up. Biomarkers of collagen metabolism were obtained at follow-up and included carboxyterminal propeptide of procollagen type I, carboxyterminal telopeptide of type I collagen, and aminoterminal propeptide of procollagen III. Multivariable linear regression analyses were used to examine the association between baseline cTnT and changes in cTnT with collagen metabolism markers at follow-up adjusting for demographics, heart failure status, and cardiovascular risk factors. Results indicated that cTnT increases over 3-years were significantly associated with higher levels of carboxyterminal telopeptide of type I collagen (β=0.22, P<0.001) and aminoterminal propeptide of procollagen III (β=0.12, P=0.035) at follow-up when adjusting for demographic, clinical, and biochemical covariates including baseline cTnT. These associations were stronger in patients with heart failure than in control subjects. Conclusions- Increases in myocardial microinjury measured by changes in cTnT adversely affect markers of collagen metabolism. These findings are important to the biology of myocardial fibrosis and tissue repair. Serial evaluation of cTnT combined with collagen metabolism markers may further elucidate the pathophysiology of heart failure.

%B Circ Heart Fail %V 5 %P 406-13 %8 2012 Jul 01 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/22685114?dopt=Abstract %R 10.1161/CIRCHEARTFAILURE.111.965327 %0 Journal Article %J Lancet %D 2012 %T Carotid intima-media thickness progression to predict cardiovascular events in the general population (the PROG-IMT collaborative project): a meta-analysis of individual participant data. %A Lorenz, Matthias W %A Polak, Joseph F %A Kavousi, Maryam %A Mathiesen, Ellisiv B %A Völzke, Henry %A Tuomainen, Tomi-Pekka %A Sander, Dirk %A Plichart, Matthieu %A Catapano, Alberico L %A Robertson, Christine M %A Kiechl, Stefan %A Rundek, Tatjana %A Desvarieux, Moïse %A Lind, Lars %A Schmid, Caroline %A DasMahapatra, Pronabesh %A Gao, Lu %A Ziegelbauer, Kathrin %A Bots, Michiel L %A Thompson, Simon G %K Cardiovascular Diseases %K Carotid Intima-Media Thickness %K Disease Progression %K Follow-Up Studies %K Humans %K Myocardial Infarction %K Prognosis %K Risk Assessment %K Stroke %X

BACKGROUND: Carotid intima-media thickness (cIMT) is related to the risk of cardiovascular events in the general population. An association between changes in cIMT and cardiovascular risk is frequently assumed but has rarely been reported. Our aim was to test this association.

METHODS: We identified general population studies that assessed cIMT at least twice and followed up participants for myocardial infarction, stroke, or death. The study teams collaborated in an individual participant data meta-analysis. Excluding individuals with previous myocardial infarction or stroke, we assessed the association between cIMT progression and the risk of cardiovascular events (myocardial infarction, stroke, vascular death, or a combination of these) for each study with Cox regression. The log hazard ratios (HRs) per SD difference were pooled by random effects meta-analysis.

FINDINGS: Of 21 eligible studies, 16 with 36,984 participants were included. During a mean follow-up of 7·0 years, 1519 myocardial infarctions, 1339 strokes, and 2028 combined endpoints (myocardial infarction, stroke, vascular death) occurred. Yearly cIMT progression was derived from two ultrasound visits 2-7 years (median 4 years) apart. For mean common carotid artery intima-media thickness progression, the overall HR of the combined endpoint was 0·97 (95% CI 0·94-1·00) when adjusted for age, sex, and mean common carotid artery intima-media thickness, and 0·98 (0·95-1·01) when also adjusted for vascular risk factors. Although we detected no associations with cIMT progression in sensitivity analyses, the mean cIMT of the two ultrasound scans was positively and robustly associated with cardiovascular risk (HR for the combined endpoint 1·16, 95% CI 1·10-1·22, adjusted for age, sex, mean common carotid artery intima-media thickness progression, and vascular risk factors). In three studies including 3439 participants who had four ultrasound scans, cIMT progression did not correlate between occassions (reproducibility correlations between r=-0·06 and r=-0·02).

INTERPRETATION: The association between cIMT progression assessed from two ultrasound scans and cardiovascular risk in the general population remains unproven. No conclusion can be derived for the use of cIMT progression as a surrogate in clinical trials.

FUNDING: Deutsche Forschungsgemeinschaft.

%B Lancet %V 379 %P 2053-62 %8 2012 Jun 02 %G eng %N 9831 %1 http://www.ncbi.nlm.nih.gov/pubmed/22541275?dopt=Abstract %R 10.1016/S0140-6736(12)60441-3 %0 Journal Article %J Neuroimage Clin %D 2012 %T Common folate gene variant, MTHFR C677T, is associated with brain structure in two independent cohorts of people with mild cognitive impairment. %A Rajagopalan, Priya %A Jahanshad, Neda %A Stein, Jason L %A Hua, Xue %A Madsen, Sarah K %A Kohannim, Omid %A Hibar, Derrek P %A Toga, Arthur W %A Jack, Clifford R %A Saykin, Andrew J %A Green, Robert C %A Weiner, Michael W %A Bis, Joshua C %A Kuller, Lewis H %A Riverol, Mario %A Becker, James T %A Lopez, Oscar L %A Thompson, Paul M %X

A commonly carried C677T polymorphism in a folate-related gene, MTHFR, is associated with higher plasma homocysteine, a well-known mediator of neuronal damage and brain atrophy. As homocysteine promotes brain atrophy, we set out to discover whether people carrying the C677T MTHFR polymorphism which increases homocysteine, might also show systematic differences in brain structure. Using tensor-based morphometry, we tested this association in 359 elderly Caucasian subjects with mild cognitive impairment (MCI) (mean age: 75 ± 7.1 years) scanned with brain MRI and genotyped as part of Alzheimer's Disease Neuroimaging Initiative. We carried out a replication study in an independent, non-overlapping sample of 51 elderly Caucasian subjects with MCI (mean age: 76 ± 5.5 years), scanned with brain MRI and genotyped for MTHFR, as part of the Cardiovascular Health Study. At each voxel in the brain, we tested to see where regional volume differences were associated with carrying one or more MTHFR 'T' alleles. In ADNI subjects, carriers of the MTHFR risk allele had detectable brain volume deficits, in the white matter, of up to 2-8% per risk T allele locally at baseline and showed accelerated brain atrophy of 0.5-1.5% per T allele at 1 year follow-up, after adjusting for age and sex. We replicated these brain volume deficits of up to 5-12% per MTHFR T allele in the independent cohort of CHS subjects. As expected, the associations weakened after controlling for homocysteine levels, which the risk gene affects. The MTHFR risk variant may thus promote brain atrophy by elevating homocysteine levels. This study aims to investigate the spatially detailed effects of this MTHFR polymorphism on brain structure in 3D, pointing to a causal pathway that may promote homocysteine-mediated brain atrophy in elderly people with MCI.

%B Neuroimage Clin %V 1 %P 179-87 %8 2012 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/24179750?dopt=Abstract %R 10.1016/j.nicl.2012.09.012 %0 Journal Article %J JAMA %D 2012 %T Comparison of risk prediction using the CKD-EPI equation and the MDRD study equation for estimated glomerular filtration rate. %A Matsushita, Kunihiro %A Mahmoodi, Bakhtawar K %A Woodward, Mark %A Emberson, Jonathan R %A Jafar, Tazeen H %A Jee, Sun Ha %A Polkinghorne, Kevan R %A Shankar, Anoop %A Smith, David H %A Tonelli, Marcello %A Warnock, David G %A Wen, Chi-Pang %A Coresh, Josef %A Gansevoort, Ron T %A Hemmelgarn, Brenda R %A Levey, Andrew S %K African Continental Ancestry Group %K Aged %K Algorithms %K Asian Continental Ancestry Group %K Cardiovascular Diseases %K Cohort Studies %K Decision Support Techniques %K European Continental Ancestry Group %K Female %K Glomerular Filtration Rate %K Humans %K Kidney Failure, Chronic %K Male %K Middle Aged %K Models, Theoretical %K Risk Assessment %K Sex Factors %X

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

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

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

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

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

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

%B JAMA %V 307 %P 1941-51 %8 2012 May 09 %G eng %N 18 %1 http://www.ncbi.nlm.nih.gov/pubmed/22570462?dopt=Abstract %R 10.1001/jama.2012.3954 %0 Journal Article %J Diabetes %D 2012 %T Consistent directions of effect for established type 2 diabetes risk variants across populations: the population architecture using Genomics and Epidemiology (PAGE) Consortium. %A Haiman, Christopher A %A Fesinmeyer, Megan D %A Spencer, Kylee L %A Bůzková, Petra %A Voruganti, V Saroja %A Wan, Peggy %A Haessler, Jeff %A Franceschini, Nora %A Monroe, Kristine R %A Howard, Barbara V %A Jackson, Rebecca D %A Florez, Jose C %A Kolonel, Laurence N %A Buyske, Steven %A Goodloe, Robert J %A Liu, Simin %A Manson, JoAnn E %A Meigs, James B %A Waters, Kevin %A Mukamal, Kenneth J %A Pendergrass, Sarah A %A Shrader, Peter %A Wilkens, Lynne R %A Hindorff, Lucia A %A Ambite, Jose Luis %A North, Kari E %A Peters, Ulrike %A Crawford, Dana C %A Le Marchand, Loïc %A Pankow, James S %K Adult %K Aged %K Aged, 80 and over %K Alleles %K Diabetes Mellitus, Type 2 %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Male %K Metagenomics %K Middle Aged %K Population Groups %K Risk %K Risk Factors %X

Common genetic risk variants for type 2 diabetes (T2D) have primarily been identified in populations of European and Asian ancestry. We tested whether the direction of association with 20 T2D risk variants generalizes across six major racial/ethnic groups in the U.S. as part of the Population Architecture using Genomics and Epidemiology Consortium (16,235 diabetes case and 46,122 control subjects of European American, African American, Hispanic, East Asian, American Indian, and Native Hawaiian ancestry). The percentage of positive (odds ratio [OR] >1 for putative risk allele) associations ranged from 69% in American Indians to 100% in European Americans. Of the nine variants where we observed significant heterogeneity of effect by racial/ethnic group (P(heterogeneity) < 0.05), eight were positively associated with risk (OR >1) in at least five groups. The marked directional consistency of association observed for most genetic variants across populations implies a shared functional common variant in each region. Fine-mapping of all loci will be required to reveal markers of risk that are important within and across populations.

%B Diabetes %V 61 %P 1642-7 %8 2012 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/22474029?dopt=Abstract %R 10.2337/db11-1296 %0 Journal Article %J J Clin Endocrinol Metab %D 2012 %T Decline in circulating insulin-like growth factors and mortality in older adults: cardiovascular health study all-stars study. %A Kaplan, Robert C %A Bůzková, Petra %A Cappola, Anne R %A Strickler, Howard D %A McGinn, Aileen P %A Mercer, Laina D %A Arnold, Alice M %A Pollak, Michael N %A Newman, Anne B %K African Continental Ancestry Group %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K European Continental Ancestry Group %K Female %K Follow-Up Studies %K Humans %K Insulin-Like Growth Factor Binding Protein 1 %K Insulin-Like Growth Factor Binding Protein 3 %K Insulin-Like Growth Factor I %K Longitudinal Studies %K Male %K Mortality %K Predictive Value of Tests %K Risk Factors %X

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

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

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

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

%B J Clin Endocrinol Metab %V 97 %P 1970-6 %8 2012 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/22442270?dopt=Abstract %R 10.1210/jc.2011-2967 %0 Journal Article %J JACC Cardiovasc Imaging %D 2012 %T Echocardiography, natriuretic peptides, and risk for incident heart failure in older adults: the Cardiovascular Health Study. %A Kalogeropoulos, Andreas P %A Georgiopoulou, Vasiliki V %A deFilippi, Christopher R %A Gottdiener, John S %A Butler, Javed %K Aged %K Biomarkers %K Cardiomegaly %K Echocardiography %K Female %K Heart Failure %K Humans %K Male %K Natriuretic Peptide, Brain %K Peptide Fragments %K Risk %K Risk Assessment %K Ventricular Function, Left %X

OBJECTIVES: This study sought to examine the potential utility of echocardiography and N-terminal pro-B-type natriuretic peptide (NT-proBNP) for heart failure (HF) risk stratification in concert with a validated clinical HF risk score in older adults.

BACKGROUND: Without clinical guidance, echocardiography and natriuretic peptides have suboptimal test characteristics for population-wide HF risk stratification. However, the value of these tests has not been examined in concert with a clinical HF risk score.

METHODS: We evaluated the improvement in 5-year HF risk prediction offered by adding an echocardiographic score and/or NT-proBNP levels to the clinical Health Aging and Body Composition (ABC) HF risk score (base model) in 3,752 participants of the CHS (Cardiovascular Health Study) (age 72.6 ± 5.4 years; 40.8% men; 86.5% white). The echocardiographic score was derived as the weighted sum of independent echocardiographic predictors of HF. We assessed changes in Bayesian information criterion (BIC), C index, integrated discrimination improvement (IDI), and net reclassification improvement (NRI). We examined also the weighted NRI across baseline HF risk categories under multiple scenarios of event versus nonevent weighting.

RESULTS: Reduced left ventricular ejection fraction, abnormal E/A ratio, enlarged left atrium, and increased left ventricular mass were independent echocardiographic predictors of HF. Adding the echocardiographic score and NT-proBNP levels to the clinical model improved BIC (echocardiography: -43, NT-proBNP: -64.1, combined: -68.9; all p < 0.001) and C index (baseline: 0.746; echocardiography: +0.031, NT-proBNP: +0.027, combined: +0.043; all p < 0.01), and yielded robust IDI (echocardiography: 43.3%, NT-proBNP: 42.2%, combined: 61.7%; all p < 0.001), and NRI (based on Health ABC HF risk groups; echocardiography: 11.3%; NT-proBNP: 10.6%, combined: 16.3%; all p < 0.01). Participants at intermediate risk by the clinical model (5% to 20% 5-yr HF risk; 35.7% of the cohort) derived the most reclassification benefit. Echocardiography yielded modest reclassification when used sequentially after NT-proBNP.

CONCLUSIONS: In older adults, echocardiography and NT-proBNP offer significant HF risk reclassification over a clinical prediction model, especially for intermediate-risk individuals.

%B JACC Cardiovasc Imaging %V 5 %P 131-40 %8 2012 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/22340818?dopt=Abstract %R 10.1016/j.jcmg.2011.11.011 %0 Journal Article %J Eur Heart J %D 2012 %T Eight genetic loci associated with variation in lipoprotein-associated phospholipase A2 mass and activity and coronary heart disease: meta-analysis of genome-wide association studies from five community-based studies. %A Grallert, Harald %A Dupuis, Josée %A Bis, Joshua C %A Dehghan, Abbas %A Barbalic, Maja %A Baumert, Jens %A Lu, Chen %A Smith, Nicholas L %A Uitterlinden, André G %A Roberts, Robert %A Khuseyinova, Natalie %A Schnabel, Renate B %A Rice, Kenneth M %A Rivadeneira, Fernando %A Hoogeveen, Ron C %A Fontes, João Daniel %A Meisinger, Christa %A Keaney, John F %A Lemaitre, Rozenn %A Aulchenko, Yurii S %A Vasan, Ramachandran S %A Ellis, Stephen %A Hazen, Stanley L %A van Duijn, Cornelia M %A Nelson, Jeanenne J %A März, Winfried %A Schunkert, Heribert %A McPherson, Ruth M %A Stirnadel-Farrant, Heide A %A Psaty, Bruce M %A Gieger, Christian %A Siscovick, David %A Hofman, Albert %A Illig, Thomas %A Cushman, Mary %A Yamamoto, Jennifer F %A Rotter, Jerome I %A Larson, Martin G %A Stewart, Alexandre F R %A Boerwinkle, Eric %A Witteman, Jacqueline C M %A Tracy, Russell P %A Koenig, Wolfgang %A Benjamin, Emelia J %A Ballantyne, Christie M %K 1-Alkyl-2-acetylglycerophosphocholine Esterase %K Aged %K Coronary Artery Disease %K Coronary Disease %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Phospholipases A2 %K Polymorphism, Single Nucleotide %X

AIMS: Lipoprotein-associated phospholipase A2 (Lp-PLA2) generates proinflammatory and proatherogenic compounds in the arterial vascular wall and is a potential therapeutic target in coronary heart disease (CHD). We searched for genetic loci related to Lp-PLA2 mass or activity by a genome-wide association study as part of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.

METHODS AND RESULTS: In meta-analyses of findings from five population-based studies, comprising 13 664 subjects, variants at two loci (PLA2G7, CETP) were associated with Lp-PLA2 mass. The strongest signal was at rs1805017 in PLA2G7 [P = 2.4 × 10(-23), log Lp-PLA2 difference per allele (beta): 0.043]. Variants at six loci were associated with Lp-PLA2 activity (PLA2G7, APOC1, CELSR2, LDL, ZNF259, SCARB1), among which the strongest signals were at rs4420638, near the APOE-APOC1-APOC4-APOC2 cluster [P = 4.9 × 10(-30); log Lp-PLA2 difference per allele (beta): -0.054]. There were no significant gene-environment interactions between these eight polymorphisms associated with Lp-PLA2 mass or activity and age, sex, body mass index, or smoking status. Four of the polymorphisms (in APOC1, CELSR2, SCARB1, ZNF259), but not PLA2G7, were significantly associated with CHD in a second study.

CONCLUSION: Levels of Lp-PLA2 mass and activity were associated with PLA2G7, the gene coding for this protein. Lipoprotein-associated phospholipase A2 activity was also strongly associated with genetic variants related to low-density lipoprotein cholesterol levels.

%B Eur Heart J %V 33 %P 238-51 %8 2012 Jan %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/22003152?dopt=Abstract %R 10.1093/eurheartj/ehr372 %0 Journal Article %J PLoS One %D 2012 %T Evaluation of the metabochip genotyping array in African Americans and implications for fine mapping of GWAS-identified loci: the PAGE study. %A Buyske, Steven %A Wu, Ying %A Carty, Cara L %A Cheng, Iona %A Assimes, Themistocles L %A Dumitrescu, Logan %A Hindorff, Lucia A %A Mitchell, Sabrina %A Ambite, Jose Luis %A Boerwinkle, Eric %A Bůzková, Petra %A Carlson, Chris S %A Cochran, Barbara %A Duggan, David %A Eaton, Charles B %A Fesinmeyer, Megan D %A Franceschini, Nora %A Haessler, Jeffrey %A Jenny, Nancy %A Kang, Hyun Min %A Kooperberg, Charles %A Lin, Yi %A Le Marchand, Loïc %A Matise, Tara C %A Robinson, Jennifer G %A Rodriguez, Carlos %A Schumacher, Fredrick R %A Voight, Benjamin F %A Young, Alicia %A Manolio, Teri A %A Mohlke, Karen L %A Haiman, Christopher A %A Peters, Ulrike %A Crawford, Dana C %A North, Kari E %K African Americans %K Cardiovascular Diseases %K Cholesterol Ester Transfer Proteins %K Cholesterol, HDL %K Cholesterol, LDL %K Chromosomes, Human %K Cohort Studies %K Gene Frequency %K Genome-Wide Association Study %K Genotype %K Humans %K Metabolic Diseases %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %X

The Metabochip is a custom genotyping array designed for replication and fine mapping of metabolic, cardiovascular, and anthropometric trait loci and includes low frequency variation content identified from the 1000 Genomes Project. It has 196,725 SNPs concentrated in 257 genomic regions. We evaluated the Metabochip in 5,863 African Americans; 89% of all SNPs passed rigorous quality control with a call rate of 99.9%. Two examples illustrate the value of fine mapping with the Metabochip in African-ancestry populations. At CELSR2/PSRC1/SORT1, we found the strongest associated SNP for LDL-C to be rs12740374 (p = 3.5 × 10(-11)), a SNP indistinguishable from multiple SNPs in European ancestry samples due to high correlation. Its distinct signal supports functional studies elsewhere suggesting a causal role in LDL-C. At CETP we found rs17231520, with risk allele frequency 0.07 in African Americans, to be associated with HDL-C (p = 7.2 × 10(-36)). This variant is very rare in Europeans and not tagged in common GWAS arrays, but was identified as associated with HDL-C in African Americans in a single-gene study. Our results, one narrowing the risk interval and the other revealing an associated variant not found in Europeans, demonstrate the advantages of high-density genotyping of common and rare variation for fine mapping of trait loci in African American samples.

%B PLoS One %V 7 %P e35651 %8 2012 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/22539988?dopt=Abstract %R 10.1371/journal.pone.0035651 %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 Fine-mapping and initial characterization of QT interval loci in African Americans. %A Avery, Christy L %A Sethupathy, Praveen %A Buyske, Steven %A He, Qianchuan %A Lin, Dan-Yu %A Arking, Dan E %A Carty, Cara L %A Duggan, David %A Fesinmeyer, Megan D %A Hindorff, Lucia A %A Jeff, Janina M %A Klein, Liviu %A Patton, Kristen K %A Peters, Ulrike %A Shohet, Ralph V %A Sotoodehnia, Nona %A Young, Alicia M %A Kooperberg, Charles %A Haiman, Christopher A %A Mohlke, Karen L %A Whitsel, Eric A %A North, Kari E %K African Americans %K Aged %K Computational Biology %K Electrocardiography %K European Continental Ancestry Group %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Linkage Disequilibrium %K Male %K Metagenomics %K Middle Aged %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Quantitative Trait, Heritable %K Risk Factors %K Tachycardia %K United States %X

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

%B PLoS Genet %V 8 %P e1002870 %8 2012 %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/22912591?dopt=Abstract %R 10.1371/journal.pgen.1002870 %0 Journal Article %J Nature %D 2012 %T FTO genotype is associated with phenotypic variability of body mass index. %A Yang, Jian %A Loos, Ruth J F %A Powell, Joseph E %A Medland, Sarah E %A Speliotes, Elizabeth K %A Chasman, Daniel I %A Rose, Lynda M %A Thorleifsson, Gudmar %A Steinthorsdottir, Valgerdur %A Mägi, Reedik %A Waite, Lindsay %A Smith, Albert Vernon %A Yerges-Armstrong, Laura M %A Monda, Keri L %A Hadley, David %A Mahajan, Anubha %A Li, Guo %A Kapur, Karen %A Vitart, Veronique %A Huffman, Jennifer E %A Wang, Sophie R %A Palmer, Cameron %A Esko, Tõnu %A Fischer, Krista %A Zhao, Jing Hua %A Demirkan, Ayse %A Isaacs, Aaron %A Feitosa, Mary F %A Luan, Jian'an %A Heard-Costa, Nancy L %A White, Charles %A Jackson, Anne U %A Preuss, Michael %A Ziegler, Andreas %A Eriksson, Joel %A Kutalik, Zoltán %A Frau, Francesca %A Nolte, Ilja M %A van Vliet-Ostaptchouk, Jana V %A Hottenga, Jouke-Jan %A Jacobs, Kevin B %A Verweij, Niek %A Goel, Anuj %A Medina-Gómez, Carolina %A Estrada, Karol %A Bragg-Gresham, Jennifer Lynn %A Sanna, Serena %A Sidore, Carlo %A Tyrer, Jonathan %A Teumer, Alexander %A Prokopenko, Inga %A Mangino, Massimo %A Lindgren, Cecilia M %A Assimes, Themistocles L %A Shuldiner, Alan R %A Hui, Jennie %A Beilby, John P %A McArdle, Wendy L %A Hall, Per %A Haritunians, Talin %A Zgaga, Lina %A Kolcic, Ivana %A Polasek, Ozren %A Zemunik, Tatijana %A Oostra, Ben A %A Junttila, M Juhani %A Grönberg, Henrik %A Schreiber, Stefan %A Peters, Annette %A Hicks, Andrew A %A Stephens, Jonathan %A Foad, Nicola S %A Laitinen, Jaana %A Pouta, Anneli %A Kaakinen, Marika %A Willemsen, Gonneke %A Vink, Jacqueline M %A Wild, Sarah H %A Navis, Gerjan %A Asselbergs, Folkert W %A Homuth, Georg %A John, Ulrich %A Iribarren, Carlos %A Harris, Tamara %A Launer, Lenore %A Gudnason, Vilmundur %A O'Connell, Jeffrey R %A Boerwinkle, Eric %A Cadby, Gemma %A Palmer, Lyle J %A James, Alan L %A Musk, Arthur W %A Ingelsson, Erik %A Psaty, Bruce M %A Beckmann, Jacques S %A Waeber, Gérard %A Vollenweider, Peter %A Hayward, Caroline %A Wright, Alan F %A Rudan, Igor %A Groop, Leif C %A Metspalu, Andres %A Khaw, Kay Tee %A van Duijn, Cornelia M %A Borecki, Ingrid B %A Province, Michael A %A Wareham, Nicholas J %A Tardif, Jean-Claude %A Huikuri, Heikki V %A Cupples, L Adrienne %A Atwood, Larry D %A Fox, Caroline S %A Boehnke, Michael %A Collins, Francis S %A Mohlke, Karen L %A Erdmann, Jeanette %A Schunkert, Heribert %A Hengstenberg, Christian %A Stark, Klaus %A Lorentzon, Mattias %A Ohlsson, Claes %A Cusi, Daniele %A Staessen, Jan A %A van der Klauw, Melanie M %A Pramstaller, Peter P %A Kathiresan, Sekar %A Jolley, Jennifer D %A Ripatti, Samuli %A Jarvelin, Marjo-Riitta %A de Geus, Eco J C %A Boomsma, Dorret I %A Penninx, Brenda %A Wilson, James F %A Campbell, Harry %A Chanock, Stephen J %A van der Harst, Pim %A Hamsten, Anders %A Watkins, Hugh %A Hofman, Albert %A Witteman, Jacqueline C %A Zillikens, M Carola %A Uitterlinden, André G %A Rivadeneira, Fernando %A Zillikens, M Carola %A Kiemeney, Lambertus A %A Vermeulen, Sita H %A Abecasis, Goncalo R %A Schlessinger, David %A Schipf, Sabine %A Stumvoll, Michael %A Tönjes, Anke %A Spector, Tim D %A North, Kari E %A Lettre, Guillaume %A McCarthy, Mark I %A Berndt, Sonja I %A Heath, Andrew C %A Madden, Pamela A F %A Nyholt, Dale R %A Montgomery, Grant W %A Martin, Nicholas G %A McKnight, Barbara %A Strachan, David P %A Hill, William G %A Snieder, Harold %A Ridker, Paul M %A Thorsteinsdottir, Unnur %A Stefansson, Kari %A Frayling, Timothy M %A Hirschhorn, Joel N %A Goddard, Michael E %A Visscher, Peter M %K Alpha-Ketoglutarate-Dependent Dioxygenase FTO %K Body Height %K Body Mass Index %K Co-Repressor Proteins %K Female %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Male %K Nerve Tissue Proteins %K Phenotype %K Polymorphism, Single Nucleotide %K Proteins %K Repressor Proteins %X

There is evidence across several species for genetic control of phenotypic variation of complex traits, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using ∼170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of ∼0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI, possibly mediated by DNA methylation. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.

%B Nature %V 490 %P 267-72 %8 2012 Oct 11 %G eng %N 7419 %1 http://www.ncbi.nlm.nih.gov/pubmed/22982992?dopt=Abstract %R 10.1038/nature11401 %0 Journal Article %J Atherosclerosis %D 2012 %T Genetic determinants of the ankle-brachial index: a meta-analysis of a cardiovascular candidate gene 50K SNP panel in the candidate gene association resource (CARe) consortium. %A Wassel, Christina L %A Lamina, Claudia %A Nambi, Vijay %A Coassin, Stefan %A Mukamal, Kenneth J %A Ganesh, Santhi K %A Jacobs, David R %A Franceschini, Nora %A Papanicolaou, George J %A Gibson, Quince %A Yanek, Lisa R %A van der Harst, Pim %A Ferguson, Jane F %A Crawford, Dana C %A Waite, Lindsay L %A Allison, Matthew A %A Criqui, Michael H %A McDermott, Mary M %A Mehra, Reena %A Cupples, L Adrienne %A Hwang, Shih-Jen %A Redline, Susan %A Kaplan, Robert C %A Heiss, Gerardo %A Rotter, Jerome I %A Boerwinkle, Eric %A Taylor, Herman A %A Eraso, Luis H %A Haun, Margot %A Li, Mingyao %A Meisinger, Christa %A O'Connell, Jeffrey R %A Shuldiner, Alan R %A Tybjærg-Hansen, Anne %A Frikke-Schmidt, Ruth %A Kollerits, Barbara %A Rantner, Barbara %A Dieplinger, Benjamin %A Stadler, Marietta %A Mueller, Thomas %A Haltmayer, Meinhard %A Klein-Weigel, Peter %A Summerer, Monika %A Wichmann, H-Erich %A Asselbergs, Folkert W %A Navis, Gerjan %A Mateo Leach, Irene %A Brown-Gentry, Kristin %A Goodloe, Robert %A Assimes, Themistocles L %A Becker, Diane M %A Cooke, John P %A Absher, Devin M %A Olin, Jeffrey W %A Mitchell, Braxton D %A Reilly, Muredach P %A Mohler, Emile R %A North, Kari E %A Reiner, Alexander P %A Kronenberg, Florian %A Murabito, Joanne M %K Adult %K African Americans %K Aged %K Ankle Brachial Index %K Aryl Hydrocarbon Hydroxylases %K Cytochrome P-450 CYP2B6 %K European Continental Ancestry Group %K Female %K Humans %K Male %K Middle Aged %K Oxidoreductases, N-Demethylating %K Peripheral Arterial Disease %K Polymorphism, Single Nucleotide %K Risk Factors %K Transcription Factor 7-Like 2 Protein %X

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

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

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

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

%B Atherosclerosis %V 222 %P 138-47 %8 2012 May %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/22361517?dopt=Abstract %R 10.1016/j.atherosclerosis.2012.01.039 %0 Journal Article %J Lancet Neurol %D 2012 %T Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): a meta-analysis of genome-wide association studies. %A Traylor, Matthew %A Farrall, Martin %A Holliday, Elizabeth G %A Sudlow, Cathie %A Hopewell, Jemma C %A Cheng, Yu-Ching %A Fornage, Myriam %A Ikram, M Arfan %A Malik, Rainer %A Bevan, Steve %A Thorsteinsdottir, Unnur %A Nalls, Mike A %A Longstreth, Wt %A Wiggins, Kerri L %A Yadav, Sunaina %A Parati, Eugenio A %A DeStefano, Anita L %A Worrall, Bradford B %A Kittner, Steven J %A Khan, Muhammad Saleem %A Reiner, Alex P %A Helgadottir, Anna %A Achterberg, Sefanja %A Fernandez-Cadenas, Israel %A Abboud, Sherine %A Schmidt, Reinhold %A Walters, Matthew %A Chen, Wei-Min %A Ringelstein, E Bernd %A O'Donnell, Martin %A Ho, Weang Kee %A Pera, Joanna %A Lemmens, Robin %A Norrving, Bo %A Higgins, Peter %A Benn, Marianne %A Sale, Michele %A Kuhlenbäumer, Gregor %A Doney, Alexander S F %A Vicente, Astrid M %A Delavaran, Hossein %A Algra, Ale %A Davies, Gail %A Oliveira, Sofia A %A Palmer, Colin N A %A Deary, Ian %A Schmidt, Helena %A Pandolfo, Massimo %A Montaner, Joan %A Carty, Cara %A de Bakker, Paul I W %A Kostulas, Konstantinos %A Ferro, Jose M %A van Zuydam, Natalie R %A Valdimarsson, Einar %A Nordestgaard, Børge G %A Lindgren, Arne %A Thijs, Vincent %A Slowik, Agnieszka %A Saleheen, Danish %A Paré, Guillaume %A Berger, Klaus %A Thorleifsson, Gudmar %A Hofman, Albert %A Mosley, Thomas H %A Mitchell, Braxton D %A Furie, Karen %A Clarke, Robert %A Levi, Christopher %A Seshadri, Sudha %A Gschwendtner, Andreas %A Boncoraglio, Giorgio B %A Sharma, Pankaj %A Bis, Joshua C %A Gretarsdottir, Solveig %A Psaty, Bruce M %A Rothwell, Peter M %A Rosand, Jonathan %A Meschia, James F %A Stefansson, Kari %A Dichgans, Martin %A Markus, Hugh S %K Brain Ischemia %K Databases, Genetic %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Risk Factors %K Stroke %X

BACKGROUND: Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes.

METHODS: We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nucleotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls.

FINDINGS: We verified previous associations for cardioembolic stroke near PITX2 (p=2·8×10(-16)) and ZFHX3 (p=2·28×10(-8)), and for large-vessel stroke at a 9p21 locus (p=3·32×10(-5)) and HDAC9 (p=2·03×10(-12)). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance (PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We also identified 12 potentially novel loci at p<5×10(-6). However, we were unable to replicate any of these novel associations in the replication cohort.

INTERPRETATION: Our results show that, although genetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations we were able to confirm are specific to a stroke subtype. This finding has two implications. First, to maximise success of genetic studies in ischaemic stroke, detailed stroke subtyping is required. Second, different genetic pathophysiological mechanisms seem to be associated with different stroke subtypes.

FUNDING: Wellcome Trust, UK Medical Research Council (MRC), Australian National and Medical Health Research Council, National Institutes of Health (NIH) including National Heart, Lung and Blood Institute (NHLBI), the National Institute on Aging (NIA), the National Human Genome Research Institute (NHGRI), and the National Institute of Neurological Disorders and Stroke (NINDS).

%B Lancet Neurol %V 11 %P 951-62 %8 2012 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/23041239?dopt=Abstract %R 10.1016/S1474-4422(12)70234-X %0 Journal Article %J JAMA %D 2012 %T Genetic variants and associations of 25-hydroxyvitamin D concentrations with major clinical outcomes. %A Levin, Gregory P %A Robinson-Cohen, Cassianne %A de Boer, Ian H %A Houston, Denise K %A Lohman, Kurt %A Liu, Yongmei %A Kritchevsky, Stephen B %A Cauley, Jane A %A Tanaka, Toshiko %A Ferrucci, Luigi %A Bandinelli, Stefania %A Patel, Kushang V %A Hagström, Emil %A Michaëlsson, Karl %A Melhus, Håkan %A Wang, Thomas %A Wolf, Myles %A Psaty, Bruce M %A Siscovick, David %A Kestenbaum, Bryan %K 25-Hydroxyvitamin D3 1-alpha-Hydroxylase %K Aged %K Chronic Disease %K Cohort Studies %K Female %K Genetic Variation %K Genotype %K Hip Fractures %K Humans %K Low Density Lipoprotein Receptor-Related Protein-2 %K Male %K Meta-Analysis as Topic %K Myocardial Infarction %K Neoplasms %K Polymorphism, Single Nucleotide %K Receptors, Calcitriol %K Receptors, Cell Surface %K Risk %K Steroid Hydroxylases %K Vitamin D %K Vitamin D3 24-Hydroxylase %X

CONTEXT: Lower serum 25-hydroxyvitamin D concentrations are associated with greater risks of many chronic diseases across large, prospective community-based studies. Substrate 25-hydroxyvitamin D must be converted to 1,25-dihydroxyvitamin D for full biological activity, and complex metabolic pathways suggest that interindividual variability in vitamin D metabolism may alter the clinical consequences of measured serum 25-hydroxyvitamin D.

OBJECTIVE: To investigate whether common variation within genes encoding the vitamin D-binding protein, megalin, cubilin, CYP27B1, CYP24A1, and the vitamin D receptor (VDR) modify associations of low 25-hydroxyvitamin D with major clinical outcomes.

DESIGN, SETTING, AND PARTICIPANTS: Examination of 141 single-nucleotide polymorphisms in a discovery cohort of 1514 white participants (who were recruited from 4 US regions) from the community-based Cardiovascular Health Study. Participants had serum 25-hydroxyvitamin D measurements in 1992-1993 and were followed up for a median of 11 years (through 2006). Replication meta-analyses were conducted across the independent, community-based US Health, Aging, and Body Composition (n = 922; follow-up: 1998-1999 through 2005), Italian Invecchiare in Chianti (n = 835; follow-up: 1998-2000 through 2006), and Swedish Uppsala Longitudinal Study of Adult Men (n = 970; follow-up: 1991-1995 through 2008) cohort studies.

MAIN OUTCOME MEASURE: Composite outcome of incident hip facture, myocardial infarction, cancer, and mortality over long-term follow-up.

RESULTS: Interactions between 5 single-nucleotide polymorphisms and low 25-hydroxyvitamin D concentration were identified in the discovery phase and 1 involving a variant in the VDR gene replicated in independent meta-analysis. Among Cardiovascular Health Study participants, low 25-hydroxyvitamin D concentration was associated with hazard ratios for risk of the composite outcome of 1.40 (95% CI, 1.12-1.74) for those who had 1 minor allele at rs7968585 and 1.82 (95% CI, 1.31-2.54) for those with 2 minor alleles at rs7968585. In contrast, there was no evidence of an association (estimated hazard ratio, 0.93 [95% CI, 0.70-1.24]) among participants who had 0 minor alleles at this single-nucleotide polymorphism.

CONCLUSION: Known associations of low 25-hydroxyvitamin D with major health outcomes may vary according to common genetic differences in the vitamin D receptor.

%B JAMA %V 308 %P 1898-905 %8 2012 Nov 14 %G eng %N 18 %1 http://www.ncbi.nlm.nih.gov/pubmed/23150009?dopt=Abstract %R 10.1001/jama.2012.17304 %0 Journal Article %J J Thromb Haemost %D 2012 %T Genetic variation in F3 (tissue factor) and the risk of incident venous thrombosis: meta-analysis of eight studies. %A Smith, N L %A Heit, J A %A Tang, W %A Teichert, M %A Chasman, D I %A Morange, P-E %K Female %K Gene Frequency %K Genetic Predisposition to Disease %K Genetic Variation %K Humans %K Incidence %K Male %K Middle Aged %K Phenotype %K Regression Analysis %K Risk Assessment %K Risk Factors %K Thromboplastin %K Venous Thrombosis %B J Thromb Haemost %V 10 %P 719-22 %8 2012 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/22340074?dopt=Abstract %R 10.1111/j.1538-7836.2012.04665.x %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 Am J Respir Crit Care Med %D 2012 %T Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction. %A Wilk, Jemma B %A Shrine, Nick R G %A Loehr, Laura R %A Zhao, Jing Hua %A Manichaikul, Ani %A Lopez, Lorna M %A Smith, Albert Vernon %A Heckbert, Susan R %A Smolonska, Joanna %A Tang, Wenbo %A Loth, Daan W %A Curjuric, Ivan %A Hui, Jennie %A Cho, Michael H %A Latourelle, Jeanne C %A Henry, Amanda P %A Aldrich, Melinda %A Bakke, Per %A Beaty, Terri H %A Bentley, Amy R %A Borecki, Ingrid B %A Brusselle, Guy G %A Burkart, Kristin M %A Chen, Ting-Hsu %A Couper, David %A Crapo, James D %A Davies, Gail %A Dupuis, Josée %A Franceschini, Nora %A Gulsvik, Amund %A Hancock, Dana B %A Harris, Tamara B %A Hofman, Albert %A Imboden, Medea %A James, Alan L %A Khaw, Kay-Tee %A Lahousse, Lies %A Launer, Lenore J %A Litonjua, Augusto %A Liu, Yongmei %A Lohman, Kurt K %A Lomas, David A %A Lumley, Thomas %A Marciante, Kristin D %A McArdle, Wendy L %A Meibohm, Bernd %A Morrison, Alanna C %A Musk, Arthur W %A Myers, Richard H %A North, Kari E %A Postma, Dirkje S %A Psaty, Bruce M %A Rich, Stephen S %A Rivadeneira, Fernando %A Rochat, Thierry %A Rotter, Jerome I %A Soler Artigas, Maria %A Starr, John M %A Uitterlinden, André G %A Wareham, Nicholas J %A Wijmenga, Cisca %A Zanen, Pieter %A Province, Michael A %A Silverman, Edwin K %A Deary, Ian J %A Palmer, Lyle J %A Cassano, Patricia A %A Gudnason, Vilmundur %A Barr, R Graham %A Loos, Ruth J F %A Strachan, David P %A London, Stephanie J %A Boezen, H Marike %A Probst-Hensch, Nicole %A Gharib, Sina A %A Hall, Ian P %A O'Connor, George T %A Tobin, Martin D %A Stricker, Bruno H %K Aged %K Female %K Forced Expiratory Volume %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Nerve Tissue Proteins %K Polymorphism, Single Nucleotide %K Pulmonary Disease, Chronic Obstructive %K Receptors, Nicotinic %K Receptors, Serotonin, 5-HT4 %K Smoking %K Vital Capacity %X

RATIONALE: Genome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known.

OBJECTIVES: Perform meta-analyses of GWAS for airflow obstruction, a key pathophysiologic characteristic of COPD assessed by spirometry, in population-based cohorts examining all participants, ever smokers, never smokers, asthma-free participants, and more severe cases.

METHODS: Fifteen cohorts were studied for discovery (3,368 affected; 29,507 unaffected), and a population-based family study and a meta-analysis of case-control studies were used for replication and regional follow-up (3,837 cases; 4,479 control subjects). Airflow obstruction was defined as FEV(1) and its ratio to FVC (FEV(1)/FVC) both less than their respective lower limits of normal as determined by published reference equations.

MEASUREMENTS AND MAIN RESULTS: The discovery meta-analyses identified one region on chromosome 15q25.1 meeting genome-wide significance in ever smokers that includes AGPHD1, IREB2, and CHRNA5/CHRNA3 genes. The region was also modestly associated among never smokers. Gene expression studies confirmed the presence of CHRNA5/3 in lung, airway smooth muscle, and bronchial epithelial cells. A single-nucleotide polymorphism in HTR4, a gene previously related to FEV(1)/FVC, achieved genome-wide statistical significance in combined meta-analysis. Top single-nucleotide polymorphisms in ADAM19, RARB, PPAP2B, and ADAMTS19 were nominally replicated in the COPD meta-analysis.

CONCLUSIONS: These results suggest an important role for the CHRNA5/3 region as a genetic risk factor for airflow obstruction that may be independent of smoking and implicate the HTR4 gene in the etiology of airflow obstruction.

%B Am J Respir Crit Care Med %V 186 %P 622-32 %8 2012 Oct 01 %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/22837378?dopt=Abstract %R 10.1164/rccm.201202-0366OC %0 Journal Article %J Blood %D 2012 %T Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation. %A Huang, Jie %A Sabater-Lleal, Maria %A Asselbergs, Folkert W %A Tregouet, David %A Shin, So-Youn %A Ding, Jingzhong %A Baumert, Jens %A Oudot-Mellakh, Tiphaine %A Folkersen, Lasse %A Johnson, Andrew D %A Smith, Nicholas L %A Williams, Scott M %A Ikram, Mohammad A %A Kleber, Marcus E %A Becker, Diane M %A Truong, Vinh %A Mychaleckyj, Josyf C %A Tang, Weihong %A Yang, Qiong %A Sennblad, Bengt %A Moore, Jason H %A Williams, Frances M K %A Dehghan, Abbas %A Silbernagel, Günther %A Schrijvers, Elisabeth M C %A Smith, Shelly %A Karakas, Mahir %A Tofler, Geoffrey H %A Silveira, Angela %A Navis, Gerjan J %A Lohman, Kurt %A Chen, Ming-Huei %A Peters, Annette %A Goel, Anuj %A Hopewell, Jemma C %A Chambers, John C %A Saleheen, Danish %A Lundmark, Per %A Psaty, Bruce M %A Strawbridge, Rona J %A Boehm, Bernhard O %A Carter, Angela M %A Meisinger, Christa %A Peden, John F %A Bis, Joshua C %A McKnight, Barbara %A Ohrvik, John %A Taylor, Kent %A Franzosi, Maria Grazia %A Seedorf, Udo %A Collins, Rory %A Franco-Cereceda, Anders %A Syvänen, Ann-Christine %A Goodall, Alison H %A Yanek, Lisa R %A Cushman, Mary %A Müller-Nurasyid, Martina %A Folsom, Aaron R %A Basu, Saonli %A Matijevic, Nena %A van Gilst, Wiek H %A Kooner, Jaspal S %A Hofman, Albert %A Danesh, John %A Clarke, Robert %A Meigs, James B %A Kathiresan, Sekar %A Reilly, Muredach P %A Klopp, Norman %A Harris, Tamara B %A Winkelmann, Bernhard R %A Grant, Peter J %A Hillege, Hans L %A Watkins, Hugh %A Spector, Timothy D %A Becker, Lewis C %A Tracy, Russell P %A März, Winfried %A Uitterlinden, André G %A Eriksson, Per %A Cambien, Francois %A Morange, Pierre-Emmanuel %A Koenig, Wolfgang %A Soranzo, Nicole %A van der Harst, Pim %A Liu, Yongmei %A O'Donnell, Christopher J %A Hamsten, Anders %K Adaptor Proteins, Signal Transducing %K ARNTL Transcription Factors %K ATPases Associated with Diverse Cellular Activities %K Cell Line %K Cell Line, Tumor %K Cohort Studies %K Coronary Artery Disease %K Diabetes Mellitus, Type 2 %K Gene Expression Profiling %K Gene Expression Regulation %K Gene Frequency %K Genome-Wide Association Study %K Genotype %K Humans %K LIM Domain Proteins %K Meta-Analysis as Topic %K Monocytes %K Mucin-3 %K Plasminogen Activator Inhibitor 1 %K Polymorphism, Single Nucleotide %K PPAR gamma %K Proteasome Endopeptidase Complex %K RNA Interference %K Transcription Factors %X

We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery meta-analysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P < 5 × 10(-8)) single nucleotide polymorphisms (SNPs) in 10 796 independent samples. We further examined associations with type 2 diabetes and coronary artery disease, assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA-silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1 (7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1 (rs6976053, discovery P = 3.4 × 10(-10)); chromosome 11p15.2 within ARNTL (rs6486122, discovery P = 3.0 × 10(-8)); and chromosome 3p25.2 within PPARG (rs11128603, discovery P = 2.9 × 10(-8)). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with type 2 diabetes and coronary artery disease at ARNTL (P < .05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL and an SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1.

%B Blood %V 120 %P 4873-81 %8 2012 Dec 06 %G eng %N 24 %1 http://www.ncbi.nlm.nih.gov/pubmed/22990020?dopt=Abstract %R 10.1182/blood-2012-06-436188 %0 Journal Article %J PLoS Genet %D 2012 %T Genome-wide joint meta-analysis of SNP and SNP-by-smoking interaction identifies novel loci for pulmonary function. %A Hancock, Dana B %A Soler Artigas, Maria %A Gharib, Sina A %A Henry, Amanda %A Manichaikul, Ani %A Ramasamy, Adaikalavan %A Loth, Daan W %A Imboden, Medea %A Koch, Beate %A McArdle, Wendy L %A Smith, Albert V %A Smolonska, Joanna %A Sood, Akshay %A Tang, Wenbo %A Wilk, Jemma B %A Zhai, Guangju %A Zhao, Jing Hua %A Aschard, Hugues %A Burkart, Kristin M %A Curjuric, Ivan %A Eijgelsheim, Mark %A Elliott, Paul %A Gu, Xiangjun %A Harris, Tamara B %A Janson, Christer %A Homuth, Georg %A Hysi, Pirro G %A Liu, Jason Z %A Loehr, Laura R %A Lohman, Kurt %A Loos, Ruth J F %A Manning, Alisa K %A Marciante, Kristin D %A Obeidat, Ma'en %A Postma, Dirkje S %A Aldrich, Melinda C %A Brusselle, Guy G %A Chen, Ting-Hsu %A Eiriksdottir, Gudny %A Franceschini, Nora %A Heinrich, Joachim %A Rotter, Jerome I %A Wijmenga, Cisca %A Williams, O Dale %A Bentley, Amy R %A Hofman, Albert %A Laurie, Cathy C %A Lumley, Thomas %A Morrison, Alanna C %A Joubert, Bonnie R %A Rivadeneira, Fernando %A Couper, David J %A Kritchevsky, Stephen B %A Liu, Yongmei %A Wjst, Matthias %A Wain, Louise V %A Vonk, Judith M %A Uitterlinden, André G %A Rochat, Thierry %A Rich, Stephen S %A Psaty, Bruce M %A O'Connor, George T %A North, Kari E %A Mirel, Daniel B %A Meibohm, Bernd %A Launer, Lenore J %A Khaw, Kay-Tee %A Hartikainen, Anna-Liisa %A Hammond, Christopher J %A Gläser, Sven %A Marchini, Jonathan %A Kraft, Peter %A Wareham, Nicholas J %A Völzke, Henry %A Stricker, Bruno H C %A Spector, Timothy D %A Probst-Hensch, Nicole M %A Jarvis, Deborah %A Jarvelin, Marjo-Riitta %A Heckbert, Susan R %A Gudnason, Vilmundur %A Boezen, H Marike %A Barr, R Graham %A Cassano, Patricia A %A Strachan, David P %A Fornage, Myriam %A Hall, Ian P %A Dupuis, Josée %A Tobin, Martin D %A London, Stephanie J %K Forced Expiratory Volume %K Gene Expression %K Genome, Human %K Genome-Wide Association Study %K HLA-DQ Antigens %K HLA-DQ beta-Chains %K Humans %K Lung %K Nerve Tissue Proteins %K Polymorphism, Single Nucleotide %K Potassium Channels, Inwardly Rectifying %K Pulmonary Disease, Chronic Obstructive %K Receptors, Cell Surface %K Smoking %K SOX9 Transcription Factor %K Vital Capacity %X

Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV(1)), and its ratio to forced vital capacity (FEV(1)/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV(1) and FEV(1)/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest P(JMA = )5.00×10(-11)), HLA-DQB1 and HLA-DQA2 (smallest P(JMA = )4.35×10(-9)), and KCNJ2 and SOX9 (smallest P(JMA = )1.28×10(-8)) were associated with FEV(1)/FVC or FEV(1) in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.

%B PLoS Genet %V 8 %P e1003098 %8 2012 %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/23284291?dopt=Abstract %R 10.1371/journal.pgen.1003098 %0 Journal Article %J Transl Psychiatry %D 2012 %T Genome-wide meta-analyses of smoking behaviors in African Americans. %A David, S P %A Hamidovic, A %A Chen, G K %A Bergen, A W %A Wessel, J %A Kasberger, J L %A Brown, W M %A Petruzella, S %A Thacker, E L %A Kim, Y %A Nalls, M A %A Tranah, G J %A Sung, Y J %A Ambrosone, C B %A Arnett, D %A Bandera, E V %A Becker, D M %A Becker, L %A Berndt, S I %A Bernstein, L %A Blot, W J %A Broeckel, U %A Buxbaum, S G %A Caporaso, N %A Casey, G %A Chanock, S J %A Deming, S L %A Diver, W R %A Eaton, C B %A Evans, D S %A Evans, M K %A Fornage, M %A Franceschini, N %A Harris, T B %A Henderson, B E %A Hernandez, D G %A Hitsman, B %A Hu, J J %A Hunt, S C %A Ingles, S A %A John, E M %A Kittles, R %A Kolb, S %A Kolonel, L N %A Le Marchand, L %A Liu, Y %A Lohman, K K %A McKnight, B %A Millikan, R C %A Murphy, A %A Neslund-Dudas, C %A Nyante, S %A Press, M %A Psaty, B M %A Rao, D C %A Redline, S %A Rodriguez-Gil, J L %A Rybicki, B A %A Signorello, L B %A Singleton, A B %A Smoller, J %A Snively, B %A Spring, B %A Stanford, J L %A Strom, S S %A Swan, G E %A Taylor, K D %A Thun, M J %A Wilson, A F %A Witte, J S %A Yamamura, Y %A Yanek, L R %A Yu, K %A Zheng, W %A Ziegler, R G %A Zonderman, A B %A Jorgenson, E %A Haiman, C A %A Furberg, H %K Adult %K African Americans %K Aged %K Chromosomes, Human, Pair 10 %K Chromosomes, Human, Pair 15 %K Female %K Genetic Loci %K Genetic Predisposition to Disease %K Genetic Variation %K Genome-Wide Association Study %K Genotype %K Humans %K Male %K Middle Aged %K Nerve Tissue Proteins %K Phenotype %K Polymorphism, Single Nucleotide %K Proteoglycans %K Receptors, Nicotinic %K Smoking %K Statistics as Topic %X

The identification and exploration of genetic loci that influence smoking behaviors have been conducted primarily in populations of the European ancestry. Here we report results of the first genome-wide association study meta-analysis of smoking behavior in African Americans in the Study of Tobacco in Minority Populations Genetics Consortium (n = 32,389). We identified one non-coding single-nucleotide polymorphism (SNP; rs2036527[A]) on chromosome 15q25.1 associated with smoking quantity (cigarettes per day), which exceeded genome-wide significance (β = 0.040, s.e. = 0.007, P = 1.84 × 10(-8)). This variant is present in the 5'-distal enhancer region of the CHRNA5 gene and defines the primary index signal reported in studies of the European ancestry. No other SNP reached genome-wide significance for smoking initiation (SI, ever vs never smoking), age of SI, or smoking cessation (SC, former vs current smoking). Informative associations that approached genome-wide significance included three modestly correlated variants, at 15q25.1 within PSMA4, CHRNA5 and CHRNA3 for smoking quantity, which are associated with a second signal previously reported in studies in European ancestry populations, and a signal represented by three SNPs in the SPOCK2 gene on chr10q22.1. The association at 15q25.1 confirms this region as an important susceptibility locus for smoking quantity in men and women of African ancestry. Larger studies will be needed to validate the suggestive loci that did not reach genome-wide significance and further elucidate the contribution of genetic variation to disparities in cigarette consumption, SC and smoking-attributable disease between African Americans and European Americans.

%B Transl Psychiatry %V 2 %P e119 %8 2012 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/22832964?dopt=Abstract %R 10.1038/tp.2012.41 %0 Journal Article %J Nat Genet %D 2012 %T Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. %A Estrada, Karol %A Styrkarsdottir, Unnur %A Evangelou, Evangelos %A Hsu, Yi-Hsiang %A Duncan, Emma L %A Ntzani, Evangelia E %A Oei, Ling %A Albagha, Omar M E %A Amin, Najaf %A Kemp, John P %A Koller, Daniel L %A Li, Guo %A Liu, Ching-Ti %A Minster, Ryan L %A Moayyeri, Alireza %A Vandenput, Liesbeth %A Willner, Dana %A Xiao, Su-Mei %A Yerges-Armstrong, Laura M %A Zheng, Hou-Feng %A Alonso, Nerea %A Eriksson, Joel %A Kammerer, Candace M %A Kaptoge, Stephen K %A Leo, Paul J %A Thorleifsson, Gudmar %A Wilson, Scott G %A Wilson, James F %A Aalto, Ville %A Alen, Markku %A Aragaki, Aaron K %A Aspelund, Thor %A Center, Jacqueline R %A Dailiana, Zoe %A Duggan, David J %A Garcia, Melissa %A García-Giralt, Natalia %A Giroux, Sylvie %A Hallmans, Göran %A Hocking, Lynne J %A Husted, Lise Bjerre %A Jameson, Karen A %A Khusainova, Rita %A Kim, Ghi Su %A Kooperberg, Charles %A Koromila, Theodora %A Kruk, Marcin %A Laaksonen, Marika %A LaCroix, Andrea Z %A Lee, Seung Hun %A Leung, Ping C %A Lewis, Joshua R %A Masi, Laura %A Mencej-Bedrac, Simona %A Nguyen, Tuan V %A Nogues, Xavier %A Patel, Millan S %A Prezelj, Janez %A Rose, Lynda M %A Scollen, Serena %A Siggeirsdottir, Kristin %A Smith, Albert V %A Svensson, Olle %A Trompet, Stella %A Trummer, Olivia %A van Schoor, Natasja M %A Woo, Jean %A Zhu, Kun %A Balcells, Susana %A Brandi, Maria Luisa %A Buckley, Brendan M %A Cheng, Sulin %A Christiansen, Claus %A Cooper, Cyrus %A Dedoussis, George %A Ford, Ian %A Frost, Morten %A Goltzman, David %A González-Macías, Jesús %A Kähönen, Mika %A Karlsson, Magnus %A Khusnutdinova, Elza %A Koh, Jung-Min %A Kollia, Panagoula %A Langdahl, Bente Lomholt %A Leslie, William D %A Lips, Paul %A Ljunggren, Osten %A Lorenc, Roman S %A Marc, Janja %A Mellström, Dan %A Obermayer-Pietsch, Barbara %A Olmos, José M %A Pettersson-Kymmer, Ulrika %A Reid, David M %A Riancho, José A %A Ridker, Paul M %A Rousseau, François %A Slagboom, P Eline %A Tang, Nelson L S %A Urreizti, Roser %A Van Hul, Wim %A Viikari, Jorma %A Zarrabeitia, María T %A Aulchenko, Yurii S %A Castano-Betancourt, Martha %A Grundberg, Elin %A Herrera, Lizbeth %A Ingvarsson, Thorvaldur %A Johannsdottir, Hrefna %A Kwan, Tony %A Li, Rui %A Luben, Robert %A Medina-Gómez, Carolina %A Palsson, Stefan Th %A Reppe, Sjur %A Rotter, Jerome I %A Sigurdsson, Gunnar %A van Meurs, Joyce B J %A Verlaan, Dominique %A Williams, Frances M K %A Wood, Andrew R %A Zhou, Yanhua %A Gautvik, Kaare M %A Pastinen, Tomi %A Raychaudhuri, Soumya %A Cauley, Jane A %A Chasman, Daniel I %A Clark, Graeme R %A Cummings, Steven R %A Danoy, Patrick %A Dennison, Elaine M %A Eastell, Richard %A Eisman, John A %A Gudnason, Vilmundur %A Hofman, Albert %A Jackson, Rebecca D %A Jones, Graeme %A Jukema, J Wouter %A Khaw, Kay-Tee %A Lehtimäki, Terho %A Liu, Yongmei %A Lorentzon, Mattias %A McCloskey, Eugene %A Mitchell, Braxton D %A Nandakumar, Kannabiran %A Nicholson, Geoffrey C %A Oostra, Ben A %A Peacock, Munro %A Pols, Huibert A P %A Prince, Richard L %A Raitakari, Olli %A Reid, Ian R %A Robbins, John %A Sambrook, Philip N %A Sham, Pak Chung %A Shuldiner, Alan R %A Tylavsky, Frances A %A van Duijn, Cornelia M %A Wareham, Nick J %A Cupples, L Adrienne %A Econs, Michael J %A Evans, David M %A Harris, Tamara B %A Kung, Annie Wai Chee %A Psaty, Bruce M %A Reeve, Jonathan %A Spector, Timothy D %A Streeten, Elizabeth A %A Zillikens, M Carola %A Thorsteinsdottir, Unnur %A Ohlsson, Claes %A Karasik, David %A Richards, J Brent %A Brown, Matthew A %A Stefansson, Kari %A Uitterlinden, André G %A Ralston, Stuart H %A Ioannidis, John P A %A Kiel, Douglas P %A Rivadeneira, Fernando %K Bone Density %K Computational Biology %K European Continental Ancestry Group %K Extracellular Matrix Proteins %K Female %K Femur Neck %K Fractures, Bone %K Gene Expression Profiling %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Glycoproteins %K Humans %K Intercellular Signaling Peptides and Proteins %K Low Density Lipoprotein Receptor-Related Protein-5 %K Lumbar Vertebrae %K Male %K Mitochondrial Membrane Transport Proteins %K Osteoporosis %K Phosphoproteins %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Risk Factors %K Spectrin %X

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

%B Nat Genet %V 44 %P 491-501 %8 2012 Apr 15 %G eng %N 5 %R 10.1038/ng.2249 %0 Journal Article %J Hum Mol Genet %D 2012 %T Genome-wide meta-analysis points to CTC1 and ZNF676 as genes regulating telomere homeostasis in humans. %A Mangino, Massimo %A Hwang, Shih-Jen %A Spector, Timothy D %A Hunt, Steven C %A Kimura, Masayuki %A Fitzpatrick, Annette L %A Christiansen, Lene %A Petersen, Inge %A Elbers, Clara C %A Harris, Tamara %A Chen, Wei %A Srinivasan, Sathanur R %A Kark, Jeremy D %A Benetos, Athanase %A El Shamieh, Said %A Visvikis-Siest, Sophie %A Christensen, Kaare %A Berenson, Gerald S %A Valdes, Ana M %A Viñuela, Ana %A Garcia, Melissa %A Arnett, Donna K %A Broeckel, Ulrich %A Province, Michael A %A Pankow, James S %A Kammerer, Candace %A Liu, Yongmei %A Nalls, Michael %A Tishkoff, Sarah %A Thomas, Fridtjof %A Ziv, Elad %A Psaty, Bruce M %A Bis, Joshua C %A Rotter, Jerome I %A Taylor, Kent D %A Smith, Erin %A Schork, Nicholas J %A Levy, Daniel %A Aviv, Abraham %K Genome-Wide Association Study %K Humans %K Kruppel-Like Transcription Factors %K Telomere %K Telomere Homeostasis %K Telomere-Binding Proteins %X

Leukocyte telomere length (LTL) is associated with a number of common age-related diseases and is a heritable trait. Previous genome-wide association studies (GWASs) identified two loci on chromosomes 3q26.2 (TERC) and 10q24.33 (OBFC1) that are associated with the inter-individual LTL variation. We performed a meta-analysis of 9190 individuals from six independent GWAS and validated our findings in 2226 individuals from four additional studies. We confirmed previously reported associations with OBFC1 (rs9419958 P = 9.1 × 10(-11)) and with the telomerase RNA component TERC (rs1317082, P = 1.1 × 10(-8)). We also identified two novel genomic regions associated with LTL variation that map near a conserved telomere maintenance complex component 1 (CTC1; rs3027234, P = 3.6 × 10(-8)) on chromosome17p13.1 and zinc finger protein 676 (ZNF676; rs412658, P = 3.3 × 10(-8)) on 19p12. The minor allele of rs3027234 was associated with both shorter LTL and lower expression of CTC1. Our findings are consistent with the recent observations that point mutations in CTC1 cause short telomeres in both Arabidopsis and humans affected by a rare Mendelian syndrome. Overall, our results provide novel insights into the genetic architecture of inter-individual LTL variation in the general population.

%B Hum Mol Genet %V 21 %P 5385-94 %8 2012 Dec 15 %G eng %N 24 %1 http://www.ncbi.nlm.nih.gov/pubmed/23001564?dopt=Abstract %R 10.1093/hmg/dds382 %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 Circ Cardiovasc Genet %D 2012 %T Impact of ancestry and common genetic variants on QT interval in African Americans. %A Smith, J Gustav %A Avery, Christy L %A Evans, Daniel S %A Nalls, Michael A %A Meng, Yan A %A Smith, Erin N %A Palmer, Cameron %A Tanaka, Toshiko %A Mehra, Reena %A Butler, Anne M %A Young, Taylor %A Buxbaum, Sarah G %A Kerr, Kathleen F %A Berenson, Gerald S %A Schnabel, Renate B %A Li, Guo %A Ellinor, Patrick T %A Magnani, Jared W %A Chen, Wei %A Bis, Joshua C %A Curb, J David %A Hsueh, Wen-Chi %A Rotter, Jerome I %A Liu, Yongmei %A Newman, Anne B %A Limacher, Marian C %A North, Kari E %A Reiner, Alexander P %A Quibrera, P Miguel %A Schork, Nicholas J %A Singleton, Andrew B %A Psaty, Bruce M %A Soliman, Elsayed Z %A Solomon, Allen J %A Srinivasan, Sathanur R %A Alonso, Alvaro %A Wallace, Robert %A Redline, Susan %A Zhang, Zhu-Ming %A Post, Wendy S %A Zonderman, Alan B %A Taylor, Herman A %A Murray, Sarah S %A Ferrucci, Luigi %A Arking, Dan E %A Evans, Michele K %A Fox, Ervin R %A Sotoodehnia, Nona %A Heckbert, Susan R %A Whitsel, Eric A %A Newton-Cheh, Christopher %K Adult %K African Americans %K Aged %K Electrocardiography %K European Continental Ancestry Group %K Female %K Genealogy and Heraldry %K Genetic Variation %K Genome, Human %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %X

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

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

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

%B Circ Cardiovasc Genet %V 5 %P 647-55 %8 2012 Dec %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/23166209?dopt=Abstract %R 10.1161/CIRCGENETICS.112.962787 %0 Journal Article %J Eur Heart J %D 2012 %T The impact of height on the risk of atrial fibrillation: the Cardiovascular Health Study. %A Rosenberg, Michael A %A Patton, Kristen K %A Sotoodehnia, Nona %A Karas, Maria G %A Kizer, Jorge R %A Zimetbaum, Peter J %A Chang, James D %A Siscovick, David %A Gottdiener, John S %A Kronmal, Richard A %A Heckbert, Susan R %A Mukamal, Kenneth J %K Aged %K Atrial Fibrillation %K Body Height %K Epidemiologic Methods %K Female %K Humans %K Male %K Sex Factors %K United States %X

AIMS: Atrial fibrillation (AF) is the most common sustained arrhythmia. Increased body size has been associated with AF, but the relationship is not well understood. In this study, we examined the effect of increased height on the risk of AF and explore potential mediators and implications for clinical practice.

METHODS AND RESULTS: We examined data from 5860 individuals taking part in the Cardiovascular Health Study, a cohort study of older US adults followed for a median of 13.6 (women) and 10.3 years (men). Multivariate linear models and age-stratified Cox proportional hazards and risk models were used, with focus on the effect of height on both prevalent and incident AF. Among 684 (22.6%) and 568 (27.1%) incident cases in women and men, respectively, greater height was significantly associated with AF risk [hazard ratio (HR)(women) per 10 cm 1.32, confidence interval (CI) 1.16-1.50, P < 0.0001; HR(men) per 10 cm 1.26, CI 1.11-1.44, P < 0.0001]. The association was such that the incremental risk from sex was completely attenuated by the inclusion of height (for men, HR 1.48, CI 1.32-1.65, without height, and HR 0.94, CI 0.85-1.20, with height included). Inclusion of height in the Framingham model for incident AF improved discrimination. In sequential models, however, we found minimal attenuation of the risk estimates for AF with adjustment for left ventricular (LV) mass and left atrial (LA) dimension. The associations of LA and LV size measurements with AF risk were weakened when indexed to height.

CONCLUSION: Independent from sex, increased height is significantly associated with the risk of AF.

%B Eur Heart J %V 33 %P 2709-17 %8 2012 Nov %G eng %N 21 %1 http://www.ncbi.nlm.nih.gov/pubmed/22977225?dopt=Abstract %R 10.1093/eurheartj/ehs301 %0 Journal Article %J Neurology %D 2012 %T Incidence of mild cognitive impairment in the Pittsburgh Cardiovascular Health Study-Cognition Study. %A Lopez, Oscar L %A Becker, James T %A Chang, Yue-Fang %A Sweet, Robert A %A DeKosky, Steven T %A Gach, Michael H %A Carmichael, Owen T %A McDade, Eric %A Kuller, Lewis H %K Aged %K Aged, 80 and over %K Cognitive Dysfunction %K Dementia %K Disease Progression %K Female %K Health Surveys %K Humans %K Incidence %K Male %K Risk Factors %K Severity of Illness Index %X

OBJECTIVES AND METHODS: The purpose of this study was to examine the incidence of mild cognitive impairment (MCI) and patterns of progression from incident MCI to dementia in 285 cognitively normal subjects (mean age, 78.9 years) in the Cardiovascular Health Study-Cognition Study from 1998-1999 to 2010-2011.

RESULTS: Two hundred (70%) of the participants progressed to MCI; the age-adjusted incidence of MCI was 111.09 (95% confidence interval, 88.13-142.95) per 1,000 person-years. A total of 107 (53.5%) of the incident MCI subjects progressed to dementia. The mean time from MCI to dementia was 2.8 ± 1.8 years. Forty (20%) of the incident MCI cases had an "unstable" course: 19 (9.5%) converted to MCI and later returned to normal; 10 (5%) converted to MCI, to normal, and later back to MCI; 7 (3.5%) converted to MCI, to normal, to MCI, and later to dementia; and 4 (2%) converted to MCI, to normal, and later to dementia. There was an increased mortality rate among the cognitively normal group (110.10 per 1,000 person-years) compared to those with incident MCI who converted to dementia (41.32 per 1,000 person-years).

CONCLUSIONS: The majority of the subjects aged >80 years developed an MCI syndrome, and half of them progressed to dementia. Once the MCI syndrome was present, the symptoms of dementia appeared within 2 to 3 years. Progression from normal to MCI or from normal to MCI to dementia is not always linear; subjects who developed MCI and later returned to normal can subsequently progress to dementia. Competing mortality and morbidity influence the study of incident MCI and dementia in population cohorts.

%B Neurology %V 79 %P 1599-606 %8 2012 Oct 09 %G eng %N 15 %1 http://www.ncbi.nlm.nih.gov/pubmed/23019262?dopt=Abstract %R 10.1212/WNL.0b013e31826e25f0 %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 J Am Geriatr Soc %D 2012 %T Kidney function and mortality in octogenarians: Cardiovascular Health Study All Stars. %A Shastri, Shani %A Katz, Ronit %A Rifkin, Dena E %A Fried, Linda F %A Odden, Michelle C %A Peralta, Carmen A %A Chonchol, Michel %A Siscovick, David %A Shlipak, Michael G %A Newman, Anne B %A Sarnak, Mark J %K Aged, 80 and over %K Analysis of Variance %K Cardiovascular Diseases %K Chi-Square Distribution %K Creatinine %K Cystatin C %K Diabetes Mellitus %K Female %K Glomerular Filtration Rate %K Humans %K Hypertension %K Kidney Diseases %K Male %K Prevalence %K Proportional Hazards Models %K Retrospective Studies %K Risk Factors %K United States %X

OBJECTIVES: To examine the association between kidney function and all-cause mortality in octogenarians.

DESIGN: Retrospective analysis of prospectively collected data.

SETTING: Community.

PARTICIPANTS: Serum creatinine and cystatin C were measured in 1,053 Cardiovascular Health Study (CHS) All Stars participants.

MEASUREMENTS: Estimated glomerular filtration rate (eGFR) was determined using the Chronic Kidney Disease Epidemiology Collaboration creatinine (eGFR(CR) ) and cystatin C one-variable (eGFR(CYS) ) equations. The association between quintiles of kidney function and all-cause mortality was analyzed using unadjusted and adjusted Cox proportional hazards models.

RESULTS: Mean age of the participants was 85, 64% were female, 66% had hypertension, 14% had diabetes mellitus, and 39% had prevalent cardiovascular disease. There were 154 deaths over a median follow-up of 2.6 years. The association between eGFR(CR) and all-cause mortality was U-shaped. In comparison with the reference quintile (64-75 mL/min per 1.73 m(2) ), the highest (≥ 75 mL/min per 1.73 m(2) ) and lowest (≤ 43 mL/min per 1.73 m(2) ) quintiles of eGFR(CR) were independently associated with mortality (hazard ratio (HR) = 2.49, 95% confidence interval (CI) = 1.36-4.55; HR = 2.28, 95% CI = 1.26-4.10, respectively). The association between eGFR(CYS) and all-cause mortality was linear in those with eGFR(CYS) of less than 60 mL/min per 1.73 m(2) , and in the multivariate analyses, the lowest quintile of eGFR(CYS) (<52 mL/min per 1.73 m(2) ) was significantly associated with mortality (HR = 2.04, 95% CI = 1.12-3.71) compared with the highest quintile (>0.88 mL/min per 1.73 m(2) ).

CONCLUSION: Moderate reduction in kidney function is a risk factor for all-cause mortality in octogenarians. The association between eGFR(CR) and all-cause mortality differed from that observed with eGFR(CYS) ; the relationship was U-shaped for eGFR(CR) , whereas the risk was primarily present in the lowest quintile for eGFR(CYS) .

%B J Am Geriatr Soc %V 60 %P 1201-7 %8 2012 Jul %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/22724391?dopt=Abstract %R 10.1111/j.1532-5415.2012.04046.x %0 Journal Article %J Nat Genet %D 2012 %T Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways. %A Scott, Robert A %A Lagou, Vasiliki %A Welch, Ryan P %A Wheeler, Eleanor %A Montasser, May E %A Luan, Jian'an %A Mägi, Reedik %A Strawbridge, Rona J %A Rehnberg, Emil %A Gustafsson, Stefan %A Kanoni, Stavroula %A Rasmussen-Torvik, Laura J %A Yengo, Loic %A Lecoeur, Cécile %A Shungin, Dmitry %A Sanna, Serena %A Sidore, Carlo %A Johnson, Paul C D %A Jukema, J Wouter %A Johnson, Toby %A Mahajan, Anubha %A Verweij, Niek %A Thorleifsson, Gudmar %A Hottenga, Jouke-Jan %A Shah, Sonia %A Smith, Albert V %A Sennblad, Bengt %A Gieger, Christian %A Salo, Perttu %A Perola, Markus %A Timpson, Nicholas J %A Evans, David M %A Pourcain, Beate St %A Wu, Ying %A Andrews, Jeanette S %A Hui, Jennie %A Bielak, Lawrence F %A Zhao, Wei %A Horikoshi, Momoko %A Navarro, Pau %A Isaacs, Aaron %A O'Connell, Jeffrey R %A Stirrups, Kathleen %A Vitart, Veronique %A Hayward, Caroline %A Esko, Tõnu %A Mihailov, Evelin %A Fraser, Ross M %A Fall, Tove %A Voight, Benjamin F %A Raychaudhuri, Soumya %A Chen, Han %A Lindgren, Cecilia M %A Morris, Andrew P %A Rayner, Nigel W %A Robertson, Neil %A Rybin, Denis %A Liu, Ching-Ti %A Beckmann, Jacques S %A Willems, Sara M %A Chines, Peter S %A Jackson, Anne U %A Kang, Hyun Min %A Stringham, Heather M %A Song, Kijoung %A Tanaka, Toshiko %A Peden, John F %A Goel, Anuj %A Hicks, Andrew A %A An, Ping %A Müller-Nurasyid, Martina %A Franco-Cereceda, Anders %A Folkersen, Lasse %A Marullo, Letizia %A Jansen, Hanneke %A Oldehinkel, Albertine J %A Bruinenberg, Marcel %A Pankow, James S %A North, Kari E %A Forouhi, Nita G %A Loos, Ruth J F %A Edkins, Sarah %A Varga, Tibor V %A Hallmans, Göran %A Oksa, Heikki %A Antonella, Mulas %A Nagaraja, Ramaiah %A Trompet, Stella %A Ford, Ian %A Bakker, Stephan J L %A Kong, Augustine %A Kumari, Meena %A Gigante, Bruna %A Herder, Christian %A Munroe, Patricia B %A Caulfield, Mark %A Antti, Jula %A Mangino, Massimo %A Small, Kerrin %A Miljkovic, Iva %A Liu, Yongmei %A Atalay, Mustafa %A Kiess, Wieland %A James, Alan L %A Rivadeneira, Fernando %A Uitterlinden, André G %A Palmer, Colin N A %A Doney, Alex S F %A Willemsen, Gonneke %A Smit, Johannes H %A Campbell, Susan %A Polasek, Ozren %A Bonnycastle, Lori L %A Hercberg, Serge %A Dimitriou, Maria %A Bolton, Jennifer L %A Fowkes, Gerard R %A Kovacs, Peter %A Lindström, Jaana %A Zemunik, Tatijana %A Bandinelli, Stefania %A Wild, Sarah H %A Basart, Hanneke V %A Rathmann, Wolfgang %A Grallert, Harald %A Maerz, Winfried %A Kleber, Marcus E %A Boehm, Bernhard O %A Peters, Annette %A Pramstaller, Peter P %A Province, Michael A %A Borecki, Ingrid B %A Hastie, Nicholas D %A Rudan, Igor %A Campbell, Harry %A Watkins, Hugh %A Farrall, Martin %A Stumvoll, Michael %A Ferrucci, Luigi %A Waterworth, Dawn M %A Bergman, Richard N %A Collins, Francis S %A Tuomilehto, Jaakko %A Watanabe, Richard M %A de Geus, Eco J C %A Penninx, Brenda W %A Hofman, Albert %A Oostra, Ben A %A Psaty, Bruce M %A Vollenweider, Peter %A Wilson, James F %A Wright, Alan F %A Hovingh, G Kees %A Metspalu, Andres %A Uusitupa, Matti %A Magnusson, Patrik K E %A Kyvik, Kirsten O %A Kaprio, Jaakko %A Price, Jackie F %A Dedoussis, George V %A Deloukas, Panos %A Meneton, Pierre %A Lind, Lars %A Boehnke, Michael %A Shuldiner, Alan R %A van Duijn, Cornelia M %A Morris, Andrew D %A Toenjes, Anke %A Peyser, Patricia A %A Beilby, John P %A Körner, Antje %A Kuusisto, Johanna %A Laakso, Markku %A Bornstein, Stefan R %A Schwarz, Peter E H %A Lakka, Timo A %A Rauramaa, Rainer %A Adair, Linda S %A Smith, George Davey %A Spector, Tim D %A Illig, Thomas %A de Faire, Ulf %A Hamsten, Anders %A Gudnason, Vilmundur %A Kivimaki, Mika %A Hingorani, Aroon %A Keinanen-Kiukaanniemi, Sirkka M %A Saaristo, Timo E %A Boomsma, Dorret I %A Stefansson, Kari %A van der Harst, Pim %A Dupuis, Josée %A Pedersen, Nancy L %A Sattar, Naveed %A Harris, Tamara B %A Cucca, Francesco %A Ripatti, Samuli %A Salomaa, Veikko %A Mohlke, Karen L %A Balkau, Beverley %A Froguel, Philippe %A Pouta, Anneli %A Jarvelin, Marjo-Riitta %A Wareham, Nicholas J %A Bouatia-Naji, Nabila %A McCarthy, Mark I %A Franks, Paul W %A Meigs, James B %A Teslovich, Tanya M %A Florez, Jose C %A Langenberg, Claudia %A Ingelsson, Erik %A Prokopenko, Inga %A Barroso, Inês %K Adult %K Animals %K Blood Glucose %K Fasting %K Female %K Gene Frequency %K Genome-Wide Association Study %K Humans %K Insulin %K Male %K Metabolic Networks and Pathways %K Mice %K Osmolar Concentration %K Quantitative Trait Loci %X

Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.

%B Nat Genet %V 44 %P 991-1005 %8 2012 Sep %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/22885924?dopt=Abstract %R 10.1038/ng.2385 %0 Journal Article %J N Engl J Med %D 2012 %T Lifetime risks of cardiovascular disease. %A Berry, Jarett D %A Dyer, Alan %A Cai, Xuan %A Garside, Daniel B %A Ning, Hongyan %A Thomas, Avis %A Greenland, Philip %A Van Horn, Linda %A Tracy, Russell P %A Lloyd-Jones, Donald M %K Adult %K African Americans %K Aged %K Cardiovascular Diseases %K Cohort Effect %K European Continental Ancestry Group %K Female %K Humans %K Male %K Middle Aged %K Risk %K Risk Assessment %K Risk Factors %K United States %X

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

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

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

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

%B N Engl J Med %V 366 %P 321-9 %8 2012 Jan 26 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/22276822?dopt=Abstract %R 10.1056/NEJMoa1012848 %0 Journal Article %J JAMA %D 2012 %T Lipid-related markers and cardiovascular disease prediction. %A Di Angelantonio, Emanuele %A Gao, Pei %A Pennells, Lisa %A Kaptoge, Stephen %A Caslake, Muriel %A Thompson, Alexander %A Butterworth, Adam S %A Sarwar, Nadeem %A Wormser, David %A Saleheen, Danish %A Ballantyne, Christie M %A Psaty, Bruce M %A Sundström, Johan %A Ridker, Paul M %A Nagel, Dorothea %A Gillum, Richard F %A Ford, Ian %A Ducimetiere, Pierre %A Kiechl, Stefan %A Koenig, Wolfgang %A Dullaart, Robin P F %A Assmann, Gerd %A D'Agostino, Ralph B %A Dagenais, Gilles R %A Cooper, Jackie A %A Kromhout, Daan %A Onat, Altan %A Tipping, Robert W %A Gómez-de-la-Cámara, Agustín %A Rosengren, Annika %A Sutherland, Susan E %A Gallacher, John %A Fowkes, F Gerry R %A Casiglia, Edoardo %A Hofman, Albert %A Salomaa, Veikko %A Barrett-Connor, Elizabeth %A Clarke, Robert %A Brunner, Eric %A Jukema, J Wouter %A Simons, Leon A %A Sandhu, Manjinder %A Wareham, Nicholas J %A Khaw, Kay-Tee %A Kauhanen, Jussi %A Salonen, Jukka T %A Howard, William J %A Nordestgaard, Børge G %A Wood, Angela M %A Thompson, Simon G %A Boekholdt, S Matthijs %A Sattar, Naveed %A Packard, Chris %A Gudnason, Vilmundur %A Danesh, John %K Aged %K Biomarkers %K Cardiovascular Diseases %K Cholesterol, HDL %K Cohort Studies %K Female %K Humans %K Lipoproteins %K Male %K Middle Aged %K Risk Assessment %X

CONTEXT: The value of assessing various emerging lipid-related markers for prediction of first cardiovascular events is debated.

OBJECTIVE: To determine whether adding information on apolipoprotein B and apolipoprotein A-I, lipoprotein(a), or lipoprotein-associated phospholipase A2 to total cholesterol and high-density lipoprotein cholesterol (HDL-C) improves cardiovascular disease (CVD) risk prediction.

DESIGN, SETTING, AND PARTICIPANTS: Individual records were available for 165,544 participants without baseline CVD in 37 prospective cohorts (calendar years of recruitment: 1968-2007) with up to 15,126 incident fatal or nonfatal CVD outcomes (10,132 CHD and 4994 stroke outcomes) during a median follow-up of 10.4 years (interquartile range, 7.6-14 years).

MAIN OUTCOME MEASURES: Discrimination of CVD outcomes and reclassification of participants across predicted 10-year risk categories of low (<10%), intermediate (10%-<20%), and high (≥20%) risk.

RESULTS: The addition of information on various lipid-related markers to total cholesterol, HDL-C, and other conventional risk factors yielded improvement in the model's discrimination: C-index change, 0.0006 (95% CI, 0.0002-0.0009) for the combination of apolipoprotein B and A-I; 0.0016 (95% CI, 0.0009-0.0023) for lipoprotein(a); and 0.0018 (95% CI, 0.0010-0.0026) for lipoprotein-associated phospholipase A2 mass. Net reclassification improvements were less than 1% with the addition of each of these markers to risk scores containing conventional risk factors. We estimated that for 100,000 adults aged 40 years or older, 15,436 would be initially classified at intermediate risk using conventional risk factors alone. Additional testing with a combination of apolipoprotein B and A-I would reclassify 1.1%; lipoprotein(a), 4.1%; and lipoprotein-associated phospholipase A2 mass, 2.7% of people to a 20% or higher predicted CVD risk category and, therefore, in need of statin treatment under Adult Treatment Panel III guidelines.

CONCLUSION: In a study of individuals without known CVD, the addition of information on the combination of apolipoprotein B and A-I, lipoprotein(a), or lipoprotein-associated phospholipase A2 mass to risk scores containing total cholesterol and HDL-C led to slight improvement in CVD prediction.

%B JAMA %V 307 %P 2499-506 %8 2012 Jun 20 %G eng %N 23 %1 http://www.ncbi.nlm.nih.gov/pubmed/22797450?dopt=Abstract %R 10.1001/jama.2012.6571 %0 Journal Article %J J Clin Endocrinol Metab %D 2012 %T Lipoprotein-associated phospholipase A2 (Lp-PLA2) and future risk of type 2 diabetes: results from the Cardiovascular Health Study. %A Nelson, T L %A Biggs, M L %A Kizer, J R %A Cushman, M %A Hokanson, J E %A Furberg, C D %A Mukamal, K J %K 1-Alkyl-2-acetylglycerophosphocholine Esterase %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Diabetes Mellitus, Type 2 %K Female %K Humans %K Incidence %K Insulin Resistance %K Male %K Middle Aged %K Predictive Value of Tests %K Prevalence %K Prospective Studies %K Risk %K Risk Factors %X

INTRODUCTION: Lipoprotein-associated phospholipase A2 (Lp-PLA(2)) has been consistently associated with cardiovascular disease (CVD) risk factors and predictive of CVD outcomes; furthermore, it is consistently higher among type 2 diabetics than nondiabetics. However, the relationships of circulating Lp-PLA(2) mass and activity with incident type 2 diabetes mellitus have not been examined. Therefore, the purpose of this study was to determine the association of Lp-PLA(2) mass and activity with type 2 diabetes among older adults.

METHODS: We conducted analyses of Lp-PLA(2) and prevalent and incident diabetes among 5474 men and women from the Cardiovascular Health Study (1989-2007). Lp-PLA(2) mass and activity were measured in baseline plasma. Diabetes status was ascertained annually with medication inventories and repeated blood glucose measurements. Generalized linear and Cox proportional hazards models were used to adjust for confounding factors including body mass index and inflammation.

RESULTS: At baseline, the top two quintiles of Lp-PLA(2) activity were significantly associated with prevalent type 2 diabetes with a multivariable relative risk = 1.35 [95% confidence interval (CI) = 1.11-1.63] for quintile 4, and relative risk = 1.33 (95% CI = 1.07-1.66) for quintile 5. Among participants free of diabetes at baseline, we found a significant positive association with both the homeostatic model assessment for insulin resistance and β-cell function per SD increase in Lp-PLA(2) activity (P values for both <0.01). In prospective analyses, the risk of incident type 2 diabetes was significantly higher among those in the highest quintile of Lp-PLA(2) activity [multivariable hazard ratio = 1.45 (95% CI = 1.01-2.07)] compared with the lowest quintile. Lp-PLA(2) mass was not significantly associated with incident type 2 diabetes.

DISCUSSION: Lp-PLA(2) activity is positively associated with insulin resistance and predicts incident type 2 diabetes among older adults independent of multiple factors associated with diabetes pathogenesis.

%B J Clin Endocrinol Metab %V 97 %P 1695-701 %8 2012 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/22399516?dopt=Abstract %R 10.1210/jc.2011-3026 %0 Journal Article %J J Clin Endocrinol Metab %D 2012 %T Longitudinal changes in thyroid function in the oldest old and survival: the cardiovascular health study all-stars study. %A Waring, Avantika C %A Arnold, Alice M %A Newman, Anne B %A Bůzková, Petra %A Hirsch, Calvin %A Cappola, Anne R %K Aged, 80 and over %K Female %K Humans %K Longitudinal Studies %K Male %K Thyroid Diseases %K Thyroid Function Tests %K Thyroid Gland %K Thyrotropin %K Thyroxine %K Triiodothyronine %X

CONTEXT: Data on thyroid function in the oldest old are sparse, and existing studies show conflicting evidence on the relationship between thyroid function and mortality in this age group.

OBJECTIVE: We describe longitudinal changes in thyroid function in a cohort of elderly individuals and determine the relationship between thyroid function and mortality.

DESIGN, SETTING, AND PARTICIPANTS: Eight hundred forty-three participants in the Cardiovascular Health Study All Stars Study who were not taking thyroid medications and had thyroid function testing in 2005-2006 (mean age 85 yr).

MAIN OUTCOME MEASURE: Thyroid-stimulating hormone (TSH), free T(4) (FT4), total T(3), and thyroid peroxidase antibody status were measured in 1992-1993 and 2005-2006. Deaths were ascertained through February 2011.

RESULTS: There was a statistically significant 13% increase in TSH, 1.7% increase in FT4, and 13% decrease in total T(3) over the 13-yr period. Two hundred eighty-seven deaths occurred over a median follow-up of 5.1 yr. There was no association between subclinical hypothyroidism[hazard ratio (HR) 0.97, 95% confidence interval (CI) 0.66-1.43], TSH level (HR per milliunits per liter 0.94, 95% CI 0.88-1.01), or persistent thyroid peroxidase antibody positivity (HR 1.09, 95% CI 0.62-1.92), and death. However, FT4 was positively associated with death (HR per nanograms per deciliter 2.57, 95% CI 1.32-5.02).

CONCLUSIONS: TSH increased over time in these older individuals. This elevation was not associated with increased or decreased mortality, although higher FT4 levels were associated with death. These findings raise concern for treatment of mild elevations of TSH in advanced age. Further studies are needed to determine the potential benefit of treating age-related changes in thyroid function.

%B J Clin Endocrinol Metab %V 97 %P 3944-50 %8 2012 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/22879629?dopt=Abstract %R 10.1210/jc.2012-2481 %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2012 %T Long-term assessment of inflammation and healthy aging in late life: the Cardiovascular Health Study All Stars. %A Jenny, Nancy S %A French, Benjamin %A Arnold, Alice M %A Strotmeyer, Elsa S %A Cushman, Mary %A Chaves, Paulo H M %A Ding, Jingzhong %A Fried, Linda P %A Kritchevsky, Stephen B %A Rifkin, Dena E %A Sarnak, Mark J %A Newman, Anne B %K Aged %K Aged, 80 and over %K Aging %K C-Reactive Protein %K Cardiovascular Diseases %K Cognition %K Cohort Studies %K Cross-Sectional Studies %K Female %K Humans %K Inflammation %K Inflammation Mediators %K Interleukin-6 %K Longitudinal Studies %K Male %K Risk Factors %K Vermont %X

BACKGROUND: Associations of inflammation with age-related pathologies are documented; however, it is not understood how changes in inflammation over time impact healthy aging.

METHODS: We examined associations of long-term change in C-reactive protein (CRP) and interleukin-6 (IL-6) with concurrent onset of physical and cognitive impairment, subsequent cardiovascular disease (CVD), and mortality in 1,051 participants in the Cardiovascular Health Study All Stars Study. Biomarkers were measured in 1996-1997 and 2005-2006.

RESULTS: In 2005-2006, median age was 84.9 years, 63% were women and 17% non-white; 21% had at least a doubling in CRP over time and 23% had at least a doubling in IL-6. Adjusting for demographics, CVD risk factors, and 1996-1997 CRP level, each doubling in CRP change over 9 years was associated with higher risk of physical or cognitive impairment (odds ratio 1.29; 95% confidence interval 1.15, 1.45). Results were similar for IL-6 (1.45; 1.20, 1.76). A doubling in IL-6 change over time, but not CRP, was associated with incident CVD events; hazard ratio (95% confidence interval) 1.34 (1.03, 1.75). Doubling in change in each biomarker was individually associated with mortality (CRP: 1.12 [1.03, 1.22]; IL-6 1.39 [1.16, 1.65]). In models containing both change and 2005-2006 level, only level was associated with CVD events and mortality.

CONCLUSIONS: Although increases in inflammation markers over 9 years were associated with higher concurrent risk of functional impairment and subsequent CVD events and mortality, final levels of each biomarker appeared to be more important in determining risk of subsequent events than change over time.

%B J Gerontol A Biol Sci Med Sci %V 67 %P 970-6 %8 2012 Sep %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/22367431?dopt=Abstract %R 10.1093/gerona/glr261 %0 Journal Article %J Parkinsonism Relat Disord %D 2012 %T Markers of inflammation in prevalent and incident Parkinson's disease in the Cardiovascular Health Study. %A Ton, Thanh G N %A Jain, Samay %A Biggs, Mary L %A Thacker, Evan L %A Strotmeyer, Elsa S %A Boudreau, Robert %A Newman, Anne B %A Longstreth, W T %A Checkoway, Harvey %K Aged %K Aged, 80 and over %K Albumins %K Biomarkers %K C-Reactive Protein %K Enzyme-Linked Immunosorbent Assay %K Female %K Fibrinogen %K Humans %K Incidence %K Inflammation %K Interleukin-6 %K Leukocyte Count %K Male %K Parkinson Disease %K Prevalence %K Risk Factors %K Tumor Necrosis Factor-alpha %X

BACKGROUND: Studies demonstrate existence of inflammation in prevalent Parkinson's disease (PD). We assessed associations of baseline levels of inflammatory markers with prevalent PD at baseline (1989) and incident PD identified over 13 years of follow-up of the Cardiovascular Health Study.

METHODS: Blood samples at baseline were measured for fibrinogen, interleukin-6, tumor necrosis factor-α, C-reactive protein, albumin, and white blood cells. The analysis included 60 prevalent and 154 incident PD cases.

RESULTS: Risk of prevalent PD was significantly higher per doubling of IL-6 among women (odds ratio [OR]=1.5, 95% confidence interval [CI]: 1.0, 2.4) and WBC among men (OR: 2.4, 95% CI: 1.2, 4.9) in multivariate models. Risk of incident PD was not associated with higher levels of any biomarker after adjusting for age, smoking, African American race, and history of diabetes. Inverse associations with incident PD were observed per doubling of C-reactive protein (OR=0.9; 95% CI: 0.8, 1.0) and of fibrinogen among women (OR=0.4; 95% CI: 0.2, 0.8).

CONCLUSIONS: Although inflammation exists in PD, it may not represent an etiologic factor. Our findings suggest the need for larger studies that measure inflammatory markers before PD onset.

%B Parkinsonism Relat Disord %V 18 %P 274-8 %8 2012 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/22119505?dopt=Abstract %R 10.1016/j.parkreldis.2011.11.003 %0 Journal Article %J Nat Genet %D 2012 %T Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways. %A Stolk, Lisette %A Perry, John R B %A Chasman, Daniel I %A He, Chunyan %A Mangino, Massimo %A Sulem, Patrick %A Barbalic, Maja %A Broer, Linda %A Byrne, Enda M %A Ernst, Florian %A Esko, Tõnu %A Franceschini, Nora %A Gudbjartsson, Daniel F %A Hottenga, Jouke-Jan %A Kraft, Peter %A McArdle, Patrick F %A Porcu, Eleonora %A Shin, So-Youn %A Smith, Albert V %A van Wingerden, Sophie %A Zhai, Guangju %A Zhuang, Wei V %A Albrecht, Eva %A Alizadeh, Behrooz Z %A Aspelund, Thor %A Bandinelli, Stefania %A Lauc, Lovorka Barac %A Beckmann, Jacques S %A Boban, Mladen %A Boerwinkle, Eric %A Broekmans, Frank J %A Burri, Andrea %A Campbell, Harry %A Chanock, Stephen J %A Chen, Constance %A Cornelis, Marilyn C %A Corre, Tanguy %A Coviello, Andrea D %A D'Adamo, Pio %A Davies, Gail %A de Faire, Ulf %A de Geus, Eco J C %A Deary, Ian J %A Dedoussis, George V Z %A Deloukas, Panagiotis %A Ebrahim, Shah %A Eiriksdottir, Gudny %A Emilsson, Valur %A Eriksson, Johan G %A Fauser, Bart C J M %A Ferreli, Liana %A Ferrucci, Luigi %A Fischer, Krista %A Folsom, Aaron R %A Garcia, Melissa E %A Gasparini, Paolo %A Gieger, Christian %A Glazer, Nicole %A Grobbee, Diederick E %A Hall, Per %A Haller, Toomas %A Hankinson, Susan E %A Hass, Merli %A Hayward, Caroline %A Heath, Andrew C %A Hofman, Albert %A Ingelsson, Erik %A Janssens, A Cecile J W %A Johnson, Andrew D %A Karasik, David %A Kardia, Sharon L R %A Keyzer, Jules %A Kiel, Douglas P %A Kolcic, Ivana %A Kutalik, Zoltán %A Lahti, Jari %A Lai, Sandra %A Laisk, Triin %A Laven, Joop S E %A Lawlor, Debbie A %A Liu, Jianjun %A Lopez, Lorna M %A Louwers, Yvonne V %A Magnusson, Patrik K E %A Marongiu, Mara %A Martin, Nicholas G %A Klaric, Irena Martinovic %A Masciullo, Corrado %A McKnight, Barbara %A Medland, Sarah E %A Melzer, David %A Mooser, Vincent %A Navarro, Pau %A Newman, Anne B %A Nyholt, Dale R %A Onland-Moret, N Charlotte %A Palotie, Aarno %A Paré, Guillaume %A Parker, Alex N %A Pedersen, Nancy L %A Peeters, Petra H M %A Pistis, Giorgio %A Plump, Andrew S %A Polasek, Ozren %A Pop, Victor J M %A Psaty, Bruce M %A Räikkönen, Katri %A Rehnberg, Emil %A Rotter, Jerome I %A Rudan, Igor %A Sala, Cinzia %A Salumets, Andres %A Scuteri, Angelo %A Singleton, Andrew %A Smith, Jennifer A %A Snieder, Harold %A Soranzo, Nicole %A Stacey, Simon N %A Starr, John M %A Stathopoulou, Maria G %A Stirrups, Kathleen %A Stolk, Ronald P %A Styrkarsdottir, Unnur %A Sun, Yan V %A Tenesa, Albert %A Thorand, Barbara %A Toniolo, Daniela %A Tryggvadottir, Laufey %A Tsui, Kim %A Ulivi, Sheila %A van Dam, Rob M %A van der Schouw, Yvonne T %A van Gils, Carla H %A van Nierop, Peter %A Vink, Jacqueline M %A Visscher, Peter M %A Voorhuis, Marlies %A Waeber, Gérard %A Wallaschofski, Henri %A Wichmann, H Erich %A Widen, Elisabeth %A Wijnands-van Gent, Colette J M %A Willemsen, Gonneke %A Wilson, James F %A Wolffenbuttel, Bruce H R %A Wright, Alan F %A Yerges-Armstrong, Laura M %A Zemunik, Tatijana %A Zgaga, Lina %A Zillikens, M Carola %A Zygmunt, Marek %A Arnold, Alice M %A Boomsma, Dorret I %A Buring, Julie E %A Crisponi, Laura %A Demerath, Ellen W %A Gudnason, Vilmundur %A Harris, Tamara B %A Hu, Frank B %A Hunter, David J %A Launer, Lenore J %A Metspalu, Andres %A Montgomery, Grant W %A Oostra, Ben A %A Ridker, Paul M %A Sanna, Serena %A Schlessinger, David %A Spector, Tim D %A Stefansson, Kari %A Streeten, Elizabeth A %A Thorsteinsdottir, Unnur %A Uda, Manuela %A Uitterlinden, André G %A van Duijn, Cornelia M %A Völzke, Henry %A Murray, Anna %A Murabito, Joanne M %A Visser, Jenny A %A Lunetta, Kathryn L %K Age Factors %K DNA Helicases %K DNA Polymerase gamma %K DNA Primase %K DNA Repair %K DNA Repair Enzymes %K DNA-Directed DNA Polymerase %K European Continental Ancestry Group %K Exodeoxyribonucleases %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Immunity %K Menopause %K Polymorphism, Single Nucleotide %K Proteins %X

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

%B Nat Genet %V 44 %P 260-8 %8 2012 Jan 22 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/22267201?dopt=Abstract %R 10.1038/ng.1051 %0 Journal Article %J Nat Genet %D 2012 %T Meta-analysis identifies six new susceptibility loci for atrial fibrillation. %A Ellinor, Patrick T %A Lunetta, Kathryn L %A Albert, Christine M %A Glazer, Nicole L %A Ritchie, Marylyn D %A Smith, Albert V %A Arking, Dan E %A Müller-Nurasyid, Martina %A Krijthe, Bouwe P %A Lubitz, Steven A %A Bis, Joshua C %A Chung, Mina K %A Dörr, Marcus %A Ozaki, Kouichi %A Roberts, Jason D %A Smith, J Gustav %A Pfeufer, Arne %A Sinner, Moritz F %A Lohman, Kurt %A Ding, Jingzhong %A Smith, Nicholas L %A Smith, Jonathan D %A Rienstra, Michiel %A Rice, Kenneth M %A Van Wagoner, David R %A Magnani, Jared W %A Wakili, Reza %A Clauss, Sebastian %A Rotter, Jerome I %A Steinbeck, Gerhard %A Launer, Lenore J %A Davies, Robert W %A Borkovich, Matthew %A Harris, Tamara B %A Lin, Honghuang %A Völker, Uwe %A Völzke, Henry %A Milan, David J %A Hofman, Albert %A Boerwinkle, Eric %A Chen, Lin Y %A Soliman, Elsayed Z %A Voight, Benjamin F %A Li, Guo %A Chakravarti, Aravinda %A Kubo, Michiaki %A Tedrow, Usha B %A Rose, Lynda M %A Ridker, Paul M %A Conen, David %A Tsunoda, Tatsuhiko %A Furukawa, Tetsushi %A Sotoodehnia, Nona %A Xu, Siyan %A Kamatani, Naoyuki %A Levy, Daniel %A Nakamura, Yusuke %A Parvez, Babar %A Mahida, Saagar %A Furie, Karen L %A Rosand, Jonathan %A Muhammad, Raafia %A Psaty, Bruce M %A Meitinger, Thomas %A Perz, Siegfried %A Wichmann, H-Erich %A Witteman, Jacqueline C M %A Kao, W H Linda %A Kathiresan, Sekar %A Roden, Dan M %A Uitterlinden, André G %A Rivadeneira, Fernando %A McKnight, Barbara %A Sjögren, Marketa %A Newman, Anne B %A Liu, Yongmei %A Gollob, Michael H %A Melander, Olle %A Tanaka, Toshihiro %A Stricker, Bruno H Ch %A Felix, Stephan B %A Alonso, Alvaro %A Darbar, Dawood %A Barnard, John %A Chasman, Daniel I %A Heckbert, Susan R %A Benjamin, Emelia J %A Gudnason, Vilmundur %A Kääb, Stefan %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Asian Continental Ancestry Group %K Atrial Fibrillation %K Child %K Child, Preschool %K European Continental Ancestry Group %K Female %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Infant %K Infant, Newborn %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Risk Factors %K Young Adult %X

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

%B Nat Genet %V 44 %P 670-5 %8 2012 Apr 29 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/22544366?dopt=Abstract %R 10.1038/ng.2261 %0 Journal Article %J Am J Epidemiol %D 2012 %T Modification of the association between ambient air pollution and lung function by frailty status among older adults in the Cardiovascular Health Study. %A Eckel, Sandrah P %A Louis, Thomas A %A Chaves, Paulo H M %A Fried, Linda P %A Margolis, And Helene G %K Aged %K Air Pollution %K Cardiovascular Diseases %K Female %K Forced Expiratory Volume %K Frail Elderly %K Geriatric Assessment %K Humans %K Male %K Prospective Studies %K Respiratory Function Tests %K Sex Factors %K Smoking %K Time Factors %K United States %K Vital Capacity %X

The susceptibility of older adults to the health effects of air pollution is well-recognized. Advanced age may act as a partial surrogate for conditions associated with aging. The authors investigated whether gerontologic frailty (a clinical health status metric) modified the association between ambient level of ozone or particulate matter with an aerodynamic diameter less than 10 µm and lung function in 3,382 older adults using 7 years of follow-up data (1990-1997) from the Cardiovascular Health Study and its Environmental Factors Ancillary Study. Monthly average pollution and annual frailty assessments were related to up to 3 repeated measurements of lung function using cumulative summaries of pollution and frailty histories that accounted for duration as well as concentration. Frailty history was found to modify long-term associations of pollutants with forced vital capacity. For example, the decrease in forced vital capacity associated with a 70-ppb/month greater cumulative sum of monthly average ozone exposure was 12.3 mL (95% confidence interval: 10.4, 14.2) for a woman who had spent the prior 7 years prefrail or frail as compared with 4.7 mL (95% confidence interval: 3.8, 5.6) for a similar woman who was robust during all 7 years (interaction P < 0.001).

%B Am J Epidemiol %V 176 %P 214-23 %8 2012 Aug 01 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/22811494?dopt=Abstract %R 10.1093/aje/kws001 %0 Journal Article %J PLoS One %D 2012 %T Multi-ethnic analysis of lipid-associated loci: the NHLBI CARe project. %A Musunuru, Kiran %A Romaine, Simon P R %A Lettre, Guillaume %A Wilson, James G %A Volcik, Kelly A %A Tsai, Michael Y %A Taylor, Herman A %A Schreiner, Pamela J %A Rotter, Jerome I %A Rich, Stephen S %A Redline, Susan %A Psaty, Bruce M %A Papanicolaou, George J %A Ordovas, Jose M %A Liu, Kiang %A Krauss, Ronald M %A Glazer, Nicole L %A Gabriel, Stacey B %A Fornage, Myriam %A Cupples, L Adrienne %A Buxbaum, Sarah G %A Boerwinkle, Eric %A Ballantyne, Christie M %A Kathiresan, Sekar %A Rader, Daniel J %K African Americans %K Cholesterol, HDL %K Cholesterol, LDL %K European Continental Ancestry Group %K Genetic Association Studies %K Genetic Loci %K Humans %K Polymorphism, Single Nucleotide %K Triglycerides %X

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

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

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

%B PLoS One %V 7 %P e36473 %8 2012 %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/22629316?dopt=Abstract %R 10.1371/journal.pone.0036473 %0 Journal Article %J J Clin Endocrinol Metab %D 2012 %T The natural history of subclinical hypothyroidism in the elderly: the cardiovascular health study. %A Somwaru, Lily L %A Rariy, Chevon M %A Arnold, Alice M %A Cappola, Anne R %K Age Distribution %K Aged %K Aged, 80 and over %K Autoantibodies %K Cardiovascular Diseases %K Cohort Studies %K Disease Progression %K Female %K Humans %K Hypothyroidism %K Iodide Peroxidase %K Logistic Models %K Longitudinal Studies %K Male %K Prevalence %K Risk Factors %K Seroepidemiologic Studies %K Severity of Illness Index %K Sex Distribution %K Thyrotropin %X

CONTEXT: Studies of long-term outcomes of subclinical hypothyroidism have assessed only baseline thyroid function, despite natural transitions to euthyroidism and overt hypothyroidism over time.

OBJECTIVE: We provide estimates of persistence, resolution, and progression of subclinical hypothyroidism over 4 yr, stratified by baseline TSH, anti-thyroid peroxidase antibody (TPOAb) status, age, and sex.

DESIGN, SETTING, AND PARTICIPANTS: Participants were 3996 U.S. individuals at least 65 yr old enrolled in the Cardiovascular Health Study. Subclinical hypothyroidism was detected at baseline in 459 individuals not taking thyroid medication.

MAIN OUTCOME MEASURE: Thyroid function was evaluated at 2 and 4 yr and initiation of thyroid medication annually. Results were stratified by baseline TSH, TPOAb status, age, and sex.

RESULTS: Persistence of subclinical hypothyroidism was 56% at 2 and 4 yr. At 2 yr, resolution was more common with a TSH of 4.5-6.9 mU/liter (46 vs. 10% with TSH 7-9.9 mU/liter and 7% with TSH ≥10 mU/liter; P < 0.001) and with TPOAb negativity (48 vs. 15% for positive; P < 0.001). Higher TSH and TPOAb positivity were independently associated with lower likelihood of reversion to euthyroidism (P < 0.05). TSH of 10 mU/liter or higher was independently associated with progression to overt hypothyroidism (P < 0.05). Transitions between euthyroidism and subclinical hypothyroidism were common between 2 and 4 yr. Age and sex did not affect transitions.

CONCLUSIONS: Subclinical hypothyroidism persists for 4 yr in just over half of older individuals, with high rates of reversion to euthyroidism in individuals with lower TSH concentrations and TPOAb negativity. Future studies should examine the impact of transitions in thyroid status on clinical outcomes.

%B J Clin Endocrinol Metab %V 97 %P 1962-9 %8 2012 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/22438233?dopt=Abstract %R 10.1210/jc.2011-3047 %0 Journal Article %J Circ Cardiovasc Genet %D 2012 %T Novel loci associated with PR interval in a genome-wide association study of 10 African American cohorts. %A Butler, Anne M %A Yin, Xiaoyan %A Evans, Daniel S %A Nalls, Michael A %A Smith, Erin N %A Tanaka, Toshiko %A Li, Guo %A Buxbaum, Sarah G %A Whitsel, Eric A %A Alonso, Alvaro %A Arking, Dan E %A Benjamin, Emelia J %A Berenson, Gerald S %A Bis, Josh C %A Chen, Wei %A Deo, Rajat %A Ellinor, Patrick T %A Heckbert, Susan R %A Heiss, Gerardo %A Hsueh, Wen-Chi %A Keating, Brendan J %A Kerr, Kathleen F %A Li, Yun %A Limacher, Marian C %A Liu, Yongmei %A Lubitz, Steven A %A Marciante, Kristin D %A Mehra, Reena %A Meng, Yan A %A Newman, Anne B %A Newton-Cheh, Christopher %A North, Kari E %A Palmer, Cameron D %A Psaty, Bruce M %A Quibrera, P Miguel %A Redline, Susan %A Reiner, Alex P %A Rotter, Jerome I %A Schnabel, Renate B %A Schork, Nicholas J %A Singleton, Andrew B %A Smith, J Gustav %A Soliman, Elsayed Z %A Srinivasan, Sathanur R %A Zhang, Zhu-Ming %A Zonderman, Alan B %A Ferrucci, Luigi %A Murray, Sarah S %A Evans, Michele K %A Sotoodehnia, Nona %A Magnani, Jared W %A Avery, Christy L %K Adult %K African Americans %K Cohort Studies %K Electrocardiography %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Male %K Meta-Analysis as Topic %K Middle Aged %K Polymorphism, Single Nucleotide %X

BACKGROUND: The PR interval, as measured by the resting, standard 12-lead ECG, reflects the duration of atrial/atrioventricular nodal depolarization. Substantial evidence exists for a genetic contribution to PR, including genome-wide association studies that have identified common genetic variants at 9 loci influencing PR in populations of European and Asian descent. However, few studies have examined loci associated with PR in African Americans.

METHODS AND RESULTS: We present results from the largest genome-wide association study to date of PR in 13 415 adults of African descent from 10 cohorts. We tested for association between PR (ms) and ≈2.8 million genotyped and imputed single-nucleotide polymorphisms. Imputation was performed using HapMap 2 YRI and CEU panels. Study-specific results, adjusted for global ancestry and clinical correlates of PR, were meta-analyzed using the inverse variance method. Variation in genome-wide test statistic distributions was noted within studies (λ range: 0.9-1.1), although not after genomic control correction was applied to the overall meta-analysis (λ: 1.008). In addition to generalizing previously reported associations with MEIS1, SCN5A, ARHGAP24, CAV1, and TBX5 to African American populations at the genome-wide significance level (P<5.0 × 10(-8)), we also identified a novel locus: ITGA9, located in a region previously implicated in SCN5A expression. The 3p21 region harboring SCN5A also contained 2 additional independent secondary signals influencing PR (P<5.0 × 10(-8)).

CONCLUSIONS: This study demonstrates the ability to map novel loci in African Americans as well as the generalizability of loci associated with PR across populations of African, European, and Asian descent.

%B Circ Cardiovasc Genet %V 5 %P 639-46 %8 2012 Dec %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/23139255?dopt=Abstract %R 10.1161/CIRCGENETICS.112.963991 %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 Geriatr Soc %D 2012 %T Persistence and remission of musculoskeletal pain in community-dwelling older adults: results from the cardiovascular health study. %A Thielke, Stephen M %A Whitson, Heather %A Diehr, Paula %A O'Hare, Ann %A Kearney, Patricia M %A Chaudhry, Sarwat I %A Zakai, Neil A %A Kim, Dae %A Sekaran, Nishant %A Sale, Joanna E M %A Arnold, Alice M %A Chaves, Paulo %A Newman, Anne %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Female %K Humans %K Male %K Musculoskeletal Pain %K Remission Induction %K Residence Characteristics %X

OBJECTIVES: To characterize longitudinal patterns of musculoskeletal pain in a community sample of older adults over a 6-year period and to identify factors associated with persistence of pain.

DESIGN: Secondary analysis of the Cardiovascular Health Study.

SETTING: Community-based cohort drawn from four U.S. counties.

PARTICIPANTS: Five thousand ninety-three men and women aged 65 and older.

MEASUREMENTS: Over a 6-year period, pain was assessed each year using a single question about the presence of pain in any bones or joints during the last year. If affirmative, participants were queried about pain in seven locations (hands, shoulders, neck, back, hips, knees, feet). Participants were categorized according to the percentage of time that pain was present and according to the intermittent or chronic pattern of pain. Factors associated with persistent pain during five remaining years of the study were identified.

RESULTS: Over 6 years, 32% of participants reported pain for three or more consecutive years, and 32% reported pain intermittently. Of those who reported pain the first year, 54% were pain free at least once during the follow-up period. Most of the pain at specific body locations was intermittent. Factors associated with remission of pain over 5 years included older age, male sex, better self-rated health, not being obese, taking fewer medications, and having fewer depressive symptoms. Approximately half of those with pain reported fewer pain locations the following year.

CONCLUSION: Musculoskeletal pain in older adults, despite high prevalence, is often intermittent. The findings refute the notion that pain is an inevitable, unremitting, or progressive consequence of aging.

%B J Am Geriatr Soc %V 60 %P 1393-400 %8 2012 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/22861385?dopt=Abstract %R 10.1111/j.1532-5415.2012.04082.x %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 J Sleep Res %D 2012 %T Probabilistic sleep architecture models in patients with and without sleep apnea. %A Bianchi, Matt T %A Eiseman, Nathaniel A %A Cash, Sydney S %A Mietus, Joseph %A Peng, Chung-Kang %A Thomas, Robert J %K Cohort Studies %K Computer Simulation %K Humans %K Models, Theoretical %K Polysomnography %K Probability %K Sleep Apnea Syndromes %K Sleep Stages %K Sleep, REM %K Time Factors %X

Sleep fragmentation of any cause is disruptive to the rejuvenating value of sleep. However, methods to quantify sleep architecture remain limited. We have previously shown that human sleep-wake stage distributions exhibit multi-exponential dynamics, which are fragmented by obstructive sleep apnea (OSA), suggesting that Markov models may be a useful method to quantify architecture in health and disease. Sleep stage data were obtained from two subsets of the Sleep Heart Health Study database: control subjects with no medications, no OSA, no medical co-morbidities and no sleepiness (n = 374); and subjects with severe OSA (n = 338). Sleep architecture was simplified into three stages: wake after sleep onset (WASO); non-rapid eye movement (NREM) sleep; and rapid eye movement (REM) sleep. The connectivity and transition rates among eight 'generator' states of a first-order continuous-time Markov model were inferred from the observed ('phenotypic') distributions: three exponentials each of NREM sleep and WASO; and two exponentials of REM sleep. Ultradian REM cycling was accomplished by imposing time-variation to REM state entry rates. Fragmentation in subjects with severe OSA involved faster transition probabilities as well as additional state transition paths within the model. The Markov models exhibit two important features of human sleep architecture: multi-exponential stage dynamics (accounting for observed bout distributions); and probabilistic transitions (an inherent source of variability). In addition, the model quantifies the fragmentation associated with severe OSA. Markov sleep models may prove important for quantifying sleep disruption to provide objective metrics to correlate with endpoints ranging from sleepiness to cardiovascular morbidity.

%B J Sleep Res %V 21 %P 330-41 %8 2012 Jun %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/21955148?dopt=Abstract %R 10.1111/j.1365-2869.2011.00937.x %0 Journal Article %J Circulation %D 2012 %T Racial differences in risks for first cardiovascular events and noncardiovascular death: the Atherosclerosis Risk in Communities study, the Cardiovascular Health Study, and the Multi-Ethnic Study of Atherosclerosis. %A Feinstein, Matthew %A Ning, Hongyan %A Kang, Joseph %A Bertoni, Alain %A Carnethon, Mercedes %A Lloyd-Jones, Donald M %K African Continental Ancestry Group %K Age Factors %K Aged %K Aged, 80 and over %K Atherosclerosis %K Cardiovascular Diseases %K Cohort Studies %K Continental Population Groups %K Ethnic Groups %K European Continental Ancestry Group %K Female %K Follow-Up Studies %K Humans %K Longitudinal Studies %K Male %K Middle Aged %K Residence Characteristics %K Risk Factors %X

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

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

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

%B Circulation %V 126 %P 50-9 %8 2012 Jul 03 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/22693351?dopt=Abstract %R 10.1161/CIRCULATIONAHA.111.057232 %0 Journal Article %J Arch Ophthalmol %D 2012 %T Retinal microvascular signs and disability in the Cardiovascular Health Study. %A Kim, Dae Hyun %A Chaves, Paulo H M %A Newman, Anne B %A Klein, Ronald %A Sarnak, Mark J %A Newton, Elizabeth %A Strotmeyer, Elsa S %A Burke, Gregory L %A Lipsitz, Lewis A %K Activities of Daily Living %K Aged %K Carotid Artery Diseases %K Cognition Disorders %K Diagnostic Techniques, Ophthalmological %K Disability Evaluation %K Follow-Up Studies %K Humans %K Hypertension %K Incidence %K Kaplan-Meier Estimate %K Microcirculation %K Predictive Value of Tests %K Prevalence %K Prognosis %K Prospective Studies %K Retinal Diseases %K Risk Factors %K Smoking %X

OBJECTIVE: To study the associations of retinal microvascular changes, which are associated with systemic conditions and cognitive decline, with disability in performing activities of daily living (ADL).

DESIGN: Prospective cohort study of 1487 community-dwelling participants in the Cardiovascular Health Study (mean age, 78 years) who were free of ADL disability and had available data on retinal signs and carotid intima-media thickness at the 1998-1999 visit. Main outcome measures were incident ADL disability, defined as self-reported difficulty in performing any ADL, by the presence of retinal signs and advanced carotid atherosclerosis, defined by carotid intima-media thickness in the 80th percentile or more or 25% or more stenosis, and potential mediation by cerebral microvascular disease on brain imaging or by executive dysfunction, slow gait, and depressive mood, which are symptoms of frontal subcortical dysfunction.

RESULTS: During the median follow-up of 3.1 years (maximum, 7.8 years), participants with 2 or more retinal signs had a higher rate of disability than those with fewer than 2 retinal signs (10.1% vs 7.1%; adjusted hazard ratio, 1.45; 95% confidence interval, 1.24-1.69; P < .001). There was no evidence of interaction by advanced carotid atherosclerosis (P > .10). The association seemed to be partially mediated by executive dysfunction, slow gait, and depressive symptoms but not by cerebral microvascular disease on brain imaging.

CONCLUSIONS: These results provide further support for the pathophysiologic and prognostic significance of microvascular disease in age-related disability. However, it remains to be determined how to best use retinal photography in clinical risk prediction.

%B Arch Ophthalmol %V 130 %P 350-6 %8 2012 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/22084159?dopt=Abstract %R 10.1001/archophthalmol.2011.360 %0 Journal Article %J Chest %D 2012 %T Sleep-disordered breathing and caffeine consumption: results of a community-based study. %A Aurora, R Nisha %A Crainiceanu, Ciprian %A Caffo, Brian %A Punjabi, Naresh M %K Age Factors %K Aged %K Caffeine %K Carbonated Beverages %K Coffee %K Data Collection %K Drinking Behavior %K Female %K Humans %K Male %K Middle Aged %K Polysomnography %K Prevalence %K Retrospective Studies %K Sex Factors %K Sleep Apnea Syndromes %K Tea %X

BACKGROUND: Sleepiness is one of the most burdensome symptoms of sleep-disordered breathing (SDB). While caffeine is frequently used to avert sleepiness, the association between SDB and caffeine use has not been thoroughly explored. The current study examined whether SDB is associated with caffeine consumption and if factors such as sex, age, and daytime sleepiness explain or modify the association.

METHODS: Data from the Sleep Heart Health Study, a community-based study on the consequences of SDB, were used to characterize the association between SDB and caffeine intake. SDB was assessed with full-montage polysomnography. Caffeine use was quantified as the number of cans of soda or the cups of coffee or tea consumed daily. The Epworth Sleepiness Scale was used to assess daytime sleepiness. Multivariable negative binomial regression models were used to characterize the independent association between SDB and caffeine use.

RESULTS: Caffeinated soda, but not tea or coffee, intake was independently associated with SDB severity. Compared with participants without SDB, the relative ratios for caffeinated soda consumption in women with mild, moderate, and severe SDB were 1.20 (CI, 1.03-1.41), 1.46 (CI, 1.14-1.87), and 1.73 (CI, 1.23-2.42), respectively. For men, an association was only noted with severe SDB and caffeinated soda use. Age did not modify the SDB-caffeine association, and sleepiness could not explain the observed associations.

CONCLUSIONS: SDB is independently associated with caffeinated soda use in the general community. Identifying excessive caffeine used in SDB has potential significance given the cardiovascular effects of caffeine and untreated SDB.

%B Chest %V 142 %P 631-638 %8 2012 Sep %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/22459776?dopt=Abstract %R 10.1378/chest.11-2894 %0 Journal Article %J Arch Intern Med %D 2012 %T Subclinical hyperthyroidism and the risk of coronary heart disease and mortality. %A Collet, Tinh-Hai %A Gussekloo, Jacobijn %A Bauer, Douglas C %A den Elzen, Wendy P J %A Cappola, Anne R %A Balmer, Philippe %A Iervasi, Giorgio %A Asvold, Bjørn O %A Sgarbi, José A %A Völzke, Henry %A Gencer, Bariş %A Maciel, Rui M B %A Molinaro, Sabrina %A Bremner, Alexandra %A Luben, Robert N %A Maisonneuve, Patrick %A Cornuz, Jacques %A Newman, Anne B %A Khaw, Kay-Tee %A Westendorp, Rudi G J %A Franklyn, Jayne A %A Vittinghoff, Eric %A Walsh, John P %A Rodondi, Nicolas %K Adolescent %K Adult %K Age Distribution %K Aged %K Aged, 80 and over %K Atrial Fibrillation %K Cause of Death %K Cohort Studies %K Coronary Artery Disease %K Female %K Humans %K Hyperthyroidism %K Male %K Middle Aged %K Prognosis %K Prospective Studies %K Risk Assessment %K Severity of Illness Index %K Sex Distribution %K Survival Analysis %K Switzerland %K Thyroid Function Tests %K Thyrotropin %K Young Adult %X

BACKGROUND: Data from prospective cohort studies regarding the association between subclinical hyperthyroidism and cardiovascular outcomes are conflicting.We aimed to assess the risks of total and coronary heart disease (CHD) mortality, CHD events, and atrial fibrillation (AF) associated with endogenous subclinical hyperthyroidism among all available large prospective cohorts.

METHODS: Individual data on 52 674 participants were pooled from 10 cohorts. Coronary heart disease events were analyzed in 22 437 participants from 6 cohorts with available data, and incident AF was analyzed in 8711 participants from 5 cohorts. Euthyroidism was defined as thyrotropin level between 0.45 and 4.49 mIU/L and endogenous subclinical hyperthyroidism as thyrotropin level lower than 0.45 mIU/L with normal free thyroxine levels, after excluding those receiving thyroid-altering medications.

RESULTS: Of 52 674 participants, 2188 (4.2%) had subclinical hyperthyroidism. During follow-up, 8527 participants died (including 1896 from CHD), 3653 of 22 437 had CHD events, and 785 of 8711 developed AF. In age- and sex-adjusted analyses, subclinical hyperthyroidism was associated with increased total mortality (hazard ratio[HR], 1.24, 95% CI, 1.06-1.46), CHD mortality (HR,1.29; 95% CI, 1.02-1.62), CHD events (HR, 1.21; 95%CI, 0.99-1.46), and AF (HR, 1.68; 95% CI, 1.16-2.43).Risks did not differ significantly by age, sex, or preexisting cardiovascular disease and were similar after further adjustment for cardiovascular risk factors, with attributable risk of 14.5% for total mortality to 41.5% forAF in those with subclinical hyperthyroidism. Risks for CHD mortality and AF (but not other outcomes) were higher for thyrotropin level lower than 0.10 mIU/L compared with thyrotropin level between 0.10 and 0.44 mIU/L(for both, P value for trend, .03).

CONCLUSION: Endogenous subclinical hyperthyroidism is associated with increased risks of total, CHD mortality, and incident AF, with highest risks of CHD mortality and AF when thyrotropin level is lower than 0.10 mIU/L.

%B Arch Intern Med %V 172 %P 799-809 %8 2012 May 28 %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/22529182?dopt=Abstract %R 10.1001/archinternmed.2012.402 %0 Journal Article %J Circulation %D 2012 %T Subclinical thyroid dysfunction and the risk of heart failure events: an individual participant data analysis from 6 prospective cohorts. %A Gencer, Bariş %A Collet, Tinh-Hai %A Virgini, Vanessa %A Bauer, Douglas C %A Gussekloo, Jacobijn %A Cappola, Anne R %A Nanchen, David %A den Elzen, Wendy P J %A Balmer, Philippe %A Luben, Robert N %A Iacoviello, Massimo %A Triggiani, Vincenzo %A Cornuz, Jacques %A Newman, Anne B %A Khaw, Kay-Tee %A Jukema, J Wouter %A Westendorp, Rudi G J %A Vittinghoff, Eric %A Aujesky, Drahomir %A Rodondi, Nicolas %K Adult %K Aged %K Aged, 80 and over %K Comorbidity %K Female %K Follow-Up Studies %K Heart Failure %K Humans %K Hypothyroidism %K Male %K Middle Aged %K Prospective Studies %K Risk %K Risk Factors %K Sensitivity and Specificity %K Thyrotropin %K Thyroxine %X

BACKGROUND: American College of Cardiology/American Heart Association guidelines for the diagnosis and management of heart failure recommend investigating exacerbating conditions such as thyroid dysfunction, but without specifying the impact of different thyroid-stimulation hormone (TSH) levels. Limited prospective data exist on the association between subclinical thyroid dysfunction and heart failure events.

METHODS AND RESULTS: We performed a pooled analysis of individual participant data using all available prospective cohorts with thyroid function tests and subsequent follow-up of heart failure events. Individual data on 25 390 participants with 216 248 person-years of follow-up were supplied from 6 prospective cohorts in the United States and Europe. Euthyroidism was defined as TSH of 0.45 to 4.49 mIU/L, subclinical hypothyroidism as TSH of 4.5 to 19.9 mIU/L, and subclinical hyperthyroidism as TSH <0.45 mIU/L, the last two with normal free thyroxine levels. Among 25 390 participants, 2068 (8.1%) had subclinical hypothyroidism and 648 (2.6%) had subclinical hyperthyroidism. In age- and sex-adjusted analyses, risks of heart failure events were increased with both higher and lower TSH levels (P for quadratic pattern <0.01); the hazard ratio was 1.01 (95% confidence interval, 0.81-1.26) for TSH of 4.5 to 6.9 mIU/L, 1.65 (95% confidence interval, 0.84-3.23) for TSH of 7.0 to 9.9 mIU/L, 1.86 (95% confidence interval, 1.27-2.72) for TSH of 10.0 to 19.9 mIU/L (P for trend <0.01) and 1.31 (95% confidence interval, 0.88-1.95) for TSH of 0.10 to 0.44 mIU/L and 1.94 (95% confidence interval, 1.01-3.72) for TSH <0.10 mIU/L (P for trend=0.047). Risks remained similar after adjustment for cardiovascular risk factors.

CONCLUSION: Risks of heart failure events were increased with both higher and lower TSH levels, particularly for TSH ≥10 and <0.10 mIU/L.

%B Circulation %V 126 %P 1040-9 %8 2012 Aug 28 %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/22821943?dopt=Abstract %R 10.1161/CIRCULATIONAHA.112.096024 %0 Journal Article %J Genetics %D 2012 %T Ultraconserved elements in the human genome: association and transmission analyses of highly constrained single-nucleotide polymorphisms. %A Chiang, Charleston W K %A Liu, Ching-Ti %A Lettre, Guillaume %A Lange, Leslie A %A Jorgensen, Neal W %A Keating, Brendan J %A Vedantam, Sailaja %A Nock, Nora L %A Franceschini, Nora %A Reiner, Alex P %A Demerath, Ellen W %A Boerwinkle, Eric %A Rotter, Jerome I %A Wilson, James G %A North, Kari E %A Papanicolaou, George J %A Cupples, L Adrienne %A Murabito, Joanne M %A Hirschhorn, Joel N %K Alleles %K Animals %K Body Height %K Body Mass Index %K Child %K Conserved Sequence %K Dogs %K Evolution, Molecular %K Female %K Genetic Fitness %K Genetic Variation %K Genome, Human %K Genotype %K Humans %K Inheritance Patterns %K Male %K Mice %K Pedigree %K Phenotype %K Polymorphism, Single Nucleotide %K Rats %K Reproduction %K Young Adult %X

Ultraconserved elements in the human genome likely harbor important biological functions as they are dosage sensitive and are able to direct tissue-specific expression. Because they are under purifying selection, variants in these elements may have a lower frequency in the population but a higher likelihood of association with complex traits. We tested a set of highly constrained SNPs (hcSNPs) distributed genome-wide among ultraconserved and nearly ultraconserved elements for association with seven traits related to reproductive (age at natural menopause, number of children, age at first child, and age at last child) and overall [longevity, body mass index (BMI), and height] fitness. Using up to 24,047 European-American samples from the National Heart, Lung, and Blood Institute Candidate Gene Association Resource (CARe), we observed an excess of associations with BMI and height. In an independent replication panel the most strongly associated SNPs showed an 8.4-fold enrichment of associations at the nominal level, including three variants in previously identified loci and one in a locus (DENND1A) previously shown to be associated with polycystic ovary syndrome. Finally, using 1430 family trios, we showed that the transmissions from heterozygous parents to offspring of the derived alleles of rare (frequency ≤ 0.5%) hcSNPs are not biased, particularly after adjusting for the rates of genotype missingness and error in the data. The lack of transmission bias ruled out an immediately and strongly deleterious effect due to the rare derived alleles, consistent with the observation that mice homozygous for the deletion of ultraconserved elements showed no overt phenotype. Our study also illustrated the importance of carefully modeling potential technical confounders when analyzing genotype data of rare variants.

%B Genetics %V 192 %P 253-66 %8 2012 Sep %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/22714408?dopt=Abstract %R 10.1534/genetics.112.141945 %0 Journal Article %J Neurobiol Aging %D 2012 %T White matter lesions and brain gray matter volume in cognitively normal elders. %A Raji, Cyrus A %A Lopez, Oscar L %A Kuller, Lewis H %A Carmichael, Owen T %A Longstreth, William T %A Gach, H Michael %A Boardman, John %A Bernick, Charles B %A Thompson, Paul M %A Becker, James T %K Aged %K Aged, 80 and over %K Aging %K Apolipoprotein E4 %K Brain %K Cognition Disorders %K Female %K Humans %K Imaging, Three-Dimensional %K Leukoaraiosis %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Memory Disorders %K Mental Status Schedule %K Neuropsychological Tests %K Regression Analysis %K Retrospective Studies %X

Cerebral white matter lesions (WMLs) reflect small vessel disease, are common in elderly individuals, and are associated with cognitive impairment. We sought to determine the relationships between WMLs, age, gray matter (GM) volume, and cognition in the Cardiovascular Health Study (CHS). From the Cardiovascular Health Study we selected 740 cognitively normal controls with a 1.5 T magnetic resonance imaging (MRI) scan of the brain and a detailed diagnostic evaluation. WML severity was determined using a standardized visual rating system. GM volumes were analyzed using voxel-based morphometry implemented in the Statistical Parametric Mapping software. WMLs were inversely correlated with GM volume, with the greatest volume loss in the frontal cortex. Age-related atrophy was observed in the hippocampus and posterior cingulate cortex. Regression analyses revealed links among age, APOE*4 allele, hypertension, WMLs, GM volume, and digit symbol substitution test scores. Both advancing age and hypertension predict higher WML load, which is itself associated with GM atrophy. Longitudinal data are needed to confirm the temporal sequence of events leading to a decline in cognitive function.

%B Neurobiol Aging %V 33 %P 834.e7-16 %8 2012 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/21943959?dopt=Abstract %R 10.1016/j.neurobiolaging.2011.08.010 %0 Journal Article %J Osteoporos Int %D 2013 %T Albuminuria is associated with hip fracture risk in older adults: the cardiovascular health study. %A Barzilay, J I %A Bůžková, P %A Chen, Z %A de Boer, I H %A Carbone, L %A Rassouli, N N %A Fink, H A %A Robbins, J A %K Aged %K Aged, 80 and over %K Albuminuria %K Bone Density %K Female %K Follow-Up Studies %K Hip Fractures %K Hip Joint %K Humans %K Incidence %K Kaplan-Meier Estimate %K Male %K Osteoporotic Fractures %K Risk Factors %K Sex Factors %K United States %X

UNLABELLED: The microcirculation plays an important role in bone health. Here, we examine whether albuminuria, a marker of renal microvascular disease, is associated with the risk of hip fracture in older adults (age, 78 years). We find a small independent association in women but not in men.

INTRODUCTION: The microvascular circulation plays an important role in bone physiology. Two studies of middle-aged adults have found that albuminuria (>30 mg albumin/g creatinine), a disorder of the renal microvasculature, is associated with fracture risk. Here, we examine whether albuminuria is related to hip fracture risk and reduced hip bone mineral density (BMD) in older adults with a mean age of 78 years.

METHODS: From the Cardiovascular Health Study (41 % male), 3,110 adults with albuminuria testing were followed up for incident hip fracture for up to 9.5 years. BMD was performed in a subset of 1,208 participants.

RESULTS: There were 313 hip fractures during follow-up (7.7 % of men; 11.7 % of women). The incidence rate for men, with and without albuminuria, was 1.43 and 0.93/100 person-years of follow-up (p = 0.02); for women, 1.84 and 1.33 (p = 0.04). After adjustment for osteoporosis-related factors, frailty and falling, a doubling of albuminuria was significantly associated with hip fracture risk in women (hazard ratio, 1.12, 95 % CI, 1.001-1.25), but not in men. In the subcohort with BMD measurement, increased urine albumin levels were significantly associated with decreased total hip BMD in men (-0.009 g calcium/cm(2) (-0.017, -0.001); p = 0.04), but not in women.

CONCLUSIONS: In older women, albuminuria is associated with a small, but statistically significant, increased risk of hip fracture independent of other explanatory factors. No such risk appears to be present in men, although their total hip BMD is lower in association with albuminuria.

%B Osteoporos Int %V 24 %P 2993-3000 %8 2013 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/23702700?dopt=Abstract %R 10.1007/s00198-013-2389-3 %0 Journal Article %J Am J Epidemiol %D 2013 %T Association of functional polymorphism rs2231142 (Q141K) in the ABCG2 gene with serum uric acid and gout in 4 US populations: the PAGE Study. %A Zhang, Lili %A Spencer, Kylee L %A Voruganti, V Saroja %A Jorgensen, Neal W %A Fornage, Myriam %A Best, Lyle G %A Brown-Gentry, Kristin D %A Cole, Shelley A %A Crawford, Dana C %A Deelman, Ewa %A Franceschini, Nora %A Gaffo, Angelo L %A Glenn, Kimberly R %A Heiss, Gerardo %A Jenny, Nancy S %A Köttgen, Anna %A Li, Qiong %A Liu, Kiang %A Matise, Tara C %A North, Kari E %A Umans, Jason G %A Kao, W H Linda %K Adult %K African Americans %K Age Distribution %K ATP-Binding Cassette Transporters %K Comorbidity %K European Continental Ancestry Group %K Female %K Genetic Predisposition to Disease %K Genetics, Population %K Genome-Wide Association Study %K Gout %K Hormone Replacement Therapy %K Humans %K Indians, North American %K Male %K Mexican Americans %K Middle Aged %K Neoplasm Proteins %K Polymorphism, Genetic %K Postmenopause %K Sex Distribution %K United States %K Uric Acid %X

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

%B Am J Epidemiol %V 177 %P 923-32 %8 2013 May 1 %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/23552988?dopt=Abstract %R 10.1093/aje/kws330 %0 Journal Article %J Circ Cardiovasc Genet %D 2013 %T Association of genome-wide variation with highly sensitive cardiac troponin-T levels in European Americans and Blacks: a meta-analysis from atherosclerosis risk in communities and cardiovascular health studies. %A Yu, Bing %A Barbalic, Maja %A Brautbar, Ariel %A Nambi, Vijay %A Hoogeveen, Ron C %A Tang, Weihong %A Mosley, Thomas H %A Rotter, Jerome I %A deFilippi, Christopher R %A O'Donnell, Christopher J %A Kathiresan, Sekar %A Rice, Ken %A Heckbert, Susan R %A Ballantyne, Christie M %A Psaty, Bruce M %A Boerwinkle, Eric %K African Continental Ancestry Group %K Atherosclerosis %K European Continental Ancestry Group %K Female %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Nuclear Receptor Coactivator 2 %K Polymorphism, Single Nucleotide %K Prospective Studies %K Residence Characteristics %K Risk Factors %K Troponin T %X

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

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

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

%B Circ Cardiovasc Genet %V 6 %P 82-8 %8 2013 Feb %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/23247143?dopt=Abstract %R 10.1161/CIRCGENETICS.112.963058 %0 Journal Article %J JAMA Intern Med %D 2013 %T Atrial fibrillation and the risk of sudden cardiac death: the atherosclerosis risk in communities study and cardiovascular health study. %A Chen, Lin Y %A Sotoodehnia, Nona %A Bůzková, Petra %A Lopez, Faye L %A Yee, Laura M %A Heckbert, Susan R %A Prineas, Ronald %A Soliman, Elsayed Z %A Adabag, Selcuk %A Konety, Suma %A Folsom, Aaron R %A Siscovick, David %A Alonso, Alvaro %K Aged %K Atrial Fibrillation %K Cardiovascular Diseases %K Death, Sudden, Cardiac %K Demography %K Ethnic Groups %K Female %K Humans %K Incidence %K Male %K Middle Aged %K Proportional Hazards Models %K Risk Assessment %K Risk Factors %K Sex Factors %K United States %X

BACKGROUND: It is unknown whether atrial fibrillation (AF) is associated with an increased risk of sudden cardiac death (SCD) in the general population. This association was examined in 2 population-based cohorts.

METHODS: In the Atherosclerosis Risk in Communities (ARIC) Study, we analyzed data from 15 439 participants (baseline age, 45-64 years; 55.2% women; and 26.6% black) from baseline (1987-1989) through December 31, 2001. In the Cardiovascular Health Study (CHS), we analyzed data from 5479 participants (baseline age, ≥65 years; 58.2% women; and 15.4% black) from baseline (first cohort, 1989-1990; second cohort, 1992-1993) through December 31, 2006. The main outcome was physician-adjudicated SCD, defined as death from a sudden, pulseless condition presumed to be due to a ventricular tachyarrhythmia. The secondary outcome was non-SCD (NSCD), defined as coronary heart disease death not meeting SCD criteria. We used Cox proportional hazards models to assess the association between AF and SCD/NSCD, adjusting for baseline demographic and cardiovascular risk factors.

RESULTS: In the ARIC Study, 894 AF, 269 SCD, and 233 NSCD events occurred during follow-up (median, 13.1 years). The crude incidence rates of SCD were 2.89 per 1000 person-years (with AF) and 1.30 per 1000 person-years (without AF). The multivariable hazard ratios (HRs) (95% CIs) of AF for SCD and NSCD were 3.26 (2.17-4.91) and 2.43 (1.60-3.71), respectively. In the CHS, 1458 AF, 292 SCD, and 581 NSCD events occurred during follow-up (median, 13.1 years). The crude incidence rates of SCD were 12.00 per 1000 person-years (with AF) and 3.82 per 1000 person-years (without AF). The multivariable HRs (95% CIs) of AF for SCD and NSCD were 2.14 (1.60-2.87) and 3.10 (2.58-3.72), respectively. The meta-analyzed HRs (95% CIs) of AF for SCD and NSCD were 2.47 (1.95-3.13) and 2.98 (2.52-3.53), respectively.

CONCLUSIONS: Incident AF is associated with an increased risk of SCD and NSCD in the general population. Additional research to identify predictors of SCD in patients with AF is warranted.

%B JAMA Intern Med %V 173 %P 29-35 %8 2013 Jan 14 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/23404043?dopt=Abstract %R 10.1001/2013.jamainternmed.744 %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 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 Heart Rhythm %D 2013 %T Common genetic variation near the connexin-43 gene is associated with resting heart rate in African Americans: a genome-wide association study of 13,372 participants. %A Deo, R %A Nalls, M A %A Avery, C L %A Smith, J G %A Evans, D S %A Keller, M F %A Butler, A M %A Buxbaum, S G %A Li, G %A Miguel Quibrera, P %A Smith, E N %A Tanaka, T %A Akylbekova, E L %A Alonso, A %A Arking, D E %A Benjamin, E J %A Berenson, G S %A Bis, J C %A Chen, L Y %A Chen, W %A Cummings, S R %A Ellinor, P T %A Evans, M K %A Ferrucci, L %A Fox, E R %A Heckbert, S R %A Heiss, G %A Hsueh, W C %A Kerr, K F %A Limacher, M C %A Liu, Y %A Lubitz, S A %A Magnani, J W %A Mehra, R %A Marcus, G M %A Murray, S S %A Newman, A B %A Njajou, O %A North, K E %A Paltoo, D N %A Psaty, B M %A Redline, S S %A Reiner, A P %A Robinson, J G %A Rotter, J I %A Samdarshi, T E %A Schnabel, R B %A Schork, N J %A Singleton, A B %A Siscovick, D %A Soliman, E Z %A Sotoodehnia, N %A Srinivasan, S R %A Taylor, H A %A Trevisan, M %A Zhang, Z %A Zonderman, A B %A Newton-Cheh, C %A Whitsel, E A %K Adult %K African Americans %K Aged %K Arrhythmias, Cardiac %K Connexin 43 %K Electrocardiography %K Female %K Genetic Variation %K Genome-Wide Association Study %K Genotype %K Heart Rate %K Humans %K Male %K Meta-Analysis as Topic %K Middle Aged %K Polymorphism, Single Nucleotide %K Rest %K United States %X

BACKGROUND: Genome-wide association studies have identified several genetic loci associated with variation in resting heart rate in European and Asian populations. No study has evaluated genetic variants associated with heart rate in African Americans.

OBJECTIVE: To identify novel genetic variants associated with resting heart rate in African Americans.

METHODS: Ten cohort studies participating in the Candidate-gene Association Resource and Continental Origins and Genetic Epidemiology Network consortia performed genome-wide genotyping of single nucleotide polymorphisms (SNPs) and imputed 2,954,965 SNPs using HapMap YRI and CEU panels in 13,372 participants of African ancestry. Each study measured the RR interval (ms) from 10-second resting 12-lead electrocardiograms and estimated RR-SNP associations using covariate-adjusted linear regression. Random-effects meta-analysis was used to combine cohort-specific measures of association and identify genome-wide significant loci (P≤2.5×10(-8)).

RESULTS: Fourteen SNPs on chromosome 6q22 exceeded the genome-wide significance threshold. The most significant association was for rs9320841 (+13 ms per minor allele; P = 4.98×10(-15)). This SNP was approximately 350 kb downstream of GJA1, a locus previously identified as harboring SNPs associated with heart rate in Europeans. Adjustment for rs9320841 also attenuated the association between the remaining 13 SNPs in this region and heart rate. In addition, SNPs in MYH6, which have been identified in European genome-wide association study, were associated with similar changes in the resting heart rate as this population of African Americans.

CONCLUSIONS: An intergenic region downstream of GJA1 (the gene encoding connexin 43, the major protein of the human myocardial gap junction) and an intragenic region within MYH6 are associated with variation in resting heart rate in African Americans as well as in populations of European and Asian origin.

%B Heart Rhythm %V 10 %P 401-8 %8 2013 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/23183192?dopt=Abstract %R 10.1016/j.hrthm.2012.11.014 %0 Journal Article %J Nat Genet %D 2013 %T Common variants associated with plasma triglycerides and risk for coronary artery disease. %A Do, Ron %A Willer, Cristen J %A Schmidt, Ellen M %A Sengupta, Sebanti %A Gao, Chi %A Peloso, Gina M %A Gustafsson, Stefan %A Kanoni, Stavroula %A Ganna, Andrea %A Chen, Jin %A Buchkovich, Martin L %A Mora, Samia %A Beckmann, Jacques S %A Bragg-Gresham, Jennifer L %A Chang, Hsing-Yi %A Demirkan, Ayse %A Den Hertog, Heleen M %A Donnelly, Louise A %A Ehret, Georg B %A Esko, Tõnu %A Feitosa, Mary F %A Ferreira, Teresa %A Fischer, Krista %A Fontanillas, Pierre %A Fraser, Ross M %A Freitag, Daniel F %A Gurdasani, Deepti %A Heikkilä, Kauko %A Hyppönen, Elina %A Isaacs, Aaron %A Jackson, Anne U %A Johansson, Asa %A Johnson, Toby %A Kaakinen, Marika %A Kettunen, Johannes %A Kleber, Marcus E %A Li, Xiaohui %A Luan, Jian'an %A Lyytikäinen, Leo-Pekka %A Magnusson, Patrik K E %A Mangino, Massimo %A Mihailov, Evelin %A Montasser, May E %A Müller-Nurasyid, Martina %A Nolte, Ilja M %A O'Connell, Jeffrey R %A Palmer, Cameron D %A Perola, Markus %A Petersen, Ann-Kristin %A Sanna, Serena %A Saxena, Richa %A Service, Susan K %A Shah, Sonia %A Shungin, Dmitry %A Sidore, Carlo %A Song, Ci %A Strawbridge, Rona J %A Surakka, Ida %A Tanaka, Toshiko %A Teslovich, Tanya M %A Thorleifsson, Gudmar %A van den Herik, Evita G %A Voight, Benjamin F %A Volcik, Kelly A %A Waite, Lindsay L %A Wong, Andrew %A Wu, Ying %A Zhang, Weihua %A Absher, Devin %A Asiki, Gershim %A Barroso, Inês %A Been, Latonya F %A Bolton, Jennifer L %A Bonnycastle, Lori L %A Brambilla, Paolo %A Burnett, Mary S %A Cesana, Giancarlo %A Dimitriou, Maria %A Doney, Alex S F %A Döring, Angela %A Elliott, Paul %A Epstein, Stephen E %A Eyjolfsson, Gudmundur Ingi %A Gigante, Bruna %A Goodarzi, Mark O %A Grallert, Harald %A Gravito, Martha L %A Groves, Christopher J %A Hallmans, Göran %A Hartikainen, Anna-Liisa %A Hayward, Caroline %A Hernandez, Dena %A Hicks, Andrew A %A Holm, Hilma %A Hung, Yi-Jen %A Illig, Thomas %A Jones, Michelle R %A Kaleebu, Pontiano %A Kastelein, John J P %A Khaw, Kay-Tee %A Kim, Eric %A Klopp, Norman %A Komulainen, Pirjo %A Kumari, Meena %A Langenberg, Claudia %A Lehtimäki, Terho %A Lin, Shih-Yi %A Lindström, Jaana %A Loos, Ruth J F %A Mach, François %A McArdle, Wendy L %A Meisinger, Christa %A Mitchell, Braxton D %A Müller, Gabrielle %A Nagaraja, Ramaiah %A Narisu, Narisu %A Nieminen, Tuomo V M %A Nsubuga, Rebecca N %A Olafsson, Isleifur %A Ong, Ken K %A Palotie, Aarno %A Papamarkou, Theodore %A Pomilla, Cristina %A Pouta, Anneli %A Rader, Daniel J %A Reilly, Muredach P %A Ridker, Paul M %A Rivadeneira, Fernando %A Rudan, Igor %A Ruokonen, Aimo %A Samani, Nilesh %A Scharnagl, Hubert %A Seeley, Janet %A Silander, Kaisa %A Stančáková, Alena %A Stirrups, Kathleen %A Swift, Amy J %A Tiret, Laurence %A Uitterlinden, André G %A van Pelt, L Joost %A Vedantam, Sailaja %A Wainwright, Nicholas %A Wijmenga, Cisca %A Wild, Sarah H %A Willemsen, Gonneke %A Wilsgaard, Tom %A Wilson, James F %A Young, Elizabeth H %A Zhao, Jing Hua %A Adair, Linda S %A Arveiler, Dominique %A Assimes, Themistocles L %A Bandinelli, Stefania %A Bennett, Franklyn %A Bochud, Murielle %A Boehm, Bernhard O %A Boomsma, Dorret I %A Borecki, Ingrid B %A Bornstein, Stefan R %A Bovet, Pascal %A Burnier, Michel %A Campbell, Harry %A Chakravarti, Aravinda %A Chambers, John C %A Chen, Yii-Der Ida %A Collins, Francis S %A Cooper, Richard S %A Danesh, John %A Dedoussis, George %A de Faire, Ulf %A Feranil, Alan B %A Ferrieres, Jean %A Ferrucci, Luigi %A Freimer, Nelson B %A Gieger, Christian %A Groop, Leif C %A Gudnason, Vilmundur %A Gyllensten, Ulf %A Hamsten, Anders %A Harris, Tamara B %A Hingorani, Aroon %A Hirschhorn, Joel N %A Hofman, Albert %A Hovingh, G Kees %A Hsiung, Chao Agnes %A Humphries, Steve E %A Hunt, Steven C %A Hveem, Kristian %A Iribarren, Carlos %A Jarvelin, Marjo-Riitta %A Jula, Antti %A Kähönen, Mika %A Kaprio, Jaakko %A Kesäniemi, Antero %A Kivimaki, Mika %A Kooner, Jaspal S %A Koudstaal, Peter J %A Krauss, Ronald M %A Kuh, Diana %A Kuusisto, Johanna %A Kyvik, Kirsten O %A Laakso, Markku %A Lakka, Timo A %A Lind, Lars %A Lindgren, Cecilia M %A Martin, Nicholas G %A März, Winfried %A McCarthy, Mark I %A McKenzie, Colin A %A Meneton, Pierre %A Metspalu, Andres %A Moilanen, Leena %A Morris, Andrew D %A Munroe, Patricia B %A Njølstad, Inger %A Pedersen, Nancy L %A Power, Chris %A Pramstaller, Peter P %A Price, Jackie F %A Psaty, Bruce M %A Quertermous, Thomas %A Rauramaa, Rainer %A Saleheen, Danish %A Salomaa, Veikko %A Sanghera, Dharambir K %A Saramies, Jouko %A Schwarz, Peter E H %A Sheu, Wayne H-H %A Shuldiner, Alan R %A Siegbahn, Agneta %A Spector, Tim D %A Stefansson, Kari %A Strachan, David P %A Tayo, Bamidele O %A Tremoli, Elena %A Tuomilehto, Jaakko %A Uusitupa, Matti %A van Duijn, Cornelia M %A Vollenweider, Peter %A Wallentin, Lars %A Wareham, Nicholas J %A Whitfield, John B %A Wolffenbuttel, Bruce H R %A Altshuler, David %A Ordovas, Jose M %A Boerwinkle, Eric %A Palmer, Colin N A %A Thorsteinsdottir, Unnur %A Chasman, Daniel I %A Rotter, Jerome I %A Franks, Paul W %A Ripatti, Samuli %A Cupples, L Adrienne %A Sandhu, Manjinder S %A Rich, Stephen S %A Boehnke, Michael %A Deloukas, Panos %A Mohlke, Karen L %A Ingelsson, Erik %A Abecasis, Goncalo R %A Daly, Mark J %A Neale, Benjamin M %A Kathiresan, Sekar %K Biological Transport %K Cholesterol, HDL %K Cholesterol, LDL %K Coronary Artery Disease %K Humans %K Polymorphism, Single Nucleotide %K Risk Factors %K Triglycerides %X

Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.

%B Nat Genet %V 45 %P 1345-52 %8 2013 Nov %G eng %N 11 %R 10.1038/ng.2795 %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 N Engl J Med %D 2013 %T Cystatin C versus creatinine in determining risk based on kidney function. %A Shlipak, Michael G %A Matsushita, Kunihiro %A Arnlöv, Johan %A Inker, Lesley A %A Katz, Ronit %A Polkinghorne, Kevan R %A Rothenbacher, Dietrich %A Sarnak, Mark J %A Astor, Brad C %A Coresh, Josef %A Levey, Andrew S %A Gansevoort, Ron T %K Creatinine %K Cystatin C %K Glomerular Filtration Rate %K Humans %K Kidney Failure, Chronic %K Kidney Function Tests %K Reference Standards %K Renal Insufficiency, Chronic %K Risk %K Risk Assessment %X

BACKGROUND: Adding the measurement of cystatin C to that of serum creatinine to determine the estimated glomerular filtration rate (eGFR) improves accuracy, but the effect on detection, staging, and risk classification of chronic kidney disease across diverse populations has not been determined.

METHODS: We performed a meta-analysis of 11 general-population studies (with 90,750 participants) and 5 studies of cohorts with chronic kidney disease (2960 participants) for whom standardized measurements of serum creatinine and cystatin C were available. We compared the association of the eGFR, as calculated by the measurement of creatinine or cystatin C alone or in combination with creatinine, with the rates of death (13,202 deaths in 15 cohorts), death from cardiovascular causes (3471 in 12 cohorts), and end-stage renal disease (1654 cases in 7 cohorts) and assessed improvement in reclassification with the use of cystatin C.

RESULTS: In the general-population cohorts, the prevalence of an eGFR of less than 60 ml per minute per 1.73 m(2) of body-surface area was higher with the cystatin C-based eGFR than with the creatinine-based eGFR (13.7% vs. 9.7%). Across all eGFR categories, the reclassification of the eGFR to a higher value with the measurement of cystatin C, as compared with creatinine, was associated with a reduced risk of all three study outcomes, and reclassification to a lower eGFR was associated with an increased risk. The net reclassification improvement with the measurement of cystatin C, as compared with creatinine, was 0.23 (95% confidence interval [CI], 0.18 to 0.28) for death and 0.10 (95% CI, 0.00 to 0.21) for end-stage renal disease. Results were generally similar for the five cohorts with chronic kidney disease and when both creatinine and cystatin C were used to calculate the eGFR.

CONCLUSIONS: The use of cystatin C alone or in combination with creatinine strengthens the association between the eGFR and the risks of death and end-stage renal disease across diverse populations. (Funded by the National Kidney Foundation and others.).

%B N Engl J Med %V 369 %P 932-43 %8 2013 Sep 05 %G eng %N 10 %R 10.1056/NEJMoa1214234 %0 Journal Article %J Nat Genet %D 2013 %T Discovery and refinement of loci associated with lipid levels. %A Willer, Cristen J %A Schmidt, Ellen M %A Sengupta, Sebanti %A Peloso, Gina M %A Gustafsson, Stefan %A Kanoni, Stavroula %A Ganna, Andrea %A Chen, Jin %A Buchkovich, Martin L %A Mora, Samia %A Beckmann, Jacques S %A Bragg-Gresham, Jennifer L %A Chang, Hsing-Yi %A Demirkan, Ayse %A Den Hertog, Heleen M %A Do, Ron %A Donnelly, Louise A %A Ehret, Georg B %A Esko, Tõnu %A Feitosa, Mary F %A Ferreira, Teresa %A Fischer, Krista %A Fontanillas, Pierre %A Fraser, Ross M %A Freitag, Daniel F %A Gurdasani, Deepti %A Heikkilä, Kauko %A Hyppönen, Elina %A Isaacs, Aaron %A Jackson, Anne U %A Johansson, Asa %A Johnson, Toby %A Kaakinen, Marika %A Kettunen, Johannes %A Kleber, Marcus E %A Li, Xiaohui %A Luan, Jian'an %A Lyytikäinen, Leo-Pekka %A Magnusson, Patrik K E %A Mangino, Massimo %A Mihailov, Evelin %A Montasser, May E %A Müller-Nurasyid, Martina %A Nolte, Ilja M %A O'Connell, Jeffrey R %A Palmer, Cameron D %A Perola, Markus %A Petersen, Ann-Kristin %A Sanna, Serena %A Saxena, Richa %A Service, Susan K %A Shah, Sonia %A Shungin, Dmitry %A Sidore, Carlo %A Song, Ci %A Strawbridge, Rona J %A Surakka, Ida %A Tanaka, Toshiko %A Teslovich, Tanya M %A Thorleifsson, Gudmar %A van den Herik, Evita G %A Voight, Benjamin F %A Volcik, Kelly A %A Waite, Lindsay L %A Wong, Andrew %A Wu, Ying %A Zhang, Weihua %A Absher, Devin %A Asiki, Gershim %A Barroso, Inês %A Been, Latonya F %A Bolton, Jennifer L %A Bonnycastle, Lori L %A Brambilla, Paolo %A Burnett, Mary S %A Cesana, Giancarlo %A Dimitriou, Maria %A Doney, Alex S F %A Döring, Angela %A Elliott, Paul %A Epstein, Stephen E %A Ingi Eyjolfsson, Gudmundur %A Gigante, Bruna %A Goodarzi, Mark O %A Grallert, Harald %A Gravito, Martha L %A Groves, Christopher J %A Hallmans, Göran %A Hartikainen, Anna-Liisa %A Hayward, Caroline %A Hernandez, Dena %A Hicks, Andrew A %A Holm, Hilma %A Hung, Yi-Jen %A Illig, Thomas %A Jones, Michelle R %A Kaleebu, Pontiano %A Kastelein, John J P %A Khaw, Kay-Tee %A Kim, Eric %A Klopp, Norman %A Komulainen, Pirjo %A Kumari, Meena %A Langenberg, Claudia %A Lehtimäki, Terho %A Lin, Shih-Yi %A Lindström, Jaana %A Loos, Ruth J F %A Mach, François %A McArdle, Wendy L %A Meisinger, Christa %A Mitchell, Braxton D %A Müller, Gabrielle %A Nagaraja, Ramaiah %A Narisu, Narisu %A Nieminen, Tuomo V M %A Nsubuga, Rebecca N %A Olafsson, Isleifur %A Ong, Ken K %A Palotie, Aarno %A Papamarkou, Theodore %A Pomilla, Cristina %A Pouta, Anneli %A Rader, Daniel J %A Reilly, Muredach P %A Ridker, Paul M %A Rivadeneira, Fernando %A Rudan, Igor %A Ruokonen, Aimo %A Samani, Nilesh %A Scharnagl, Hubert %A Seeley, Janet %A Silander, Kaisa %A Stančáková, Alena %A Stirrups, Kathleen %A Swift, Amy J %A Tiret, Laurence %A Uitterlinden, André G %A van Pelt, L Joost %A Vedantam, Sailaja %A Wainwright, Nicholas %A Wijmenga, Cisca %A Wild, Sarah H %A Willemsen, Gonneke %A Wilsgaard, Tom %A Wilson, James F %A Young, Elizabeth H %A Zhao, Jing Hua %A Adair, Linda S %A Arveiler, Dominique %A Assimes, Themistocles L %A Bandinelli, Stefania %A Bennett, Franklyn %A Bochud, Murielle %A Boehm, Bernhard O %A Boomsma, Dorret I %A Borecki, Ingrid B %A Bornstein, Stefan R %A Bovet, Pascal %A Burnier, Michel %A Campbell, Harry %A Chakravarti, Aravinda %A Chambers, John C %A Chen, Yii-Der Ida %A Collins, Francis S %A Cooper, Richard S %A Danesh, John %A Dedoussis, George %A de Faire, Ulf %A Feranil, Alan B %A Ferrieres, Jean %A Ferrucci, Luigi %A Freimer, Nelson B %A Gieger, Christian %A Groop, Leif C %A Gudnason, Vilmundur %A Gyllensten, Ulf %A Hamsten, Anders %A Harris, Tamara B %A Hingorani, Aroon %A Hirschhorn, Joel N %A Hofman, Albert %A Hovingh, G Kees %A Hsiung, Chao Agnes %A Humphries, Steve E %A Hunt, Steven C %A Hveem, Kristian %A Iribarren, Carlos %A Jarvelin, Marjo-Riitta %A Jula, Antti %A Kähönen, Mika %A Kaprio, Jaakko %A Kesäniemi, Antero %A Kivimaki, Mika %A Kooner, Jaspal S %A Koudstaal, Peter J %A Krauss, Ronald M %A Kuh, Diana %A Kuusisto, Johanna %A Kyvik, Kirsten O %A Laakso, Markku %A Lakka, Timo A %A Lind, Lars %A Lindgren, Cecilia M %A Martin, Nicholas G %A März, Winfried %A McCarthy, Mark I %A McKenzie, Colin A %A Meneton, Pierre %A Metspalu, Andres %A Moilanen, Leena %A Morris, Andrew D %A Munroe, Patricia B %A Njølstad, Inger %A Pedersen, Nancy L %A Power, Chris %A Pramstaller, Peter P %A Price, Jackie F %A Psaty, Bruce M %A Quertermous, Thomas %A Rauramaa, Rainer %A Saleheen, Danish %A Salomaa, Veikko %A Sanghera, Dharambir K %A Saramies, Jouko %A Schwarz, Peter E H %A Sheu, Wayne H-H %A Shuldiner, Alan R %A Siegbahn, Agneta %A Spector, Tim D %A Stefansson, Kari %A Strachan, David P %A Tayo, Bamidele O %A Tremoli, Elena %A Tuomilehto, Jaakko %A Uusitupa, Matti %A van Duijn, Cornelia M %A Vollenweider, Peter %A Wallentin, Lars %A Wareham, Nicholas J %A Whitfield, John B %A Wolffenbuttel, Bruce H R %A Ordovas, Jose M %A Boerwinkle, Eric %A Palmer, Colin N A %A Thorsteinsdottir, Unnur %A Chasman, Daniel I %A Rotter, Jerome I %A Franks, Paul W %A Ripatti, Samuli %A Cupples, L Adrienne %A Sandhu, Manjinder S %A Rich, Stephen S %A Boehnke, Michael %A Deloukas, Panos %A Kathiresan, Sekar %A Mohlke, Karen L %A Ingelsson, Erik %A Abecasis, Goncalo R %K African Continental Ancestry Group %K Asian Continental Ancestry Group %K Cholesterol, HDL %K Cholesterol, LDL %K Coronary Artery Disease %K European Continental Ancestry Group %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Lipids %K Triglycerides %X

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

%B Nat Genet %V 45 %P 1274-1283 %8 2013 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/24097068?dopt=Abstract %R 10.1038/ng.2797 %0 Journal Article %J BMC Med Genet %D 2013 %T Effects of smoking on the genetic risk of obesity: the population architecture using genomics and epidemiology study. %A Fesinmeyer, Megan D %A North, Kari E %A Lim, Unhee %A Bůzková, Petra %A Crawford, Dana C %A Haessler, Jeffrey %A Gross, Myron D %A Fowke, Jay H %A Goodloe, Robert %A Love, Shelley-Ann %A Graff, Misa %A Carlson, Christopher S %A Kuller, Lewis H %A Matise, Tara C %A Hong, Ching-Ping %A Henderson, Brian E %A Allen, Melissa %A Rohde, Rebecca R %A Mayo, Ping %A Schnetz-Boutaud, Nathalie %A Monroe, Kristine R %A Ritchie, Marylyn D %A Prentice, Ross L %A Kolonel, Lawrence N %A Manson, JoAnn E %A Pankow, James %A Hindorff, Lucia A %A Franceschini, Nora %A Wilkens, Lynne R %A Haiman, Christopher A %A Le Marchand, Loïc %A Peters, Ulrike %K Adolescent %K Adult %K African Americans %K Aged %K Alpha-Ketoglutarate-Dependent Dioxygenase FTO %K Body Mass Index %K European Continental Ancestry Group %K Female %K Genetic Predisposition to Disease %K Humans %K Male %K Membrane Proteins %K Middle Aged %K Obesity %K Polymorphism, Single Nucleotide %K Proteins %K Risk Factors %K Smoking %K Young Adult %X

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

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

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

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

CLINICAL TRIAL REGISTRATION: NCT00000611.

%B BMC Med Genet %V 14 %P 6 %8 2013 Jan 11 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/23311614?dopt=Abstract %R 10.1186/1471-2350-14-6 %0 Journal Article %J Lifetime Data Anal %D 2013 %T Evaluating subject-level incremental values of new markers for risk classification rule. %A Cai, T %A Tian, L %A Lloyd-Jones, D %A Wei, L J %K Aged %K Antihypertensive Agents %K Biomarkers %K Biostatistics %K C-Reactive Protein %K Confidence Intervals %K Coronary Disease %K Female %K Humans %K Risk %K Risk Factors %K Statistics, Nonparametric %K United States %X

Suppose that we need to classify a population of subjects into several well-defined ordered risk categories for disease prevention or management with their "baseline" risk factors/markers. In this article, we present a systematic approach to identify subjects using their conventional risk factors/markers who would benefit from a new set of risk markers for more accurate classification. Specifically for each subgroup of individuals with the same conventional risk estimate, we present inference procedures for the reclassification and the corresponding correct re-categorization rates with the new markers. We then apply these new tools to analyze the data from the Cardiovascular Health Study sponsored by the US National Heart, Lung, and Blood Institute. We used Framingham risk factors plus the information of baseline anti-hypertensive drug usage to identify adult American women who may benefit from the measurement of a new blood biomarker, CRP, for better risk classification in order to intensify prevention of coronary heart disease for the subsequent 10 years.

%B Lifetime Data Anal %V 19 %P 547-67 %8 2013 Oct %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/23807696?dopt=Abstract %R 10.1007/s10985-013-9272-6 %0 Journal Article %J J Clin Endocrinol Metab %D 2013 %T Fibroblast growth factor 23, bone mineral density, and risk of hip fracture among older adults: the cardiovascular health study. %A Jovanovich, Anna %A Bůzková, Petra %A Chonchol, Michel %A Robbins, John %A Fink, Howard A %A de Boer, Ian H %A Kestenbaum, Bryan %A Katz, Ronit %A Carbone, Laura %A Lee, Jennifer %A Laughlin, Gail A %A Mukamal, Kenneth J %A Fried, Linda F %A Shlipak, Michael G %A Ix, Joachim H %K Aged %K Aged, 80 and over %K Bone Density %K Female %K Fibroblast Growth Factors %K Hip Fractures %K Humans %K Longitudinal Studies %K Male %K Middle Aged %K Prospective Studies %K Risk %K Spinal Fractures %X

CONTEXT: Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone that also inhibits calcitriol synthesis.

OBJECTIVE: Our objective was to evaluate the relationships of plasma FGF23 concentrations with bone mineral density (BMD) and hip fracture in community-dwelling older adults.

DESIGN AND SETTING: Linear regression and Cox proportional hazard models were used to examine the associations of plasma FGF23 concentrations with BMD and incident hip fracture, respectively. Analyses were also stratified by chronic kidney disease.

PARTICIPANTS: Participants included 2008 women and 1329 men ≥65 years from the 1996 to 1997 Cardiovascular Health Study visit.

MAIN OUTCOME MEASURES: Dual x-ray absorptiometry measured total hip (TH) and lumbar spine (LS) BMD in 1291 participants. Hip fracture incidence was assessed prospectively through June 30, 2008 by hospitalization records in all participants.

RESULTS: Women had higher plasma FGF23 concentrations than men (75 [56-107] vs 66 [interquartile range = 52-92] relative units/mL; P < .001). After adjustment, higher FGF23 concentrations were associated with greater total hip and lumbar spine BMD in men only (β per doubling of FGF23 = 0.02, with 95% confidence interval [CI] = 0.001-0.04 g/cm(2), and 0.03 with 95% CI = 0.01-0.06 g/cm(2)). During 9.6 ± 5.1-11.0 years of follow-up, 328 hip fractures occurred. Higher FGF23 concentrations were not associated with hip fracture risk in women or men (adjusted hazard ratio = 0.95, with 95% CI = 0.78-1.15, and 1.09 with 95% CI = 0.82-1.46 per doubling of FGF23). Results did not differ by chronic kidney disease status (P > .4 for interactions).

CONCLUSIONS: In this large prospective cohort of community-dwelling older adults, higher FGF23 concentrations were weakly associated with greater lumbar spine and total hip BMD but not with hip fracture risk.

%B J Clin Endocrinol Metab %V 98 %P 3323-31 %8 2013 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/23771921?dopt=Abstract %R 10.1210/jc.2013-1152 %0 Journal Article %J Atherosclerosis %D 2013 %T Fibroblast growth factor 23, left ventricular mass, and left ventricular hypertrophy in community-dwelling older adults. %A Jovanovich, Anna %A Ix, Joachim H %A Gottdiener, John %A McFann, Kim %A Katz, Ronit %A Kestenbaum, Bryan %A de Boer, Ian H %A Sarnak, Mark %A Shlipak, Michael G %A Mukamal, Kenneth J %A Siscovick, David %A Chonchol, Michel %K Aged %K Female %K Fibroblast Growth Factors %K Heart Ventricles %K Humans %K Hypertrophy, Left Ventricular %K Longitudinal Studies %K Male %K Renal Insufficiency, Chronic %K Risk Factors %K Ultrasonography %X

OBJECTIVES: In chronic kidney disease (CKD), high FGF23 concentrations are associated with left ventricular hypertrophy (LVH), cardiovascular events, and death. The associations of FGF23 with left ventricular mass (LVM) and LVH in the general population and the influence of CKD remains uncertain.

METHODS: C-terminal plasma FGF23 concentrations were measured, and LVM and LVH evaluated by echocardiogram among 2255 individuals ≥65 years in the Cardiovascular Health Study. Linear regression analysis adjusting for demographics, cardiovascular, and kidney related risk factors examined the associations of FGF23 concentrations with LVM. Analyses were stratified by CKD status and adjusted linear and logistic regression analysis explored the associations of FGF23 with LVM and LVH.

RESULTS: Among the entire cohort, higher FGF23 concentrations were associated with greater LVM in adjusted analyses (β = 6.71 [95% CI 4.35-9.01] g per doubling of FGF23). 32% (n = 624) had CKD (eGFR <60 mL/min/1.73 m(2) and/or urine albumin-to-creatinine ratio >30 mg/g). Associations were stronger among participants with CKD (p interaction = 0.006): LVM β = 9.71 [95% CI 5.86-13.56] g per doubling of FGF23 compared to those without CKD (β = 3.44 [95% CI 0.77, 6.11] g per doubling of FGF23). While there was no significant interaction between FGF23 and CKD for LVH (p interaction = 0.25), the OR (1.46 95% CI [1.20-1.77]) in the CKD group was statistically significant and of larger magnitude than the OR for in the no CKD group (1.12 [95% CI 0.97-1.48]).

CONCLUSION: In a large cohort of older community-dwelling adults, higher FGF23 concentrations were associated with greater LVM and LVH with stronger relationships in participants with CKD.

%B Atherosclerosis %V 231 %P 114-9 %8 2013 Nov %G eng %N 1 %R 10.1016/j.atherosclerosis.2013.09.002 %0 Journal Article %J Am J Hum Genet %D 2013 %T Fine Mapping and Identification of BMI Loci in African Americans. %A Gong, Jian %A Schumacher, Fredrick %A Lim, Unhee %A Hindorff, Lucia A %A Haessler, Jeff %A Buyske, Steven %A Carlson, Christopher S %A Rosse, Stephanie %A Bůzková, Petra %A Fornage, Myriam %A Gross, Myron %A Pankratz, Nathan %A Pankow, James S %A Schreiner, Pamela J %A Cooper, Richard %A Ehret, Georg %A Gu, C Charles %A Houston, Denise %A Irvin, Marguerite R %A Jackson, Rebecca %A Kuller, Lew %A Henderson, Brian %A Cheng, Iona %A Wilkens, Lynne %A Leppert, Mark %A Lewis, Cora E %A Li, Rongling %A Nguyen, Khanh-Dung H %A Goodloe, Robert %A Farber-Eger, Eric %A Boston, Jonathan %A Dilks, Holli H %A Ritchie, Marylyn D %A Fowke, Jay %A Pooler, Loreall %A Graff, Misa %A Fernandez-Rhodes, Lindsay %A Cochrane, Barbara %A Boerwinkle, Eric %A Kooperberg, Charles %A Matise, Tara C %A Le Marchand, Loïc %A Crawford, Dana C %A Haiman, Christopher A %A North, Kari E %A Peters, Ulrike %K Adult %K African Americans %K Aged %K Aged, 80 and over %K Body Mass Index %K Female %K Genetic Loci %K Genetic Predisposition to Disease %K Genome, Human %K Genome-Wide Association Study %K Genotype %K Humans %K Linkage Disequilibrium %K Male %K Middle Aged %K Obesity %K Polymorphism, Single Nucleotide %K Young Adult %X

Genome-wide association studies (GWASs) primarily performed in European-ancestry (EA) populations have identified numerous loci associated with body mass index (BMI). However, it is still unclear whether these GWAS loci can be generalized to other ethnic groups, such as African Americans (AAs). Furthermore, the putative functional variant or variants in these loci mostly remain under investigation. The overall lower linkage disequilibrium in AA compared to EA populations provides the opportunity to narrow in or fine-map these BMI-related loci. Therefore, we used the Metabochip to densely genotype and evaluate 21 BMI GWAS loci identified in EA studies in 29,151 AAs from the Population Architecture using Genomics and Epidemiology (PAGE) study. Eight of the 21 loci (SEC16B, TMEM18, ETV5, GNPDA2, TFAP2B, BDNF, FTO, and MC4R) were found to be associated with BMI in AAs at 5.8 × 10(-5). Within seven out of these eight loci, we found that, on average, a substantially smaller number of variants was correlated (r(2) > 0.5) with the most significant SNP in AA than in EA populations (16 versus 55). Conditional analyses revealed GNPDA2 harboring a potential additional independent signal. Moreover, Metabochip-wide discovery analyses revealed two BMI-related loci, BRE (rs116612809, p = 3.6 × 10(-8)) and DHX34 (rs4802349, p = 1.2 × 10(-7)), which were significant when adjustment was made for the total number of SNPs tested across the chip. These results demonstrate that fine mapping in AAs is a powerful approach for both narrowing in on the underlying causal variants in known loci and discovering BMI-related loci.

%B Am J Hum Genet %V 93 %P 661-71 %8 2013 Oct 3 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/24094743?dopt=Abstract %R 10.1016/j.ajhg.2013.08.012 %0 Journal Article %J PLoS Biol %D 2013 %T Generalization and dilution of association results from European GWAS in populations of non-European ancestry: the PAGE study. %A Carlson, Christopher S %A Matise, Tara C %A North, Kari E %A Haiman, Christopher A %A Fesinmeyer, Megan D %A Buyske, Steven %A Schumacher, Fredrick R %A Peters, Ulrike %A Franceschini, Nora %A Ritchie, Marylyn D %A Duggan, David J %A Spencer, Kylee L %A Dumitrescu, Logan %A Eaton, Charles B %A Thomas, Fridtjof %A Young, Alicia %A Carty, Cara %A Heiss, Gerardo %A Le Marchand, Loïc %A Crawford, Dana C %A Hindorff, Lucia A %A Kooperberg, Charles L %K African Americans %K Asian Americans %K Body Mass Index %K Diabetes Mellitus, Type 2 %K European Continental Ancestry Group %K Gene Frequency %K Genetic Predisposition to Disease %K Genetic Variation %K Genome-Wide Association Study %K Hispanic Americans %K Humans %K Indians, North American %K Lipids %K Metagenomics %K Oceanic Ancestry Group %K Polymorphism, Single Nucleotide %X

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

%B PLoS Biol %V 11 %P e1001661 %8 2013 Sep %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/24068893?dopt=Abstract %R 10.1371/journal.pbio.1001661 %0 Journal Article %J J Clin Psychopharmacol %D 2013 %T Genetic analysis of a population heavy drinking phenotype identifies risk variants in whites. %A Hamidovic, Ajna %A Goodloe, Robert J %A Young, Taylor R %A Styn, Mindi A %A Mukamal, Kenneth J %A Choquet, Helene %A Kasberger, Jay L %A Buxbaum, Sarah G %A Papanicolaou, George J %A White, Wendy %A Volcik, Kelly %A Spring, Bonnie %A Hitsman, Brian %A Levy, Daniel %A Jorgenson, Eric %K Aged %K Alcohol Drinking %K Alcoholism %K Case-Control Studies %K European Continental Ancestry Group %K Feasibility Studies %K Genetic Association Studies %K Genetic Loci %K Genetic Predisposition to Disease %K Genetic Variation %K Humans %K Incidence %K Male %K Middle Aged %K Phenotype %K Polymorphism, Single Nucleotide %K Risk %X

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

%B J Clin Psychopharmacol %V 33 %P 206-10 %8 2013 Apr %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/23422394?dopt=Abstract %& 206 %R 10.1097/JCP.0b013e318287009a %0 Journal Article %J Invest Ophthalmol Vis Sci %D 2013 %T Genetic association of COL5A1 variants in keratoconus patients suggests a complex connection between corneal thinning and keratoconus. %A Li, Xiaohui %A Bykhovskaya, Yelena %A Canedo, Ana Laura Caiado %A Haritunians, Talin %A Siscovick, David %A Aldave, Anthony J %A Szczotka-Flynn, Loretta %A Iyengar, Sudha K %A Rotter, Jerome I %A Taylor, Kent D %A Rabinowitz, Yaron S %K Adult %K Aged %K Collagen Type V %K Cornea %K Corneal Topography %K DNA %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Keratoconus %K Male %K Microscopy, Acoustic %K Middle Aged %K Polymorphism, Single Nucleotide %K Tomography, Optical Coherence %X

PURPOSE: Single nucleotide polymorphisms (SNPs) located near or within the COL5A1 gene, at 9q34.2-q34.3 chromosomal region have been reported in association with central corneal thickness (CCT). Using family linkage analysis, we identified a keratoconus susceptibility locus at 9q34. These findings led us to perform an association study between COL5A1 variation and keratoconus susceptibility.

METHODS: A Caucasian case-control cohort of 222 keratoconus patients and 3324 controls was selected as the discovery panel. An independent case-control panel of 304 cases and 518 controls and a family panel of 186 subjects were replicated for genotyping and association. Forty-four SNPs (21 for discovery and 23 for fine-mapping) spanning 300 kilobases in and around COL5A1 were genotyped and tested for genetic association. Logistic regression models implemented in PLINK were used to test for association in case controls. Generalized estimating equation models accounting for familial correlations implemented in genome-wide interaction analyses with family data were used for association testing in families.

RESULTS: Two CCT associated SNPs (rs1536482 and rs7044529 near and within COL5A1) were identified in the keratoconus discovery cohort (P values of 6.5 × 10(-3) and 7.4 × 10(-3)). SNP rs1536482 was replicated in the second case-control sample (P = 0.02), and SNP rs7044529 was replicated in a keratoconus family panel (P = 0.03). Meta P values of rs1536482 and rs7044529 in the keratoconus cohorts were 1.5 × 10(-4) (odds ratio [OR] = 1.30) and 2.9 × 10(-3) (OR = 1.39). After Bonferroni correction, the association of SNP rs1536482 remained significant (P = 6.5 × 10(-3)).

CONCLUSIONS: SNPs in the COL5A1 region, which regulate normal variation in CCT, may play a role in the thinning associated with keratoconus.

%B Invest Ophthalmol Vis Sci %V 54 %P 2696-704 %8 2013 Apr 12 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/23513063?dopt=Abstract %R 10.1167/iovs.13-11601 %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 Obesity (Silver Spring) %D 2013 %T Genetic risk factors for BMI and obesity in an ethnically diverse population: results from the population architecture using genomics and epidemiology (PAGE) study. %A Fesinmeyer, Megan D %A North, Kari E %A Ritchie, Marylyn D %A Lim, Unhee %A Franceschini, Nora %A Wilkens, Lynne R %A Gross, Myron D %A Bůzková, Petra %A Glenn, Kimberly %A Quibrera, P Miguel %A Fernandez-Rhodes, Lindsay %A Li, Qiong %A Fowke, Jay H %A Li, Rongling %A Carlson, Christopher S %A Prentice, Ross L %A Kuller, Lewis H %A Manson, JoAnn E %A Matise, Tara C %A Cole, Shelley A %A Chen, Christina T L %A Howard, Barbara V %A Kolonel, Laurence N %A Henderson, Brian E %A Monroe, Kristine R %A Crawford, Dana C %A Hindorff, Lucia A %A Buyske, Steven %A Haiman, Christopher A %A Le Marchand, Loïc %A Peters, Ulrike %K Alleles %K Body Mass Index %K Ethnic Groups %K Gene Frequency %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Linkage Disequilibrium %K Metagenomics %K Obesity %K Phenotype %K Polymorphism, Single Nucleotide %K Risk Factors %X

OBJECTIVE: Several genome-wide association studies (GWAS) have demonstrated that common genetic variants contribute to obesity. However, studies of this complex trait have focused on ancestrally European populations, despite the high prevalence of obesity in some minority groups.

DESIGN AND METHODS: As part of the "Population Architecture using Genomics and Epidemiology (PAGE)" Consortium, we investigated the association between 13 GWAS-identified single-nucleotide polymorphisms (SNPs) and BMI and obesity in 69,775 subjects, including 6,149 American Indians, 15,415 African-Americans, 2,438 East Asians, 7,346 Hispanics, 604 Pacific Islanders, and 37,823 European Americans. For the BMI-increasing allele of each SNP, we calculated β coefficients using linear regression (for BMI) and risk estimates using logistic regression (for obesity defined as BMI ≥ 30) followed by fixed-effects meta-analysis to combine results across PAGE sites. Analyses stratified by racial/ethnic group assumed an additive genetic model and were adjusted for age, sex, and current smoking. We defined "replicating SNPs" (in European Americans) and "generalizing SNPs" (in other racial/ethnic groups) as those associated with an allele frequency-specific increase in BMI.

RESULTS: By this definition, we replicated 9/13 SNP associations (5 out of 8 loci) in European Americans. We also generalized 8/13 SNP associations (5/8 loci) in East Asians, 7/13 (5/8 loci) in African Americans, 6/13 (4/8 loci) in Hispanics, 5/8 in Pacific Islanders (5/8 loci), and 5/9 (4/8 loci) in American Indians.

CONCLUSION: Linkage disequilibrium patterns suggest that tagSNPs selected for European Americans may not adequately tag causal variants in other ancestry groups. Accordingly, fine-mapping in large samples is needed to comprehensively explore these loci in diverse populations.

%B Obesity (Silver Spring) %V 21 %P 835-46 %8 2013 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/23712987?dopt=Abstract %R 10.1002/oby.20268 %0 Journal Article %J BMC Med Genet %D 2013 %T Genetic variants associated with fasting glucose and insulin concentrations in an ethnically diverse population: results from the Population Architecture using Genomics and Epidemiology (PAGE) study. %A Fesinmeyer, Megan D %A Meigs, James B %A North, Kari E %A Schumacher, Fredrick R %A Bůzková, Petra %A Franceschini, Nora %A Haessler, Jeffrey %A Goodloe, Robert %A Spencer, Kylee L %A Voruganti, Venkata Saroja %A Howard, Barbara V %A Jackson, Rebecca %A Kolonel, Laurence N %A Liu, Simin %A Manson, JoAnn E %A Monroe, Kristine R %A Mukamal, Kenneth %A Dilks, Holli H %A Pendergrass, Sarah A %A Nato, Andrew %A Wan, Peggy %A Wilkens, Lynne R %A Le Marchand, Loïc %A Ambite, Jose Luis %A Buyske, Steven %A Florez, Jose C %A Crawford, Dana C %A Hindorff, Lucia A %A Haiman, Christopher A %A Peters, Ulrike %A Pankow, James S %K Adaptor Proteins, Signal Transducing %K Adult %K African Americans %K Aged %K Alleles %K Asian Continental Ancestry Group %K Blood Glucose %K Diabetes Mellitus, Type 2 %K European Continental Ancestry Group %K Female %K Gene Frequency %K Genetic Loci %K Genome-Wide Association Study %K Genomics %K Hispanic Americans %K Humans %K Indians, North American %K Insulin %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Transcription Factor 7-Like 2 Protein %X

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

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

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

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

%B BMC Med Genet %V 14 %P 98 %8 2013 Sep 25 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/24063630?dopt=Abstract %R 10.1186/1471-2350-14-98 %0 Journal Article %J Hum Mol Genet %D 2013 %T Genome-wide and gene-centric analyses of circulating myeloperoxidase levels in the charge and care consortia. %A Reiner, Alexander P %A Hartiala, Jaana %A Zeller, Tanja %A Bis, Joshua C %A Dupuis, Josée %A Fornage, Myriam %A Baumert, Jens %A Kleber, Marcus E %A Wild, Philipp S %A Baldus, Stephan %A Bielinski, Suzette J %A Fontes, João D %A Illig, Thomas %A Keating, Brendan J %A Lange, Leslie A %A Ojeda, Francisco %A Müller-Nurasyid, Martina %A Munzel, Thomas F %A Psaty, Bruce M %A Rice, Kenneth %A Rotter, Jerome I %A Schnabel, Renate B %A Tang, W H Wilson %A Thorand, Barbara %A Erdmann, Jeanette %A Jacobs, David R %A Wilson, James G %A Koenig, Wolfgang %A Tracy, Russell P %A Blankenberg, Stefan %A März, Winfried %A Gross, Myron D %A Benjamin, Emelia J %A Hazen, Stanley L %A Allayee, Hooman %K Adult %K African Americans %K Aged %K Case-Control Studies %K Complement Factor H %K Coronary Artery Disease %K European Continental Ancestry Group %K Female %K Gene Expression Regulation, Enzymologic %K Genetic Association Studies %K Genetic Variation %K Genome-Wide Association Study %K Genotype %K Humans %K Male %K Middle Aged %K Peroxidase %K Polymorphism, Single Nucleotide %K Young Adult %X

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

%B Hum Mol Genet %V 22 %P 3381-93 %8 2013 Aug 15 %G eng %N 16 %1 http://www.ncbi.nlm.nih.gov/pubmed/23620142?dopt=Abstract %R 10.1093/hmg/ddt189 %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 Genet %D 2013 %T Genome-wide association of body fat distribution in African ancestry populations suggests new loci. %A Liu, Ching-Ti %A Monda, Keri L %A Taylor, Kira C %A Lange, Leslie %A Demerath, Ellen W %A Palmas, Walter %A Wojczynski, Mary K %A Ellis, Jaclyn C %A Vitolins, Mara Z %A Liu, Simin %A Papanicolaou, George J %A Irvin, Marguerite R %A Xue, Luting %A Griffin, Paula J %A Nalls, Michael A %A Adeyemo, Adebowale %A Liu, Jiankang %A Li, Guo %A Ruiz-Narvaez, Edward A %A Chen, Wei-Min %A Chen, Fang %A Henderson, Brian E %A Millikan, Robert C %A Ambrosone, Christine B %A Strom, Sara S %A Guo, Xiuqing %A Andrews, Jeanette S %A Sun, Yan V %A Mosley, Thomas H %A Yanek, Lisa R %A Shriner, Daniel %A Haritunians, Talin %A Rotter, Jerome I %A Speliotes, Elizabeth K %A Smith, Megan %A Rosenberg, Lynn %A Mychaleckyj, Josyf %A Nayak, Uma %A Spruill, Ida %A Garvey, W Timothy %A Pettaway, Curtis %A Nyante, Sarah %A Bandera, Elisa V %A Britton, Angela F %A Zonderman, Alan B %A Rasmussen-Torvik, Laura J %A Chen, Yii-Der Ida %A Ding, Jingzhong %A Lohman, Kurt %A Kritchevsky, Stephen B %A Zhao, Wei %A Peyser, Patricia A %A Kardia, Sharon L R %A Kabagambe, Edmond %A Broeckel, Ulrich %A Chen, Guanjie %A Zhou, Jie %A Wassertheil-Smoller, Sylvia %A Neuhouser, Marian L %A Rampersaud, Evadnie %A Psaty, Bruce %A Kooperberg, Charles %A Manson, JoAnn E %A Kuller, Lewis H %A Ochs-Balcom, Heather M %A Johnson, Karen C %A Sucheston, Lara %A Ordovas, Jose M %A Palmer, Julie R %A Haiman, Christopher A %A McKnight, Barbara %A Howard, Barbara V %A Becker, Diane M %A Bielak, Lawrence F %A Liu, Yongmei %A Allison, Matthew A %A Grant, Struan F A %A Burke, Gregory L %A Patel, Sanjay R %A Schreiner, Pamela J %A Borecki, Ingrid B %A Evans, Michele K %A Taylor, Herman %A Sale, Michèle M %A Howard, Virginia %A Carlson, Christopher S %A Rotimi, Charles N %A Cushman, Mary %A Harris, Tamara B %A Reiner, Alexander P %A Cupples, L Adrienne %A North, Kari E %A Fox, Caroline S %K Adiposity %K African Continental Ancestry Group %K Body Fat Distribution %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 %K Waist-Hip Ratio %X

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

%B PLoS Genet %V 9 %P e1003681 %8 2013 %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/23966867?dopt=Abstract %R 10.1371/journal.pgen.1003681 %0 Journal Article %J Genet Epidemiol %D 2013 %T A genome-wide association study for venous thromboembolism: the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium. %A Tang, Weihong %A Teichert, Martina %A Chasman, Daniel I %A Heit, John A %A Morange, Pierre-Emmanuel %A Li, Guo %A Pankratz, Nathan %A Leebeek, Frank W %A Paré, Guillaume %A de Andrade, Mariza %A Tzourio, Christophe %A Psaty, Bruce M %A Basu, Saonli %A Ruiter, Rikje %A Rose, Lynda %A Armasu, Sebastian M %A Lumley, Thomas %A Heckbert, Susan R %A Uitterlinden, André G %A Lathrop, Mark %A Rice, Kenneth M %A Cushman, Mary %A Hofman, Albert %A Lambert, Jean-Charles %A Glazer, Nicole L %A Pankow, James S %A Witteman, Jacqueline C %A Amouyel, Philippe %A Bis, Joshua C %A Bovill, Edwin G %A Kong, Xiaoxiao %A Tracy, Russell P %A Boerwinkle, Eric %A Rotter, Jerome I %A Trégouët, David-Alexandre %A Loth, Daan W %A Stricker, Bruno H Ch %A Ridker, Paul M %A Folsom, Aaron R %A Smith, Nicholas L %K Aged %K Aging %K Case-Control Studies %K Cohort Studies %K Female %K Genome-Wide Association Study %K Humans %K Male %K Meta-Analysis as Topic %K Middle Aged %K Polymorphism, Single Nucleotide %K Regression Analysis %K Risk Factors %K Venous Thromboembolism %X

Venous thromboembolism (VTE) is a common, heritable disease resulting in high rates of hospitalization and mortality. Yet few associations between VTE and genetic variants, all in the coagulation pathway, have been established. To identify additional genetic determinants of VTE, we conducted a two-stage genome-wide association study (GWAS) among individuals of European ancestry in the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) VTE consortium. The discovery GWAS comprised 1,618 incident VTE cases out of 44,499 participants from six community-based studies. Genotypes for genome-wide single-nucleotide polymorphisms (SNPs) were imputed to approximately 2.5 million SNPs in HapMap and association with VTE assessed using study-design appropriate regression methods. Meta-analysis of these results identified two known loci, in F5 and ABO. Top 1,047 tag SNPs (P ≤ 0.0016) from the discovery GWAS were tested for association in an additional 3,231 cases and 3,536 controls from three case-control studies. In the combined data from these two stages, additional genome-wide significant associations were observed on 4q35 at F11 (top SNP rs4253399, intronic to F11) and on 4q28 at FGG (rs6536024, 9.7 kb from FGG; P < 5.0 × 10(-13) for both). The associations at the FGG locus were not completely explained by previously reported variants. Loci at or near SUSD1 and OTUD7A showed borderline yet novel associations (P < 5.0 × 10(-6) ) and constitute new candidate genes. In conclusion, this large GWAS replicated key genetic associations in F5 and ABO, and confirmed the importance of F11 and FGG loci for VTE. Future studies are warranted to better characterize the associations with F11 and FGG and to replicate the new candidate associations.

%B Genet Epidemiol %V 37 %P 512-521 %8 2013 Jul %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/23650146?dopt=Abstract %R 10.1002/gepi.21731 %0 Journal Article %J Circ Cardiovasc Genet %D 2013 %T Genome-wide association study identifies novel loci associated with concentrations of four plasma phospholipid fatty acids in the de novo lipogenesis pathway: results from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortiu %A Wu, Jason H Y %A Lemaitre, Rozenn N %A Manichaikul, Ani %A Guan, Weihua %A Tanaka, Toshiko %A Foy, Millennia %A Kabagambe, Edmond K %A Djoussé, Luc %A Siscovick, David %A Fretts, Amanda M %A Johnson, Catherine %A King, Irena B %A Psaty, Bruce M %A McKnight, Barbara %A Rich, Stephen S %A Chen, Yii-der I %A Nettleton, Jennifer A %A Tang, Weihong %A Bandinelli, Stefania %A Jacobs, David R %A Browning, Brian L %A Laurie, Cathy C %A Gu, Xiangjun %A Tsai, Michael Y %A Steffen, Lyn M %A Ferrucci, Luigi %A Fornage, Myriam %A Mozaffarian, Dariush %K Adult %K Aged %K Chromosomes, Human, Pair 2 %K Cohort Studies %K Coronary Disease %K Diabetes Mellitus, Type 2 %K Fatty Acids, Monounsaturated %K Female %K Genetic Loci %K Genome-Wide Association Study %K Genotype %K Humans %K Linkage Disequilibrium %K Lipogenesis %K Male %K Middle Aged %K Oleic Acid %K Palmitic Acid %K Polymorphism, Single Nucleotide %K Stearic Acids %X

BACKGROUND- Palmitic acid (16:0), stearic acid (18:0), palmitoleic acid (16:1n-7), and oleic acid (18:1n-9) are major saturated and monounsaturated fatty acids that affect cellular signaling and metabolic pathways. They are synthesized via de novo lipogenesis and are the main saturated and monounsaturated fatty acids in the diet. Levels of these fatty acids have been linked to diseases including type 2 diabetes mellitus and coronary heart disease. METHODS AND RESULTS- Genome-wide association studies were conducted in 5 population-based cohorts comprising 8961 participants of European ancestry to investigate the association of common genetic variation with plasma levels of these 4 fatty acids. We identified polymorphisms in 7 novel loci associated with circulating levels of ≥1 of these fatty acids. ALG14 (asparagine-linked glycosylation 14 homolog) polymorphisms were associated with higher 16:0 (P=2.7×10(-11)) and lower 18:0 (P=2.2×10(-18)). FADS1 and FADS2 (desaturases) polymorphisms were associated with higher 16:1n-7 (P=6.6×10(-13)) and 18:1n-9 (P=2.2×10(-32)) and lower 18:0 (P=1.3×10(-20)). LPGAT1 (lysophosphatidylglycerol acyltransferase) polymorphisms were associated with lower 18:0 (P=2.8×10(-9)). GCKR (glucokinase regulator; P=9.8×10(-10)) and HIF1AN (factor inhibiting hypoxia-inducible factor-1; P=5.7×10(-9)) polymorphisms were associated with higher 16:1n-7, whereas PKD2L1 (polycystic kidney disease 2-like 1; P=5.7×10(-15)) and a locus on chromosome 2 (not near known genes) were associated with lower 16:1n-7 (P=4.1×10(-8)). CONCLUSIONS- Our findings provide novel evidence that common variations in genes with diverse functions, including protein-glycosylation, polyunsaturated fatty acid metabolism, phospholipid modeling, and glucose- and oxygen-sensing pathways, are associated with circulating levels of 4 fatty acids in the de novo lipogenesis pathway. These results expand our knowledge of genetic factors relevant to de novo lipogenesis and fatty acid biology.

%B Circ Cardiovasc Genet %V 6 %P 171-83 %8 2013 Apr %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/23362303?dopt=Abstract %R 10.1161/CIRCGENETICS.112.964619 %0 Journal Article %J Circ Cardiovasc Genet %D 2013 %T Genome-wide association study of cardiac structure and systolic function in African Americans: the Candidate Gene Association Resource (CARe) study. %A Fox, Ervin R %A Musani, Solomon K %A Barbalic, Maja %A Lin, Honghuang %A Yu, Bing %A Ogunyankin, Kofo O %A Smith, Nicholas L %A Kutlar, Abdullah %A Glazer, Nicole L %A Post, Wendy S %A Paltoo, Dina N %A Dries, Daniel L %A Farlow, Deborah N %A Duarte, Christine W %A Kardia, Sharon L %A Meyers, Kristin J %A Sun, Yan V %A Arnett, Donna K %A Patki, Amit A %A Sha, Jin %A Cui, Xiangqui %A Samdarshi, Tandaw E %A Penman, Alan D %A Bibbins-Domingo, Kirsten %A Bůzková, Petra %A Benjamin, Emelia J %A Bluemke, David A %A Morrison, Alanna C %A Heiss, Gerardo %A Carr, J Jeffrey %A Tracy, Russell P %A Mosley, Thomas H %A Taylor, Herman A %A Psaty, Bruce M %A Heckbert, Susan R %A Cappola, Thomas P %A Vasan, Ramachandran S %K African Americans %K Aged %K Cohort Studies %K Diastole %K Echocardiography %K European Continental Ancestry Group %K Female %K Genome-Wide Association Study %K Genotype %K Heart %K Humans %K Male %K Middle Aged %K Phenotype %K Polymorphism, Single Nucleotide %K Systole %X

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

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

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

%B Circ Cardiovasc Genet %V 6 %P 37-46 %8 2013 Feb %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/23275298?dopt=Abstract %R 10.1161/CIRCGENETICS.111.962365 %0 Journal Article %J Biol Psychiatry %D 2013 %T A genome-wide association study of depressive symptoms. %A Hek, Karin %A Demirkan, Ayse %A Lahti, Jari %A Terracciano, Antonio %A Teumer, Alexander %A Cornelis, Marilyn C %A Amin, Najaf %A Bakshis, Erin %A Baumert, Jens %A Ding, Jingzhong %A Liu, Yongmei %A Marciante, Kristin %A Meirelles, Osorio %A Nalls, Michael A %A Sun, Yan V %A Vogelzangs, Nicole %A Yu, Lei %A Bandinelli, Stefania %A Benjamin, Emelia J %A Bennett, David A %A Boomsma, Dorret %A Cannas, Alessandra %A Coker, Laura H %A de Geus, Eco %A De Jager, Philip L %A Diez-Roux, Ana V %A Purcell, Shaun %A Hu, Frank B %A Rimma, Eric B %A Hunter, David J %A Jensen, Majken K %A Curhan, Gary %A Rice, Kenneth %A Penman, Alan D %A Rotter, Jerome I %A Sotoodehnia, Nona %A Emeny, Rebecca %A Eriksson, Johan G %A Evans, Denis A %A Ferrucci, Luigi %A Fornage, Myriam %A Gudnason, Vilmundur %A Hofman, Albert %A Illig, Thomas %A Kardia, Sharon %A Kelly-Hayes, Margaret %A Koenen, Karestan %A Kraft, Peter %A Kuningas, Maris %A Massaro, Joseph M %A Melzer, David %A Mulas, Antonella %A Mulder, Cornelis L %A Murray, Anna %A Oostra, Ben A %A Palotie, Aarno %A Penninx, Brenda %A Petersmann, Astrid %A Pilling, Luke C %A Psaty, Bruce %A Rawal, Rajesh %A Reiman, Eric M %A Schulz, Andrea %A Shulman, Joshua M %A Singleton, Andrew B %A Smith, Albert V %A Sutin, Angelina R %A Uitterlinden, André G %A Völzke, Henry %A Widen, Elisabeth %A Yaffe, Kristine %A Zonderman, Alan B %A Cucca, Francesco %A Harris, Tamara %A Ladwig, Karl-Heinz %A Llewellyn, David J %A Räikkönen, Katri %A Tanaka, Toshiko %A van Duijn, Cornelia M %A Grabe, Hans J %A Launer, Lenore J %A Lunetta, Kathryn L %A Mosley, Thomas H %A Newman, Anne B %A Tiemeier, Henning %A Murabito, Joanne %K Aged %K Aged, 80 and over %K Chromosomes, Human, Pair 5 %K Depression %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %X

BACKGROUND: Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms.

METHODS: In this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p<1×10(-5)) was performed in five studies assessing depressive symptoms with other instruments. In addition, we performed a combined meta-analysis of all 22 discovery and replication studies.

RESULTS: The discovery sample comprised 34,549 individuals (mean age of 66.5) and no loci reached genome-wide significance (lowest p = 1.05×10(-7)). Seven independent single nucleotide polymorphisms were considered for replication. In the replication set (n = 16,709), we found suggestive association of one single nucleotide polymorphism with depressive symptoms (rs161645, 5q21, p = 9.19×10(-3)). This 5q21 region reached genome-wide significance (p = 4.78×10(-8)) in the overall meta-analysis combining discovery and replication studies (n = 51,258).

CONCLUSIONS: The results suggest that only a large sample comprising more than 50,000 subjects may be sufficiently powered to detect genes for depressive symptoms.

%B Biol Psychiatry %V 73 %P 667-78 %8 2013 Apr 01 %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/23290196?dopt=Abstract %R 10.1016/j.biopsych.2012.09.033 %0 Journal Article %J Hum Mol Genet %D 2013 %T A genome-wide association study of early menopause and the combined impact of identified variants. %A Perry, John R B %A Corre, Tanguy %A Esko, Tõnu %A Chasman, Daniel I %A Fischer, Krista %A Franceschini, Nora %A He, Chunyan %A Kutalik, Zoltán %A Mangino, Massimo %A Rose, Lynda M %A Vernon Smith, Albert %A Stolk, Lisette %A Sulem, Patrick %A Weedon, Michael N %A Zhuang, Wei V %A Arnold, Alice %A Ashworth, Alan %A Bergmann, Sven %A Buring, Julie E %A Burri, Andrea %A Chen, Constance %A Cornelis, Marilyn C %A Couper, David J %A Goodarzi, Mark O %A Gudnason, Vilmundur %A Harris, Tamara %A Hofman, Albert %A Jones, Michael %A Kraft, Peter %A Launer, Lenore %A Laven, Joop S E %A Li, Guo %A McKnight, Barbara %A Masciullo, Corrado %A Milani, Lili %A Orr, Nicholas %A Psaty, Bruce M %A Ridker, Paul M %A Rivadeneira, Fernando %A Sala, Cinzia %A Salumets, Andres %A Schoemaker, Minouk %A Traglia, Michela %A Waeber, Gérard %A Chanock, Stephen J %A Demerath, Ellen W %A Garcia, Melissa %A Hankinson, Susan E %A Hu, Frank B %A Hunter, David J %A Lunetta, Kathryn L %A Metspalu, Andres %A Montgomery, Grant W %A Murabito, Joanne M %A Newman, Anne B %A Ong, Ken K %A Spector, Tim D %A Stefansson, Kari %A Swerdlow, Anthony J %A Thorsteinsdottir, Unnur %A van Dam, Rob M %A Uitterlinden, André G %A Visser, Jenny A %A Vollenweider, Peter %A Toniolo, Daniela %A Murray, Anna %K Case-Control Studies %K Female %K Gene Frequency %K Genome-Wide Association Study %K Humans %K Menopause, Premature %K Polymorphism, Single Nucleotide %K Primary Ovarian Insufficiency %K Quantitative Trait Loci %K Risk %X

Early menopause (EM) affects up to 10% of the female population, reducing reproductive lifespan considerably. Currently, it constitutes the leading cause of infertility in the western world, affecting mainly those women who postpone their first pregnancy beyond the age of 30 years. The genetic aetiology of EM is largely unknown in the majority of cases. We have undertaken a meta-analysis of genome-wide association studies (GWASs) in 3493 EM cases and 13 598 controls from 10 independent studies. No novel genetic variants were discovered, but the 17 variants previously associated with normal age at natural menopause as a quantitative trait (QT) were also associated with EM and primary ovarian insufficiency (POI). Thus, EM has a genetic aetiology which overlaps variation in normal age at menopause and is at least partly explained by the additive effects of the same polygenic variants. The combined effect of the common variants captured by the single nucleotide polymorphism arrays was estimated to account for ∼30% of the variance in EM. The association between the combined 17 variants and the risk of EM was greater than the best validated non-genetic risk factor, smoking.

%B Hum Mol Genet %V 22 %P 1465-72 %8 2013 Apr 01 %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/23307926?dopt=Abstract %R 10.1093/hmg/dds551 %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 Nat Genet %D 2013 %T Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture. %A Berndt, Sonja I %A Gustafsson, Stefan %A Mägi, Reedik %A Ganna, Andrea %A Wheeler, Eleanor %A Feitosa, Mary F %A Justice, Anne E %A Monda, Keri L %A Croteau-Chonka, Damien C %A Day, Felix R %A Esko, Tõnu %A Fall, Tove %A Ferreira, Teresa %A Gentilini, Davide %A Jackson, Anne U %A Luan, Jian'an %A Randall, Joshua C %A Vedantam, Sailaja %A Willer, Cristen J %A Winkler, Thomas W %A Wood, Andrew R %A Workalemahu, Tsegaselassie %A Hu, Yi-Juan %A Lee, Sang Hong %A Liang, Liming %A Lin, Dan-Yu %A Min, Josine L %A Neale, Benjamin M %A Thorleifsson, Gudmar %A Yang, Jian %A Albrecht, Eva %A Amin, Najaf %A Bragg-Gresham, Jennifer L %A Cadby, Gemma %A den Heijer, Martin %A Eklund, Niina %A Fischer, Krista %A Goel, Anuj %A Hottenga, Jouke-Jan %A Huffman, Jennifer E %A Jarick, Ivonne %A Johansson, Asa %A Johnson, Toby %A Kanoni, Stavroula %A Kleber, Marcus E %A König, Inke R %A Kristiansson, Kati %A Kutalik, Zoltán %A Lamina, Claudia %A Lecoeur, Cécile %A Li, Guo %A Mangino, Massimo %A McArdle, Wendy L %A Medina-Gómez, Carolina %A Müller-Nurasyid, Martina %A Ngwa, Julius S %A Nolte, Ilja M %A Paternoster, Lavinia %A Pechlivanis, Sonali %A Perola, Markus %A Peters, Marjolein J %A Preuss, Michael %A Rose, Lynda M %A Shi, Jianxin %A Shungin, Dmitry %A Smith, Albert Vernon %A Strawbridge, Rona J %A Surakka, Ida %A Teumer, Alexander %A Trip, Mieke D %A Tyrer, Jonathan %A van Vliet-Ostaptchouk, Jana V %A Vandenput, Liesbeth %A Waite, Lindsay L %A Zhao, Jing Hua %A Absher, Devin %A Asselbergs, Folkert W %A Atalay, Mustafa %A Attwood, Antony P %A Balmforth, Anthony J %A Basart, Hanneke %A Beilby, John %A Bonnycastle, Lori L %A Brambilla, Paolo %A Bruinenberg, Marcel %A Campbell, Harry %A Chasman, Daniel I %A Chines, Peter S %A Collins, Francis S %A Connell, John M %A Cookson, William O %A de Faire, Ulf %A de Vegt, Femmie %A Dei, Mariano %A Dimitriou, Maria %A Edkins, Sarah %A Estrada, Karol %A Evans, David M %A Farrall, Martin %A Ferrario, Marco M %A Ferrieres, Jean %A Franke, Lude %A Frau, Francesca %A Gejman, Pablo V %A Grallert, Harald %A Grönberg, Henrik %A Gudnason, Vilmundur %A Hall, Alistair S %A Hall, Per %A Hartikainen, Anna-Liisa %A Hayward, Caroline %A Heard-Costa, Nancy L %A Heath, Andrew C %A Hebebrand, Johannes %A Homuth, Georg %A Hu, Frank B %A Hunt, Sarah E %A Hyppönen, Elina %A Iribarren, Carlos %A Jacobs, Kevin B %A Jansson, John-Olov %A Jula, Antti %A Kähönen, Mika %A Kathiresan, Sekar %A Kee, Frank %A Khaw, Kay-Tee %A Kivimaki, Mika %A Koenig, Wolfgang %A Kraja, Aldi T %A Kumari, Meena %A Kuulasmaa, Kari %A Kuusisto, Johanna %A Laitinen, Jaana H %A Lakka, Timo A %A Langenberg, Claudia %A Launer, Lenore J %A Lind, Lars %A Lindström, Jaana %A Liu, Jianjun %A Liuzzi, Antonio %A Lokki, Marja-Liisa %A Lorentzon, Mattias %A Madden, Pamela A %A Magnusson, Patrik K %A Manunta, Paolo %A Marek, Diana %A März, Winfried %A Mateo Leach, Irene %A McKnight, Barbara %A Medland, Sarah E %A Mihailov, Evelin %A Milani, Lili %A Montgomery, Grant W %A Mooser, Vincent %A Mühleisen, Thomas W %A Munroe, Patricia B %A Musk, Arthur W %A Narisu, Narisu %A Navis, Gerjan %A Nicholson, George %A Nohr, Ellen A %A Ong, Ken K %A Oostra, Ben A %A Palmer, Colin N A %A Palotie, Aarno %A Peden, John F %A Pedersen, Nancy %A Peters, Annette %A Polasek, Ozren %A Pouta, Anneli %A Pramstaller, Peter P %A Prokopenko, Inga %A Pütter, Carolin %A Radhakrishnan, Aparna %A Raitakari, Olli %A Rendon, Augusto %A Rivadeneira, Fernando %A Rudan, Igor %A Saaristo, Timo E %A Sambrook, Jennifer G %A Sanders, Alan R %A Sanna, Serena %A Saramies, Jouko %A Schipf, Sabine %A Schreiber, Stefan %A Schunkert, Heribert %A Shin, So-Youn %A Signorini, Stefano %A Sinisalo, Juha %A Skrobek, Boris %A Soranzo, Nicole %A Stančáková, Alena %A Stark, Klaus %A Stephens, Jonathan C %A Stirrups, Kathleen %A Stolk, Ronald P %A Stumvoll, Michael %A Swift, Amy J %A Theodoraki, Eirini V %A Thorand, Barbara %A Trégouët, David-Alexandre %A Tremoli, Elena %A van der Klauw, Melanie M %A van Meurs, Joyce B J %A Vermeulen, Sita H %A Viikari, Jorma %A Virtamo, Jarmo %A Vitart, Veronique %A Waeber, Gérard %A Wang, Zhaoming %A Widen, Elisabeth %A Wild, Sarah H %A Willemsen, Gonneke %A Winkelmann, Bernhard R %A Witteman, Jacqueline C M %A Wolffenbuttel, Bruce H R %A Wong, Andrew %A Wright, Alan F %A Zillikens, M Carola %A Amouyel, Philippe %A Boehm, Bernhard O %A Boerwinkle, Eric %A Boomsma, Dorret I %A Caulfield, Mark J %A Chanock, Stephen J %A Cupples, L Adrienne %A Cusi, Daniele %A Dedoussis, George V %A Erdmann, Jeanette %A Eriksson, Johan G %A Franks, Paul W %A Froguel, Philippe %A Gieger, Christian %A Gyllensten, Ulf %A Hamsten, Anders %A Harris, Tamara B %A Hengstenberg, Christian %A Hicks, Andrew A %A Hingorani, Aroon %A Hinney, Anke %A Hofman, Albert %A Hovingh, Kees G %A Hveem, Kristian %A Illig, Thomas %A Jarvelin, Marjo-Riitta %A Jöckel, Karl-Heinz %A Keinanen-Kiukaanniemi, Sirkka M %A Kiemeney, Lambertus A %A Kuh, Diana %A Laakso, Markku %A Lehtimäki, Terho %A Levinson, Douglas F %A Martin, Nicholas G %A Metspalu, Andres %A Morris, Andrew D %A Nieminen, Markku S %A Njølstad, Inger %A Ohlsson, Claes %A Oldehinkel, Albertine J %A Ouwehand, Willem H %A Palmer, Lyle J %A Penninx, Brenda %A Power, Chris %A Province, Michael A %A Psaty, Bruce M %A Qi, Lu %A Rauramaa, Rainer %A Ridker, Paul M %A Ripatti, Samuli %A Salomaa, Veikko %A Samani, Nilesh J %A Snieder, Harold %A Sørensen, Thorkild I A %A Spector, Timothy D %A Stefansson, Kari %A Tönjes, Anke %A Tuomilehto, Jaakko %A Uitterlinden, André G %A Uusitupa, Matti %A van der Harst, Pim %A Vollenweider, Peter %A Wallaschofski, Henri %A Wareham, Nicholas J %A Watkins, Hugh %A Wichmann, H-Erich %A Wilson, James F %A Abecasis, Goncalo R %A Assimes, Themistocles L %A Barroso, Inês %A Boehnke, Michael %A Borecki, Ingrid B %A Deloukas, Panos %A Fox, Caroline S %A Frayling, Timothy %A Groop, Leif C %A Haritunian, Talin %A Heid, Iris M %A Hunter, David %A Kaplan, Robert C %A Karpe, Fredrik %A Moffatt, Miriam F %A Mohlke, Karen L %A O'Connell, Jeffrey R %A Pawitan, Yudi %A Schadt, Eric E %A Schlessinger, David %A Steinthorsdottir, Valgerdur %A Strachan, David P %A Thorsteinsdottir, Unnur %A van Duijn, Cornelia M %A Visscher, Peter M %A Di Blasio, Anna Maria %A Hirschhorn, Joel N %A Lindgren, Cecilia M %A Morris, Andrew P %A Meyre, David %A Scherag, Andre %A McCarthy, Mark I %A Speliotes, Elizabeth K %A North, Kari E %A Loos, Ruth J F %A Ingelsson, Erik %K Anthropometry %K Body Height %K Body Mass Index %K Case-Control Studies %K European Continental Ancestry Group %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Meta-Analysis as Topic %K Obesity %K Phenotype %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Waist-Hip Ratio %X

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

%B Nat Genet %V 45 %P 501-12 %8 2013 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/23563607?dopt=Abstract %R 10.1038/ng.2606 %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 Hum Genet %D 2013 %T Genome-wide study identifies two loci associated with lung function decline in mild to moderate COPD. %A Hansel, Nadia N %A Ruczinski, Ingo %A Rafaels, Nicholas %A Sin, Don D %A Daley, Denise %A Malinina, Alla %A Huang, Lili %A Sandford, Andrew %A Murray, Tanda %A Kim, Yoonhee %A Vergara, Candelaria %A Heckbert, Susan R %A Psaty, Bruce M %A Li, Guo %A Elliott, W Mark %A Aminuddin, Farzian %A Dupuis, Josée %A O'Connor, George T %A Doheny, Kimberly %A Scott, Alan F %A Boezen, H Marike %A Postma, Dirkje S %A Smolonska, Joanna %A Zanen, Pieter %A Mohamed Hoesein, Firdaus A %A de Koning, Harry J %A Crystal, Ronald G %A Tanaka, Toshiko %A Ferrucci, Luigi %A Silverman, Edwin %A Wan, Emily %A Vestbo, Jorgen %A Lomas, David A %A Connett, John %A Wise, Robert A %A Neptune, Enid R %A Mathias, Rasika A %A Paré, Peter D %A Beaty, Terri H %A Barnes, Kathleen C %K Adult %K Ankyrins %K Chromosomes, Human, Pair 10 %K Chromosomes, Human, Pair 14 %K Cohort Studies %K Female %K Genome-Wide Association Study %K Hepatocyte Nuclear Factor 3-alpha %K Humans %K Linkage Disequilibrium %K Lung %K Male %K Membrane Proteins %K Middle Aged %K Polymorphism, Single Nucleotide %K Pulmonary Disease, Chronic Obstructive %X

Accelerated lung function decline is a key COPD phenotype; however, its genetic control remains largely unknown. We performed a genome-wide association study using the Illumina Human660W-Quad v.1_A BeadChip. Generalized estimation equations were used to assess genetic contributions to lung function decline over a 5-year period in 4,048 European American Lung Health Study participants with largely mild COPD. Genotype imputation was performed using reference HapMap II data. To validate regions meeting genome-wide significance, replication of top SNPs was attempted in independent cohorts. Three genes (TMEM26, ANK3 and FOXA1) within the regions of interest were selected for tissue expression studies using immunohistochemistry. Two intergenic SNPs (rs10761570, rs7911302) on chromosome 10 and one SNP on chromosome 14 (rs177852) met genome-wide significance after Bonferroni. Further support for the chromosome 10 region was obtained by imputation, the most significantly associated imputed SNPs (rs10761571, rs7896712) being flanked by observed markers rs10761570 and rs7911302. Results were not replicated in four general population cohorts or a smaller cohort of subjects with moderate to severe COPD; however, we show novel expression of genes near regions of significantly associated SNPS, including TMEM26 and FOXA1 in airway epithelium and lung parenchyma, and ANK3 in alveolar macrophages. Levels of expression were associated with lung function and COPD status. We identified two novel regions associated with lung function decline in mild COPD. Genes within these regions were expressed in relevant lung cells and their expression related to airflow limitation suggesting they may represent novel candidate genes for COPD susceptibility.

%B Hum Genet %V 132 %P 79-90 %8 2013 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/22986903?dopt=Abstract %R 10.1007/s00439-012-1219-6 %0 Journal Article %J Am J Hematol %D 2013 %T Hemoglobin decline, function, and mortality in the elderly: the cardiovascular health study. %A Zakai, Neil A %A French, Benjamin %A Arnold, Alice M %A Newman, Anne B %A Fried, Linda F %A Robbins, John %A Chaves, Paulo %A Cushman, Mary %K African Americans %K Age Factors %K Aged %K Aged, 80 and over %K Anemia %K Diabetes Complications %K Female %K Follow-Up Studies %K Hemoglobins %K Humans %K Kidney Diseases %K Male %K Prospective Studies %K Quality of Life %K Risk Factors %K Sex Factors %K Survival Rate %K Time Factors %K World Health Organization %X

While anemia is associated with poor functional and mortality outcomes in the elderly, the impact of hemoglobin decline is less studied. We evaluated the determinants and consequences of hemoglobin decline in 3,758 non-anemic participants from the Cardiovascular Health Study, a prospective cohort of community-dwelling elderly ≥65 years old at baseline and followed for up to 16 years. Hemoglobin was measured at baseline and 3 years later and anemia defined by World Health Organization (WHO) criteria. We modeled hemoglobin decline in two ways: (1) per each 1 g/dL decrease in hemoglobin and (2) development of anemia by the WHO criteria. Among participants without baseline anemia, hemoglobin decreased by 0.4 g/dL and 9% developed anemia over 3 years. Baseline increasing age, female sex, diabetes, and kidney disease predicted hemoglobin decline over 3 years. Baseline increasing age, being African-American, and kidney disease predicted anemia development over 3 years. Hemoglobin decline was associated with subsequent worse cognitive function in men and anemia development with subsequent worse cognitive function in women. Both anemia development (HR 1.39, 95% CI 1.15, 1.69) and hemoglobin decline (HR 1.11, 95% CI 1.04, 1.18 per 1 g/dL decrease) predicted subsequent mortality in men and women. Hemoglobin decreases identified a large group of elderly individuals at risk for subsequent adverse outcomes who would not be identified using the WHO anemia criteria. These data may allow clinicians to identify at-risk elderly individuals for early intervention to improve the quality and quantity of life.

%B Am J Hematol %V 88 %P 5-9 %8 2013 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/23044913?dopt=Abstract %R 10.1002/ajh.23336 %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 Nat Genet %D 2013 %T Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders. %A den Hoed, Marcel %A Eijgelsheim, Mark %A Esko, Tõnu %A Brundel, Bianca J J M %A Peal, David S %A Evans, David M %A Nolte, Ilja M %A Segrè, Ayellet V %A Holm, Hilma %A Handsaker, Robert E %A Westra, Harm-Jan %A Johnson, Toby %A Isaacs, Aaron %A Yang, Jian %A Lundby, Alicia %A Zhao, Jing Hua %A Kim, Young Jin %A Go, Min Jin %A Almgren, Peter %A Bochud, Murielle %A Boucher, Gabrielle %A Cornelis, Marilyn C %A Gudbjartsson, Daniel %A Hadley, David %A van der Harst, Pim %A Hayward, Caroline %A den Heijer, Martin %A Igl, Wilmar %A Jackson, Anne U %A Kutalik, Zoltán %A Luan, Jian'an %A Kemp, John P %A Kristiansson, Kati %A Ladenvall, Claes %A Lorentzon, Mattias %A Montasser, May E %A Njajou, Omer T %A O'Reilly, Paul F %A Padmanabhan, Sandosh %A St Pourcain, Beate %A Rankinen, Tuomo %A Salo, Perttu %A Tanaka, Toshiko %A Timpson, Nicholas J %A Vitart, Veronique %A Waite, Lindsay %A Wheeler, William %A Zhang, Weihua %A Draisma, Harmen H M %A Feitosa, Mary F %A Kerr, Kathleen F %A Lind, Penelope A %A Mihailov, Evelin %A Onland-Moret, N Charlotte %A Song, Ci %A Weedon, Michael N %A Xie, Weijia %A Yengo, Loic %A Absher, Devin %A Albert, Christine M %A Alonso, Alvaro %A Arking, Dan E %A de Bakker, Paul I W %A Balkau, Beverley %A Barlassina, Cristina %A Benaglio, Paola %A Bis, Joshua C %A Bouatia-Naji, Nabila %A Brage, Søren %A Chanock, Stephen J %A Chines, Peter S %A Chung, Mina %A Darbar, Dawood %A Dina, Christian %A Dörr, Marcus %A Elliott, Paul %A Felix, Stephan B %A Fischer, Krista %A Fuchsberger, Christian %A de Geus, Eco J C %A Goyette, Philippe %A Gudnason, Vilmundur %A Harris, Tamara B %A Hartikainen, Anna-Liisa %A Havulinna, Aki S %A Heckbert, Susan R %A Hicks, Andrew A %A Hofman, Albert %A Holewijn, Suzanne %A Hoogstra-Berends, Femke %A Hottenga, Jouke-Jan %A Jensen, Majken K %A Johansson, Asa %A Junttila, Juhani %A Kääb, Stefan %A Kanon, Bart %A Ketkar, Shamika %A Khaw, Kay-Tee %A Knowles, Joshua W %A Kooner, Angrad S %A Kors, Jan A %A Kumari, Meena %A Milani, Lili %A Laiho, Päivi %A Lakatta, Edward G %A Langenberg, Claudia %A Leusink, Maarten %A Liu, Yongmei %A Luben, Robert N %A Lunetta, Kathryn L %A Lynch, Stacey N %A Markus, Marcello R P %A Marques-Vidal, Pedro %A Mateo Leach, Irene %A McArdle, Wendy L %A McCarroll, Steven A %A Medland, Sarah E %A Miller, Kathryn A %A Montgomery, Grant W %A Morrison, Alanna C %A Müller-Nurasyid, Martina %A Navarro, Pau %A Nelis, Mari %A O'Connell, Jeffrey R %A O'Donnell, Christopher J %A Ong, Ken K %A Newman, Anne B %A Peters, Annette %A Polasek, Ozren %A Pouta, Anneli %A Pramstaller, Peter P %A Psaty, Bruce M %A Rao, Dabeeru C %A Ring, Susan M %A Rossin, Elizabeth J %A Rudan, Diana %A Sanna, Serena %A Scott, Robert A %A Sehmi, Jaban S %A Sharp, Stephen %A Shin, Jordan T %A Singleton, Andrew B %A Smith, Albert V %A Soranzo, Nicole %A Spector, Tim D %A Stewart, Chip %A Stringham, Heather M %A Tarasov, Kirill V %A Uitterlinden, André G %A Vandenput, Liesbeth %A Hwang, Shih-Jen %A Whitfield, John B %A Wijmenga, Cisca %A Wild, Sarah H %A Willemsen, Gonneke %A Wilson, James F %A Witteman, Jacqueline C M %A Wong, Andrew %A Wong, Quenna %A Jamshidi, Yalda %A Zitting, Paavo %A Boer, Jolanda M A %A Boomsma, Dorret I %A Borecki, Ingrid B %A van Duijn, Cornelia M %A Ekelund, Ulf %A Forouhi, Nita G %A Froguel, Philippe %A Hingorani, Aroon %A Ingelsson, Erik %A Kivimaki, Mika %A Kronmal, Richard A %A Kuh, Diana %A Lind, Lars %A Martin, Nicholas G %A Oostra, Ben A %A Pedersen, Nancy L %A Quertermous, Thomas %A Rotter, Jerome I %A van der Schouw, Yvonne T %A Verschuren, W M Monique %A Walker, Mark %A Albanes, Demetrius %A Arnar, David O %A Assimes, Themistocles L %A Bandinelli, Stefania %A Boehnke, Michael %A de Boer, Rudolf A %A Bouchard, Claude %A Caulfield, W L Mark %A Chambers, John C %A Curhan, Gary %A Cusi, Daniele %A Eriksson, Johan %A Ferrucci, Luigi %A van Gilst, Wiek H %A Glorioso, Nicola %A de Graaf, Jacqueline %A Groop, Leif %A Gyllensten, Ulf %A Hsueh, Wen-Chi %A Hu, Frank B %A Huikuri, Heikki V %A Hunter, David J %A Iribarren, Carlos %A Isomaa, Bo %A Jarvelin, Marjo-Riitta %A Jula, Antti %A Kähönen, Mika %A Kiemeney, Lambertus A %A van der Klauw, Melanie M %A Kooner, Jaspal S %A Kraft, Peter %A Iacoviello, Licia %A Lehtimäki, Terho %A Lokki, Marja-Liisa L %A Mitchell, Braxton D %A Navis, Gerjan %A Nieminen, Markku S %A Ohlsson, Claes %A Poulter, Neil R %A Qi, Lu %A Raitakari, Olli T %A Rimm, Eric B %A Rioux, John D %A Rizzi, Federica %A Rudan, Igor %A Salomaa, Veikko %A Sever, Peter S %A Shields, Denis C %A Shuldiner, Alan R %A Sinisalo, Juha %A Stanton, Alice V %A Stolk, Ronald P %A Strachan, David P %A Tardif, Jean-Claude %A Thorsteinsdottir, Unnur %A Tuomilehto, Jaako %A van Veldhuisen, Dirk J %A Virtamo, Jarmo %A Viikari, Jorma %A Vollenweider, Peter %A Waeber, Gérard %A Widen, Elisabeth %A Cho, Yoon Shin %A Olsen, Jesper V %A Visscher, Peter M %A Willer, Cristen %A Franke, Lude %A Erdmann, Jeanette %A Thompson, John R %A Pfeufer, Arne %A Sotoodehnia, Nona %A Newton-Cheh, Christopher %A Ellinor, Patrick T %A Stricker, Bruno H Ch %A Metspalu, Andres %A Perola, Markus %A Beckmann, Jacques S %A Smith, George Davey %A Stefansson, Kari %A Wareham, Nicholas J %A Munroe, Patricia B %A Sibon, Ody C M %A Milan, David J %A Snieder, Harold %A Samani, Nilesh J %A Loos, Ruth J F %K Animals %K Arrhythmias, Cardiac %K Gene Frequency %K Genetic Loci %K Genome-Wide Association Study %K Heart Conduction System %K Heart Rate %K Humans %K Metabolic Networks and Pathways %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %X

Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.

%B Nat Genet %V 45 %P 621-31 %8 2013 Jun %G eng %N 6 %R 10.1038/ng.2610 %0 Journal Article %J Diabetes %D 2013 %T The influence of obesity-related single nucleotide polymorphisms on BMI across the life course: the PAGE study. %A Graff, Mariaelisa %A Gordon-Larsen, Penny %A Lim, Unhee %A Fowke, Jay H %A Love, Shelly-Ann %A Fesinmeyer, Megan %A Wilkens, Lynne R %A Vertilus, Shawyntee %A Ritchie, Marilyn D %A Prentice, Ross L %A Pankow, Jim %A Monroe, Kristine %A Manson, JoAnn E %A Le Marchand, Loïc %A Kuller, Lewis H %A Kolonel, Laurence N %A Hong, Ching P %A Henderson, Brian E %A Haessler, Jeff %A Gross, Myron D %A Goodloe, Robert %A Franceschini, Nora %A Carlson, Christopher S %A Buyske, Steven %A Bůzková, Petra %A Hindorff, Lucia A %A Matise, Tara C %A Crawford, Dana C %A Haiman, Christopher A %A Peters, Ulrike %A North, Kari E %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Aging %K Body Mass Index %K Cohort Studies %K Cross-Sectional Studies %K European Continental Ancestry Group %K Female %K Genetic Association Studies %K Health Surveys %K Humans %K Male %K Middle Aged %K Obesity %K Polymorphism, Single Nucleotide %K Proteins %K United States %K Young Adult %X

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

%B Diabetes %V 62 %P 1763-7 %8 2013 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/23300277?dopt=Abstract %R 10.2337/db12-0863 %0 Journal Article %J PLoS One %D 2013 %T Insights into the genetic architecture of early stage age-related macular degeneration: a genome-wide association study meta-analysis. %A Holliday, Elizabeth G %A Smith, Albert V %A Cornes, Belinda K %A Buitendijk, Gabriëlle H S %A Jensen, Richard A %A Sim, Xueling %A Aspelund, Thor %A Aung, Tin %A Baird, Paul N %A Boerwinkle, Eric %A Cheng, Ching Yu %A van Duijn, Cornelia M %A Eiriksdottir, Gudny %A Gudnason, Vilmundur %A Harris, Tamara %A Hewitt, Alex W %A Inouye, Michael %A Jonasson, Fridbert %A Klein, Barbara E K %A Launer, Lenore %A Li, Xiaohui %A Liew, Gerald %A Lumley, Thomas %A McElduff, Patrick %A McKnight, Barbara %A Mitchell, Paul %A Psaty, Bruce M %A Rochtchina, Elena %A Rotter, Jerome I %A Scott, Rodney J %A Tay, Wanting %A Taylor, Kent %A Teo, Yik Ying %A Uitterlinden, André G %A Viswanathan, Ananth %A Xie, Sophia %A Vingerling, Johannes R %A Klaver, Caroline C W %A Tai, E Shyong %A Siscovick, David %A Klein, Ronald %A Cotch, Mary Frances %A Wong, Tien Y %A Attia, John %A Wang, Jie Jin %K Apolipoproteins E %K Complement Factor H %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Kruppel-Like Transcription Factors %K Macular Degeneration %K Nerve Tissue Proteins %K Polymorphism, Single Nucleotide %K Proteins %K Risk Factors %K Zinc Finger Protein Gli3 %X

Genetic factors explain a majority of risk variance for age-related macular degeneration (AMD). While genome-wide association studies (GWAS) for late AMD implicate genes in complement, inflammatory and lipid pathways, the genetic architecture of early AMD has been relatively under studied. We conducted a GWAS meta-analysis of early AMD, including 4,089 individuals with prevalent signs of early AMD (soft drusen and/or retinal pigment epithelial changes) and 20,453 individuals without these signs. For various published late AMD risk loci, we also compared effect sizes between early and late AMD using an additional 484 individuals with prevalent late AMD. GWAS meta-analysis confirmed previously reported association of variants at the complement factor H (CFH) (peak P = 1.5×10(-31)) and age-related maculopathy susceptibility 2 (ARMS2) (P = 4.3×10(-24)) loci, and suggested Apolipoprotein E (ApoE) polymorphisms (rs2075650; P = 1.1×10(-6)) associated with early AMD. Other possible loci that did not reach GWAS significance included variants in the zinc finger protein gene GLI3 (rs2049622; P = 8.9×10(-6)) and upstream of GLI2 (rs6721654; P = 6.5×10(-6)), encoding retinal Sonic hedgehog signalling regulators, and in the tyrosinase (TYR) gene (rs621313; P = 3.5×10(-6)), involved in melanin biosynthesis. For a range of published, late AMD risk loci, estimated effect sizes were significantly lower for early than late AMD. This study confirms the involvement of multiple established AMD risk variants in early AMD, but suggests weaker genetic effects on the risk of early AMD relative to late AMD. Several biological processes were suggested to be potentially specific for early AMD, including pathways regulating RPE cell melanin content and signalling pathways potentially involved in retinal regeneration, generating hypotheses for further investigation.

%B PLoS One %V 8 %P e53830 %8 2013 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/23326517?dopt=Abstract %R 10.1371/journal.pone.0053830 %0 Journal Article %J Circ Heart Fail %D 2013 %T Insulin resistance and risk of incident heart failure: Cardiovascular Health Study. %A Banerjee, Dipanjan %A Biggs, Mary L %A Mercer, Laina %A Mukamal, Kenneth %A Kaplan, Robert %A Barzilay, Joshua %A Kuller, Lewis %A Kizer, Jorge R %A Djoussé, Luc %A Tracy, Russell %A Zieman, Susan %A Lloyd-Jones, Donald %A Siscovick, David %A Carnethon, Mercedes %K Aged %K Female %K Heart Atria %K Heart Failure %K Heart Ventricles %K Humans %K Incidence %K Insulin %K Insulin Resistance %K Male %K Middle Aged %K Myocardial Infarction %K Organ Size %K Proportional Hazards Models %K Prospective Studies %X

BACKGROUND: Patients with heart failure (HF) have higher fasting insulin levels and a higher prevalence of insulin resistance as compared with matched controls. Insulin resistance leads to structural abnormalities in the heart, such as increased left atrial size, left ventricular mass, and alterations in transmitral velocity that can precede the diagnosis of HF. It is not known whether insulin resistance precedes the development of HF or whether the relationship between insulin resistance and HF is present among adults with HF caused by nonischemic heart disease.

METHODS AND RESULTS: We examined 4425 participants (60% women) from the Cardiovascular Health Study after excluding those with HF, myocardial infarction, or treated diabetes mellitus at baseline. We used Cox proportional hazards models to estimate the relative risk of incident HF associated with fasting insulin measured at study entry. There were 1216 cases of incident HF (1103 without antecedent myocardial infarction) during a median follow-up of 12 years (maximum, 19 years). Fasting insulin levels were positively associated with the risk of incident HF (hazard ratio, 1.10; 95% confidence interval, 1.05-1.15, per SD change) when adjusted for age, sex, race, field center, physical activity, smoking, alcohol intake, high-density lipoprotein-cholesterol, total cholesterol, systolic blood pressure, and waist circumference. The association between fasting insulin levels and incident HF was similar for HF without antecedent myocardial infarction (hazard ratio, 1.10; 95% confidence interval, 1.05-1.15). Measures of left atrial size, left ventricular mass, and peak A velocity at baseline were associated both with fasting insulin levels and with HF; however, additional statistical adjustment for these parameters did not completely attenuate the insulin-HF estimate (hazard ratio, 1.08; 95% confidence interval, 1.03-1.14 per 1-SD increase in fasting insulin).

CONCLUSIONS: Fasting insulin was positively associated with adverse echocardiographic features and risk of subsequent HF in Cardiovascular Health Study participants, including those without an antecedent myocardial infarction.

CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00005133.

%B Circ Heart Fail %V 6 %P 364-70 %8 2013 May %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/23575256?dopt=Abstract %R 10.1161/CIRCHEARTFAILURE.112.000022 %0 Journal Article %J BMC Genet %D 2013 %T Investigation of gene-by-sex interactions for lipid traits in diverse populations from the population architecture using genomics and epidemiology study. %A Taylor, Kira C %A Carty, Cara L %A Dumitrescu, Logan %A Bůzková, Petra %A Cole, Shelley A %A Hindorff, Lucia %A Schumacher, Fred R %A Wilkens, Lynne R %A Shohet, Ralph V %A Quibrera, P Miguel %A Johnson, Karen C %A Henderson, Brian E %A Haessler, Jeff %A Franceschini, Nora %A Eaton, Charles B %A Duggan, David J %A Cochran, Barbara %A Cheng, Iona %A Carlson, Chris S %A Brown-Gentry, Kristin %A Anderson, Garnet %A Ambite, Jose Luis %A Haiman, Christopher %A Le Marchand, Loïc %A Kooperberg, Charles %A Crawford, Dana C %A Buyske, Steven %A North, Kari E %A Fornage, Myriam %K Female %K Genetic Heterogeneity %K Genome, Human %K Genome-Wide Association Study %K Humans %K Lipids %K Male %K Polymorphism, Single Nucleotide %K Population Groups %X

BACKGROUND: High-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels are influenced by both genes and the environment. Genome-wide association studies (GWAS) have identified ~100 common genetic variants associated with HDL-C, LDL-C, and/or TG levels, mostly in populations of European descent, but little is known about the modifiers of these associations. Here, we investigated whether GWAS-identified SNPs for lipid traits exhibited heterogeneity by sex in the Population Architecture using Genomics and Epidemiology (PAGE) study.

RESULTS: A sex-stratified meta-analysis was performed for 49 GWAS-identified SNPs for fasting HDL-C, LDL-C, and ln(TG) levels among adults self-identified as European American (25,013). Heterogeneity by sex was established when phet < 0.001. There was evidence for heterogeneity by sex for two SNPs for ln(TG) in the APOA1/C3/A4/A5/BUD13 gene cluster: rs28927680 (p(het) = 7.4 x 10(-7)) and rs3135506 (p(het) = 4.3 x 10(-4)one SNP in PLTP for HDL levels (rs7679; p(het) = 9.9 x 10(-4)), and one in HMGCR for LDL levels (rs12654264; p(het) = 3.1 x 10(-5)). We replicated heterogeneity by sex in five of seventeen loci previously reported by genome-wide studies (binomial p = 0.0009). We also present results for other racial/ethnic groups in the supplementary materials, to provide a resource for future meta-analyses.

CONCLUSIONS: We provide further evidence for sex-specific effects of SNPs in the APOA1/C3/A4/A5/BUD13 gene cluster, PLTP, and HMGCR on fasting triglyceride levels in European Americans from the PAGE study. Our findings emphasize the need for considering context-specific effects when interpreting genetic associations emerging from GWAS, and also highlight the difficulties in replicating interaction effects across studies and across racial/ethnic groups.

%B BMC Genet %V 14 %P 33 %8 2013 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/23634756?dopt=Abstract %R 10.1186/1471-2156-14-33 %0 Journal Article %J Ann Neurol %D 2013 %T Ischemic stroke is associated with the ABO locus: the EuroCLOT study. %A Williams, Frances M K %A Carter, Angela M %A Hysi, Pirro G %A Surdulescu, Gabriela %A Hodgkiss, Dylan %A Soranzo, Nicole %A Traylor, Matthew %A Bevan, Steve %A Dichgans, Martin %A Rothwell, Peter M W %A Sudlow, Cathie %A Farrall, Martin %A Silander, Kaisa %A Kaunisto, Mari %A Wagner, Peter %A Saarela, Olli %A Kuulasmaa, Kari %A Virtamo, Jarmo %A Salomaa, Veikko %A Amouyel, Philippe %A Arveiler, Dominique %A Ferrieres, Jean %A Wiklund, Per-Gunnar %A Ikram, M Arfan %A Hofman, Albert %A Boncoraglio, Giorgio B %A Parati, Eugenio A %A Helgadottir, Anna %A Gretarsdottir, Solveig %A Thorsteinsdottir, Unnur %A Thorleifsson, Gudmar %A Stefansson, Kari %A Seshadri, Sudha %A DeStefano, Anita %A Gschwendtner, Andreas %A Psaty, Bruce %A Longstreth, Will %A Mitchell, Braxton D %A Cheng, Yu-Ching %A Clarke, Robert %A Ferrario, Marco %A Bis, Joshua C %A Levi, Christopher %A Attia, John %A Holliday, Elizabeth G %A Scott, Rodney J %A Fornage, Myriam %A Sharma, Pankaj %A Furie, Karen L %A Rosand, Jonathan %A Nalls, Mike %A Meschia, James %A Mosely, Thomas H %A Evans, Alun %A Palotie, Aarno %A Markus, Hugh S %A Grant, Peter J %A Spector, Tim D %K ABO Blood-Group System %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Blood Coagulation %K Brain Ischemia %K Cohort Studies %K Europe %K Female %K Genetic Loci %K Genetic Predisposition to Disease %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Stroke %K Young Adult %X

OBJECTIVE: End-stage coagulation and the structure/function of fibrin are implicated in the pathogenesis of ischemic stroke. We explored whether genetic variants associated with end-stage coagulation in healthy volunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype.

METHODS: Common genetic variants identified through genome-wide association studies of coagulation factors and fibrin structure/function in healthy twins (n = 2,100, Stage 1) were examined in ischemic stroke (n = 4,200 cases) using 2 independent samples of European ancestry (Stage 2). A third clinical collection having stroke subtyping (total 8,900 cases, 55,000 controls) was used for replication (Stage 3).

RESULTS: Stage 1 identified 524 single nucleotide polymorphisms (SNPs) from 23 linkage disequilibrium blocks having significant association (p < 5 × 10(-8)) with 1 or more coagulation/fibrin phenotypes. The most striking associations included SNP rs5985 with factor XIII activity (p = 2.6 × 10(-186)), rs10665 with FVII (p = 2.4 × 10(-47)), and rs505922 in the ABO gene with both von Willebrand factor (p = 4.7 × 10(-57)) and factor VIII (p = 1.2 × 10(-36)). In Stage 2, the 23 independent SNPs were examined in stroke cases/noncases using MOnica Risk, Genetics, Archiving and Monograph (MORGAM) and Wellcome Trust Case Control Consortium 2 collections. SNP rs505922 was nominally associated with ischemic stroke (odds ratio = 0.94, 95% confidence interval = 0.88-0.99, p = 0.023). Independent replication in Meta-Stroke confirmed the rs505922 association with stroke, beta (standard error, SE) = 0.066 (0.02), p = 0.001, a finding specific to large-vessel and cardioembolic stroke (p = 0.001 and p = < 0.001, respectively) but not seen with small-vessel stroke (p = 0.811).

INTERPRETATION: ABO gene variants are associated with large-vessel and cardioembolic stroke but not small-vessel disease. This work sheds light on the different pathogenic mechanisms underpinning stroke subtype.

%B Ann Neurol %V 73 %P 16-31 %8 2013 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/23381943?dopt=Abstract %R 10.1002/ana.23838 %0 Journal Article %J Atherosclerosis %D 2013 %T Lack of associations of ten candidate coronary heart disease risk genetic variants and subclinical atherosclerosis in four US populations: the Population Architecture using Genomics and Epidemiology (PAGE) study. %A Zhang, Lili %A Bůzková, Petra %A Wassel, Christina L %A Roman, Mary J %A North, Kari E %A Crawford, Dana C %A Boston, Jonathan %A Brown-Gentry, Kristin D %A Cole, Shelley A %A Deelman, Ewa %A Goodloe, Robert %A Wilson, Sarah %A Heiss, Gerardo %A Jenny, Nancy S %A Jorgensen, Neal W %A Matise, Tara C %A McClellan, Bob E %A Nato, Alejandro Q %A Ritchie, Marylyn D %A Franceschini, Nora %A Kao, W H Linda %K African Americans %K Aged %K Ankle Brachial Index %K Asymptomatic Diseases %K Carotid Artery Diseases %K Carotid Intima-Media Thickness %K Coronary Disease %K European Continental Ancestry Group %K Female %K Gene Frequency %K Genetic Association Studies %K Genetic Predisposition to Disease %K Humans %K Indians, North American %K Linear Models %K Logistic Models %K Male %K Mexican Americans %K Middle Aged %K Odds Ratio %K Phenotype %K Polymorphism, Single Nucleotide %K Predictive Value of Tests %K Risk Assessment %K Risk Factors %K United States %X

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

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

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

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

%B Atherosclerosis %V 228 %P 390-9 %8 2013 Jun %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/23587283?dopt=Abstract %R 10.1016/j.atherosclerosis.2013.02.038 %0 Journal Article %J J Am Coll Cardiol %D 2013 %T Lifetime risk for heart failure among white and black Americans: cardiovascular lifetime risk pooling project. %A Huffman, Mark D %A Berry, Jarett D %A Ning, Hongyan %A Dyer, Alan R %A Garside, Daniel B %A Cai, Xuan %A Daviglus, Martha L %A Lloyd-Jones, Donald M %K Adolescent %K Adult %K African Americans %K Age Factors %K Aged %K Anthropometry %K Body Mass Index %K Cardiovascular Diseases %K Cohort Studies %K European Continental Ancestry Group %K Female %K Health Surveys %K Heart Failure %K Humans %K Kaplan-Meier Estimate %K Male %K Middle Aged %K Predictive Value of Tests %K Prognosis %K Risk Assessment %K Severity of Illness Index %K Sex Factors %K Survival Analysis %K Time Factors %K United States %K Young Adult %X

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

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

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

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

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

%B J Am Coll Cardiol %V 61 %P 1510-7 %8 2013 Apr 09 %G eng %N 14 %1 http://www.ncbi.nlm.nih.gov/pubmed/23500287?dopt=Abstract %& 1510 %R 10.1016/j.jacc.2013.01.022 %0 Journal Article %J Int J Obes (Lond) %D 2013 %T Lipoprotein receptor-related protein 1 variants and dietary fatty acids: meta-analysis of European origin and African American studies. %A Smith, C E %A Ngwa, J %A Tanaka, T %A Qi, Q %A Wojczynski, M K %A Lemaitre, R N %A Anderson, J S %A Manichaikul, A %A Mikkilä, V %A van Rooij, F J A %A Ye, Z %A Bandinelli, S %A Frazier-Wood, A C %A Houston, D K %A Hu, F %A Langenberg, C %A McKeown, N M %A Mozaffarian, D %A North, K E %A Viikari, J %A Zillikens, M C %A Djoussé, L %A Hofman, A %A Kähönen, M %A Kabagambe, E K %A Loos, R J F %A Saylor, G B %A Forouhi, N G %A Liu, Y %A Mukamal, K J %A Chen, Y-D I %A Tsai, M Y %A Uitterlinden, A G %A Raitakari, O %A van Duijn, C M %A Arnett, D K %A Borecki, I B %A Cupples, L A %A Ferrucci, L %A Kritchevsky, S B %A Lehtimäki, T %A Qi, Lu %A Rotter, J I %A Siscovick, D S %A Wareham, N J %A Witteman, J C M %A Ordovás, J M %A Nettleton, J A %K Adipose Tissue %K Adult %K African Continental Ancestry Group %K Aged %K Aged, 80 and over %K Body Mass Index %K Europe %K European Continental Ancestry Group %K Fatty Acids %K Female %K Gene Frequency %K Gene-Environment Interaction %K Genetic Predisposition to Disease %K Genotype %K Humans %K Low Density Lipoprotein Receptor-Related Protein-1 %K Male %K Middle Aged %K Obesity %K Phenotype %K Polymorphism, Single Nucleotide %K Prevalence %K United States %X

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

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

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

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

%B Int J Obes (Lond) %V 37 %P 1211-20 %8 2013 Sep %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/23357958?dopt=Abstract %R 10.1038/ijo.2012.215 %0 Journal Article %J Psychosom Med %D 2013 %T Long-term survival in adults 65 years and older with white matter hyperintensity: association with performance on the digit symbol substitution test. %A Rosano, Caterina %A Chang, Yue-Fang %A Kuller, Lewis H %A Guralnik, Jack M %A Studenski, Stephanie A %A Aizenstein, Howard J %A Gianaros, Peter J %A Lopez, Oscar L %A Longstreth, William T %A Newman, Anne B %K Aged %K Apolipoprotein E4 %K Biomarkers %K Brain %K Cardiovascular Diseases %K Epidemiologic Methods %K Female %K Humans %K Life Style %K Magnetic Resonance Imaging %K Male %K Neuroimaging %K Neuropsychological Tests %K Reaction Time %K Sex Factors %K Stroke %K Survivors %X

OBJECTIVE: White matter hyperintensity (WMH) confers increased mortality risk in patients with cardiovascular diseases. However, little is known about differences in survival times among adults 65 years and older who have WMH and live in the community. To characterize the factors that may reduce mortality risk in the presence of WMH, measures of race, sex, apolipoprotein E4, neuroimaging, and cardiometabolic, physiological, and psychosocial characteristics were examined, with a particular focus on information processing as measured by the Digit Symbol Substitution Test (DSST).

METHODS: Cox proportional models were used to estimate mortality risks in a cohort of 3513 adults (74.8 years, 58% women, 84% white) with WMH (0-9 points), DSST (0-90 points), risk factor assessment in 1992 to 1994, and data on mortality and incident stroke in 2009 (median follow-up [range] = 14.2 [0.5-18.1] years).

RESULTS: WMH predicted a 48% greater mortality risk (age-adjusted hazard ratio [HR; 95% confidence interval {CI}] for WMH >3 points = 1.48 [1.35-1.62]). This association was attenuated after adjustment for DSST (HR [CI] = 1.38 [1.27-1.51]) or lacunar infarcts (HR [CI] = 1.37 [1.25,1.50]) but not after adjustment for other factors. The interaction between DSST and WMH was significant (p = .011). In fully adjusted models stratified by WMH of 3 or higher, participants with DSST greater than or equal to median had a 34% lower mortality risk among those with WMH of 3 or higher (n = 532/1217) and a 28% lower mortality risk among those with WMH lower than 3 (n = 1364/2296), compared with participants with DSST less than median (HR [95% CI] = 0.66 [0.55-0.81] and 0.72 [0.62-0.83], respectively).

CONCLUSIONS: WMH is associated with increased long-term mortality risk in community-dwelling adults 65 years and older. The increased risk is attenuated for those with higher DSST. Assessment of cognitive function with DSST may improve risk stratification of individuals with WMH.

%B Psychosom Med %V 75 %P 624-31 %8 2013 Sep %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/23886735?dopt=Abstract %R 10.1097/PSY.0b013e31829c1df2 %0 Journal Article %J JACC Heart Fail %D 2013 %T Long-term trajectory of two unique cardiac biomarkers and subsequent left ventricular structural pathology and risk of incident heart failure in community-dwelling older adults at low baseline risk. %A Glick, Danielle %A deFilippi, Christopher R %A Christenson, Robert %A Gottdiener, John S %A Seliger, Stephen L %K Aged %K Biomarkers %K Female %K Heart Failure %K Heart Ventricles %K Humans %K Male %K Natriuretic Peptide, Brain %K Peptide Fragments %K Prospective Studies %K Risk Assessment %K Time Factors %K Troponin T %K Ultrasonography %X

OBJECTIVES: This study sought to determine whether the combined trajectories of cardiac biomarkers identify those older adults with initial low levels who have an increased risk for structural heart disease, incident heart failure (HF), and cardiovascular (CV) death.

BACKGROUND: Initial low levels of high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) identify older adults at lower risk for CV events.

METHODS: We performed an observational study among older adults without prevalent HF in the CHS (Cardiovascular Health Study). NT-proBNP and hs-cTnT were measured at baseline and after 2 to 3 years. In those with low baseline levels, a significant increase was defined as cardiac troponin T (cTnT) >50% and NT-proBNP >25% increase to >190 pg/ml. Left ventricular ejection fraction and left ventricular mass were measured by echocardiography at baseline and 5 years. Cox regression was used to estimate the association of change in biomarkers with HF and CV mortality.

RESULTS: Among 2,008 participants with initially low biomarker concentrations, significant increases occurred in 14.8% for cTnT only, 13.2% for NT-proBNP only, and 6.1% for both. After 10 years, cumulative HF incidence was 50.4% versus 12.2% among those with both biomarkers versus neither biomarker increased. The adjusted relative risk comparing those with increases in both biomarkers versus neither biomarker was 3.56 for incident HF (95% confidence interval: 2.56 to 4.97) and 2.98 for CV mortality (95% confidence interval: 2.98 to 4.26). Among 1,340 participants with serial echocardiography, the frequency of new abnormal left ventricular ejection fraction was 11.8% versus 4% for those with increases in both biomarkers versus neither biomarker (p = 0.007).

CONCLUSIONS: Among older adults without HF with initially low cTnT and NT-proBNP, the long-term trajectory of both biomarkers predicts systolic dysfunction, incident HF, and CV death.

%B JACC Heart Fail %V 1 %P 353-360 %8 2013 Aug %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/24621939?dopt=Abstract %R 10.1016/j.jchf.2013.04.007 %0 Journal Article %J Nat Genet %D 2013 %T A meta-analysis identifies new loci associated with body mass index in individuals of African ancestry. %A Monda, Keri L %A Chen, Gary K %A Taylor, Kira C %A Palmer, Cameron %A Edwards, Todd L %A Lange, Leslie A %A Ng, Maggie C Y %A Adeyemo, Adebowale A %A Allison, Matthew A %A Bielak, Lawrence F %A Chen, Guanjie %A Graff, Mariaelisa %A Irvin, Marguerite R %A Rhie, Suhn K %A Li, Guo %A Liu, Yongmei %A Liu, Youfang %A Lu, Yingchang %A Nalls, Michael A %A Sun, Yan V %A Wojczynski, Mary K %A Yanek, Lisa R %A Aldrich, Melinda C %A Ademola, Adeyinka %A Amos, Christopher I %A Bandera, Elisa V %A Bock, Cathryn H %A Britton, Angela %A Broeckel, Ulrich %A Cai, Quiyin %A Caporaso, Neil E %A Carlson, Chris S %A Carpten, John %A Casey, Graham %A Chen, Wei-Min %A Chen, Fang %A Chen, Yii-der I %A Chiang, Charleston W K %A Coetzee, Gerhard A %A Demerath, Ellen %A Deming-Halverson, Sandra L %A Driver, Ryan W %A Dubbert, Patricia %A Feitosa, Mary F %A Feng, Ye %A Freedman, Barry I %A Gillanders, Elizabeth M %A Gottesman, Omri %A Guo, Xiuqing %A Haritunians, Talin %A Harris, Tamara %A Harris, Curtis C %A Hennis, Anselm J M %A Hernandez, Dena G %A McNeill, Lorna H %A Howard, Timothy D %A Howard, Barbara V %A Howard, Virginia J %A Johnson, Karen C %A Kang, Sun J %A Keating, Brendan J %A Kolb, Suzanne %A Kuller, Lewis H %A Kutlar, Abdullah %A Langefeld, Carl D %A Lettre, Guillaume %A Lohman, Kurt %A Lotay, Vaneet %A Lyon, Helen %A Manson, JoAnn E %A Maixner, William %A Meng, Yan A %A Monroe, Kristine R %A Morhason-Bello, Imran %A Murphy, Adam B %A Mychaleckyj, Josyf C %A Nadukuru, Rajiv %A Nathanson, Katherine L %A Nayak, Uma %A N'diaye, Amidou %A Nemesure, Barbara %A Wu, Suh-Yuh %A Leske, M Cristina %A Neslund-Dudas, Christine %A Neuhouser, Marian %A Nyante, Sarah %A Ochs-Balcom, Heather %A Ogunniyi, Adesola %A Ogundiran, Temidayo O %A Ojengbede, Oladosu %A Olopade, Olufunmilayo I %A Palmer, Julie R %A Ruiz-Narvaez, Edward A %A Palmer, Nicholette D %A Press, Michael F %A Rampersaud, Evandine %A Rasmussen-Torvik, Laura J %A Rodriguez-Gil, Jorge L %A Salako, Babatunde %A Schadt, Eric E %A Schwartz, Ann G %A Shriner, Daniel A %A Siscovick, David %A Smith, Shad B %A Wassertheil-Smoller, Sylvia %A Speliotes, Elizabeth K %A Spitz, Margaret R %A Sucheston, Lara %A Taylor, Herman %A Tayo, Bamidele O %A Tucker, Margaret A %A Van Den Berg, David J %A Edwards, Digna R Velez %A Wang, Zhaoming %A Wiencke, John K %A Winkler, Thomas W %A Witte, John S %A Wrensch, Margaret %A Wu, Xifeng %A Yang, James J %A Levin, Albert M %A Young, Taylor R %A Zakai, Neil A %A Cushman, Mary %A Zanetti, Krista A %A Zhao, Jing Hua %A Zhao, Wei %A Zheng, Yonglan %A Zhou, Jie %A Ziegler, Regina G %A Zmuda, Joseph M %A Fernandes, Jyotika K %A Gilkeson, Gary S %A Kamen, Diane L %A Hunt, Kelly J %A Spruill, Ida J %A Ambrosone, Christine B %A Ambs, Stefan %A Arnett, Donna K %A Atwood, Larry %A Becker, Diane M %A Berndt, Sonja I %A Bernstein, Leslie %A Blot, William J %A Borecki, Ingrid B %A Bottinger, Erwin P %A Bowden, Donald W %A Burke, Gregory %A Chanock, Stephen J %A Cooper, Richard S %A Ding, Jingzhong %A Duggan, David %A Evans, Michele K %A Fox, Caroline %A Garvey, W Timothy %A Bradfield, Jonathan P %A Hakonarson, Hakon %A Grant, Struan F A %A Hsing, Ann %A Chu, Lisa %A Hu, Jennifer J %A Huo, Dezheng %A Ingles, Sue A %A John, Esther M %A Jordan, Joanne M %A Kabagambe, Edmond K %A Kardia, Sharon L R %A Kittles, Rick A %A Goodman, Phyllis J %A Klein, Eric A %A Kolonel, Laurence N %A Le Marchand, Loïc %A Liu, Simin %A McKnight, Barbara %A Millikan, Robert C %A Mosley, Thomas H %A Padhukasahasram, Badri %A Williams, L Keoki %A Patel, Sanjay R %A Peters, Ulrike %A Pettaway, Curtis A %A Peyser, Patricia A %A Psaty, Bruce M %A Redline, Susan %A Rotimi, Charles N %A Rybicki, Benjamin A %A Sale, Michèle M %A Schreiner, Pamela J %A Signorello, Lisa B %A Singleton, Andrew B %A Stanford, Janet L %A Strom, Sara S %A Thun, Michael J %A Vitolins, Mara %A Zheng, Wei %A Moore, Jason H %A Williams, Scott M %A Ketkar, Shamika %A Zhu, Xiaofeng %A Zonderman, Alan B %A Kooperberg, Charles %A Papanicolaou, George J %A Henderson, Brian E %A Reiner, Alex P %A Hirschhorn, Joel N %A Loos, Ruth J F %A North, Kari E %A Haiman, Christopher A %K African Americans %K Body Mass Index %K Case-Control Studies %K Gene Frequency %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Linkage Disequilibrium %K Obesity %K Polymorphism, Single Nucleotide %X

Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one new locus at 5q33 (GALNT10, rs7708584, P = 3.4 × 10(-11)) and another at 7p15 when we included data from the GIANT consortium (MIR148A-NFE2L3, rs10261878, P = 1.2 × 10(-10)). We also found suggestive evidence of an association at a third locus at 6q16 in the African-ancestry sample (KLHL32, rs974417, P = 6.9 × 10(-8)). Thirty-two of the 36 previously established BMI variants showed directionally consistent effect estimates in our GWAS (binomial P = 9.7 × 10(-7)), five of which reached genome-wide significance. These findings provide strong support for shared BMI loci across populations, as well as for the utility of studying ancestrally diverse populations.

%B Nat Genet %V 45 %P 690-6 %8 2013 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/23583978?dopt=Abstract %R 10.1038/ng.2608 %0 Journal Article %J Nat Genet %D 2013 %T Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. %A Lambert, J C %A Ibrahim-Verbaas, C A %A Harold, D %A Naj, A C %A Sims, R %A Bellenguez, C %A DeStafano, A L %A Bis, J C %A Beecham, G W %A Grenier-Boley, B %A Russo, G %A Thorton-Wells, T A %A Jones, N %A Smith, A V %A Chouraki, V %A Thomas, C %A Ikram, M A %A Zelenika, D %A Vardarajan, B N %A Kamatani, Y %A Lin, C F %A Gerrish, A %A Schmidt, H %A Kunkle, B %A Dunstan, M L %A Ruiz, A %A Bihoreau, M T %A Choi, S H %A Reitz, C %A Pasquier, F %A Cruchaga, C %A Craig, D %A Amin, N %A Berr, C %A Lopez, O L %A De Jager, P L %A Deramecourt, V %A Johnston, J A %A Evans, D %A Lovestone, S %A Letenneur, L %A Morón, F J %A Rubinsztein, D C %A Eiriksdottir, G %A Sleegers, K %A Goate, A M %A Fiévet, N %A Huentelman, M W %A Gill, M %A Brown, K %A Kamboh, M I %A Keller, L %A Barberger-Gateau, P %A McGuiness, B %A Larson, E B %A Green, R %A Myers, A J %A Dufouil, C %A Todd, S %A Wallon, D %A Love, S %A Rogaeva, E %A Gallacher, J %A St George-Hyslop, P %A Clarimon, J %A Lleo, A %A Bayer, A %A Tsuang, D W %A Yu, L %A Tsolaki, M %A Bossù, P %A Spalletta, G %A Proitsi, P %A Collinge, J %A Sorbi, S %A Sanchez-Garcia, F %A Fox, N C %A Hardy, J %A Deniz Naranjo, M C %A Bosco, P %A Clarke, R %A Brayne, C %A Galimberti, D %A Mancuso, M %A Matthews, F %A Moebus, S %A Mecocci, P %A Del Zompo, M %A Maier, W %A Hampel, H %A Pilotto, A %A Bullido, M %A Panza, F %A Caffarra, P %A Nacmias, B %A Gilbert, J R %A Mayhaus, M %A Lannefelt, L %A Hakonarson, H %A Pichler, S %A Carrasquillo, M M %A Ingelsson, M %A Beekly, D %A Alvarez, V %A Zou, F %A Valladares, O %A Younkin, S G %A Coto, E %A Hamilton-Nelson, K L %A Gu, W %A Razquin, C %A Pastor, P %A Mateo, I %A Owen, M J %A Faber, K M %A Jonsson, P V %A Combarros, O %A O'Donovan, M C %A Cantwell, L B %A Soininen, H %A Blacker, D %A Mead, S %A Mosley, T H %A Bennett, D A %A Harris, T B %A Fratiglioni, L %A Holmes, C %A de Bruijn, R F %A Passmore, P %A Montine, T J %A Bettens, K %A Rotter, J I %A Brice, A %A Morgan, K %A Foroud, T M %A Kukull, W A %A Hannequin, D %A Powell, J F %A Nalls, M A %A Ritchie, K %A Lunetta, K L %A Kauwe, J S %A Boerwinkle, E %A Riemenschneider, M %A Boada, M %A Hiltuenen, M %A Martin, E R %A Schmidt, R %A Rujescu, D %A Wang, L S %A Dartigues, J F %A Mayeux, R %A Tzourio, C %A Hofman, A %A Nöthen, M M %A Graff, C %A Psaty, B M %A Jones, L %A Haines, J L %A Holmans, P A %A Lathrop, M %A Pericak-Vance, M A %A Launer, L J %A Farrer, L A %A van Duijn, C M %A Van Broeckhoven, C %A Moskvina, V %A Seshadri, S %A Williams, J %A Schellenberg, G D %A Amouyel, P %K Age of Onset %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Case-Control Studies %K Cohort Studies %K Female %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %X

Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10(-8)) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.

%B Nat Genet %V 45 %P 1452-8 %8 2013 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/24162737?dopt=Abstract %R 10.1038/ng.2802 %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 PLoS Genet %D 2013 %T A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function. %A Porcu, Eleonora %A Medici, Marco %A Pistis, Giorgio %A Volpato, Claudia B %A Wilson, Scott G %A Cappola, Anne R %A Bos, Steffan D %A Deelen, Joris %A den Heijer, Martin %A Freathy, Rachel M %A Lahti, Jari %A Liu, Chunyu %A Lopez, Lorna M %A Nolte, Ilja M %A O'Connell, Jeffrey R %A Tanaka, Toshiko %A Trompet, Stella %A Arnold, Alice %A Bandinelli, Stefania %A Beekman, Marian %A Böhringer, Stefan %A Brown, Suzanne J %A Buckley, Brendan M %A Camaschella, Clara %A de Craen, Anton J M %A Davies, Gail %A de Visser, Marieke C H %A Ford, Ian %A Forsen, Tom %A Frayling, Timothy M %A Fugazzola, Laura %A Gögele, Martin %A Hattersley, Andrew T %A Hermus, Ad R %A Hofman, Albert %A Houwing-Duistermaat, Jeanine J %A Jensen, Richard A %A Kajantie, Eero %A Kloppenburg, Margreet %A Lim, Ee M %A Masciullo, Corrado %A Mariotti, Stefano %A Minelli, Cosetta %A Mitchell, Braxton D %A Nagaraja, Ramaiah %A Netea-Maier, Romana T %A Palotie, Aarno %A Persani, Luca %A Piras, Maria G %A Psaty, Bruce M %A Räikkönen, Katri %A Richards, J Brent %A Rivadeneira, Fernando %A Sala, Cinzia %A Sabra, Mona M %A Sattar, Naveed %A Shields, Beverley M %A Soranzo, Nicole %A Starr, John M %A Stott, David J %A Sweep, Fred C G J %A Usala, Gianluca %A van der Klauw, Melanie M %A van Heemst, Diana %A van Mullem, Alies %A Vermeulen, Sita H %A Visser, W Edward %A Walsh, John P %A Westendorp, Rudi G J %A Widen, Elisabeth %A Zhai, Guangju %A Cucca, Francesco %A Deary, Ian J %A Eriksson, Johan G %A Ferrucci, Luigi %A Fox, Caroline S %A Jukema, J Wouter %A Kiemeney, Lambertus A %A Pramstaller, Peter P %A Schlessinger, David %A Shuldiner, Alan R %A Slagboom, Eline P %A Uitterlinden, André G %A Vaidya, Bijay %A Visser, Theo J %A Wolffenbuttel, Bruce H R %A Meulenbelt, Ingrid %A Rotter, Jerome I %A Spector, Tim D %A Hicks, Andrew A %A Toniolo, Daniela %A Sanna, Serena %A Peeters, Robin P %A Naitza, Silvia %K Female %K Genome-Wide Association Study %K Humans %K Hyperthyroidism %K Hypothyroidism %K Male %K Phenotype %K Polymorphism, Genetic %K Polymorphism, Single Nucleotide %K Sex Characteristics %K Signal Transduction %K Thyroid Gland %K Thyrotropin %K Thyroxine %X

Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.

%B PLoS Genet %V 9 %P e1003266 %8 2013 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/23408906?dopt=Abstract %R 10.1371/journal.pgen.1003266 %0 Journal Article %J Circulation %D 2013 %T Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease. %A Sabater-Lleal, Maria %A Huang, Jie %A Chasman, Daniel %A Naitza, Silvia %A Dehghan, Abbas %A Johnson, Andrew D %A Teumer, Alexander %A Reiner, Alex P %A Folkersen, Lasse %A Basu, Saonli %A Rudnicka, Alicja R %A Trompet, Stella %A Mälarstig, Anders %A Baumert, Jens %A Bis, Joshua C %A Guo, Xiuqing %A Hottenga, Jouke J %A Shin, So-Youn %A Lopez, Lorna M %A Lahti, Jari %A Tanaka, Toshiko %A Yanek, Lisa R %A Oudot-Mellakh, Tiphaine %A Wilson, James F %A Navarro, Pau %A Huffman, Jennifer E %A Zemunik, Tatijana %A Redline, Susan %A Mehra, Reena %A Pulanic, Drazen %A Rudan, Igor %A Wright, Alan F %A Kolcic, Ivana %A Polasek, Ozren %A Wild, Sarah H %A Campbell, Harry %A Curb, J David %A Wallace, Robert %A Liu, Simin %A Eaton, Charles B %A Becker, Diane M %A Becker, Lewis C %A Bandinelli, Stefania %A Räikkönen, Katri %A Widen, Elisabeth %A Palotie, Aarno %A Fornage, Myriam %A Green, David %A Gross, Myron %A Davies, Gail %A Harris, Sarah E %A Liewald, David C %A Starr, John M %A Williams, Frances M K %A Grant, Peter J %A Spector, Timothy D %A Strawbridge, Rona J %A Silveira, Angela %A Sennblad, Bengt %A Rivadeneira, Fernando %A Uitterlinden, André G %A Franco, Oscar H %A Hofman, Albert %A van Dongen, Jenny %A Willemsen, Gonneke %A Boomsma, Dorret I %A Yao, Jie %A Swords Jenny, Nancy %A Haritunians, Talin %A McKnight, Barbara %A Lumley, Thomas %A Taylor, Kent D %A Rotter, Jerome I %A Psaty, Bruce M %A Peters, Annette %A Gieger, Christian %A Illig, Thomas %A Grotevendt, Anne %A Homuth, Georg %A Völzke, Henry %A Kocher, Thomas %A Goel, Anuj %A Franzosi, Maria Grazia %A Seedorf, Udo %A Clarke, Robert %A Steri, Maristella %A Tarasov, Kirill V %A Sanna, Serena %A Schlessinger, David %A Stott, David J %A Sattar, Naveed %A Buckley, Brendan M %A Rumley, Ann %A Lowe, Gordon D %A McArdle, Wendy L %A Chen, Ming-Huei %A Tofler, Geoffrey H %A Song, Jaejoon %A Boerwinkle, Eric %A Folsom, Aaron R %A Rose, Lynda M %A Franco-Cereceda, Anders %A Teichert, Martina %A Ikram, M Arfan %A Mosley, Thomas H %A Bevan, Steve %A Dichgans, Martin %A Rothwell, Peter M %A Sudlow, Cathie L M %A Hopewell, Jemma C %A Chambers, John C %A Saleheen, Danish %A Kooner, Jaspal S %A Danesh, John %A Nelson, Christopher P %A Erdmann, Jeanette %A Reilly, Muredach P %A Kathiresan, Sekar %A Schunkert, Heribert %A Morange, Pierre-Emmanuel %A Ferrucci, Luigi %A Eriksson, Johan G %A Jacobs, David %A Deary, Ian J %A Soranzo, Nicole %A Witteman, Jacqueline C M %A de Geus, Eco J C %A Tracy, Russell P %A Hayward, Caroline %A Koenig, Wolfgang %A Cucca, Francesco %A Jukema, J Wouter %A Eriksson, Per %A Seshadri, Sudha %A Markus, Hugh S %A Watkins, Hugh %A Samani, Nilesh J %A Wallaschofski, Henri %A Smith, Nicholas L %A Tregouet, David %A Ridker, Paul M %A Tang, Weihong %A Strachan, David P %A Hamsten, Anders %A O'Donnell, Christopher J %K Adolescent %K Adult %K African Continental Ancestry Group %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Coronary Artery Disease %K European Continental Ancestry Group %K Female %K Fibrinogen %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Hispanic Americans %K Humans %K Male %K Middle Aged %K Myocardial Infarction %K Polymorphism, Single Nucleotide %K Risk Factors %K Stroke %K Venous Thromboembolism %K Young Adult %X

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

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

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

%B Circulation %V 128 %P 1310-24 %8 2013 Sep 17 %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/23969696?dopt=Abstract %R 10.1161/CIRCULATIONAHA.113.002251 %0 Journal Article %J Hum Genet %D 2013 %T No evidence of interaction between known lipid-associated genetic variants and smoking in the multi-ethnic PAGE population. %A Dumitrescu, Logan %A Carty, Cara L %A Franceschini, Nora %A Hindorff, Lucia A %A Cole, Shelley A %A Bůzková, Petra %A Schumacher, Fredrick R %A Eaton, Charles B %A Goodloe, Robert J %A Duggan, David J %A Haessler, Jeff %A Cochran, Barbara %A Henderson, Brian E %A Cheng, Iona %A Johnson, Karen C %A Carlson, Chris S %A Love, Shelly-Anne %A Brown-Gentry, Kristin %A Nato, Alejandro Q %A Quibrera, Miguel %A Shohet, Ralph V %A Ambite, Jose Luis %A Wilkens, Lynne R %A Le Marchand, Loïc %A Haiman, Christopher A %A Buyske, Steven %A Kooperberg, Charles %A North, Kari E %A Fornage, Myriam %A Crawford, Dana C %K Cholesterol, HDL %K Cholesterol, LDL %K Cohort Studies %K Ethnic Groups %K Female %K Gene Frequency %K Gene-Environment Interaction %K Genetics, Population %K Genome-Wide Association Study %K Humans %K Lipid Metabolism %K Male %K Polymorphism, Single Nucleotide %K Prevalence %K Smoking %K Triglycerides %K Young Adult %X

Genome-wide association studies (GWAS) have identified many variants that influence high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and/or triglycerides. However, environmental modifiers, such as smoking, of these known genotype-phenotype associations are just recently emerging in the literature. We have tested for interactions between smoking and 49 GWAS-identified variants in over 41,000 racially/ethnically diverse samples with lipid levels from the Population Architecture Using Genomics and Epidemiology (PAGE) study. Despite their biological plausibility, we were unable to detect significant SNP × smoking interactions.

%B Hum Genet %V 132 %P 1427-31 %8 2013 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/24100633?dopt=Abstract %R 10.1007/s00439-013-1375-3 %0 Journal Article %J J Clin Endocrinol Metab %D 2013 %T Persistent subclinical hypothyroidism and cardiovascular risk in the elderly: the cardiovascular health study. %A Hyland, Kristen A %A Arnold, Alice M %A Lee, Jennifer S %A Cappola, Anne R %K Aged %K Aged, 80 and over %K Coronary Disease %K Female %K Heart Failure %K Humans %K Hypothyroidism %K Incidence %K Longitudinal Studies %K Male %K Risk %K Thyroid Function Tests %X

CONTEXT: Use of a single set of thyroid function tests to define subclinical hypothyroidism may lead to misclassification over time and could influence findings from longitudinal studies.

OBJECTIVE: We assessed the risks of coronary heart disease (CHD), heart failure (HF), and cardiovascular (CV) death in older adults with persistent subclinical hypothyroidism.

DESIGN, SETTING, AND PARTICIPANTS: The study included 679 subclinically hypothyroid and 4184 euthyroid U.S. individuals at least 65 yr old enrolled in the Cardiovascular Health Study and not taking thyroid preparations.

MAIN OUTCOME MEASURE: We measured the 10-yr risk of incident CHD, HF, and CV death from persistent subclinical hypothyroidism, overall and stratified by degree of TSH elevation (4.5-6.9, 7.0-9.9, and 10.0-19.9 mU/liter).

RESULTS: There was no association between persistent subclinical hypothyroidism and incident CHD [hazard ratio (HR), 1.12; 95% confidence interval (CI), 0.93-1.36], HF (HR, 1.05; 95% CI, 0.97-1.27), or CV death (HR, 1.07; 95% CI, 0.87-1.31) in adjusted analyses in which subclinical hypothyroidism was modeled as a time-varying exposure using up to four serial thyroid function tests. When subclinical hypothyroidism was stratified by degree of TSH elevation, no significant associations were found in any stratum. Findings were similar in fixed exposure analyses in which only participants with testing 2 yr apart were considered, with no association between persistent or transient subclinical hypothyroidism and incident CHD, HF, or CV death.

CONCLUSIONS: Our data do not support increased risk of CHD, HF, or CV death in older adults with persistent subclinical hypothyroidism.

%B J Clin Endocrinol Metab %V 98 %P 533-40 %8 2013 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/23162099?dopt=Abstract %R 10.1210/jc.2012-2180 %0 Journal Article %J Ann Hum Genet %D 2013 %T Post-genome-wide association study challenges for lipid traits: describing age as a modifier of gene-lipid associations in the Population Architecture using Genomics and Epidemiology (PAGE) study. %A Dumitrescu, Logan %A Carty, Cara L %A Franceschini, Nora %A Hindorff, Lucia A %A Cole, Shelley A %A Bůzková, Petra %A Schumacher, Fredrick R %A Eaton, Charles B %A Goodloe, Robert J %A Duggan, David J %A Haessler, Jeff %A Cochran, Barbara %A Henderson, Brian E %A Cheng, Iona %A Johnson, Karen C %A Carlson, Chris S %A Love, Shelly-Ann %A Brown-Gentry, Kristin %A Nato, Alejandro Q %A Quibrera, Miguel %A Anderson, Garnet %A Shohet, Ralph V %A Ambite, Jose Luis %A Wilkens, Lynne R %A Marchand, Loic Le %A Haiman, Christopher A %A Buyske, Steven %A Kooperberg, Charles %A North, Kari E %A Fornage, Myriam %A Crawford, Dana C %K Adult %K Aged %K European Continental Ancestry Group %K Female %K Genetic Association Studies %K Genome-Wide Association Study %K Humans %K Lipids %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Quantitative Trait, Heritable %K Risk Factors %X

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

%B Ann Hum Genet %V 77 %P 416-25 %8 2013 Sep %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/23808484?dopt=Abstract %R 10.1111/ahg.12027 %0 Journal Article %J Heart Rhythm %D 2013 %T The QT interval and risk of incident atrial fibrillation. %A Mandyam, Mala C %A Soliman, Elsayed Z %A Alonso, Alvaro %A Dewland, Thomas A %A Heckbert, Susan R %A Vittinghoff, Eric %A Cummings, Steven R %A Ellinor, Patrick T %A Chaitman, Bernard R %A Stocke, Karen %A Applegate, William B %A Arking, Dan E %A Butler, Javed %A Loehr, Laura R %A Magnani, Jared W %A Murphy, Rachel A %A Satterfield, Suzanne %A Newman, Anne B %A Marcus, Gregory M %K Aged %K Atrial Fibrillation %K Cohort Studies %K Electrocardiography %K Female %K Humans %K Incidence %K Long QT Syndrome %K Male %K Middle Aged %K Risk Factors %X

BACKGROUND: Abnormal atrial repolarization is important in the development of atrial fibrillation (AF), but no direct measurement is available in clinical medicine.

OBJECTIVE: To determine whether the QT interval, a marker of ventricular repolarization, could be used to predict incident AF.

METHODS: We examined a prolonged QT interval corrected by using the Framingham formula (QT(Fram)) as a predictor of incident AF in the Atherosclerosis Risk in Communities (ARIC) study. The Cardiovascular Health Study (CHS) and Health, Aging, and Body Composition (ABC) study were used for validation. Secondary predictors included QT duration as a continuous variable, a short QT interval, and QT intervals corrected by using other formulas.

RESULTS: Among 14,538 ARIC study participants, a prolonged QT(Fram) predicted a roughly 2-fold increased risk of AF (hazard ratio [HR] 2.05; 95% confidence interval [CI] 1.42-2.96; P < .001). No substantive attenuation was observed after adjustment for age, race, sex, study center, body mass index, hypertension, diabetes, coronary disease, and heart failure. The findings were validated in Cardiovascular Health Study and Health, Aging, and Body Composition study and were similar across various QT correction methods. Also in the ARIC study, each 10-ms increase in QT(Fram) was associated with an increased unadjusted (HR 1.14; 95% CI 1.10-1.17; P < .001) and adjusted (HR 1.11; 95% CI 1.07-1.14; P < .001) risk of AF. Findings regarding a short QT interval were inconsistent across cohorts.

CONCLUSIONS: A prolonged QT interval is associated with an increased risk of incident AF.

%B Heart Rhythm %V 10 %P 1562-8 %8 2013 Oct %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/23872693?dopt=Abstract %R 10.1016/j.hrthm.2013.07.023 %0 Journal Article %J Hum Reprod %D 2013 %T Replication of genetic loci for ages at menarche and menopause in the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) study. %A Carty, C L %A Spencer, K L %A Setiawan, V W %A Fernandez-Rhodes, L %A Malinowski, J %A Buyske, S %A Young, A %A Jorgensen, N W %A Cheng, I %A Carlson, C S %A Brown-Gentry, K %A Goodloe, R %A Park, A %A Parikh, N I %A Henderson, B %A Le Marchand, L %A Wactawski-Wende, J %A Fornage, M %A Matise, T C %A Hindorff, L A %A Arnold, A M %A Haiman, C A %A Franceschini, N %A Peters, U %A Crawford, D C %K Age Factors %K Cross-Sectional Studies %K Female %K Genome-Wide Association Study %K Genotype %K Humans %K Menarche %K Menopause %K Polymorphism, Single Nucleotide %X

STUDY QUESTION: Do genetic associations identified in genome-wide association studies (GWAS) of age at menarche (AM) and age at natural menopause (ANM) replicate in women of diverse race/ancestry from the Population Architecture using Genomics and Epidemiology (PAGE) Study?

SUMMARY ANSWER: We replicated GWAS reproductive trait single nucleotide polymorphisms (SNPs) in our European descent population and found that many SNPs were also associated with AM and ANM in populations of diverse ancestry.

WHAT IS KNOWN ALREADY: Menarche and menopause mark the reproductive lifespan in women and are important risk factors for chronic diseases including obesity, cardiovascular disease and cancer. Both events are believed to be influenced by environmental and genetic factors, and vary in populations differing by genetic ancestry and geography. Most genetic variants associated with these traits have been identified in GWAS of European-descent populations.

STUDY DESIGN, SIZE, DURATION: A total of 42 251 women of diverse ancestry from PAGE were included in cross-sectional analyses of AM and ANM.

MATERIALS, SETTING, METHODS: SNPs previously associated with ANM (n = 5 SNPs) and AM (n = 3 SNPs) in GWAS were genotyped in American Indians, African Americans, Asians, European Americans, Hispanics and Native Hawaiians. To test SNP associations with ANM or AM, we used linear regression models stratified by race/ethnicity and PAGE sub-study. Results were then combined in race-specific fixed effect meta-analyses for each outcome. For replication and generalization analyses, significance was defined at P < 0.01 for ANM analyses and P < 0.017 for AM analyses.

MAIN RESULTS AND THE ROLE OF CHANCE: We replicated findings for AM SNPs in the LIN28B locus and an intergenic region on 9q31 in European Americans. The LIN28B SNPs (rs314277 and rs314280) were also significantly associated with AM in Asians, but not in other race/ethnicity groups. Linkage disequilibrium (LD) patterns at this locus varied widely among the ancestral groups. With the exception of an intergenic SNP at 13q34, all ANM SNPs replicated in European Americans. Three were significantly associated with ANM in other race/ethnicity populations: rs2153157 (6p24.2/SYCP2L), rs365132 (5q35/UIMC1) and rs16991615 (20p12.3/MCM8). While rs1172822 (19q13/BRSK1) was not significant in the populations of non-European descent, effect sizes showed similar trends.

LIMITATIONS, REASONS FOR CAUTION: Lack of association for the GWAS SNPs in the non-European American groups may be due to differences in locus LD patterns between these groups and the European-descent populations included in the GWAS discovery studies; and in some cases, lower power may also contribute to non-significant findings.

WIDER IMPLICATIONS OF THE FINDINGS: The discovery of genetic variants associated with the reproductive traits provides an important opportunity to elucidate the biological mechanisms involved with normal variation and disorders of menarche and menopause. In this study we replicated most, but not all reported SNPs in European descent populations and examined the epidemiologic architecture of these early reported variants, describing their generalizability and effect size across differing ancestral populations. Such data will be increasingly important for prioritizing GWAS SNPs for follow-up in fine-mapping and resequencing studies, as well as in translational research.

%B Hum Reprod %V 28 %P 1695-706 %8 2013 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/23508249?dopt=Abstract %R 10.1093/humrep/det071 %0 Journal Article %J Circulation %D 2013 %T Resequencing and clinical associations of the 9p21.3 region: a comprehensive investigation in the Framingham heart study. %A Johnson, Andrew D %A Hwang, Shih-Jen %A Voorman, Arend %A Morrison, Alanna %A Peloso, Gina M %A Hsu, Yi-Hsiang %A Thanassoulis, George %A Newton-Cheh, Christopher %A Rogers, Ian S %A Hoffmann, Udo %A Freedman, Jane E %A Fox, Caroline S %A Psaty, Bruce M %A Boerwinkle, Eric %A Cupples, L Adrienne %A O'Donnell, Christopher J %K Calcinosis %K Chromosomes, Human, Pair 9 %K Coronary Artery Disease %K Cyclin-Dependent Kinase Inhibitor p15 %K Cyclin-Dependent Kinase Inhibitor p16 %K DNA Copy Number Variations %K Female %K Follow-Up Studies %K Genetic Predisposition to Disease %K Genotype %K Humans %K Longitudinal Studies %K Male %K Massachusetts %K Middle Aged %K Myocardial Infarction %K Phenotype %K Polymorphism, Single Nucleotide %K Risk Factors %K RNA, Long Noncoding %K Sequence Analysis, DNA %X

BACKGROUND: 9p21.3 is among the most strongly replicated regions for cardiovascular disease. There are few reports of sequencing the associated 9p21.3 interval. We set out to sequence the 9p21.3 region followed by a comprehensive study of genetic associations with clinical and subclinical cardiovascular disease and its risk factors, as well as with copy number variation and gene expression, in the Framingham Heart Study (FHS).

METHODS AND RESULTS: We sequenced 281 individuals (94 with myocardial infarction, 94 with high coronary artery calcium levels, and 93 control subjects free of elevated coronary artery calcium or myocardial infarction), followed by genotyping and association in >7000 additional FHS individuals. We assessed genetic associations with clinical and subclinical cardiovascular disease, risk factor phenotypes, and gene expression levels of the protein-coding genes CDKN2A and CDKN2B and the noncoding gene ANRIL in freshly harvested leukocytes and platelets. Within this large sample, we found strong associations of 9p21.3 variants with increased risk for myocardial infarction, higher coronary artery calcium levels, and larger abdominal aorta diameters and no evidence for association with traditional cardiovascular disease risk factors. No common protein-coding variation, variants in splice donor or acceptor sites, or copy number variation events were observed. By contrast, strong associations were observed between genetic variants and gene expression, particularly for a short isoform of ANRIL and for CDKN2B.

CONCLUSIONS: Our thorough genomic characterization of 9p21.3 suggests common variants likely account for observed disease associations and provides further support for the hypothesis that complex regulatory variation affecting ANRIL and CDKN2B gene expression may contribute to increased risk for clinically apparent and subclinical coronary artery disease and aortic disease.

%B Circulation %V 127 %P 799-810 %8 2013 Feb 19 %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/23315372?dopt=Abstract %R 10.1161/CIRCULATIONAHA.112.111559 %0 Journal Article %J Exp Aging Res %D 2013 %T Results differ by applying distinctive multiple imputation approaches on the longitudinal cardiovascular health study data. %A Ning, Yuming %A McAvay, Gail %A Chaudhry, Sarwat I %A Arnold, Alice M %A Allore, Heather G %K Activities of Daily Living %K Aged %K Arthritis %K Cardiac Rehabilitation %K Cardiovascular Diseases %K Data Interpretation, Statistical %K Female %K Humans %K Longitudinal Studies %K Male %K Outcome Assessment (Health Care) %K Regression Analysis %K Social Support %X

UNLABELLED: BACKGROUND/STUDY CONTEXT: The objective of this study was to examine sequential and simultaneous approaches to multiple imputation of missing data in a longitudinal data set where losses due to death were common.

METHODS: Comparison of results from analyses and simulations of time to incident difficulty of activities of daily living (ADL) in the Cardiovascular Health Study when missing data were imputed simultaneously or sequentially.

RESULTS: Results differed with imputation methods. The largest proportional differences in 12 risk factor parameter estimates were heart failure by 106%, social support by 33%, and arthritis by 27%.

CONCLUSION: Decedents' final characteristics were influential on future imputations of those with missing values.

%B Exp Aging Res %V 39 %P 27-43 %8 2013 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/23316735?dopt=Abstract %R 10.1080/0361073X.2013.741968 %0 Journal Article %J J Am Coll Cardiol %D 2013 %T Risk factors for hospital admission among older persons with newly diagnosed heart failure: findings from the Cardiovascular Health Study. %A Chaudhry, Sarwat I %A McAvay, Gail %A Chen, Shu %A Whitson, Heather %A Newman, Anne B %A Krumholz, Harlan M %A Gill, Thomas M %K Age Factors %K Aged %K Aged, 80 and over %K Comorbidity %K Effect Modifier, Epidemiologic %K Female %K Geriatric Assessment %K Health Surveys %K Heart Failure %K Hospitalization %K Humans %K Longitudinal Studies %K Male %K Mental Competency %K Risk Assessment %K Risk Factors %K Severity of Illness Index %K Stroke Volume %K Time-to-Treatment %K United States %X

OBJECTIVES: This study sought to identify risk factors for the occurrence of all-cause hospital admissions among older persons after heart failure diagnosis, and to determine whether geriatric conditions would emerge as independent risk factors for admission when evaluated in the context of other relevant clinical data.

BACKGROUND: Efforts to reduce costs in heart failure have focused on hospital utilization, yet few studies have examined how geriatric conditions affect the long-term risk for hospital admission after heart failure diagnosis. With the aging of the population with heart failure, geriatric conditions such as slow gait and muscle weakness are becoming increasingly common.

METHODS: The study population included participants with a new diagnosis of heart failure in the Cardiovascular Health Study, a longitudinal study of community-living older persons. Data were collected through annual examinations and medical-record reviews. Geriatric conditions assessed were slow gait, muscle weakness (defined as weak grip), cognitive impairment, and depressive symptoms. Anderson-Gill regression modeling was used to determine the predictors of hospital admission after heart failure diagnosis.

RESULTS: Of the 758 participants with a new diagnosis of heart failure, the mean rate of hospital admission was 7.9 per 10 person-years (95% CI: 7.4 to 8.4). Independent risk factors for hospital admission included diabetes mellitus (HR: 1.36; 95% CI: 1.13 to 1.64), New York Heart Association functional class III or IV (HR: 1.32; 95% CI: 1.11 to 1.57), chronic kidney disease (HR: 1.32; 95% CI: 1.14 to 1.53), slow gait (HR: 1.28; 95% CI: 1.06 to 1.55), depressed ejection fraction (HR: 1.25; 95% CI: 1.04 to 1.51), depression (HR: 1.23; 95% CI: 1.05 to 1.45), and muscle weakness (HR: 1.19; 95% CI: 1.00 to 1.42).

CONCLUSIONS: Geriatric conditions are important, and potentially modifiable, risk factors for hospital admission in heart failure that should be routinely assessed at the time of heart failure diagnosis.

%B J Am Coll Cardiol %V 61 %P 635-42 %8 2013 Feb 12 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/23391194?dopt=Abstract %& 635 %R 10.1016/j.jacc.2012.11.027 %0 Journal Article %J Eur J Epidemiol %D 2013 %T Risk of venous thromboembolism associated with single and combined effects of Factor V Leiden, Prothrombin 20210A and Methylenetethraydrofolate reductase C677T: a meta-analysis involving over 11,000 cases and 21,000 controls. %A Simone, Benedetto %A De Stefano, Valerio %A Leoncini, Emanuele %A Zacho, Jeppe %A Martinelli, Ida %A Emmerich, Joseph %A Rossi, Elena %A Folsom, Aaron R %A Almawi, Wassim Y %A Scarabin, Pierre Y %A den Heijer, Martin %A Cushman, Mary %A Penco, Silvana %A Vaya, Amparo %A Angchaisuksiri, Pantep %A Okumus, Gulfer %A Gemmati, Donato %A Cima, Simona %A Akar, Nejat %A Oguzulgen, Kivilcim I %A Ducros, Véronique %A Lichy, Christoph %A Fernandez-Miranda, Consuelo %A Szczeklik, Andrzej %A Nieto, José A %A Torres, Jose Domingo %A Le Cam-Duchez, Véronique %A Ivanov, Petar %A Cantu-Brito, Carlos %A Shmeleva, Veronika M %A Stegnar, Mojka %A Ogunyemi, Dotun %A Eid, Suhair S %A Nicolotti, Nicola %A De Feo, Emma %A Ricciardi, Walter %A Boccia, Stefania %K Case-Control Studies %K Factor V %K Genetic Predisposition to Disease %K Humans %K Methylenetetrahydrofolate Reductase (NADPH2) %K Prothrombin %K Risk Factors %K Venous Thromboembolism %X

Genetic and environmental factors interact in determining the risk of venous thromboembolism (VTE). The risk associated with the polymorphic variants G1691A of factor V (Factor V Leiden, FVL), G20210A of prothrombin (PT20210A) and C677T of methylentetrahydrofolate reductase (C677T MTHFR) genes has been investigated in many studies. We performed a pooled analysis of case-control and cohort studies investigating in adults the association between each variant and VTE, published on Pubmed, Embase or Google through January 2010. Authors of eligible papers, were invited to provide all available individual data for the pooling. The Odds Ratio (OR) for first VTE associated with each variant, individually and combined with the others, were calculated with a random effect model, in heterozygotes and homozygotes (dominant model for FVL and PT20210A; recessive for C677T MTHFR). We analysed 31 databases, including 11,239 cases and 21,521 controls. No significant association with VTE was found for homozygous C677T MTHFR (OR: 1.38; 95 % confidence intervals [CI]: 0.98-1.93), whereas the risk was increased in carriers of either heterozygous FVL or PT20210 (OR = 4.22; 95 % CI: 3.35-5.32; and OR = 2.79;95 % CI: 2.25-3.46, respectively), in double heterozygotes (OR = 3.42; 95 %CI 1.64-7.13), and in homozygous FVL or PT20210A (OR = 11.45; 95 %CI: 6.79-19.29; and OR: 6.74 (CI 95 % 2.19-20.72), respectively). The stratified analyses showed a stronger effect of FVL on individuals ≤ 45 years (p value for interaction = 0.036) and of PT20210A in women using oral contraceptives (p-value for interaction = 0.045). In this large pooled analysis, inclusive of large studies like MEGA, no effect was found for C677T MTHFR on VTE; FVL and PT20210A were confirmed to be moderate risk factors. Notably, double carriers of the two genetic variants produced an impact on VTE risk significantly increased but weaker than previously thought.

%B Eur J Epidemiol %V 28 %P 621-47 %8 2013 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/23900608?dopt=Abstract %R 10.1007/s10654-013-9825-8 %0 Journal Article %J PLoS Genet %D 2013 %T Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits. %A Randall, Joshua C %A Winkler, Thomas W %A Kutalik, Zoltán %A Berndt, Sonja I %A Jackson, Anne U %A Monda, Keri L %A Kilpeläinen, Tuomas O %A Esko, Tõnu %A Mägi, Reedik %A Li, Shengxu %A Workalemahu, Tsegaselassie %A Feitosa, Mary F %A Croteau-Chonka, Damien C %A Day, Felix R %A Fall, Tove %A Ferreira, Teresa %A Gustafsson, Stefan %A Locke, Adam E %A Mathieson, Iain %A Scherag, Andre %A Vedantam, Sailaja %A Wood, Andrew R %A Liang, Liming %A Steinthorsdottir, Valgerdur %A Thorleifsson, Gudmar %A Dermitzakis, Emmanouil T %A Dimas, Antigone S %A Karpe, Fredrik %A Min, Josine L %A Nicholson, George %A Clegg, Deborah J %A Person, Thomas %A Krohn, Jon P %A Bauer, Sabrina %A Buechler, Christa %A Eisinger, Kristina %A Bonnefond, Amélie %A Froguel, Philippe %A Hottenga, Jouke-Jan %A Prokopenko, Inga %A Waite, Lindsay L %A Harris, Tamara B %A Smith, Albert Vernon %A Shuldiner, Alan R %A McArdle, Wendy L %A Caulfield, Mark J %A Munroe, Patricia B %A Grönberg, Henrik %A Chen, Yii-Der Ida %A Li, Guo %A Beckmann, Jacques S %A Johnson, Toby %A Thorsteinsdottir, Unnur %A Teder-Laving, Maris %A Khaw, Kay-Tee %A Wareham, Nicholas J %A Zhao, Jing Hua %A Amin, Najaf %A Oostra, Ben A %A Kraja, Aldi T %A Province, Michael A %A Cupples, L Adrienne %A Heard-Costa, Nancy L %A Kaprio, Jaakko %A Ripatti, Samuli %A Surakka, Ida %A Collins, Francis S %A Saramies, Jouko %A Tuomilehto, Jaakko %A Jula, Antti %A Salomaa, Veikko %A Erdmann, Jeanette %A Hengstenberg, Christian %A Loley, Christina %A Schunkert, Heribert %A Lamina, Claudia %A Wichmann, H Erich %A Albrecht, Eva %A Gieger, Christian %A Hicks, Andrew A %A Johansson, Asa %A Pramstaller, Peter P %A Kathiresan, Sekar %A Speliotes, Elizabeth K %A Penninx, Brenda %A Hartikainen, Anna-Liisa %A Jarvelin, Marjo-Riitta %A Gyllensten, Ulf %A Boomsma, Dorret I %A Campbell, Harry %A Wilson, James F %A Chanock, Stephen J %A Farrall, Martin %A Goel, Anuj %A Medina-Gómez, Carolina %A Rivadeneira, Fernando %A Estrada, Karol %A Uitterlinden, André G %A Hofman, Albert %A Zillikens, M Carola %A den Heijer, Martin %A Kiemeney, Lambertus A %A Maschio, Andrea %A Hall, Per %A Tyrer, Jonathan %A Teumer, Alexander %A Völzke, Henry %A Kovacs, Peter %A Tönjes, Anke %A Mangino, Massimo %A Spector, Tim D %A Hayward, Caroline %A Rudan, Igor %A Hall, Alistair S %A Samani, Nilesh J %A Attwood, Antony Paul %A Sambrook, Jennifer G %A Hung, Joseph %A Palmer, Lyle J %A Lokki, Marja-Liisa %A Sinisalo, Juha %A Boucher, Gabrielle %A Huikuri, Heikki %A Lorentzon, Mattias %A Ohlsson, Claes %A Eklund, Niina %A Eriksson, Johan G %A Barlassina, Cristina %A Rivolta, Carlo %A Nolte, Ilja M %A Snieder, Harold %A van der Klauw, Melanie M %A van Vliet-Ostaptchouk, Jana V %A Gejman, Pablo V %A Shi, Jianxin %A Jacobs, Kevin B %A Wang, Zhaoming %A Bakker, Stephan J L %A Mateo Leach, Irene %A Navis, Gerjan %A van der Harst, Pim %A Martin, Nicholas G %A Medland, Sarah E %A Montgomery, Grant W %A Yang, Jian %A Chasman, Daniel I %A Ridker, Paul M %A Rose, Lynda M %A Lehtimäki, Terho %A Raitakari, Olli %A Absher, Devin %A Iribarren, Carlos %A Basart, Hanneke %A Hovingh, Kees G %A Hyppönen, Elina %A Power, Chris %A Anderson, Denise %A Beilby, John P %A Hui, Jennie %A Jolley, Jennifer %A Sager, Hendrik %A Bornstein, Stefan R %A Schwarz, Peter E H %A Kristiansson, Kati %A Perola, Markus %A Lindström, Jaana %A Swift, Amy J %A Uusitupa, Matti %A Atalay, Mustafa %A Lakka, Timo A %A Rauramaa, Rainer %A Bolton, Jennifer L %A Fowkes, Gerry %A Fraser, Ross M %A Price, Jackie F %A Fischer, Krista %A Krjutå Kov, Kaarel %A Metspalu, Andres %A Mihailov, Evelin %A Langenberg, Claudia %A Luan, Jian'an %A Ong, Ken K %A Chines, Peter S %A Keinanen-Kiukaanniemi, Sirkka M %A Saaristo, Timo E %A Edkins, Sarah %A Franks, Paul W %A Hallmans, Göran %A Shungin, Dmitry %A Morris, Andrew David %A Palmer, Colin N A %A Erbel, Raimund %A Moebus, Susanne %A Nöthen, Markus M %A Pechlivanis, Sonali %A Hveem, Kristian %A Narisu, Narisu %A Hamsten, Anders %A Humphries, Steve E %A Strawbridge, Rona J %A Tremoli, Elena %A Grallert, Harald %A Thorand, Barbara %A Illig, Thomas %A Koenig, Wolfgang %A Müller-Nurasyid, Martina %A Peters, Annette %A Boehm, Bernhard O %A Kleber, Marcus E %A März, Winfried %A Winkelmann, Bernhard R %A Kuusisto, Johanna %A Laakso, Markku %A Arveiler, Dominique %A Cesana, Giancarlo %A Kuulasmaa, Kari %A Virtamo, Jarmo %A Yarnell, John W G %A Kuh, Diana %A Wong, Andrew %A Lind, Lars %A de Faire, Ulf %A Gigante, Bruna %A Magnusson, Patrik K E %A Pedersen, Nancy L %A Dedoussis, George %A Dimitriou, Maria %A Kolovou, Genovefa %A Kanoni, Stavroula %A Stirrups, Kathleen %A Bonnycastle, Lori L %A Njølstad, Inger %A Wilsgaard, Tom %A Ganna, Andrea %A Rehnberg, Emil %A Hingorani, Aroon %A Kivimaki, Mika %A Kumari, Meena %A Assimes, Themistocles L %A Barroso, Inês %A Boehnke, Michael %A Borecki, Ingrid B %A Deloukas, Panos %A Fox, Caroline S %A Frayling, Timothy %A Groop, Leif C %A Haritunians, Talin %A Hunter, David %A Ingelsson, Erik %A Kaplan, Robert %A Mohlke, Karen L %A O'Connell, Jeffrey R %A Schlessinger, David %A Strachan, David P %A Stefansson, Kari %A van Duijn, Cornelia M %A Abecasis, Goncalo R %A McCarthy, Mark I %A Hirschhorn, Joel N %A Qi, Lu %A Loos, Ruth J F %A Lindgren, Cecilia M %A North, Kari E %A Heid, Iris M %K Anthropometry %K Body Height %K Body Mass Index %K Body Weight %K Body Weights and Measures %K Female %K Genetic Loci %K Genome, Human %K Genome-Wide Association Study %K Humans %K Male %K Polymorphism, Single Nucleotide %K Sex Characteristics %K Waist Circumference %K Waist-Hip Ratio %X

Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.

%B PLoS Genet %V 9 %P e1003500 %8 2013 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/23754948?dopt=Abstract %R 10.1371/journal.pgen.1003500 %0 Journal Article %J J Am Heart Assoc %D 2013 %T Simple risk model predicts incidence of atrial fibrillation in a racially and geographically diverse population: the CHARGE-AF consortium. %A Alonso, Alvaro %A Krijthe, Bouwe P %A Aspelund, Thor %A Stepas, Katherine A %A Pencina, Michael J %A Moser, Carlee B %A Sinner, Moritz F %A Sotoodehnia, Nona %A Fontes, João D %A Janssens, A Cecile J W %A Kronmal, Richard A %A Magnani, Jared W %A Witteman, Jacqueline C %A Chamberlain, Alanna M %A Lubitz, Steven A %A Schnabel, Renate B %A Agarwal, Sunil K %A McManus, David D %A Ellinor, Patrick T %A Larson, Martin G %A Burke, Gregory L %A Launer, Lenore J %A Hofman, Albert %A Levy, Daniel %A Gottdiener, John S %A Kääb, Stefan %A Couper, David %A Harris, Tamara B %A Soliman, Elsayed Z %A Stricker, Bruno H C %A Gudnason, Vilmundur %A Heckbert, Susan R %A Benjamin, Emelia J %K African Americans %K Age Factors %K Aged %K Aged, 80 and over %K Atrial Fibrillation %K Cohort Studies %K Diabetes Mellitus %K European Continental Ancestry Group %K Female %K Heart Failure %K Humans %K Hypertension %K Iceland %K Incidence %K Male %K Middle Aged %K Myocardial Infarction %K Netherlands %K Proportional Hazards Models %K Risk Assessment %K Smoking %K United States %X

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

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

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

%B J Am Heart Assoc %V 2 %P e000102 %8 2013 Mar 18 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/23537808?dopt=Abstract %R 10.1161/JAHA.112.000102 %0 Journal Article %J Arterioscler Thromb Vasc Biol %D 2013 %T Soluble CD14: genomewide association analysis and relationship to cardiovascular risk and mortality in older adults. %A Reiner, Alex P %A Lange, Ethan M %A Jenny, Nancy S %A Chaves, Paulo H M %A Ellis, Jaclyn %A Li, Jin %A Walston, Jeremy %A Lange, Leslie A %A Cushman, Mary %A Tracy, Russell P %K African Americans %K Age Factors %K Aged %K Biomarkers %K Cardiovascular Diseases %K Chromosomes, Human, Pair 5 %K European Continental Ancestry Group %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Haplotypes %K Hexosyltransferases %K Humans %K Incidence %K Inflammation Mediators %K Linear Models %K Lipopolysaccharide Receptors %K Logistic Models %K Male %K Membrane Proteins %K Multivariate Analysis %K Phenotype %K Polymorphism, Single Nucleotide %K Principal Component Analysis %K Prognosis %K Proportional Hazards Models %K Prospective Studies %K Risk Assessment %K Risk Factors %K Time Factors %K United States %X

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

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

CONCLUSIONS: CD14 independently predicts risk mortality in older adults.

%B Arterioscler Thromb Vasc Biol %V 33 %P 158-64 %8 2013 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/23162014?dopt=Abstract %R 10.1161/ATVBAHA.112.300421 %0 Journal Article %J PLoS Genet %D 2013 %T A systematic mapping approach of 16q12.2/FTO and BMI in more than 20,000 African Americans narrows in on the underlying functional variation: results from the Population Architecture using Genomics and Epidemiology (PAGE) study. %A Peters, Ulrike %A North, Kari E %A Sethupathy, Praveen %A Buyske, Steve %A Haessler, Jeff %A Jiao, Shuo %A Fesinmeyer, Megan D %A Jackson, Rebecca D %A Kuller, Lew H %A Rajkovic, Aleksandar %A Lim, Unhee %A Cheng, Iona %A Schumacher, Fred %A Wilkens, Lynne %A Li, Rongling %A Monda, Keri %A Ehret, Georg %A Nguyen, Khanh-Dung H %A Cooper, Richard %A Lewis, Cora E %A Leppert, Mark %A Irvin, Marguerite R %A Gu, C Charles %A Houston, Denise %A Bůzková, Petra %A Ritchie, Marylyn %A Matise, Tara C %A Le Marchand, Loïc %A Hindorff, Lucia A %A Crawford, Dana C %A Haiman, Christopher A %A Kooperberg, Charles %K Adaptor Proteins, Signal Transducing %K Adult %K African Americans %K Aged %K Aged, 80 and over %K Alleles %K Body Mass Index %K Chromosome Mapping %K Continental Population Groups %K European Continental Ancestry Group %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Linkage Disequilibrium %K Male %K Metagenomics %K Middle Aged %K Obesity %K Proteins %X

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

%B PLoS Genet %V 9 %P e1003171 %8 2013 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/23341774?dopt=Abstract %R 10.1371/journal.pgen.1003171 %0 Journal Article %J PLoS Genet %D 2013 %T Trans-ethnic fine-mapping of lipid loci identifies population-specific signals and allelic heterogeneity that increases the trait variance explained. %A Wu, Ying %A Waite, Lindsay L %A Jackson, Anne U %A Sheu, Wayne H-H %A Buyske, Steven %A Absher, Devin %A Arnett, Donna K %A Boerwinkle, Eric %A Bonnycastle, Lori L %A Carty, Cara L %A Cheng, Iona %A Cochran, Barbara %A Croteau-Chonka, Damien C %A Dumitrescu, Logan %A Eaton, Charles B %A Franceschini, Nora %A Guo, Xiuqing %A Henderson, Brian E %A Hindorff, Lucia A %A Kim, Eric %A Kinnunen, Leena %A Komulainen, Pirjo %A Lee, Wen-Jane %A Le Marchand, Loïc %A Lin, Yi %A Lindström, Jaana %A Lingaas-Holmen, Oddgeir %A Mitchell, Sabrina L %A Narisu, Narisu %A Robinson, Jennifer G %A Schumacher, Fred %A Stančáková, Alena %A Sundvall, Jouko %A Sung, Yun-Ju %A Swift, Amy J %A Wang, Wen-Chang %A Wilkens, Lynne %A Wilsgaard, Tom %A Young, Alicia M %A Adair, Linda S %A Ballantyne, Christie M %A Bůzková, Petra %A Chakravarti, Aravinda %A Collins, Francis S %A Duggan, David %A Feranil, Alan B %A Ho, Low-Tone %A Hung, Yi-Jen %A Hunt, Steven C %A Hveem, Kristian %A Juang, Jyh-Ming J %A Kesäniemi, Antero Y %A Kuusisto, Johanna %A Laakso, Markku %A Lakka, Timo A %A Lee, I-Te %A Leppert, Mark F %A Matise, Tara C %A Moilanen, Leena %A Njølstad, Inger %A Peters, Ulrike %A Quertermous, Thomas %A Rauramaa, Rainer %A Rotter, Jerome I %A Saramies, Jouko %A Tuomilehto, Jaakko %A Uusitupa, Matti %A Wang, Tzung-Dau %A Boehnke, Michael %A Haiman, Christopher A %A Chen, Yii-der I %A Kooperberg, Charles %A Assimes, Themistocles L %A Crawford, Dana C %A Hsiung, Chao A %A North, Kari E %A Mohlke, Karen L %K African Americans %K Apolipoproteins A %K Cholesterol, HDL %K Cholesterol, LDL %K European Continental Ancestry Group %K Genome-Wide Association Study %K Humans %K Lipoproteins, HDL %K Lipoproteins, LDL %K Proprotein Convertases %K Serine Endopeptidases %K Triglycerides %X

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

%B PLoS Genet %V 9 %P e1003379 %8 2013 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/23555291?dopt=Abstract %R 10.1371/journal.pgen.1003379 %0 Journal Article %J Nat Genet %D 2013 %T Whole-genome sequence-based analysis of high-density lipoprotein cholesterol. %A Morrison, Alanna C %A Voorman, Arend %A Johnson, Andrew D %A Liu, Xiaoming %A Yu, Jin %A Li, Alexander %A Muzny, Donna %A Yu, Fuli %A Rice, Kenneth %A Zhu, Chengsong %A Bis, Joshua %A Heiss, Gerardo %A O'Donnell, Christopher J %A Psaty, Bruce M %A Cupples, L Adrienne %A Gibbs, Richard %A Boerwinkle, Eric %K Cholesterol, HDL %K Computational Biology %K Databases, Genetic %K Genetic Variation %K Genome, Human %K Genome-Wide Association Study %K Genomics %K Heterozygote %K Humans %K Open Reading Frames %X

We describe initial steps for interrogating whole-genome sequence data to characterize the genetic architecture of a complex trait, levels of high-density lipoprotein cholesterol (HDL-C). We report whole-genome sequencing and analysis of 962 individuals from the Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) studies. From this analysis, we estimate that common variation contributes more to heritability of HDL-C levels than rare variation, and screening for mendelian variants for dyslipidemia identified individuals with extreme HDL-C levels. Whole-genome sequencing analyses highlight the value of regulatory and non-protein-coding regions of the genome in addition to protein-coding regions.

%B Nat Genet %V 45 %P 899-901 %8 2013 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/23770607?dopt=Abstract %R 10.1038/ng.2671 %0 Journal Article %J Circ Cardiovasc Genet %D 2014 %T ADAM19 and HTR4 variants and pulmonary function: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. %A London, Stephanie J %A Gao, Wei %A Gharib, Sina A %A Hancock, Dana B %A Wilk, Jemma B %A House, John S %A Gibbs, Richard A %A Muzny, Donna M %A Lumley, Thomas %A Franceschini, Nora %A North, Kari E %A Psaty, Bruce M %A Kovar, Christie L %A Coresh, Josef %A Zhou, Yanhua %A Heckbert, Susan R %A Brody, Jennifer A %A Morrison, Alanna C %A Dupuis, Josée %K ADAM Proteins %K Aged %K Aged, 80 and over %K Aging %K Cohort Studies %K Female %K Genetic Variation %K Genome-Wide Association Study %K Genomics %K Heart Diseases %K Humans %K Lung %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Sequence Analysis, DNA %X

BACKGROUND: The pulmonary function measures of forced expiratory volume in 1 second (FEV1) and its ratio to forced vital capacity (FVC) are used in the diagnosis and monitoring of lung diseases and predict cardiovascular mortality in the general population. Genome-wide association studies (GWASs) have identified numerous loci associated with FEV1 and FEV1/FVC, but the causal variants remain uncertain. We hypothesized that novel or rare variants poorly tagged by GWASs may explain the significant associations between FEV1/FVC and 2 genes: ADAM19 and HTR4.

METHODS AND RESULTS: We sequenced ADAM19 and its promoter region along with the ≈21-kb portion of HTR4 harboring GWAS single-nucleotide polymorphisms for pulmonary function and analyzed associations with FEV1/FVC among 3983 participants of European ancestry from Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Meta-analysis of common variants in each region identified statistically significant associations (316 tests; P<1.58×10(-4)) with FEV1/FVC for 14 ADAM19 single-nucleotide polymorphisms and 24 HTR4 single-nucleotide polymorphisms. After conditioning on the sentinel GWASs hit in each gene (ADAM19 rs1422795, minor allele frequency=0.33 and HTR4 rs11168048, minor allele frequency=0.40], 1 single-nucleotide polymorphism remained statistically significant (ADAM19 rs13155908, minor allele frequency=0.12; P=1.56×10(-4)). Analysis of rare variants (minor allele frequency <1%) using sequence kernel association test did not identify associations with either region.

CONCLUSIONS: Sequencing identified 1 common variant associated with FEV1/FVC independent of the sentinel ADAM19 GWAS hit and supports the original HTR4 GWAS findings. Rare variants do not seem to underlie GWAS associations with pulmonary function for common variants in ADAM19 and HTR4.

%B Circ Cardiovasc Genet %V 7 %P 350-8 %8 2014 Jun %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/24951661?dopt=Abstract %R 10.1161/CIRCGENETICS.113.000066 %0 Journal Article %J J Am Coll Cardiol %D 2014 %T Age- and sex-dependent upper reference limits for the high-sensitivity cardiac troponin T assay. %A Gore, M Odette %A Seliger, Stephen L %A deFilippi, Christopher R %A Nambi, Vijay %A Christenson, Robert H %A Hashim, Ibrahim A %A Hoogeveen, Ron C %A Ayers, Colby R %A Sun, Wensheng %A McGuire, Darren K %A Ballantyne, Christie M %A de Lemos, James A %K Adult %K Age Factors %K Aged %K Biological Assay %K Biomarkers %K Blood Chemical Analysis %K Cohort Studies %K Cross-Sectional Studies %K Female %K Humans %K Male %K Middle Aged %K Myocardial Infarction %K Reference Values %K Risk Assessment %K Sensitivity and Specificity %K Severity of Illness Index %K Sex Factors %K Troponin T %X

OBJECTIVES: The study sought to determine the 99th percentile upper reference limit for the high-sensitivity cardiac troponin T assay (hs-cTnT) in 3 large independent cohorts.

BACKGROUND: The presently recommended 14 ng/l cut point for the diagnosis of myocardial infarction using the hs-cTnT assay was derived from small studies of presumably healthy individuals, with relatively little phenotypic characterization.

METHODS: Data were included from 3 well-characterized population-based studies: the Dallas Heart Study (DHS), the Atherosclerosis Risk in Communities (ARIC) Study, and the Cardiovascular Health Study (CHS). Within each cohort, reference subcohorts were defined excluding individuals with recent hospitalization, overt cardiovascular disease, and kidney disease (subcohort 1), and further excluding those with subclinical structural heart disease (subcohort 2). Data were analyzed stratified by age, sex, and race.

RESULTS: The 99th percentile values for the hs-cTnT assay in DHS, ARIC, and CHS were 18, 22, and 36 ng/l (subcohort 1) and 14, 21, and 28 ng/l (subcohort 2), respectively. These differences in 99th percentile values paralleled age differences across cohorts. Analyses within sex/age strata yielded similar results between cohorts. Within each cohort, 99th percentile values increased with age and were higher in men. More than 10% of men 65 to 74 years of age with no cardiovascular disease in our study had cardiac troponin T values above the current myocardial infarction threshold.

CONCLUSIONS: Use of a uniform 14 ng/l cutoff for the hs-cTnT assay may lead to over-diagnosis of myocardial infarction, particularly in men and the elderly. Clinical validation is needed of new age- and sex-specific cutoff values for this assay.

%B J Am Coll Cardiol %V 63 %P 1441-8 %8 2014 Apr 15 %G eng %N 14 %1 http://www.ncbi.nlm.nih.gov/pubmed/24530665?dopt=Abstract %R 10.1016/j.jacc.2013.12.032 %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 Arterioscler Thromb Vasc Biol %D 2014 %T Association between the metabolic syndrome, its individual components, and unprovoked venous thromboembolism: results of a patient-level meta-analysis. %A Ageno, Walter %A Di Minno, Matteo N D %A Ay, Cihan %A Jang, Moon Ju %A Hansen, John-Bjarne %A Steffen, Lyn M %A Vaya, Amparo %A Rattazzi, Marcello %A Pabinger, Ingrid %A Oh, Doyeun %A Di Minno, Giovanni %A Braekkan, Sigrid K %A Cushman, Mary %A Bonet, Elena %A Pauletto, Paolo %A Squizzato, Alessandro %A Dentali, Francesco %K Adult %K Aged %K Case-Control Studies %K Cohort Studies %K Female %K Humans %K Logistic Models %K Male %K Metabolic Syndrome %K Middle Aged %K Obesity, Abdominal %K Risk Factors %K Venous Thromboembolism %X

OBJECTIVE: The metabolic syndrome (MetS) may contribute to the pathogenesis of venous thromboembolism (VTE), but this association requires additional investigation.

APPROACH AND RESULTS: We performed a patient-level meta-analysis of case-control and cohort studies that evaluated the role of MetS and risk of unprovoked VTE. For case-control studies, odds ratios and 95% confidence intervals were calculated using logistic regression analysis to estimate the influence of individual variables on the risk of VTE; χ(2) tests for trend were used to investigate the effect of increasing number of components of MetS on the risk of VTE and to explore the influence of abdominal obesity on this relationship. For cohort studies, hazard ratios and 95% confidence interval were calculated using multivariable Cox regression analysis. Six case-control studies were included (908 cases with unprovoked VTE and 1794 controls): in multivariate analysis, MetS was independently associated with VTE (odds ratio, 1.91; 95% confidence interval, 1.57-2.33), and both MetS and abdominal obesity were better predictors of unprovoked VTE than obesity defined by the body mass index. Two prospective cohort studies were included (26,531 subjects and 289 unprovoked VTE events): age, obesity, and abdominal obesity, but not MetS were associated with VTE.

CONCLUSIONS: Case-control but not prospective cohort studies support an association between MetS and VTE. Abdominal adiposity is a strong risk factor for VTE.

%B Arterioscler Thromb Vasc Biol %V 34 %P 2478-85 %8 2014 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/25212233?dopt=Abstract %R 10.1161/ATVBAHA.114.304085 %0 Journal Article %J Am J Kidney Dis %D 2014 %T Association of a cystatin C gene variant with cystatin C levels, CKD, and risk of incident cardiovascular disease and mortality. %A O'Seaghdha, Conall M %A Tin, Adrienne %A Yang, Qiong %A Katz, Ronit %A Liu, Yongmei %A Harris, Tamara %A Astor, Brad %A Coresh, Josef %A Fox, Caroline S %A Kao, W H Linda %A Shlipak, Michael G %K Aged %K Bias %K Biomarkers %K Cardiovascular Diseases %K Creatinine %K Cystatin C %K Female %K Genetic Variation %K Glomerular Filtration Rate %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Renal Insufficiency, Chronic %K Risk Assessment %K Risk Factors %K Severity of Illness Index %K Statistics as Topic %K Survival Rate %X

BACKGROUND: Carriers of the T allele of the single-nucleotide polymorphism rs13038305 tend to have lower cystatin C levels and higher cystatin C-based estimated glomerular filtration rate (eGFRcys). Adjusting for this genetic effect on cystatin C concentrations may improve GFR estimation, reclassify cases of chronic kidney disease (CKD), and strengthen risk estimates for cardiovascular disease (CVD) and mortality.

STUDY DESIGN: Observational.

SETTING & POPULATION: 4 population-based cohorts: Atherosclerosis Risk in Communities (ARIC), Cardiovascular Health (CHS), Framingham Heart (FHS), and Health, Aging, and Body Composition (Health ABC) studies.

PREDICTORS: We estimated the association of rs13038305 with eGFRcys and serum creatinine-based eGFR (eGFRcr) and performed longitudinal analyses of the associations of eGFRcys with mortality and cardiovascular events following adjustment for rs13038305.

OUTCOMES: We assessed reclassification by genotype-adjusted eGFRcys across CKD categories: <45, 45-59, 60-89, and ≥ 90 mL/min/1.73 m(2). We compared mortality and CVD outcomes in those reclassified to a worse eGFRcys category with those unaffected. Results were combined using fixed-effect inverse-variance meta-analysis.

RESULTS: In 14,645 participants, each copy of the T allele of rs13038305 (frequency, 21%) was associated with a 6.4% lower cystatin C concentration, 5.5-mL/min/1.73 m(2) higher eGFRcys, and 36% [95% CI, 29%-41%] lower odds of CKD. Associations with CVD (HR, 1.17; 95% CI, 1.14-1.20) and mortality (HR, 1.22; 95% CI, 1.19-1.24) per 10-mL/min/1.73 m(2) lower eGFRcys were similar with or without rs13038305 adjustment. 1,134 (7.7%) participants were reclassified to a worse CKD category following rs13038305 adjustment, and rates of CVD and mortality were higher in individuals who were reclassified. However, the overall net reclassification index was not significant for either outcome, at 0.009 (95% CI, -0.003 to 0.022) for mortality and 0.014 (95% CI, 0.0 to 0.028) for CVD.

LIMITATIONS: rs13038305 explains only a small proportion of cystatin C variation.

CONCLUSIONS: Statistical adjustment can correct a genetic bias in GFR estimates based on cystatin C in carriers of the T allele of rs13038305 and result in changes in disease classification. However, on a population level, the effects on overall reclassification of CKD status are modest.

%B Am J Kidney Dis %V 63 %P 16-22 %8 2014 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/23932088?dopt=Abstract %R 10.1053/j.ajkd.2013.06.015 %0 Journal Article %J Stroke %D 2014 %T Association of kidney disease measures with ischemic versus hemorrhagic strokes: pooled analyses of 4 prospective community-based cohorts. %A Mahmoodi, Bakhtawar K %A Yatsuya, Hiroshi %A Matsushita, Kunihiro %A Sang, Yinying %A Gottesman, Rebecca F %A Astor, Brad C %A Woodward, Mark %A Longstreth, W T %A Psaty, Bruce M %A Shlipak, Michael G %A Folsom, Aaron R %A Gansevoort, Ron T %A Coresh, Josef %K Aged %K Albuminuria %K Brain Ischemia %K Comorbidity %K Female %K Glomerular Filtration Rate %K Humans %K Intracranial Hemorrhages %K Kidney Diseases %K Male %K Middle Aged %K Netherlands %K Proportional Hazards Models %K Prospective Studies %K Risk Factors %K Stroke %K United States %X

BACKGROUND AND PURPOSE: Although low glomerular filtration rate (GFR) and albuminuria are associated with increased risk of stroke, few studies compared their contribution to risk of ischemic versus hemorrhagic stroke separately. We contrasted the association of these kidney measures with ischemic versus hemorrhagic stroke.

METHODS: We pooled individual participant data from 4 community-based cohorts: 3 from the United States and 1 from The Netherlands. GFR was estimated using both creatinine and cystatin C, and albuminuria was quantified by urinary albumin-to-creatinine ratio (ACR). Associations of estimated GFR and ACR were compared for each stroke type (ischemic versus intraparenchymal hemorrhagic) using study-stratified Cox regression.

RESULTS: Among 29,595 participants (mean age, 61 [SD 12.5] years; 46% men; 17% black), 1261 developed stroke (12% hemorrhagic) during 280,549 person-years. Low estimated GFR was significantly associated with increased risk of ischemic stroke, but not hemorrhagic stroke, whereas high ACR was associated with both stroke types. Adjusted hazard ratios for ischemic and hemorrhagic stroke at estimated GFR of 45 (versus 95) mL/min per 1.73 m2 were 1.30 (95% confidence interval, 1.01-1.68) and 0.92 (0.47-1.81), respectively. In contrast, the corresponding hazard ratios for ACR of 300 (versus 5) mg/g were 1.62 (1.27-2.07) for ischemic and 2.57 (1.37-4.83) for hemorrhagic stroke, with significantly stronger association with hemorrhagic stroke (P=0.04). For hemorrhagic stroke, the association of elevated ACR was of similar magnitude as that of elevated systolic blood pressure.

CONCLUSIONS: Whereas albuminuria showed significant association with both stroke types, the association of decreased estimated GFR was only significant for ischemic stroke. The strong association of albuminuria with both stroke types warrants clinical attention and further investigations.

%B Stroke %V 45 %P 1925-31 %8 2014 Jul %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/24876078?dopt=Abstract %R 10.1161/STROKEAHA.114.004900 %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 PLoS One %D 2014 %T Association of sick sinus syndrome with incident cardiovascular disease and mortality: the Atherosclerosis Risk in Communities study and Cardiovascular Health Study. %A Alonso, Alvaro %A Jensen, Paul N %A Lopez, Faye L %A Chen, Lin Y %A Psaty, Bruce M %A Folsom, Aaron R %A Heckbert, Susan R %K Age Distribution %K Atherosclerosis %K Cohort Studies %K Continental Population Groups %K Female %K Humans %K Incidence %K Male %K Middle Aged %K Residence Characteristics %K Risk %K Sex Distribution %K Sick Sinus Syndrome %X

BACKGROUND: Sick sinus syndrome (SSS) is a common indication for pacemaker implantation. Limited information exists on the association of sick sinus syndrome (SSS) with mortality and cardiovascular disease (CVD) in the general population.

METHODS: We studied 19,893 men and women age 45 and older in the Atherosclerosis Risk in Communities (ARIC) study and the Cardiovascular Health Study (CHS), two community-based cohorts, who were without a pacemaker or atrial fibrillation (AF) at baseline. Incident SSS cases were validated by review of medical charts. Incident CVD and mortality were ascertained using standardized protocols. Multivariable Cox models were used to estimate the association of incident SSS with selected outcomes.

RESULTS: During a mean follow-up of 17 years, 213 incident SSS events were identified and validated (incidence, 0.6 events per 1,000 person-years). After adjustment for confounders, SSS incidence was associated with increased mortality (hazard ratio [HR] 1.39, 95% confidence interval [CI] 1.14-1.70), coronary heart disease (HR 1.72, 95%CI 1.11-2.66), heart failure (HR 2.87, 95%CI 2.17-3.80), stroke (HR 1.56, 95%CI 0.99-2.46), AF (HR 5.75, 95%CI 4.43-7.46), and pacemaker implantation (HR 53.7, 95%CI 42.9-67.2). After additional adjustment for other incident CVD during follow-up, SSS was no longer associated with increased mortality, coronary heart disease, or stroke, but remained associated with higher risk of heart failure (HR 2.00, 95%CI 1.51-2.66), AF (HR 4.25, 95%CI 3.28-5.51), and pacemaker implantation (HR 25.2, 95%CI 19.8-32.1).

CONCLUSION: Individuals who develop SSS are at increased risk of death and CVD. The mechanisms underlying these associations warrant further investigation.

%B PLoS One %V 9 %P e109662 %8 2014 %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/25285853?dopt=Abstract %R 10.1371/journal.pone.0109662 %0 Journal Article %J PLoS One %D 2014 %T Associations of NINJ2 sequence variants with incident ischemic stroke in the Cohorts for Heart and Aging in Genomic Epidemiology (CHARGE) consortium. %A Bis, Joshua C %A DeStefano, Anita %A Liu, Xiaoming %A Brody, Jennifer A %A Choi, Seung Hoan %A Verhaaren, Benjamin F J %A Debette, Stephanie %A Ikram, M Arfan %A Shahar, Eyal %A Butler, Kenneth R %A Gottesman, Rebecca F %A Muzny, Donna %A Kovar, Christie L %A Psaty, Bruce M %A Hofman, Albert %A Lumley, Thomas %A Gupta, Mayetri %A Wolf, Philip A %A van Duijn, Cornelia %A Gibbs, Richard A %A Mosley, Thomas H %A Longstreth, W T %A Boerwinkle, Eric %A Seshadri, Sudha %A Fornage, Myriam %K Cell Adhesion Molecules, Neuronal %K European Continental Ancestry Group %K Female %K Genetic Association Studies %K Genetic Heterogeneity %K Humans %K Introns %K Ischemia %K Male %K Myocardial Infarction %K Polymorphism, Single Nucleotide %K Prospective Studies %K Sequence Analysis, DNA %X

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

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

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

%B PLoS One %V 9 %P e99798 %8 2014 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/24959832?dopt=Abstract %R 10.1371/journal.pone.0099798 %0 Journal Article %J Europace %D 2014 %T B-type natriuretic peptide and C-reactive protein in the prediction of atrial fibrillation risk: the CHARGE-AF Consortium of community-based cohort studies. %A Sinner, Moritz F %A Stepas, Katherine A %A Moser, Carlee B %A Krijthe, Bouwe P %A Aspelund, Thor %A Sotoodehnia, Nona %A Fontes, João D %A Janssens, A Cecile J W %A Kronmal, Richard A %A Magnani, Jared W %A Witteman, Jacqueline C %A Chamberlain, Alanna M %A Lubitz, Steven A %A Schnabel, Renate B %A Vasan, Ramachandran S %A Wang, Thomas J %A Agarwal, Sunil K %A McManus, David D %A Franco, Oscar H %A Yin, Xiaoyan %A Larson, Martin G %A Burke, Gregory L %A Launer, Lenore J %A Hofman, Albert %A Levy, Daniel %A Gottdiener, John S %A Kääb, Stefan %A Couper, David %A Harris, Tamara B %A Astor, Brad C %A Ballantyne, Christie M %A Hoogeveen, Ron C %A Arai, Andrew E %A Soliman, Elsayed Z %A Ellinor, Patrick T %A Stricker, Bruno H C %A Gudnason, Vilmundur %A Heckbert, Susan R %A Pencina, Michael J %A Benjamin, Emelia J %A Alonso, Alvaro %K Aged %K Atrial Fibrillation %K Biomarkers %K C-Reactive Protein %K Europe %K Female %K Humans %K Incidence %K Male %K Natriuretic Peptide, Brain %K Peptide Fragments %K Predictive Value of Tests %K Risk Assessment %K Risk Factors %K United States %X

AIMS: B-type natriuretic peptide (BNP) and C-reactive protein (CRP) predict atrial fibrillation (AF) risk. However, their risk stratification abilities in the broad community remain uncertain. We sought to improve risk stratification for AF using biomarker information.

METHODS AND RESULTS: We ascertained AF incidence in 18 556 Whites and African Americans from the Atherosclerosis Risk in Communities Study (ARIC, n=10 675), Cardiovascular Health Study (CHS, n = 5043), and Framingham Heart Study (FHS, n = 2838), followed for 5 years (prediction horizon). We added BNP (ARIC/CHS: N-terminal pro-B-type natriuretic peptide; FHS: BNP), CRP, or both to a previously reported AF risk score, and assessed model calibration and predictive ability [C-statistic, integrated discrimination improvement (IDI), and net reclassification improvement (NRI)]. We replicated models in two independent European cohorts: Age, Gene/Environment Susceptibility Reykjavik Study (AGES), n = 4467; Rotterdam Study (RS), n = 3203. B-type natriuretic peptide and CRP were significantly associated with AF incidence (n = 1186): hazard ratio per 1-SD ln-transformed biomarker 1.66 [95% confidence interval (CI), 1.56-1.76], P < 0.0001 and 1.18 (95% CI, 1.11-1.25), P < 0.0001, respectively. Model calibration was sufficient (BNP, χ(2) = 17.0; CRP, χ(2) = 10.5; BNP and CRP, χ(2) = 13.1). B-type natriuretic peptide improved the C-statistic from 0.765 to 0.790, yielded an IDI of 0.027 (95% CI, 0.022-0.032), a relative IDI of 41.5%, and a continuous NRI of 0.389 (95% CI, 0.322-0.455). The predictive ability of CRP was limited (C-statistic increment 0.003). B-type natriuretic peptide consistently improved prediction in AGES and RS.

CONCLUSION: B-type natriuretic peptide, not CRP, substantially improved AF risk prediction beyond clinical factors in an independently replicated, heterogeneous population. B-type natriuretic peptide may serve as a benchmark to evaluate novel putative AF risk biomarkers.

%B Europace %V 16 %P 1426-33 %8 2014 Oct %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/25037055?dopt=Abstract %R 10.1093/europace/euu175 %0 Journal Article %J PLoS One %D 2014 %T The challenges of genome-wide interaction studies: lessons to learn from the analysis of HDL blood levels. %A van Leeuwen, Elisabeth M %A Smouter, Françoise A S %A Kam-Thong, Tony %A Karbalai, Nazanin %A Smith, Albert V %A Harris, Tamara B %A Launer, Lenore J %A Sitlani, Colleen M %A Li, Guo %A Brody, Jennifer A %A Bis, Joshua C %A White, Charles C %A Jaiswal, Alok %A Oostra, Ben A %A Hofman, Albert %A Rivadeneira, Fernando %A Uitterlinden, André G %A Boerwinkle, Eric %A Ballantyne, Christie M %A Gudnason, Vilmundur %A Psaty, Bruce M %A Cupples, L Adrienne %A Jarvelin, Marjo-Riitta %A Ripatti, Samuli %A Isaacs, Aaron %A Müller-Myhsok, Bertram %A Karssen, Lennart C %A van Duijn, Cornelia M %K Cholesterol, HDL %K Female %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %X

Genome-wide association studies (GWAS) have revealed 74 single nucleotide polymorphisms (SNPs) associated with high-density lipoprotein cholesterol (HDL) blood levels. This study is, to our knowledge, the first genome-wide interaction study (GWIS) to identify SNP×SNP interactions associated with HDL levels. We performed a GWIS in the Rotterdam Study (RS) cohort I (RS-I) using the GLIDE tool which leverages the massively parallel computing power of Graphics Processing Units (GPUs) to perform linear regression on all genome-wide pairs of SNPs. By performing a meta-analysis together with Rotterdam Study cohorts II and III (RS-II and RS-III), we were able to filter 181 interaction terms with a p-value<1 · 10-8 that replicated in the two independent cohorts. We were not able to replicate any of these interaction term in the AGES, ARIC, CHS, ERF, FHS and NFBC-66 cohorts (Ntotal = 30,011) when adjusting for multiple testing. Our GWIS resulted in the consistent finding of a possible interaction between rs774801 in ARMC8 (ENSG00000114098) and rs12442098 in SPATA8 (ENSG00000185594) being associated with HDL levels. However, p-values do not reach the preset Bonferroni correction of the p-values. Our study suggest that even for highly genetically determined traits such as HDL the sample sizes needed to detect SNP×SNP interactions are large and the 2-step filtering approaches do not yield a solution. Here we present our analysis plan and our reservations concerning GWIS.

%B PLoS One %V 9 %P e109290 %8 2014 %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/25329471?dopt=Abstract %R 10.1371/journal.pone.0109290 %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 J Cardiovasc Electrophysiol %D 2014 %T A common SCN5A variant is associated with PR interval and atrial fibrillation among African Americans. %A Ilkhanoff, Leonard %A Arking, Dan E %A Lemaitre, Rozenn N %A Alonso, Alvaro %A Chen, Lin Y %A Durda, Peter %A Hesselson, Stephanie E %A Kerr, Kathleen F %A Magnani, Jared W %A Marcus, Gregory M %A Schnabel, Renate B %A Smith, J Gustav %A Soliman, Elsayed Z %A Reiner, Alexander P %A Sotoodehnia, Nona %K Adult %K African Americans %K Aged %K Aged, 80 and over %K Atrial Fibrillation %K Case-Control Studies %K Cohort Studies %K Death, Sudden, Cardiac %K Female %K Genetic Variation %K Humans %K Male %K Middle Aged %K NAV1.5 Voltage-Gated Sodium Channel %K Prospective Studies %K Risk Factors %K Single-Blind Method %X

OBJECTIVE: We examined the association of rs7626962 (S1103Y) or rs7629265, a variant in high linkage disequilibrium with S1103Y (r(2) = 0.87 - 1), with sudden cardiac death (SCD) and atrial fibrillation (AF) among African Americans.

BACKGROUND: The SCN5A missense variant S1103Y has been associated with SCD among African Americans in small case-control studies, but larger population-based studies are needed to validate these findings. The association of this variant with AF has not been fully explored.

METHODS: Using genotyping data on over 7,000 African Americans from 5 cohorts (Atherosclerosis Risk in Communities [ARIC], Cleveland Family Study [CFS], Jackson Heart Study [JHS], Multi-Ethnic Study of Atherosclerosis [MESA], Cardiovascular Health Study [CHS]), we examined the association of rs7629265 with electrocardiographic PR, QRS, and QT intervals, and with incident AF and SCD. We examined association of S1103Y (rs7626962) with SCD using a population-based case-control study of SCD Cardiac Arrest Blood Study (CABS).

RESULTS: Meta-analyses across 5 cohorts demonstrated that rs7629265 was significantly associated with PR duration (β = -4.1 milliseconds; P = 2.2×10(-6) ), but not significantly associated with QRS or QT intervals. In meta-analyses of prospectively followed ARIC and CHS participants (n = 3,656), rs7629265 was associated with increased AF risk (n = 299 AF cases; HR = 1.74, P = 1.9 × 10(-4) ). By contrast, rs7629265 was not significantly associated with SCD risk in ARIC (n = 83 SCD cases; P = 0.30) or CHS (n = 54 SCD cases; P = 0.47). Similarly, S1103Y was not significantly associated with SCD risk in CABS (n = 225 SCD cases; P = 0.29).

CONCLUSION: The common SCN5A variant, rs7629265, is associated with increased AF risk and shorter PR interval among African Americans. In contrast to prior reports, we found no evidence of association of rs7629265 or rs7626962 (S1103Y) with SCD risk in the general population.

%B J Cardiovasc Electrophysiol %V 25 %P 1150-7 %8 2014 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/25065297?dopt=Abstract %R 10.1111/jce.12483 %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 J Am Heart Assoc %D 2014 %T Coronary heart disease risks associated with high levels of HDL cholesterol. %A Wilkins, John T %A Ning, Hongyan %A Stone, Neil J %A Criqui, Michael H %A Zhao, Lihui %A Greenland, Philip %A Lloyd-Jones, Donald M %K Aged %K Biomarkers %K Cholesterol, HDL %K Coronary Disease %K Female %K Humans %K Linear Models %K Male %K Middle Aged %K Multivariate Analysis %K Prognosis %K Proportional Hazards Models %K Risk Assessment %K Risk Factors %K Time Factors %K United States %K Up-Regulation %X

BACKGROUND: The association between high-density lipoprotein cholesterol (HDL-C) and coronary heart disease (CHD) events is not well described in individuals with very high levels of HDL-C (>80 mg/dL).

METHODS AND RESULTS: Using pooled data from 6 community-based cohorts we examined CHD and total mortality risks across a broad range of HDL-C, including values in excess of 80 mg/dL. We used Cox proportional hazards models with penalized splines to assess multivariable, adjusted, sex-stratified associations of HDL-C with the hazard for CHD events and total mortality, using HDL-C 45 mg/dL and 55 mg/dL as the referent in men and women, respectively. Analyses included 11 515 men and 12 925 women yielding 307 245 person-years of follow-up. In men, the association between HDL-C and CHD events was inverse and linear across most HDL-C values; however at HDL-C values >90 mg/dL there was a plateau effect in the pattern of association. In women, the association between HDL-C and CHD events was inverse and linear across lower values of HDL-C, however at HDL-C values >75 mg/dL there were no further reductions in the hazard ratio point estimates for CHD. In unadjusted models there were increased total mortality risks in men with very high HDL-C, however mortality risks observed in participants with very high HDL-C were attenuated after adjustment for traditional risk factors.

CONCLUSIONS: We did not observe further reductions in CHD risk with HDL-C values higher than 90 mg/dL in men and 75 mg/dL in women.

%B J Am Heart Assoc %V 3 %P e000519 %8 2014 Mar 13 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24627418?dopt=Abstract %R 10.1161/JAHA.113.000519 %0 Journal Article %J JAMA %D 2014 %T Decline in estimated glomerular filtration rate and subsequent risk of end-stage renal disease and mortality. %A Coresh, Josef %A Turin, Tanvir Chowdhury %A Matsushita, Kunihiro %A Sang, Yingying %A Ballew, Shoshana H %A Appel, Lawrence J %A Arima, Hisatomi %A Chadban, Steven J %A Cirillo, Massimo %A Djurdjev, Ognjenka %A Green, Jamie A %A Heine, Gunnar H %A Inker, Lesley A %A Irie, Fujiko %A Ishani, Areef %A Ix, Joachim H %A Kovesdy, Csaba P %A Marks, Angharad %A Ohkubo, Takayoshi %A Shalev, Varda %A Shankar, Anoop %A Wen, Chi Pang %A de Jong, Paul E %A Iseki, Kunitoshi %A Stengel, Bénédicte %A Gansevoort, Ron T %A Levey, Andrew S %K Adult %K Aged %K Aged, 80 and over %K Cohort Studies %K Creatinine %K Disease Progression %K Endpoint Determination %K Female %K Glomerular Filtration Rate %K Humans %K Kidney Failure, Chronic %K Male %K Middle Aged %K Reference Values %K Risk %X

IMPORTANCE: The established chronic kidney disease (CKD) progression end point of end-stage renal disease (ESRD) or a doubling of serum creatinine concentration (corresponding to a change in estimated glomerular filtration rate [GFR] of −57% or greater) is a late event.

OBJECTIVE: To characterize the association of decline in estimated GFR with subsequent progression to ESRD with implications for using lesser declines in estimated GFR as potential alternative end points for CKD progression. Because most people with CKD die before reaching ESRD, mortality risk also was investigated.

DATA SOURCES AND STUDY SELECTION: Individual meta-analysis of 1.7 million participants with 12,344 ESRD events and 223,944 deaths from 35 cohorts in the CKD Prognosis Consortium with a repeated measure of serum creatinine concentration over 1 to 3 years and outcome data.

DATA EXTRACTION AND SYNTHESIS: Transfer of individual participant data or standardized analysis of outputs for random-effects meta-analysis conducted between July 2012 and September 2013, with baseline estimated GFR values collected from 1975 through 2012.

MAIN OUTCOMES AND MEASURES: End-stage renal disease (initiation of dialysis or transplantation) or all-cause mortality risk related to percentage change in estimated GFR over 2 years, adjusted for potential confounders and first estimated GFR.

RESULTS: The adjusted hazard ratios (HRs) of ESRD and mortality were higher with larger estimated GFR decline. Among participants with baseline estimated GFR of less than 60 mL/min/1.73 m2, the adjusted HRs for ESRD were 32.1 (95% CI, 22.3-46.3) for changes of −57% in estimated GFR and 5.4 (95% CI, 4.5-6.4) for changes of −30%. However, changes of −30% or greater (6.9% [95% CI, 6.4%-7.4%] of the entire consortium) were more common than changes of −57% (0.79% [95% CI, 0.52%-1.06%]). This association was strong and consistent across the length of the baseline period (1 to 3 years), baseline estimated GFR, age, diabetes status, or albuminuria. Average adjusted 10-year risk of ESRD (in patients with a baseline estimated GFR of 35 mL/min/1.73 m2) was 99% (95% CI, 95%-100%) for estimated GFR change of −57%, was 83% (95% CI, 71%-93%) for estimated GFR change of −40%, and was 64% (95% CI, 52%-77%) for estimated GFR change of −30% vs 18% (95% CI, 15%-22%) for estimated GFR change of 0%. Corresponding mortality risks were 77% (95% CI, 71%-82%), 60% (95% CI, 56%-63%), and 50% (95% CI, 47%-52%) vs 32% (95% CI, 31%-33%), showing a similar but weaker pattern.

CONCLUSIONS AND RELEVANCE: Declines in estimated GFR smaller than a doubling of serum creatinine concentration occurred more commonly and were strongly and consistently associated with the risk of ESRD and mortality, supporting consideration of lesser declines in estimated GFR (such as a 30% reduction over 2 years) as an alternative end point for CKD progression.

%B JAMA %V 311 %P 2518-2531 %8 2014 Jun 25 %G eng %N 24 %1 http://www.ncbi.nlm.nih.gov/pubmed/24892770?dopt=Abstract %R 10.1001/jama.2014.6634 %0 Journal Article %J Eur J Prev Cardiol %D 2014 %T Development and validation of an ankle brachial index risk model for the prediction of cardiovascular events. %A Fowkes, F G R %A Murray, G D %A Butcher, I %A Folsom, A R %A Hirsch, A T %A Couper, D J %A deBacker, G %A Kornitzer, M %A Newman, A B %A Sutton-Tyrrell, K C %A Cushman, M %A Lee, A J %A Price, J F %A D'Agostino, R B %A Murabito, J M %A Norman, Pe %A Masaki, K H %A Bouter, L M %A Heine, R J %A Stehouwer, C D A %A McDermott, M M %A Stoffers, H E J H %A Knottnerus, J A %A Ogren, M %A Hedblad, B %A Koenig, W %A Meisinger, C %A Cauley, J A %A Franco, Oh %A Hunink, M G M %A Hofman, A %A Witteman, J C %A Criqui, M H %A Langer, R D %A Hiatt, W R %A Hamman, R F %K Adult %K Aged %K Aged, 80 and over %K Ankle Brachial Index %K Cardiovascular Diseases %K Europe %K European Continental Ancestry Group %K Female %K Humans %K Male %K Middle Aged %K Models, Statistical %K Predictive Value of Tests %K Prognosis %K Reproducibility of Results %K Risk Assessment %K Risk Factors %K Sex Factors %K Time Factors %K United States %K Young Adult %X

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

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

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

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

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

%B Eur J Prev Cardiol %V 21 %P 310-20 %8 2014 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/24367001?dopt=Abstract %R 10.1177/2047487313516564 %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2014 %T Do changes in circulating biomarkers track with each other and with functional changes in older adults? %A Sanders, Jason L %A Ding, Victoria %A Arnold, Alice M %A Kaplan, Robert C %A Cappola, Anne R %A Kizer, Jorge R %A Boudreau, Robert M %A Cushman, Mary %A Newman, Anne B %K Adiponectin %K Aged %K Aged, 80 and over %K Aging %K Biomarkers %K Cholesterol %K Cognition %K Cohort Studies %K Dehydroepiandrosterone Sulfate %K Female %K Gait %K Hand Strength %K Humans %K Insulin-Like Growth Factor Binding Protein 1 %K Insulin-Like Growth Factor Binding Protein 3 %K Insulin-Like Growth Factor I %K Interleukin-6 %K Male %K Neuropsychological Tests %K Psychomotor Performance %K Time Factors %X

BACKGROUND: It is unclear if changes in proposed circulating biomarkers of aging are strongly correlated to each other or functional change. We tested if biomarker changes track with each other and with functional measures over 9 years in older adults.

METHODS: Dehydroepiandrosterone sulfate (DHEAS), adiponectin, insulin-like growth factor 1 (IGF-1), IGF binding proteins 1 (IGFBP-1) and 3 (IGFBP-3), interleukin-6 (IL-6), cholesterol, and function (gait speed, grip strength, Modified Mini Mental Status Exam [3MSE] and Digit Symbol Substitution Test [DSST] scores) were measured in 1996-1997 and 2005-2006 in the Cardiovascular Health Study All Stars study (N = 901, mean [standard deviation, SD] age 85.3 [3.6] years in 2005-2006). Adjusted Pearson correlations illustrated if biomarkers tracked together. Multivariable linear regression demonstrated if biomarker changes tracked with functional changes.

RESULTS: Correlations among biomarker changes were mostly <0.2. In models with each biomarker entered separately, a 1-SD increase biomarker change was associated with change in function as follows: grip strength (DHEAS β = 0.61kg, p = .001; IL-6 β = -0.46kg, p = .012; cholesterol men β = 0.79kg, p = .016); gait speed (DHEAS β = 0.02 meters per second, p = .039; IL-6 β = -0.018 meters per second, p = .049); and DSST score (DHEAS women β = 1.46, p = .004; IL-6 β = -0.83, p = .027). When biomarkers were entered in the same model, significant associations remaining were as follows: grip strength (DHEAS β = 0.54kg, p = .005; IL-6 β = -0.43kg, p = .022); 3MSE score (IGF-1 β = 0.96, p = .04; IGFBP-3 β = -1.07, p = .024); and DSST score (DHEAS women β = 1.27, p = .012; IL-6 β = -0.80, p = .04).

CONCLUSION: Changes in biomarkers were poorly correlated, supporting a model of stochastic, independent change across systems. DHEAS and IL-6 tracked most closely with function, illustrating that changes in inflammation and sex steroids may play dominant roles in changes of these functional outcomes.

%B J Gerontol A Biol Sci Med Sci %V 69 %P 174-81 %8 2014 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/23811185?dopt=Abstract %R 10.1093/gerona/glt088 %0 Journal Article %J Pharmacogenomics J %D 2014 %T Drug-gene interactions and the search for missing heritability: a cross-sectional pharmacogenomics study of the QT interval. %A Avery, C L %A Sitlani, C M %A Arking, D E %A Arnett, D K %A Bis, J C %A Boerwinkle, E %A Buckley, B M %A Ida Chen, Y-D %A de Craen, A J M %A Eijgelsheim, M %A Enquobahrie, D %A Evans, D S %A Ford, I %A Garcia, M E %A Gudnason, V %A Harris, T B %A Heckbert, S R %A Hochner, H %A Hofman, A %A Hsueh, W-C %A Isaacs, A %A Jukema, J W %A Knekt, P %A Kors, J A %A Krijthe, B P %A Kristiansson, K %A Laaksonen, M %A Liu, Y %A Li, X %A Macfarlane, P W %A Newton-Cheh, C %A Nieminen, M S %A Oostra, B A %A Peloso, G M %A Porthan, K %A Rice, K %A Rivadeneira, F F %A Rotter, J I %A Salomaa, V %A Sattar, N %A Siscovick, D S %A Slagboom, P E %A Smith, A V %A Sotoodehnia, N %A Stott, D J %A Stricker, B H %A Stürmer, T %A Trompet, S %A Uitterlinden, A G %A van Duijn, C %A Westendorp, R G J %A Witteman, J C %A Whitsel, E A %A Psaty, B M %K Computer Simulation %K Cross-Sectional Studies %K Drug-Related Side Effects and Adverse Reactions %K Electrocardiography %K European Continental Ancestry Group %K Gene-Environment Interaction %K Genome-Wide Association Study %K Humans %K Linear Models %K Long QT Syndrome %K Markov Chains %K Pharmacogenetics %K Polymorphism, Single Nucleotide %K Quantitative Trait, Heritable %X

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

%B Pharmacogenomics J %V 14 %P 6-13 %8 2014 Feb %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/23459443?dopt=Abstract %R 10.1038/tpj.2013.4 %0 Journal Article %J J Aging Res %D 2014 %T Effect of dementia on the use of drugs for secondary prevention of ischemic heart disease. %A Fowler, Nicole R %A Barnato, Amber E %A Degenholtz, Howard B %A Curcio, Angela M %A Becker, James T %A Kuller, Lewis H %A Lopez, Oscar L %X

Background. Dementia and cardiovascular disease (CVD) are frequently comorbid. The presence of dementia may have an effect on how CVD is treated. Objective. To examine the effect of dementia on the use of four medications recommended for secondary prevention of ischemic heart disease (IHD): angiotensin-converting enzyme inhibitors, beta-blockers, lipid-lowering medications, and antiplatelet medications. Design. Retrospective analysis of data from the Cardiovascular Health Study: Cognition Study. Setting and Subjects. 1,087 older adults in four US states who had or developed IHD between 1989 and 1998. Methods. Generalized estimating equations to explore the association between dementia and the use of guideline-recommended medications for the secondary prevention of IHD. Results. The length of follow-up for the cohort was 8.7 years and 265 (24%) had or developed dementia during the study. Use of medications for the secondary prevention of IHD for patients with and without dementia increased during the study period. In models, subjects with dementia were not less likely to use any one particular class of medication but were less likely to use two or more classes of medications as a group (OR, 0.60; 95% CI, 0.36-0.99). Conclusions. Subjects with dementia used fewer guideline-recommended medications for the secondary prevention of IHD than those without dementia.

%B J Aging Res %V 2014 %P 897671 %8 2014 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/24719764?dopt=Abstract %R 10.1155/2014/897671 %0 Journal Article %J Stroke %D 2014 %T Effect of genetic variants associated with plasma homocysteine levels on stroke risk. %A Cotlarciuc, Ioana %A Malik, Rainer %A Holliday, Elizabeth G %A Ahmadi, Kourosh R %A Paré, Guillaume %A Psaty, Bruce M %A Fornage, Myriam %A Hasan, Nazeeha %A Rinne, Paul E %A Ikram, M Arfan %A Markus, Hugh S %A Rosand, Jonathan %A Mitchell, Braxton D %A Kittner, Steven J %A Meschia, James F %A van Meurs, Joyce B J %A Uitterlinden, André G %A Worrall, Bradford B %A Dichgans, Martin %A Sharma, Pankaj %K Brain Ischemia %K Cohort Studies %K Europe %K Genetic Association Studies %K Genetic Loci %K Genetic Predisposition to Disease %K Genetic Variation %K Genome %K Homocysteine %K Humans %K Polymorphism, Single Nucleotide %K Risk %K Stroke %X

BACKGROUND AND PURPOSE: Elevated total plasma homocysteine (tHcy) levels are known to be associated with increased risk of ischemic stroke (IS). Given that both tHcy and IS are heritable traits, we investigated a potential genetic relationship between homocysteine levels and stroke risk by assessing 18 polymorphisms previously associated with tHcy levels for their association with IS and its subtypes.

METHODS: Previous meta-analysis results from an international stroke collaborative network, METASTROKE, were used to assess association of the 18 tHcy-associated single-nucleotide polymorphisms (SNPs) in 12 389 IS cases and 62 004 controls. We also investigated the associations in regions located within 50 kb from the 18 tHcy-related SNPs and the association of a genetic risk score, including the 18 SNPs.

RESULTS: One SNP located in the RASIP1 gene and a cluster of 3 SNPs located at and near SLC17A3 were significantly associated with IS (P<0.0003) after correcting for multiple testing. For stroke subtypes, the sentinel SNP located upstream of MUT was significantly associated with small-vessel disease (P=0.0022), whereas 1 SNP located in MTHFR was significantly associated with large-vessel disease (P=0.00019). A genetic risk score, including the 18 SNPs, did not show significant association with IS or its subtypes.

CONCLUSIONS: This study found several potential associations with IS and its subtypes: an association of an MUT variant with small-vessel disease, an MTHFR variant with large-vessel disease, and associations of RASIP1 and SLC17A3 variants with overall IS.

%B Stroke %V 45 %P 1920-4 %8 2014 Jul %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/24846872?dopt=Abstract %R 10.1161/STROKEAHA.114.005208 %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 Pharmacoepidemiol Drug Saf %D 2014 %T Enhancing case ascertainment of Parkinson's disease using Medicare claims data in a population-based cohort: the Cardiovascular Health Study. %A Ton, Thanh G N %A Biggs, Mary Lou %A Comer, Diane %A Curtis, Lesley %A Hu, Shu-Ching %A Thacker, Evan L %A Searles Nielsen, Susan %A Delaney, Joseph A %A Landsittel, Douglas %A Longstreth, William T %A Checkoway, Harvey %A Jain, Samay %K Aged %K Aged, 80 and over %K Algorithms %K Antiparkinson Agents %K Cohort Studies %K Databases, Factual %K Female %K Hospitalization %K Humans %K Incidence %K Logistic Models %K Male %K Medicare %K Parkinson Disease %K Prevalence %K Prospective Studies %K Smoking %K Time Factors %K United States %X

PURPOSE: We sought to improve a previous algorithm to ascertain Parkinson's disease (PD) in the Cardiovascular Health Study by incorporating additional data from Medicare outpatient claims. We compared our results to the previous algorithm in terms of baseline prevalence and incidence of PD, as well as associations with baseline smoking characteristics.

METHODS: Our original case ascertainment used self-reported diagnosis, antiparkinsonian medication, and hospitalization discharge International Classification of Diseases-Ninth version code. In this study, we incorporated additional data from fee-for-service Medicare claims, extended follow-up time, review of hospitalization records, and adjudicated cause of death. Two movement disorders specialists adjudicated final PD status. We used logistic regression models and controlled for age, sex, African American race, and education.

RESULTS: We identified 75 additional cases but reclassified 80 previously identified cases as not having PD. We observed significant inverse association with smoking status (odds ratio = 0.42; 95% confidence interval (CI) = 0.22, 0.79), and inverse linear trends with pack-years (p = 0.005), and cigarettes per day (p = 0.019) with incident PD. All estimates were stronger than those from the previous algorithm.

CONCLUSIONS: Our enhanced method did not alter prevalence and incidence estimates compared with our previous algorithm. However, our enhanced method provided stronger estimates of association, potentially due to reduced level of disease misclassification.

%B Pharmacoepidemiol Drug Saf %V 23 %P 119-27 %8 2014 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24357102?dopt=Abstract %R 10.1002/pds.3552 %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 Epidemiology %D 2014 %T Evidence of heterogeneity by race/ethnicity in genetic determinants of QT interval. %A Seyerle, Amanda A %A Young, Alicia M %A Jeff, Janina M %A Melton, Phillip E %A Jorgensen, Neal W %A Lin, Yi %A Carty, Cara L %A Deelman, Ewa %A Heckbert, Susan R %A Hindorff, Lucia A %A Jackson, Rebecca D %A Martin, Lisa W %A Okin, Peter M %A Perez, Marco V %A Psaty, Bruce M %A Soliman, Elsayed Z %A Whitsel, Eric A %A North, Kari E %A Laston, Sandra %A Kooperberg, Charles %A Avery, Christy L %K Aged %K Continental Population Groups %K Electrocardiography %K Female %K Genetic Predisposition to Disease %K Haplotypes %K Humans %K Long QT Syndrome %K Male %K Middle Aged %K Phenotype %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Quantitative Trait, Heritable %K Risk Factors %X

BACKGROUND: QT interval (QT) prolongation is an established risk factor for ventricular tachyarrhythmia and sudden cardiac death. Previous genome-wide association studies in populations of the European descent have identified multiple genetic loci that influence QT, but few have examined these loci in ethnically diverse populations.

METHODS: Here, we examine the direction, magnitude, and precision of effect sizes for 21 previously reported SNPs from 12 QT loci, in populations of European (n = 16,398), African (n = 5,437), American Indian (n = 5,032), Hispanic (n = 1,143), and Asian (n = 932) descent as part of the Population Architecture using Genomics and Epidemiology (PAGE) study. Estimates obtained from linear regression models stratified by race/ethnicity were combined using inverse-variance weighted meta-analysis. Heterogeneity was evaluated using Cochran's Q test.

RESULTS: Of 21 SNPs, 7 showed consistent direction of effect across all 5 populations, and an additional 9 had estimated effects that were consistent across 4 populations. Despite consistent direction of effect, 9 of 16 SNPs had evidence (P < 0.05) of heterogeneity by race/ethnicity. For these 9 SNPs, linkage disequilibrium plots often indicated substantial variation in linkage disequilibrium patterns among the various racial/ethnic groups, as well as possible allelic heterogeneity.

CONCLUSIONS: These results emphasize the importance of analyzing racial/ethnic groups separately in genetic studies. Furthermore, they underscore the possible utility of trans-ethnic studies to pinpoint underlying casual variants influencing heritable traits such as QT.

%B Epidemiology %V 25 %P 790-8 %8 2014 Nov %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/25166880?dopt=Abstract %R 10.1097/EDE.0000000000000168 %0 Journal Article %J Cerebrovasc Dis %D 2014 %T Extreme deep white matter hyperintensity volumes are associated with African American race. %A Nyquist, Paul A %A Bilgel, Murat S %A Gottesman, Rebecca %A Yanek, Lisa R %A Moy, Taryn F %A Becker, Lewis C %A Cuzzocreo, Jennifer %A Prince, Jerry %A Yousem, David M %A Becker, Diane M %A Kral, Brian G %A Vaidya, Dhananjay %K Adult %K African Americans %K Age Factors %K Aged %K Cerebrovascular Disorders %K European Continental Ancestry Group %K Female %K Humans %K Hypertension %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Prevalence %K Risk Factors %K White Matter %X

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

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

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

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

%B Cerebrovasc Dis %V 37 %P 244-50 %8 2014 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/24686322?dopt=Abstract %R 10.1159/000358117 %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 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 Exp Gerontol %D 2014 %T Gender and telomere length: systematic review and meta-analysis. %A Gardner, Michael %A Bann, David %A Wiley, Laura %A Cooper, Rachel %A Hardy, Rebecca %A Nitsch, Dorothea %A Martin-Ruiz, Carmen %A Shiels, Paul %A Sayer, Avan Aihie %A Barbieri, Michelangela %A Bekaert, Sofie %A Bischoff, Claus %A Brooks-Wilson, Angela %A Chen, Wei %A Cooper, Cyrus %A Christensen, Kaare %A De Meyer, Tim %A Deary, Ian %A Der, Geoff %A Diez Roux, Ana %A Fitzpatrick, Annette %A Hajat, Anjum %A Halaschek-Wiener, Julius %A Harris, Sarah %A Hunt, Steven C %A Jagger, Carol %A Jeon, Hyo-Sung %A Kaplan, Robert %A Kimura, Masayuki %A Lansdorp, Peter %A Li, Changyong %A Maeda, Toyoki %A Mangino, Massimo %A Nawrot, Tim S %A Nilsson, Peter %A Nordfjall, Katarina %A Paolisso, Giuseppe %A Ren, Fu %A Riabowol, Karl %A Robertson, Tony %A Roos, Goran %A Staessen, Jan A %A Spector, Tim %A Tang, Nelson %A Unryn, Brad %A van der Harst, Pim %A Woo, Jean %A Xing, Chao %A Yadegarfar, Mohammad E %A Park, Jae Yong %A Young, Neal %A Kuh, Diana %A von Zglinicki, Thomas %A Ben-Shlomo, Yoav %K Adult %K Aged %K Aged, 80 and over %K Aging %K Female %K Humans %K Male %K Middle Aged %K Sex Factors %K Telomere %X

BACKGROUND: It is widely believed that females have longer telomeres than males, although results from studies have been contradictory.

METHODS: We carried out a systematic review and meta-analyses to test the hypothesis that in humans, females have longer telomeres than males and that this association becomes stronger with increasing age. Searches were conducted in EMBASE and MEDLINE (by November 2009) and additional datasets were obtained from study investigators. Eligible observational studies measured telomeres for both females and males of any age, had a minimum sample size of 100 and included participants not part of a diseased group. We calculated summary estimates using random-effects meta-analyses. Heterogeneity between studies was investigated using sub-group analysis and meta-regression.

RESULTS: Meta-analyses from 36 cohorts (36,230 participants) showed that on average females had longer telomeres than males (standardised difference in telomere length between females and males 0.090, 95% CI 0.015, 0.166; age-adjusted). There was little evidence that these associations varied by age group (p=1.00) or cell type (p=0.29). However, the size of this difference did vary by measurement methods, with only Southern blot but neither real-time PCR nor Flow-FISH showing a significant difference. This difference was not associated with random measurement error.

CONCLUSIONS: Telomere length is longer in females than males, although this difference was not universally found in studies that did not use Southern blot methods. Further research on explanations for the methodological differences is required.

%B Exp Gerontol %V 51 %P 15-27 %8 2014 Mar %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/24365661?dopt=Abstract %R 10.1016/j.exger.2013.12.004 %0 Journal Article %J Int J Mol Epidemiol Genet %D 2014 %T Gene expression in thiazide diuretic or statin users in relation to incident type 2 diabetes. %A Suchy-Dicey, Astrid %A Heckbert, Susan R %A Smith, Nicholas L %A McKnight, Barbara %A Rotter, Jerome I %A Chen, Yd Ida %A Psaty, Bruce M %A Enquobahrie, Daniel A %X Thiazide diuretics and statins are used to improve cardiovascular outcomes, but may also cause type 2 diabetes (T2DM), although mechanisms are unknown. Gene expression studies may facilitate understanding of these associations. Participants from ongoing population-based studies were sampled for these longitudinal studies of peripheral blood microarray gene expression, and followed to incident diabetes. All sampled subjects were statin or thiazide users. Those who developed diabetes during follow-up comprised cases (44 thiazide users; 19 statin users), and were matched to drug-using controls who did not develop diabetes on several factors. Supervised normalization, surrogate variable analyses removed technical bias and confounding. Differentially-expressed genes were those with a false discovery rate Q-value<0.05. Among thiazide users, diabetes cases had significantly different expression of CCL14 (down-regulated 6%, Q-value=0.0257), compared with controls. Among statin users, diabetes cases had marginal but insignificantly different expression of ZNF532 (up-regulated 15%, Q-value=0.0584), CXORF21 (up-regulated 11%, Q-value=0.0584), and ZNHIT3 (up-regulated 19%, Q-value=0.0959), compared with controls. These genes comprise potential targets for future expression or mechanistic research on medication-related diabetes development. %B Int J Mol Epidemiol Genet %V 5 %P 22-30 %8 2014 %G eng %N 1 %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 Hum Mol Genet %D 2014 %T Gene-centric meta-analyses for central adiposity traits in up to 57 412 individuals of European descent confirm known loci and reveal several novel associations. %A Yoneyama, Sachiko %A Guo, Yiran %A Lanktree, Matthew B %A Barnes, Michael R %A Elbers, Clara C %A Karczewski, Konrad J %A Padmanabhan, Sandosh %A Bauer, Florianne %A Baumert, Jens %A Beitelshees, Amber %A Berenson, Gerald S %A Boer, Jolanda M A %A Burke, Gregory %A Cade, Brian %A Chen, Wei %A Cooper-Dehoff, Rhonda M %A Gaunt, Tom R %A Gieger, Christian %A Gong, Yan %A Gorski, Mathias %A Heard-Costa, Nancy %A Johnson, Toby %A Lamonte, Michael J %A McDonough, Caitrin %A Monda, Keri L %A Onland-Moret, N Charlotte %A Nelson, Christopher P %A O'Connell, Jeffrey R %A Ordovas, Jose %A Peter, Inga %A Peters, Annette %A Shaffer, Jonathan %A Shen, Haiqinq %A Smith, Erin %A Speilotes, Liz %A Thomas, Fridtjof %A Thorand, Barbara %A Monique Verschuren, W M %A Anand, Sonia S %A Dominiczak, Anna %A Davidson, Karina W %A Hegele, Robert A %A Heid, Iris %A Hofker, Marten H %A Huggins, Gordon S %A Illig, Thomas %A Johnson, Julie A %A Kirkland, Susan %A König, Wolfgang %A Langaee, Taimour Y %A McCaffery, Jeanne %A Melander, Olle %A Mitchell, Braxton D %A Munroe, Patricia %A Murray, Sarah S %A Papanicolaou, George %A Redline, Susan %A Reilly, Muredach %A Samani, Nilesh J %A Schork, Nicholas J %A van der Schouw, Yvonne T %A Shimbo, Daichi %A Shuldiner, Alan R %A Tobin, Martin D %A Wijmenga, Cisca %A Yusuf, Salim %A Hakonarson, Hakon %A Lange, Leslie A %A Demerath, Ellen W %A Fox, Caroline S %A North, Kari E %A Reiner, Alex P %A Keating, Brendan %A Taylor, Kira C %K Adiposity %K Adult %K Aged %K Aged, 80 and over %K Body Mass Index %K European Continental Ancestry Group %K Female %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Waist Circumference %K Waist-Hip Ratio %K Young Adult %X

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

%B Hum Mol Genet %V 23 %P 2498-510 %8 2014 May 01 %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/24345515?dopt=Abstract %R 10.1093/hmg/ddt626 %0 Journal Article %J Thromb Res %D 2014 %T A genetic association study of D-dimer levels with 50K SNPs from a candidate gene chip in four ethnic groups. %A Weng, Lu-Chen %A Tang, Weihong %A Rich, Stephen S %A Smith, Nicholas L %A Redline, Susan %A O'Donnell, Christopher J %A Basu, Saonli %A Reiner, Alexander P %A Delaney, Joseph A %A Tracy, Russell P %A Palmer, Cameron D %A Young, Taylor %A Yang, Qiong %A Folsom, Aaron R %A Cushman, Mary %K Adult %K Aged %K Cardiovascular Diseases %K Ethnic Groups %K Factor V %K Female %K Fibrin Fibrinogen Degradation Products %K Fibrinogen %K Genetic Association Studies %K Genotype %K Humans %K Male %K Middle Aged %K Oligonucleotide Array Sequence Analysis %K Polymorphism, Single Nucleotide %K Young Adult %X

INTRODUCTION: D-dimer, a fibrin degradation product, is related to risk of cardiovascular disease and venous thromboembolism. Genetic determinants of D-dimer are not well characterized; notably, few data have been reported for African American (AA), Asian, and Hispanic populations.

MATERIALS AND METHODS: We conducted a large-scale candidate gene association study to identify variants in genes associated with D-dimer levels in multi-ethnic populations. Four cohorts, comprising 6,848 European Americans (EAs), 2,192 AAs, 670 Asians, and 1,286 Hispanics in the National Heart, Lung, and Blood Institute Candidate Gene Association Resource consortium, were assembled. Approximately 50,000 genotyped single nucleotide polymorphisms (SNPs) in 2,000 cardiovascular disease gene loci were analyzed by linear regression, adjusting for age, sex, study site, and principal components in each cohort and ethnic group. Results across studies were combined within each ethnic group by meta-analysis.

RESULTS: Twelve SNPs in coagulation factor V (F5) and 3 SNPs in the fibrinogen alpha chain (FGA) were significantly associated with D-dimer level in EAs with p<2.0×10(-6). The signal for the most associated SNP in F5 (rs6025, factor V Leiden) was replicated in Hispanics (p=0.023), while that for the top functional SNP in FGA (rs6050) was replicated in AAs (p=0.006). No additional SNPs were significantly associated with D-dimer.

CONCLUSIONS: Our study replicated previously reported associations of D-dimer with SNPs in F5 and FGA in EAs; we demonstrated replication of the association of D-dimer with FGA rs6050 in AAs and the factor V Leiden variant in Hispanics.

%B Thromb Res %V 134 %P 462-7 %8 2014 Aug %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24908450?dopt=Abstract %R 10.1016/j.thromres.2014.05.018 %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 Invest Ophthalmol Vis Sci %D 2014 %T Genetic determinants of age-related macular degeneration in diverse populations from the PAGE study. %A Restrepo, Nicole A %A Spencer, Kylee L %A Goodloe, Robert %A Garrett, Tiana A %A Heiss, Gerardo %A Bůzková, Petra %A Jorgensen, Neal %A Jensen, Richard A %A Matise, Tara C %A Hindorff, Lucia A %A Klein, Barbara E K %A Klein, Ronald %A Wong, Tien Y %A Cheng, Ching-Yu %A Cornes, Belinda K %A Tai, E-Shyong %A Ritchie, Marylyn D %A Haines, Jonathan L %A Crawford, Dana C %K Adult %K Aged %K Aged, 80 and over %K Complement Factor H %K DNA %K Ethnic Groups %K Female %K Gene Frequency %K Genetic Predisposition to Disease %K Genotype %K Humans %K Macular Degeneration %K Male %K Middle Aged %K Phenotype %K Polymorphism, Single Nucleotide %K Prevalence %K Prospective Studies %K Proteins %K Risk Factors %K United States %X

PURPOSE: Substantial progress has been made in identifying susceptibility variants for AMD in European populations; however, few studies have been conducted to understand the role these variants play in AMD risk in diverse populations. The present study aims to examine AMD risk across diverse populations in known and suspected AMD complement factor and lipid-related loci.

METHODS: Targeted genotyping was performed across study sites for AMD and lipid trait-associated single nucleotide polymorphism (SNPs). Genetic association tests were performed at individual sites and then meta-analyzed using logistic regression assuming an additive genetic model stratified by self-described race/ethnicity. Participants included cases with early or late AMD and controls with no signs of AMD as determined by fundus photography. Populations included in this study were European Americans, African Americans, Mexican Americans, and Singaporeans from the Population Architecture using Genomics and Epidemiology (PAGE) study.

RESULTS: Index variants of AMD, rs1061170 (CFH) and rs10490924 (ARMS2), were associated with AMD at P=3.05×10(-8) and P=6.36×10(-6), respectively, in European Americans. In general, none of the major AMD index variants generalized to our non-European populations with the exception of rs10490924 in Mexican Americans at an uncorrected P value<0.05. Four lipid-associated SNPS (LPL rs328, TRIB1 rs6987702, CETP rs1800775, and KCTD10/MVK rs2338104) were associated with AMD in African Americans and Mexican Americans (P<0.05), but these associations did not survive strict corrections for multiple testing.

CONCLUSIONS: While most associations did not generalize in the non-European populations, variants within lipid-related genes were found to be associated with AMD. This study highlights the need for larger well-powered studies in non-European populations.

%B Invest Ophthalmol Vis Sci %V 55 %P 6839-50 %8 2014 Sep 9 %G eng %N 10 %R 10.1167/iovs.14-14246 %0 Journal Article %J BMC Genet %D 2014 %T Genetic diversity is a predictor of mortality in humans. %A Bihlmeyer, Nathan A %A Brody, Jennifer A %A Smith, Albert Vernon %A Lunetta, Kathryn L %A Nalls, Mike %A Smith, Jennifer A %A Tanaka, Toshiko %A Davies, Gail %A Yu, Lei %A Mirza, Saira Saeed %A Teumer, Alexander %A Coresh, Josef %A Pankow, James S %A Franceschini, Nora %A Scaria, Anish %A Oshima, Junko %A Psaty, Bruce M %A Gudnason, Vilmundur %A Eiriksdottir, Gudny %A Harris, Tamara B %A Li, Hanyue %A Karasik, David %A Kiel, Douglas P %A Garcia, Melissa %A Liu, Yongmei %A Faul, Jessica D %A Kardia, Sharon Lr %A Zhao, Wei %A Ferrucci, Luigi %A Allerhand, Michael %A Liewald, David C %A Redmond, Paul %A Starr, John M %A De Jager, Philip L %A Evans, Denis A %A Direk, Nese %A Ikram, Mohammed Arfan %A Uitterlinden, Andre %A Homuth, Georg %A Lorbeer, Roberto %A Grabe, Hans J %A Launer, Lenore %A Murabito, Joanne M %A Singleton, Andrew B %A Weir, David R %A Bandinelli, Stefania %A Deary, Ian J %A Bennett, David A %A Tiemeier, Henning %A Kocher, Thomas %A Lumley, Thomas %A Arking, Dan E %K Genome-Wide Association Study %K Heterozygote %K Humans %K Mortality %K Polymorphism, Single Nucleotide %K Proportional Hazards Models %X

BACKGROUND: It has been well-established, both by population genetics theory and direct observation in many organisms, that increased genetic diversity provides a survival advantage. However, given the limitations of both sample size and genome-wide metrics, this hypothesis has not been comprehensively tested in human populations. Moreover, the presence of numerous segregating small effect alleles that influence traits that directly impact health directly raises the question as to whether global measures of genomic variation are themselves associated with human health and disease.

RESULTS: We performed a meta-analysis of 17 cohorts followed prospectively, with a combined sample size of 46,716 individuals, including a total of 15,234 deaths. We find a significant association between increased heterozygosity and survival (P = 0.03). We estimate that within a single population, every standard deviation of heterozygosity an individual has over the mean decreases that person's risk of death by 1.57%.

CONCLUSIONS: This effect was consistent between European and African ancestry cohorts, men and women, and major causes of death (cancer and cardiovascular disease), demonstrating the broad positive impact of genomic diversity on human survival.

%B BMC Genet %V 15 %P 159 %8 2014 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/25543667?dopt=Abstract %R 10.1186/s12863-014-0159-7 %0 Journal Article %J PLoS One %D 2014 %T Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease. %A Escott-Price, Valentina %A Bellenguez, Céline %A Wang, Li-San %A Choi, Seung-Hoan %A Harold, Denise %A Jones, Lesley %A Holmans, Peter %A Gerrish, Amy %A Vedernikov, Alexey %A Richards, Alexander %A DeStefano, Anita L %A Lambert, Jean-Charles %A Ibrahim-Verbaas, Carla A %A Naj, Adam C %A Sims, Rebecca %A Jun, Gyungah %A Bis, Joshua C %A Beecham, Gary W %A Grenier-Boley, Benjamin %A Russo, Giancarlo %A Thornton-Wells, Tricia A %A Denning, Nicola %A Smith, Albert V %A Chouraki, Vincent %A Thomas, Charlene %A Ikram, M Arfan %A Zelenika, Diana %A Vardarajan, Badri N %A Kamatani, Yoichiro %A Lin, Chiao-Feng %A Schmidt, Helena %A Kunkle, Brian %A Dunstan, Melanie L %A Vronskaya, Maria %A Johnson, Andrew D %A Ruiz, Agustin %A Bihoreau, Marie-Thérèse %A Reitz, Christiane %A Pasquier, Florence %A Hollingworth, Paul %A Hanon, Olivier %A Fitzpatrick, Annette L %A Buxbaum, Joseph D %A Campion, Dominique %A Crane, Paul K %A Baldwin, Clinton %A Becker, Tim %A Gudnason, Vilmundur %A Cruchaga, Carlos %A Craig, David %A Amin, Najaf %A Berr, Claudine %A Lopez, Oscar L %A De Jager, Philip L %A Deramecourt, Vincent %A Johnston, Janet A %A Evans, Denis %A Lovestone, Simon %A Letenneur, Luc %A Hernandez, Isabel %A Rubinsztein, David C %A Eiriksdottir, Gudny %A Sleegers, Kristel %A Goate, Alison M %A Fiévet, Nathalie %A Huentelman, Matthew J %A Gill, Michael %A Brown, Kristelle %A Kamboh, M Ilyas %A Keller, Lina %A Barberger-Gateau, Pascale %A McGuinness, Bernadette %A Larson, Eric B %A Myers, Amanda J %A Dufouil, Carole %A Todd, Stephen %A Wallon, David %A Love, Seth %A Rogaeva, Ekaterina %A Gallacher, John %A George-Hyslop, Peter St %A Clarimon, Jordi %A Lleo, Alberto %A Bayer, Anthony %A Tsuang, Debby W %A Yu, Lei %A Tsolaki, Magda %A Bossù, Paola %A Spalletta, Gianfranco %A Proitsi, Petra %A Collinge, John %A Sorbi, Sandro %A Garcia, Florentino Sanchez %A Fox, Nick C %A Hardy, John %A Naranjo, Maria Candida Deniz %A Bosco, Paolo %A Clarke, Robert %A Brayne, Carol %A Galimberti, Daniela %A Scarpini, Elio %A Bonuccelli, Ubaldo %A Mancuso, Michelangelo %A Siciliano, Gabriele %A Moebus, Susanne %A Mecocci, Patrizia %A Zompo, Maria Del %A Maier, Wolfgang %A Hampel, Harald %A Pilotto, Alberto %A Frank-García, Ana %A Panza, Francesco %A Solfrizzi, Vincenzo %A Caffarra, Paolo %A Nacmias, Benedetta %A Perry, William %A Mayhaus, Manuel %A Lannfelt, Lars %A Hakonarson, Hakon %A Pichler, Sabrina %A Carrasquillo, Minerva M %A Ingelsson, Martin %A Beekly, Duane %A Alvarez, Victoria %A Zou, Fanggeng %A Valladares, Otto %A Younkin, Steven G %A Coto, Eliecer %A Hamilton-Nelson, Kara L %A Gu, Wei %A Razquin, Cristina %A Pastor, Pau %A Mateo, Ignacio %A Owen, Michael J %A Faber, Kelley M %A Jonsson, Palmi V %A Combarros, Onofre %A O'Donovan, Michael C %A Cantwell, Laura B %A Soininen, Hilkka %A Blacker, Deborah %A Mead, Simon %A Mosley, Thomas H %A Bennett, David A %A Harris, Tamara B %A Fratiglioni, Laura %A Holmes, Clive %A de Bruijn, Renee F A G %A Passmore, Peter %A Montine, Thomas J %A Bettens, Karolien %A Rotter, Jerome I %A Brice, Alexis %A Morgan, Kevin %A Foroud, Tatiana M %A Kukull, Walter A %A Hannequin, Didier %A Powell, John F %A Nalls, Michael A %A Ritchie, Karen %A Lunetta, Kathryn L %A Kauwe, John S K %A Boerwinkle, Eric %A Riemenschneider, Matthias %A Boada, Merce %A Hiltunen, Mikko %A Martin, Eden R %A Schmidt, Reinhold %A Rujescu, Dan %A Dartigues, Jean-François %A Mayeux, Richard %A Tzourio, Christophe %A Hofman, Albert %A Nöthen, Markus M %A Graff, Caroline %A Psaty, Bruce M %A Haines, Jonathan L %A Lathrop, Mark %A Pericak-Vance, Margaret A %A Launer, Lenore J %A Van Broeckhoven, Christine %A Farrer, Lindsay A %A van Duijn, Cornelia M %A Ramirez, Alfredo %A Seshadri, Sudha %A Schellenberg, Gerard D %A Amouyel, Philippe %A Williams, Julie %K Alzheimer Disease %K Carrier Proteins %K Case-Control Studies %K Genome-Wide Association Study %K Heat-Shock Proteins %K Humans %K Polymorphism, Single Nucleotide %K Receptors, Antigen, B-Cell %X

BACKGROUND: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.

PRINCIPAL FINDINGS: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci.

SIGNIFICANCE: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.

%B PLoS One %V 9 %P e94661 %8 2014 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/24922517?dopt=Abstract %R 10.1371/journal.pone.0094661 %0 Journal Article %J Nat Genet %D 2014 %T Genome-wide association analysis identifies six new loci associated with forced vital capacity. %A Loth, Daan W %A Soler Artigas, Maria %A Gharib, Sina A %A Wain, Louise V %A Franceschini, Nora %A Koch, Beate %A Pottinger, Tess D %A Smith, Albert Vernon %A Duan, Qing %A Oldmeadow, Chris %A Lee, Mi Kyeong %A Strachan, David P %A James, Alan L %A Huffman, Jennifer E %A Vitart, Veronique %A Ramasamy, Adaikalavan %A Wareham, Nicholas J %A Kaprio, Jaakko %A Wang, Xin-Qun %A Trochet, Holly %A Kähönen, Mika %A Flexeder, Claudia %A Albrecht, Eva %A Lopez, Lorna M %A de Jong, Kim %A Thyagarajan, Bharat %A Alves, Alexessander Couto %A Enroth, Stefan %A Omenaas, Ernst %A Joshi, Peter K %A Fall, Tove %A Viñuela, Ana %A Launer, Lenore J %A Loehr, Laura R %A Fornage, Myriam %A Li, Guo %A Wilk, Jemma B %A Tang, Wenbo %A Manichaikul, Ani %A Lahousse, Lies %A Harris, Tamara B %A North, Kari E %A Rudnicka, Alicja R %A Hui, Jennie %A Gu, Xiangjun %A Lumley, Thomas %A Wright, Alan F %A Hastie, Nicholas D %A Campbell, Susan %A Kumar, Rajesh %A Pin, Isabelle %A Scott, Robert A %A Pietiläinen, Kirsi H %A Surakka, Ida %A Liu, Yongmei %A Holliday, Elizabeth G %A Schulz, Holger %A Heinrich, Joachim %A Davies, Gail %A Vonk, Judith M %A Wojczynski, Mary %A Pouta, Anneli %A Johansson, Asa %A Wild, Sarah H %A Ingelsson, Erik %A Rivadeneira, Fernando %A Völzke, Henry %A Hysi, Pirro G %A Eiriksdottir, Gudny %A Morrison, Alanna C %A Rotter, Jerome I %A Gao, Wei %A Postma, Dirkje S %A White, Wendy B %A Rich, Stephen S %A Hofman, Albert %A Aspelund, Thor %A Couper, David %A Smith, Lewis J %A Psaty, Bruce M %A Lohman, Kurt %A Burchard, Esteban G %A Uitterlinden, André G %A Garcia, Melissa %A Joubert, Bonnie R %A McArdle, Wendy L %A Musk, A Bill %A Hansel, Nadia %A Heckbert, Susan R %A Zgaga, Lina %A van Meurs, Joyce B J %A Navarro, Pau %A Rudan, Igor %A Oh, Yeon-Mok %A Redline, Susan %A Jarvis, Deborah L %A Zhao, Jing Hua %A Rantanen, Taina %A O'Connor, George T %A Ripatti, Samuli %A Scott, Rodney J %A Karrasch, Stefan %A Grallert, Harald %A Gaddis, Nathan C %A Starr, John M %A Wijmenga, Cisca %A Minster, Ryan L %A Lederer, David J %A Pekkanen, Juha %A Gyllensten, Ulf %A Campbell, Harry %A Morris, Andrew P %A Gläser, Sven %A Hammond, Christopher J %A Burkart, Kristin M %A Beilby, John %A Kritchevsky, Stephen B %A Gudnason, Vilmundur %A Hancock, Dana B %A Williams, O Dale %A Polasek, Ozren %A Zemunik, Tatijana %A Kolcic, Ivana %A Petrini, Marcy F %A Wjst, Matthias %A Kim, Woo Jin %A Porteous, David J %A Scotland, Generation %A Smith, Blair H %A Viljanen, Anne %A Heliövaara, Markku %A Attia, John R %A Sayers, Ian %A Hampel, Regina %A Gieger, Christian %A Deary, Ian J %A Boezen, H Marike %A Newman, Anne %A Jarvelin, Marjo-Riitta %A Wilson, James F %A Lind, Lars %A Stricker, Bruno H %A Teumer, Alexander %A Spector, Timothy D %A Melén, Erik %A Peters, Marjolein J %A Lange, Leslie A %A Barr, R Graham %A Bracke, Ken R %A Verhamme, Fien M %A Sung, Joohon %A Hiemstra, Pieter S %A Cassano, Patricia A %A Sood, Akshay %A Hayward, Caroline %A Dupuis, Josée %A Hall, Ian P %A Brusselle, Guy G %A Tobin, Martin D %A London, Stephanie J %K Cohort Studies %K Databases, Genetic %K Follow-Up Studies %K Forced Expiratory Volume %K Genetic Loci %K Genetic Predisposition to Disease %K Genome, Human %K Genome-Wide Association Study %K Humans %K Lung Diseases %K Meta-Analysis as Topic %K Polymorphism, Single Nucleotide %K Prognosis %K Quantitative Trait Loci %K Respiratory Function Tests %K Spirometry %K Vital Capacity %X

Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.

%B Nat Genet %V 46 %P 669-77 %8 2014 Jul %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/24929828?dopt=Abstract %R 10.1038/ng.3011 %0 Journal Article %J Arterioscler Thromb Vasc Biol %D 2014 %T Genome-wide association study for circulating tissue plasminogen activator levels and functional follow-up implicates endothelial STXBP5 and STX2. %A Huang, Jie %A Huffman, Jennifer E %A Yamakuchi, Munekazu %A Yamkauchi, Munekazu %A Trompet, Stella %A Asselbergs, Folkert W %A Sabater-Lleal, Maria %A Trégouët, David-Alexandre %A Chen, Wei-Min %A Smith, Nicholas L %A Kleber, Marcus E %A Shin, So-Youn %A Becker, Diane M %A Tang, Weihong %A Dehghan, Abbas %A Johnson, Andrew D %A Truong, Vinh %A Folkersen, Lasse %A Yang, Qiong %A Oudot-Mellkah, Tiphaine %A Buckley, Brendan M %A Moore, Jason H %A Williams, Frances M K %A Campbell, Harry %A Silbernagel, Günther %A Vitart, Veronique %A Rudan, Igor %A Tofler, Geoffrey H %A Navis, Gerjan J %A DeStefano, Anita %A Wright, Alan F %A Chen, Ming-Huei %A de Craen, Anton J M %A Worrall, Bradford B %A Rudnicka, Alicja R %A Rumley, Ann %A Bookman, Ebony B %A Psaty, Bruce M %A Chen, Fang %A Keene, Keith L %A Franco, Oscar H %A Böhm, Bernhard O %A Uitterlinden, André G %A Carter, Angela M %A Jukema, J Wouter %A Sattar, Naveed %A Bis, Joshua C %A Ikram, Mohammad A %A Sale, Michèle M %A McKnight, Barbara %A Fornage, Myriam %A Ford, Ian %A Taylor, Kent %A Slagboom, P Eline %A McArdle, Wendy L %A Hsu, Fang-Chi %A Franco-Cereceda, Anders %A Goodall, Alison H %A Yanek, Lisa R %A Furie, Karen L %A Cushman, Mary %A Hofman, Albert %A Witteman, Jacqueline C M %A Folsom, Aaron R %A Basu, Saonli %A Matijevic, Nena %A van Gilst, Wiek H %A Wilson, James F %A Westendorp, Rudi G J %A Kathiresan, Sekar %A Reilly, Muredach P %A Tracy, Russell P %A Polasek, Ozren %A Winkelmann, Bernhard R %A Grant, Peter J %A Hillege, Hans L %A Cambien, Francois %A Stott, David J %A Lowe, Gordon D %A Spector, Timothy D %A Meigs, James B %A März, Winfried %A Eriksson, Per %A Becker, Lewis C %A Morange, Pierre-Emmanuel %A Soranzo, Nicole %A Williams, Scott M %A Hayward, Caroline %A van der Harst, Pim %A Hamsten, Anders %A Lowenstein, Charles J %A Strachan, David P %A O'Donnell, Christopher J %K Aged %K Cells, Cultured %K Coronary Artery Disease %K Endothelial Cells %K Europe %K Female %K Gene Expression Regulation %K Gene Silencing %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Nerve Tissue Proteins %K Phenotype %K Polymorphism, Single Nucleotide %K R-SNARE Proteins %K Risk Factors %K Stroke %K Syntaxin 1 %K Tissue Plasminogen Activator %K Transfection %K United States %K Up-Regulation %X

OBJECTIVE: Tissue plasminogen activator (tPA), a serine protease, catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for endogenous fibrinolysis. In some populations, elevated plasma levels of tPA have been associated with myocardial infarction and other cardiovascular diseases. We conducted a meta-analysis of genome-wide association studies to identify novel correlates of circulating levels of tPA.

APPROACH AND RESULTS: Fourteen cohort studies with tPA measures (N=26 929) contributed to the meta-analysis. Three loci were significantly associated with circulating tPA levels (P<5.0×10(-8)). The first locus is on 6q24.3, with the lead single nucleotide polymorphism (SNP; rs9399599; P=2.9×10(-14)) within STXBP5. The second locus is on 8p11.21. The lead SNP (rs3136739; P=1.3×10(-9)) is intronic to POLB and <200 kb away from the tPA encoding the gene PLAT. We identified a nonsynonymous SNP (rs2020921) in modest linkage disequilibrium with rs3136739 (r(2)=0.50) within exon 5 of PLAT (P=2.0×10(-8)). The third locus is on 12q24.33, with the lead SNP (rs7301826; P=1.0×10(-9)) within intron 7 of STX2. We further found evidence for the association of lead SNPs in STXBP5 and STX2 with expression levels of the respective transcripts. In in vitro cell studies, silencing STXBP5 decreased the release of tPA from vascular endothelial cells, whereas silencing STX2 increased the tPA release. Through an in silico lookup, we found no associations of the 3 lead SNPs with coronary artery disease or stroke.

CONCLUSIONS: We identified 3 loci associated with circulating tPA levels, the PLAT region, STXBP5, and STX2. Our functional studies implicate a novel role for STXBP5 and STX2 in regulating tPA release.

%B Arterioscler Thromb Vasc Biol %V 34 %P 1093-101 %8 2014 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/24578379?dopt=Abstract %R 10.1161/ATVBAHA.113.302088 %0 Journal Article %J Circ Cardiovasc Genet %D 2014 %T Genome-wide association study of L-arginine and dimethylarginines reveals novel metabolic pathway for symmetric dimethylarginine. %A Lüneburg, Nicole %A Lieb, Wolfgang %A Zeller, Tanja %A Chen, Ming-Huei %A Maas, Renke %A Carter, Angela M %A Xanthakis, Vanessa %A Glazer, Nicole L %A Schwedhelm, Edzard %A Seshadri, Sudha %A Ikram, Mohammad Arfan %A Longstreth, William T %A Fornage, Myriam %A König, Inke R %A Loley, Christina %A Ojeda, Francisco M %A Schillert, Arne %A Wang, Thomas J %A Sticht, Heinrich %A Kittel, Anja %A König, Jörg %A Benjamin, Emelia J %A Sullivan, Lisa M %A Bernges, Isabel %A Anderssohn, Maike %A Ziegler, Andreas %A Gieger, Christian %A Illig, Thomas %A Meisinger, Christa %A Wichmann, H-Erich %A Wild, Philipp S %A Schunkert, Heribert %A Psaty, Bruce M %A Wiggins, Kerri L %A Heckbert, Susan R %A Smith, Nicholas %A Lackner, Karl %A Lunetta, Kathryn L %A Blankenberg, Stefan %A Erdmann, Jeanette %A Münzel, Thomas %A Grant, Peter J %A Vasan, Ramachandran S %A Böger, Rainer H %K Adult %K Aged %K Amidohydrolases %K Arginine %K Binding Sites %K Cohort Studies %K Female %K Genetic Loci %K Genome-Wide Association Study %K Genotype %K HEK293 Cells %K Humans %K Male %K Mediator Complex %K Middle Aged %K Polymorphism, Single Nucleotide %K Protein Structure, Tertiary %K Risk Factors %K Stroke %K Substrate Specificity %K Transaminases %X

BACKGROUND: Dimethylarginines (DMA) interfere with nitric oxide formation by inhibiting nitric oxide synthase (asymmetrical DMA [ADMA]) and l-arginine uptake into the cell (ADMA and symmetrical DMA [SDMA]). In prospective clinical studies, ADMA has been characterized as a cardiovascular risk marker, whereas SDMA is a novel marker for renal function and associated with all-cause mortality after ischemic stroke. The aim of the current study was to characterize the environmental and genetic contributions to interindividual variability of these biomarkers.

METHODS AND RESULTS: This study comprised a genome-wide association analysis of 3 well-characterized population-based cohorts (Framingham Heart Study [FHS; n=2992], Gutenberg Health Study [GHS; n=4354], and Multinational Monitoring of Trends and Determinants in Cardiovascular Disease Study [MONICA]/Cooperative Health Research in the Augsburg Area, Augsburg, Bavaria, Germany [KORA] F3 [n=581]) and identified replicated loci (DDAH1, MED23, Arg1, and AGXT2) associated with the interindividual variability in ADMA, l-arginine, and SDMA. Experimental in silico and in vitro studies confirmed functional significance of the identified AGXT2 variants. Clinical outcome analysis in 384 patients of the Leeds stroke study demonstrated an association between increased plasma levels of SDMA, AGXT2 variants, and various cardiometabolic risk factors. AGXT2 variants were not associated with poststroke survival in the Leeds study or were they associated with incident stroke in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.

CONCLUSIONS: These genome-wide association study support the importance of DDAH1 and MED23/Arg1 in regulating ADMA and l-arginine metabolism, respectively, and identify a novel regulatory renal pathway for SDMA by AGXT2. AGXT2 variants might explain part of the pathogenic link between SDMA, renal function, and outcome. An association between AGXT2 variants and stroke is unclear and warrants further investigation.

%B Circ Cardiovasc Genet %V 7 %P 864-72 %8 2014 Dec %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/25245031?dopt=Abstract %R 10.1161/CIRCGENETICS.113.000264 %0 Journal Article %J Circ Cardiovasc Genet %D 2014 %T Genome-wide association study of plasma N6 polyunsaturated fatty acids within the cohorts for heart and aging research in genomic epidemiology consortium. %A Guan, Weihua %A Steffen, Brian T %A Lemaitre, Rozenn N %A Wu, Jason H Y %A Tanaka, Toshiko %A Manichaikul, Ani %A Foy, Millennia %A Rich, Stephen S %A Wang, Lu %A Nettleton, Jennifer A %A Tang, Weihong %A Gu, Xiangjun %A Bandinelli, Stafania %A King, Irena B %A McKnight, Barbara %A Psaty, Bruce M %A Siscovick, David %A Djoussé, Luc %A Chen, Yii-Der Ida %A Ferrucci, Luigi %A Fornage, Myriam %A Mozafarrian, Dariush %A Tsai, Michael Y %A Steffen, Lyn M %K Adult %K Aged %K Aged, 80 and over %K Aging %K Chromosomes, Human, Pair 10 %K Chromosomes, Human, Pair 16 %K Chromosomes, Human, Pair 6 %K Fatty Acid Desaturases %K Fatty Acids, Omega-6 %K Female %K Genome-Wide Association Study %K Genomics %K Heart Diseases %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Prospective Studies %K Sequence Analysis, DNA %X

BACKGROUND: Omega6 (n6) polyunsaturated fatty acids (PUFAs) and their metabolites are involved in cell signaling, inflammation, clot formation, and other crucial biological processes. Genetic components, such as variants of fatty acid desaturase (FADS) genes, determine the composition of n6 PUFAs.

METHODS AND RESULTS: To elucidate undiscovered biological pathways that may influence n6 PUFA composition, we conducted genome-wide association studies and meta-analyses of associations of common genetic variants with 6 plasma n6 PUFAs in 8631 white adults (55% women) across 5 prospective studies. Plasma phospholipid or total plasma fatty acids were analyzed by similar gas chromatography techniques. The n6 fatty acids linoleic acid (LA), γ-linolenic acid (GLA), dihomo-GLA, arachidonic acid, and adrenic acid were expressed as percentage of total fatty acids. We performed linear regression with robust SEs to test for single-nucleotide polymorphism-fatty acid associations, with pooling using inverse-variance-weighted meta-analysis. Novel regions were identified on chromosome 10 associated with LA (rs10740118; P=8.1×10(-9); near NRBF2), on chromosome 16 with LA, GLA, dihomo-GLA, and arachidonic acid (rs16966952; P=1.2×10(-15), 5.0×10(-11), 7.6×10(-65), and 2.4×10(-10), respectively; NTAN1), and on chromosome 6 with adrenic acid after adjustment for arachidonic acid (rs3134950; P=2.1×10(-10); AGPAT1). We confirmed previous findings of the FADS cluster on chromosome 11 with LA and arachidonic acid, and further observed novel genome-wide significant association of this cluster with GLA, dihomo-GLA, and adrenic acid (P=2.3×10(-72), 2.6×10(-151), and 6.3×10(-140), respectively).

CONCLUSIONS: Our findings suggest that along with the FADS gene cluster, additional genes may influence n6 PUFA composition.

%B Circ Cardiovasc Genet %V 7 %P 321-331 %8 2014 Jun %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/24823311?dopt=Abstract %R 10.1161/CIRCGENETICS.113.000208 %0 Journal Article %J JAMA %D 2014 %T Glycated hemoglobin measurement and prediction of cardiovascular disease. %A Di Angelantonio, Emanuele %A Gao, Pei %A Khan, Hassan %A Butterworth, Adam S %A Wormser, David %A Kaptoge, Stephen %A Kondapally Seshasai, Sreenivasa Rao %A Thompson, Alex %A Sarwar, Nadeem %A Willeit, Peter %A Ridker, Paul M %A Barr, Elizabeth L M %A Khaw, Kay-Tee %A Psaty, Bruce M %A Brenner, Hermann %A Balkau, Beverley %A Dekker, Jacqueline M %A Lawlor, Debbie A %A Daimon, Makoto %A Willeit, Johann %A Njølstad, Inger %A Nissinen, Aulikki %A Brunner, Eric J %A Kuller, Lewis H %A Price, Jackie F %A Sundström, Johan %A Knuiman, Matthew W %A Feskens, Edith J M %A Verschuren, W M M %A Wald, Nicholas %A Bakker, Stephan J L %A Whincup, Peter H %A Ford, Ian %A Goldbourt, Uri %A Gómez-de-la-Cámara, Agustín %A Gallacher, John %A Simons, Leon A %A Rosengren, Annika %A Sutherland, Susan E %A Björkelund, Cecilia %A Blazer, Dan G %A Wassertheil-Smoller, Sylvia %A Onat, Altan %A Marín Ibañez, Alejandro %A Casiglia, Edoardo %A Jukema, J Wouter %A Simpson, Lara M %A Giampaoli, Simona %A Nordestgaard, Børge G %A Selmer, Randi %A Wennberg, Patrik %A Kauhanen, Jussi %A Salonen, Jukka T %A Dankner, Rachel %A Barrett-Connor, Elizabeth %A Kavousi, Maryam %A Gudnason, Vilmundur %A Evans, Denis %A Wallace, Robert B %A Cushman, Mary %A D'Agostino, Ralph B %A Umans, Jason G %A Kiyohara, Yutaka %A Nakagawa, Hidaeki %A Sato, Shinichi %A Gillum, Richard F %A Folsom, Aaron R %A van der Schouw, Yvonne T %A Moons, Karel G %A Griffin, Simon J %A Sattar, Naveed %A Wareham, Nicholas J %A Selvin, Elizabeth %A Thompson, Simon G %A Danesh, John %K Aged %K C-Reactive Protein %K Cholesterol, HDL %K Coronary Disease %K Diabetes Mellitus %K Female %K Glycated Hemoglobin A %K Humans %K Male %K Middle Aged %K Predictive Value of Tests %K Prospective Studies %K Risk Assessment %K Stroke %X

IMPORTANCE: The value of measuring levels of glycated hemoglobin (HbA1c) for the prediction of first cardiovascular events is uncertain.

OBJECTIVE: To determine whether adding information on HbA1c values to conventional cardiovascular risk factors is associated with improvement in prediction of cardiovascular disease (CVD) risk.

DESIGN, SETTING, AND PARTICIPANTS: Analysis of individual-participant data available from 73 prospective studies involving 294,998 participants without a known history of diabetes mellitus or CVD at the baseline assessment.

MAIN OUTCOMES AND MEASURES: Measures of risk discrimination for CVD outcomes (eg, C-index) and reclassification (eg, net reclassification improvement) of participants across predicted 10-year risk categories of low (<5%), intermediate (5% to <7.5%), and high (≥ 7.5%) risk.

RESULTS: During a median follow-up of 9.9 (interquartile range, 7.6-13.2) years, 20,840 incident fatal and nonfatal CVD outcomes (13,237 coronary heart disease and 7603 stroke outcomes) were recorded. In analyses adjusted for several conventional cardiovascular risk factors, there was an approximately J-shaped association between HbA1c values and CVD risk. The association between HbA1c values and CVD risk changed only slightly after adjustment for total cholesterol and triglyceride concentrations or estimated glomerular filtration rate, but this association attenuated somewhat after adjustment for concentrations of high-density lipoprotein cholesterol and C-reactive protein. The C-index for a CVD risk prediction model containing conventional cardiovascular risk factors alone was 0.7434 (95% CI, 0.7350 to 0.7517). The addition of information on HbA1c was associated with a C-index change of 0.0018 (0.0003 to 0.0033) and a net reclassification improvement of 0.42 (-0.63 to 1.48) for the categories of predicted 10-year CVD risk. The improvement provided by HbA1c assessment in prediction of CVD risk was equal to or better than estimated improvements for measurement of fasting, random, or postload plasma glucose levels.

CONCLUSIONS AND RELEVANCE: In a study of individuals without known CVD or diabetes, additional assessment of HbA1c values in the context of CVD risk assessment provided little incremental benefit for prediction of CVD risk.

%B JAMA %V 311 %P 1225-33 %8 2014 Mar 26 %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/24668104?dopt=Abstract %R 10.1001/jama.2014.1873 %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 Gerontol A Biol Sci Med Sci %D 2014 %T Heritability of and mortality prediction with a longevity phenotype: the healthy aging index. %A Sanders, Jason L %A Minster, Ryan L %A Barmada, M Michael %A Matteini, Amy M %A Boudreau, Robert M %A Christensen, Kaare %A Mayeux, Richard %A Borecki, Ingrid B %A Zhang, Qunyuan %A Perls, Thomas %A Newman, Anne B %K Aged %K Aging %K Cardiovascular Diseases %K Female %K Genetic Predisposition to Disease %K Genotype %K Health Behavior %K Humans %K Longevity %K Male %K Phenotype %K Retrospective Studies %K Risk Factors %K Survival Rate %K United States %X

BACKGROUND: Longevity-associated genes may modulate risk for age-related diseases and survival. The Healthy Aging Index (HAI) may be a subphenotype of longevity, which can be constructed in many studies for genetic analysis. We investigated the HAI's association with survival in the Cardiovascular Health Study and heritability in the Long Life Family Study.

METHODS: The HAI includes systolic blood pressure, pulmonary vital capacity, creatinine, fasting glucose, and Modified Mini-Mental Status Examination score, each scored 0, 1, or 2 using approximate tertiles and summed from 0 (healthy) to 10 (unhealthy). In Cardiovascular Health Study, the association with mortality and accuracy predicting death were determined with Cox proportional hazards analysis and c-statistics, respectively. In Long Life Family Study, heritability was determined with a variance component-based family analysis using a polygenic model.

RESULTS: Cardiovascular Health Study participants with unhealthier index scores (7-10) had 2.62-fold (95% confidence interval: 2.22, 3.10) greater mortality than participants with healthier scores (0-2). The HAI alone predicted death moderately well (c-statistic = 0.643, 95% confidence interval: 0.626, 0.661, p < .0001) and slightly worse than age alone (c-statistic = 0.700, 95% confidence interval: 0.684, 0.717, p < .0001; p < .0001 for comparison of c-statistics). Prediction increased significantly with adjustment for demographics, health behaviors, and clinical comorbidities (c-statistic = 0.780, 95% confidence interval: 0.765, 0.794, p < .0001). In Long Life Family Study, the heritability of the HAI was 0.295 (p < .0001) overall, 0.387 (p < .0001) in probands, and 0.238 (p = .0004) in offspring.

CONCLUSION: The HAI should be investigated further as a candidate phenotype for uncovering longevity-associated genes in humans.

%B J Gerontol A Biol Sci Med Sci %V 69 %P 479-85 %8 2014 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/23913930?dopt=Abstract %R 10.1093/gerona/glt117 %0 Journal Article %J PLoS Genet %D 2014 %T Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease. %A Medici, Marco %A Porcu, Eleonora %A Pistis, Giorgio %A Teumer, Alexander %A Brown, Suzanne J %A Jensen, Richard A %A Rawal, Rajesh %A Roef, Greet L %A Plantinga, Theo S %A Vermeulen, Sita H %A Lahti, Jari %A Simmonds, Matthew J %A Husemoen, Lise Lotte N %A Freathy, Rachel M %A Shields, Beverley M %A Pietzner, Diana %A Nagy, Rebecca %A Broer, Linda %A Chaker, Layal %A Korevaar, Tim I M %A Plia, Maria Grazia %A Sala, Cinzia %A Völker, Uwe %A Richards, J Brent %A Sweep, Fred C %A Gieger, Christian %A Corre, Tanguy %A Kajantie, Eero %A Thuesen, Betina %A Taes, Youri E %A Visser, W Edward %A Hattersley, Andrew T %A Kratzsch, Jürgen %A Hamilton, Alexander %A Li, Wei %A Homuth, Georg %A Lobina, Monia %A Mariotti, Stefano %A Soranzo, Nicole %A Cocca, Massimiliano %A Nauck, Matthias %A Spielhagen, Christin %A Ross, Alec %A Arnold, Alice %A van de Bunt, Martijn %A Liyanarachchi, Sandya %A Heier, Margit %A Grabe, Hans Jörgen %A Masciullo, Corrado %A Galesloot, Tessel E %A Lim, Ee M %A Reischl, Eva %A Leedman, Peter J %A Lai, Sandra %A Delitala, Alessandro %A Bremner, Alexandra P %A Philips, David I W %A Beilby, John P %A Mulas, Antonella %A Vocale, Matteo %A Abecasis, Goncalo %A Forsen, Tom %A James, Alan %A Widen, Elisabeth %A Hui, Jennie %A Prokisch, Holger %A Rietzschel, Ernst E %A Palotie, Aarno %A Feddema, Peter %A Fletcher, Stephen J %A Schramm, Katharina %A Rotter, Jerome I %A Kluttig, Alexander %A Radke, Dörte %A Traglia, Michela %A Surdulescu, Gabriela L %A He, Huiling %A Franklyn, Jayne A %A Tiller, Daniel %A Vaidya, Bijay %A De Meyer, Tim %A Jørgensen, Torben %A Eriksson, Johan G %A O'Leary, Peter C %A Wichmann, Eric %A Hermus, Ad R %A Psaty, Bruce M %A Ittermann, Till %A Hofman, Albert %A Bosi, Emanuele %A Schlessinger, David %A Wallaschofski, Henri %A Pirastu, Nicola %A Aulchenko, Yurii S %A de la Chapelle, Albert %A Netea-Maier, Romana T %A Gough, Stephen C L %A Meyer Zu Schwabedissen, Henriette %A Frayling, Timothy M %A Kaufman, Jean-Marc %A Linneberg, Allan %A Räikkönen, Katri %A Smit, Johannes W A %A Kiemeney, Lambertus A %A Rivadeneira, Fernando %A Uitterlinden, André G %A Walsh, John P %A Meisinger, Christa %A den Heijer, Martin %A Visser, Theo J %A Spector, Timothy D %A Wilson, Scott G %A Völzke, Henry %A Cappola, Anne %A Toniolo, Daniela %A Sanna, Serena %A Naitza, Silvia %A Peeters, Robin P %K Autoantibodies %K Genetic Loci %K Genome-Wide Association Study %K Graves Disease %K Hashimoto Disease %K Humans %K Iodide Peroxidase %K Risk Factors %K Thyroiditis, Autoimmune %K Thyrotropin %X

Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P<5×10(-8)) were detected at TPO-rs11675434, ATXN2-rs653178, and BACH2-rs10944479 for TPOAb-positivity, and at TPO-rs11675434, MAGI3-rs1230666, and KALRN-rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95% CI 1.68-2.81, P = 8.1×10(-8)), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26-1.82, P = 2.9×10(-6)), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66-0.89, P = 6.5×10(-4)). The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, which was replicated in an independent cohort of patients with Graves' disease (OR: 1.37, 95% CI 1.22-1.54, P = 1.2×10(-7) and OR: 1.25, 95% CI 1.12-1.39, P = 6.2×10(-5)). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18-2.10, P = 1.9×10(-3)). This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. The results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which TPOAb-positives are particularly at risk of developing clinical thyroid dysfunction.

%B PLoS Genet %V 10 %P e1004123 %8 2014 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24586183?dopt=Abstract %R 10.1371/journal.pgen.1004123 %0 Journal Article %J J Am Coll Cardiol %D 2014 %T Incidence of and risk factors for sick sinus syndrome in the general population. %A Jensen, Paul N %A Gronroos, Noelle N %A Chen, Lin Y %A Folsom, Aaron R %A deFilippi, Chris %A Heckbert, Susan R %A Alonso, Alvaro %K African Continental Ancestry Group %K Aged %K Aged, 80 and over %K Cohort Studies %K European Continental Ancestry Group %K Female %K Follow-Up Studies %K Humans %K Incidence %K Male %K Middle Aged %K Population Surveillance %K Prospective Studies %K Risk Factors %K Sick Sinus Syndrome %X

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

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

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

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

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

%B J Am Coll Cardiol %V 64 %P 531-8 %8 2014 Aug 12 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/25104519?dopt=Abstract %R 10.1016/j.jacc.2014.03.056 %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 Circulation %D 2014 %T Integrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation. %A Sinner, Moritz F %A Tucker, Nathan R %A Lunetta, Kathryn L %A Ozaki, Kouichi %A Smith, J Gustav %A Trompet, Stella %A Bis, Joshua C %A Lin, Honghuang %A Chung, Mina K %A Nielsen, Jonas B %A Lubitz, Steven A %A Krijthe, Bouwe P %A Magnani, Jared W %A Ye, Jiangchuan %A Gollob, Michael H %A Tsunoda, Tatsuhiko %A Müller-Nurasyid, Martina %A Lichtner, Peter %A Peters, Annette %A Dolmatova, Elena %A Kubo, Michiaki %A Smith, Jonathan D %A Psaty, Bruce M %A Smith, Nicholas L %A Jukema, J Wouter %A Chasman, Daniel I %A Albert, Christine M %A Ebana, Yusuke %A Furukawa, Tetsushi %A Macfarlane, Peter W %A Harris, Tamara B %A Darbar, Dawood %A Dörr, Marcus %A Holst, Anders G %A Svendsen, Jesper H %A Hofman, Albert %A Uitterlinden, André G %A Gudnason, Vilmundur %A Isobe, Mitsuaki %A Malik, Rainer %A Dichgans, Martin %A Rosand, Jonathan %A Van Wagoner, David R %A Benjamin, Emelia J %A Milan, David J %A Melander, Olle %A Heckbert, Susan R %A Ford, Ian %A Liu, Yongmei %A Barnard, John %A Olesen, Morten S %A Stricker, Bruno H C %A Tanaka, Toshihiro %A Kääb, Stefan %A Ellinor, Patrick T %K Aged %K Animals %K Atrial Fibrillation %K Chromosome Mapping %K Connexin 43 %K Europe %K Female %K Gene Knockdown Techniques %K Genetic Loci %K Genetic Predisposition to Disease %K Genotype %K Homeodomain Proteins %K Humans %K Japan %K Male %K Middle Aged %K Muscle Proteins %K Nuclear Proteins %K Quantitative Trait Loci %K Repressor Proteins %K T-Box Domain Proteins %K Transcription Factors %K Ubiquitin-Protein Ligases %K Zebrafish %K Zebrafish Proteins %X

BACKGROUND: Atrial fibrillation (AF) affects >30 million individuals worldwide and is associated with an increased risk of stroke, heart failure, and death. AF is highly heritable, yet the genetic basis for the arrhythmia remains incompletely understood.

METHODS AND RESULTS: To identify new AF-related genes, we used a multifaceted approach, combining large-scale genotyping in 2 ethnically distinct populations, cis-eQTL (expression quantitative trait loci) mapping, and functional validation. Four novel loci were identified in individuals of European descent near the genes NEURL (rs12415501; relative risk [RR]=1.18; 95% confidence interval [CI], 1.13-1.23; P=6.5×10(-16)), GJA1 (rs13216675; RR=1.10; 95% CI, 1.06-1.14; P=2.2×10(-8)), TBX5 (rs10507248; RR=1.12; 95% CI, 1.08-1.16; P=5.7×10(-11)), and CAND2 (rs4642101; RR=1.10; 95% CI, 1.06-1.14; P=9.8×10(-9)). In Japanese, novel loci were identified near NEURL (rs6584555; RR=1.32; 95% CI, 1.26-1.39; P=2.0×10(-25)) and CUX2 (rs6490029; RR=1.12; 95% CI, 1.08-1.16; P=3.9×10(-9)). The top single-nucleotide polymorphisms or their proxies were identified as cis-eQTLs for the genes CAND2 (P=2.6×10(-19)), GJA1 (P=2.66×10(-6)), and TBX5 (P=1.36×10(-5)). Knockdown of the zebrafish orthologs of NEURL and CAND2 resulted in prolongation of the atrial action potential duration (17% and 45%, respectively).

CONCLUSIONS: We have identified 5 novel loci for AF. Our results expand the diversity of genetic pathways implicated in AF and provide novel molecular targets for future biological and pharmacological investigation.

%B Circulation %V 130 %P 1225-35 %8 2014 Oct 7 %G eng %N 15 %1 http://www.ncbi.nlm.nih.gov/pubmed/25124494?dopt=Abstract %R 10.1161/CIRCULATIONAHA.114.009892 %0 Journal Article %J PLoS One %D 2014 %T Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function. %A Tang, Wenbo %A Kowgier, Matthew %A Loth, Daan W %A Soler Artigas, Maria %A Joubert, Bonnie R %A Hodge, Emily %A Gharib, Sina A %A Smith, Albert V %A Ruczinski, Ingo %A Gudnason, Vilmundur %A Mathias, Rasika A %A Harris, Tamara B %A Hansel, Nadia N %A Launer, Lenore J %A Barnes, Kathleen C %A Hansen, Joyanna G %A Albrecht, Eva %A Aldrich, Melinda C %A Allerhand, Michael %A Barr, R Graham %A Brusselle, Guy G %A Couper, David J %A Curjuric, Ivan %A Davies, Gail %A Deary, Ian J %A Dupuis, Josée %A Fall, Tove %A Foy, Millennia %A Franceschini, Nora %A Gao, Wei %A Gläser, Sven %A Gu, Xiangjun %A Hancock, Dana B %A Heinrich, Joachim %A Hofman, Albert %A Imboden, Medea %A Ingelsson, Erik %A James, Alan %A Karrasch, Stefan %A Koch, Beate %A Kritchevsky, Stephen B %A Kumar, Ashish %A Lahousse, Lies %A Li, Guo %A Lind, Lars %A Lindgren, Cecilia %A Liu, Yongmei %A Lohman, Kurt %A Lumley, Thomas %A McArdle, Wendy L %A Meibohm, Bernd %A Morris, Andrew P %A Morrison, Alanna C %A Musk, Bill %A North, Kari E %A Palmer, Lyle J %A Probst-Hensch, Nicole M %A Psaty, Bruce M %A Rivadeneira, Fernando %A Rotter, Jerome I %A Schulz, Holger %A Smith, Lewis J %A Sood, Akshay %A Starr, John M %A Strachan, David P %A Teumer, Alexander %A Uitterlinden, André G %A Völzke, Henry %A Voorman, Arend %A Wain, Louise V %A Wells, Martin T %A Wilk, Jemma B %A Williams, O Dale %A Heckbert, Susan R %A Stricker, Bruno H %A London, Stephanie J %A Fornage, Myriam %A Tobin, Martin D %A O'Connor, George T %A Hall, Ian P %A Cassano, Patricia A %K Adult %K Chromosomes, Human, Pair 11 %K Female %K Gene Expression Regulation %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Longitudinal Studies %K Male %K Respiration %X

BACKGROUND: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function.

METHODS: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis.

RESULTS: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively.

CONCLUSIONS: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.

%B PLoS One %V 9 %P e100776 %8 2014 %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/24983941?dopt=Abstract %R 10.1371/journal.pone.0100776 %0 Journal Article %J Nat Genet %D 2014 %T Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease. %A Nalls, Mike A %A Pankratz, Nathan %A Lill, Christina M %A Do, Chuong B %A Hernandez, Dena G %A Saad, Mohamad %A DeStefano, Anita L %A Kara, Eleanna %A Bras, Jose %A Sharma, Manu %A Schulte, Claudia %A Keller, Margaux F %A Arepalli, Sampath %A Letson, Christopher %A Edsall, Connor %A Stefansson, Hreinn %A Liu, Xinmin %A Pliner, Hannah %A Lee, Joseph H %A Cheng, Rong %A Ikram, M Arfan %A Ioannidis, John P A %A Hadjigeorgiou, Georgios M %A Bis, Joshua C %A Martinez, Maria %A Perlmutter, Joel S %A Goate, Alison %A Marder, Karen %A Fiske, Brian %A Sutherland, Margaret %A Xiromerisiou, Georgia %A Myers, Richard H %A Clark, Lorraine N %A Stefansson, Kari %A Hardy, John A %A Heutink, Peter %A Chen, Honglei %A Wood, Nicholas W %A Houlden, Henry %A Payami, Haydeh %A Brice, Alexis %A Scott, William K %A Gasser, Thomas %A Bertram, Lars %A Eriksson, Nicholas %A Foroud, Tatiana %A Singleton, Andrew B %K Case-Control Studies %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Parkinson Disease %K Polymorphism, Single Nucleotide %K Risk Factors %X

We conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant association; these and 6 additional previously reported loci were then tested in an independent set of 5,353 cases and 5,551 controls. Of the 32 tested SNPs, 24 replicated, including 6 newly identified loci. Conditional analyses within loci showed that four loci, including GBA, GAK-DGKQ, SNCA and the HLA region, contain a secondary independent risk variant. In total, we identified and replicated 28 independent risk variants for Parkinson's disease across 24 loci. Although the effect of each individual locus was small, risk profile analysis showed substantial cumulative risk in a comparison of the highest and lowest quintiles of genetic risk (odds ratio (OR) = 3.31, 95% confidence interval (CI) = 2.55-4.30; P = 2 × 10(-16)). We also show six risk loci associated with proximal gene expression or DNA methylation.

%B Nat Genet %V 46 %P 989-93 %8 2014 Sep %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/25064009?dopt=Abstract %R 10.1038/ng.3043 %0 Journal Article %J Atherosclerosis %D 2014 %T Lipoprotein-associated phospholipase A2 and risk of dementia in the Cardiovascular Health Study. %A Fitzpatrick, Annette L %A Irizarry, Michael C %A Cushman, Mary %A Jenny, Nancy S %A Chi, Gloria C %A Koro, Carol %K 1-Alkyl-2-acetylglycerophosphocholine Esterase %K Aged %K Alzheimer Disease %K Dementia %K Female %K Humans %K Male %K Risk %K Risk Factors %X

OBJECTIVE: To evaluate associations between Lipoprotein-associated phospholipase A2 (Lp-PLA2) mass and activity with risk of dementia and its subtypes.

METHODS: Analysis were completed on 3320 participants of the Cardiovascular Health Study (CHS), a population-based longitudinal study of community-dwelling adults age ≥65 years followed for an average of 5.4 years. Baseline serum Lp-PLA2 mass was measured using a sandwich enzyme immunoassay and Lp-PLA2 activity utilized a tritiated-platelet activating factor activity assay. Cox proportional hazards regression assessed the relative risk of incident dementia with higher baseline Lp-PLA2 adjusting for demographics, cardiovascular disease (CVD) and risk factors, inflammation markers and apolipoprotein E (APOE) genotype.

RESULTS: Each standard deviation higher Lp-PLA2 mass and activity were related to increased risk of dementia (fully adjusted HR: 1.11 per SD, 95% CI: 1.00-1.24 for mass; HR: 1.12 per SD, 95% CI: 1.00-1.26 for activity). Persons in the highest quartile of Lp-PLA2 mass were 50% more likely to develop dementia than those in the lowest quartile in adjusted models (HR: 1.49; 95% CI: 1.08-2.06). Among dementia subtypes, the risk of AD was increased two-fold in the highest compared to lowest quartile of Lp-PLA2 mass (adjusted HR: 1.98, 95% CI: 1.22-3.21). Results were attenuated in models of mixed dementia and VaD. Lp-PLA2 activity also doubled the risk of mixed dementia in the highest compared to lowest quartile (HR: 2.21, 95% CI: 1.12-4.373).

INTERPRETATION: These data support Lp-PLA2 as a risk factor for dementia independent of CVD and its risk factors. Further study is required to clarify the role of Lp-PLA2-related mechanisms in dementia subtypes.

%B Atherosclerosis %V 235 %P 384-91 %8 2014 Aug %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24929287?dopt=Abstract %R 10.1016/j.atherosclerosis.2014.04.032 %0 Journal Article %J N Engl J Med %D 2014 %T Loss-of-function mutations in APOC3, triglycerides, and coronary disease. %A Crosby, Jacy %A Peloso, Gina M %A Auer, Paul L %A Crosslin, David R %A Stitziel, Nathan O %A Lange, Leslie A %A Lu, Yingchang %A Tang, Zheng-Zheng %A Zhang, He %A Hindy, George %A Masca, Nicholas %A Stirrups, Kathleen %A Kanoni, Stavroula %A Do, Ron %A Jun, Goo %A Hu, Youna %A Kang, Hyun Min %A Xue, Chenyi %A Goel, Anuj %A Farrall, Martin %A Duga, Stefano %A Merlini, Pier Angelica %A Asselta, Rosanna %A Girelli, Domenico %A Olivieri, Oliviero %A Martinelli, Nicola %A Yin, Wu %A Reilly, Dermot %A Speliotes, Elizabeth %A Fox, Caroline S %A Hveem, Kristian %A Holmen, Oddgeir L %A Nikpay, Majid %A Farlow, Deborah N %A Assimes, Themistocles L %A Franceschini, Nora %A Robinson, Jennifer %A North, Kari E %A Martin, Lisa W %A DePristo, Mark %A Gupta, Namrata %A Escher, Stefan A %A Jansson, Jan-Håkan %A Van Zuydam, Natalie %A Palmer, Colin N A %A Wareham, Nicholas %A Koch, Werner %A Meitinger, Thomas %A Peters, Annette %A Lieb, Wolfgang %A Erbel, Raimund %A König, Inke R %A Kruppa, Jochen %A Degenhardt, Franziska %A Gottesman, Omri %A Bottinger, Erwin P %A O'Donnell, Christopher J %A Psaty, Bruce M %A Ballantyne, Christie M %A Abecasis, Goncalo %A Ordovas, Jose M %A Melander, Olle %A Watkins, Hugh %A Orho-Melander, Marju %A Ardissino, Diego %A Loos, Ruth J F %A McPherson, Ruth %A Willer, Cristen J %A Erdmann, Jeanette %A Hall, Alistair S %A Samani, Nilesh J %A Deloukas, Panos %A Schunkert, Heribert %A Wilson, James G %A Kooperberg, Charles %A Rich, Stephen S %A Tracy, Russell P %A Lin, Dan-Yu %A Altshuler, David %A Gabriel, Stacey %A Nickerson, Deborah A %A Jarvik, Gail P %A Cupples, L Adrienne %A Reiner, Alex P %A Boerwinkle, Eric %A Kathiresan, Sekar %K African Continental Ancestry Group %K Apolipoprotein C-III %K Coronary Disease %K European Continental Ancestry Group %K Exome %K Genotype %K Heterozygote %K Humans %K Liver %K Mutation %K Risk Factors %K Sequence Analysis, DNA %K Triglycerides %X

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

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

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

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

%B N Engl J Med %V 371 %P 22-31 %8 2014 Jul 3 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/24941081?dopt=Abstract %R 10.1056/NEJMoa1307095 %0 Journal Article %J J Am Heart Assoc %D 2014 %T A low-frequency variant in MAPK14 provides mechanistic evidence of a link with myeloperoxidase: a prognostic cardiovascular risk marker. %A Waterworth, Dawn M %A Li, Li %A Scott, Robert %A Warren, Liling %A Gillson, Christopher %A Aponte, Jennifer %A Sarov-Blat, Lea %A Sprecher, Dennis %A Dupuis, Josée %A Reiner, Alex %A Psaty, Bruce M %A Tracy, Russell P %A Lin, Honghuang %A McPherson, Ruth %A Chissoe, Stephanie %A Wareham, Nick %A Ehm, Margaret G %K Adult %K Aged %K Cardiovascular Diseases %K Dyslipidemias %K Exome %K Female %K Genotype %K Humans %K Linear Models %K Logistic Models %K Male %K Metabolic Syndrome X %K Middle Aged %K Mitogen-Activated Protein Kinase 11 %K Mitogen-Activated Protein Kinase 14 %K Obesity %K Peroxidase %K Polymorphism, Single Nucleotide %K Prognosis %K Risk Factors %K Sequence Analysis, DNA %X

BACKGROUND: Genetics can be used to predict drug effects and generate hypotheses around alternative indications. To support Losmapimod, a p38 mitogen-activated protein kinase inhibitor in development for acute coronary syndrome, we characterized gene variation in MAPK11/14 genes by exome sequencing and follow-up genotyping or imputation in participants well-phenotyped for cardiovascular and metabolic traits.

METHODS AND RESULTS: Investigation of genetic variation in MAPK11 and MAPK14 genes using additive genetic models in linear or logistic regression with cardiovascular, metabolic, and biomarker phenotypes highlighted an association of RS2859144 in MAPK14 with myeloperoxidase in a dyslipidemic population (Genetic Epidemiology of Metabolic Syndrome Study), P=2.3×10(-6)). This variant (or proxy) was consistently associated with myeloperoxidase in the Framingham Heart Study and Cardiovascular Health Study studies (replication meta-P=0.003), leading to a meta-P value of 9.96×10(-7) in the 3 dyslipidemic groups. The variant or its proxy was then profiled in additional population-based cohorts (up to a total of 58 930 subjects) including Cohorte Lausannoise, Ely, Fenland, European Prospective Investigation of Cancer, London Life Sciences Prospective Population Study, and the Genetics of Obesity Associations study obesity case-control for up to 40 cardiovascular and metabolic traits. Overall analysis identified the same single nucleotide polymorphisms to be nominally associated consistently with glomerular filtration rate (P=0.002) and risk of obesity (body mass index ≥30 kg/m(2), P=0.004).

CONCLUSIONS: As myeloperoxidase is a prognostic marker of coronary events, the MAPK14 variant may provide a mechanistic link between p38 map kinase and these events, providing information consistent with current indication of Losmapimod for acute coronary syndrome. If replicated, the association with glomerular filtration rate, along with previous biological findings, also provides support for kidney diseases as alternative indications.

%B J Am Heart Assoc %V 3 %8 2014 Aug %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/25164947?dopt=Abstract %R 10.1161/JAHA.114.001074 %0 Journal Article %J Neurology %D 2014 %T Meta-analysis in more than 17,900 cases of ischemic stroke reveals a novel association at 12q24.12. %A Kilarski, Laura L %A Achterberg, Sefanja %A Devan, William J %A Traylor, Matthew %A Malik, Rainer %A Lindgren, Arne %A Pare, Guillame %A Sharma, Pankaj %A Slowik, Agniesczka %A Thijs, Vincent %A Walters, Matthew %A Worrall, Bradford B %A Sale, Michèle M %A Algra, Ale %A Kappelle, L Jaap %A Wijmenga, Cisca %A Norrving, Bo %A Sandling, Johanna K %A Rönnblom, Lars %A Goris, An %A Franke, Andre %A Sudlow, Cathie %A Rothwell, Peter M %A Levi, Christopher %A Holliday, Elizabeth G %A Fornage, Myriam %A Psaty, Bruce %A Gretarsdottir, Solveig %A Thorsteinsdottir, Unnar %A Seshadri, Sudha %A Mitchell, Braxton D %A Kittner, Steven %A Clarke, Robert %A Hopewell, Jemma C %A Bis, Joshua C %A Boncoraglio, Giorgio B %A Meschia, James %A Ikram, M Arfan %A Hansen, Bjorn M %A Montaner, Joan %A Thorleifsson, Gudmar %A Stefanson, Kari %A Rosand, Jonathan %A de Bakker, Paul I W %A Farrall, Martin %A Dichgans, Martin %A Markus, Hugh S %A Bevan, Steve %K Brain Ischemia %K Cerebral Hemorrhage %K Chromosomes, Human, Pair 12 %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Polymorphism, Single Nucleotide %K Risk %K Stroke %X

OBJECTIVES: To perform a genome-wide association study (GWAS) using the Immunochip array in 3,420 cases of ischemic stroke and 6,821 controls, followed by a meta-analysis with data from more than 14,000 additional ischemic stroke cases.

METHODS: Using the Immunochip, we genotyped 3,420 ischemic stroke cases and 6,821 controls. After imputation we meta-analyzed the results with imputed GWAS data from 3,548 cases and 5,972 controls recruited from the ischemic stroke WTCCC2 study, and with summary statistics from a further 8,480 cases and 56,032 controls in the METASTROKE consortium. A final in silico "look-up" of 2 single nucleotide polymorphisms in 2,522 cases and 1,899 controls was performed. Associations were also examined in 1,088 cases with intracerebral hemorrhage and 1,102 controls.

RESULTS: In an overall analysis of 17,970 cases of ischemic stroke and 70,764 controls, we identified a novel association on chromosome 12q24 (rs10744777, odds ratio [OR] 1.10 [1.07-1.13], p = 7.12 × 10(-11)) with ischemic stroke. The association was with all ischemic stroke rather than an individual stroke subtype, with similar effect sizes seen in different stroke subtypes. There was no association with intracerebral hemorrhage (OR 1.03 [0.90-1.17], p = 0.695).

CONCLUSION: Our results show, for the first time, a genetic risk locus associated with ischemic stroke as a whole, rather than in a subtype-specific manner. This finding was not associated with intracerebral hemorrhage.

%B Neurology %V 83 %P 678-85 %8 2014 Aug 19 %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/25031287?dopt=Abstract %R 10.1212/WNL.0000000000000707 %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 Hum Mol Genet %D 2014 %T Meta-analysis of loci associated with age at natural menopause in African-American women. %A Chen, Christina T L %A Liu, Ching-Ti %A Chen, Gary K %A Andrews, Jeanette S %A Arnold, Alice M %A Dreyfus, Jill %A Franceschini, Nora %A Garcia, Melissa E %A Kerr, Kathleen F %A Li, Guo %A Lohman, Kurt K %A Musani, Solomon K %A Nalls, Michael A %A Raffel, Leslie J %A Smith, Jennifer %A Ambrosone, Christine B %A Bandera, Elisa V %A Bernstein, Leslie %A Britton, Angela %A Brzyski, Robert G %A Cappola, Anne %A Carlson, Christopher S %A Couper, David %A Deming, Sandra L %A Goodarzi, Mark O %A Heiss, Gerardo %A John, Esther M %A Lu, Xiaoning %A Le Marchand, Loïc %A Marciante, Kristin %A McKnight, Barbara %A Millikan, Robert %A Nock, Nora L %A Olshan, Andrew F %A Press, Michael F %A Vaiyda, Dhananjay %A Woods, Nancy F %A Taylor, Herman A %A Zhao, Wei %A Zheng, Wei %A Evans, Michele K %A Harris, Tamara B %A Henderson, Brian E %A Kardia, Sharon L R %A Kooperberg, Charles %A Liu, Yongmei %A Mosley, Thomas H %A Psaty, Bruce %A Wellons, Melissa %A Windham, Beverly G %A Zonderman, Alan B %A Cupples, L Adrienne %A Demerath, Ellen W %A Haiman, Christopher %A Murabito, Joanne M %A Rajkovic, Aleksandar %K African Americans %K Age Factors %K Chromosomes, Human %K European Continental Ancestry Group %K Female %K Genetic Loci %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Menopause %K United States %X

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

%B Hum Mol Genet %V 23 %P 3327-42 %8 2014 Jun 15 %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/24493794?dopt=Abstract %R 10.1093/hmg/ddu041 %0 Journal Article %J Hypertension %D 2014 %T Metabolic syndrome and risk of incident peripheral artery disease: the cardiovascular health study. %A Garg, Parveen K %A Biggs, Mary L %A Carnethon, Mercedes %A Ix, Joachim H %A Criqui, Michael H %A Britton, Kathryn A %A Djoussé, Luc %A Sutton-Tyrrell, Kim %A Newman, Anne B %A Cushman, Mary %A Mukamal, Kenneth J %K Aged %K Ankle Brachial Index %K C-Reactive Protein %K Female %K Fibrinogen %K Follow-Up Studies %K Humans %K Incidence %K Longitudinal Studies %K Male %K Metabolic Syndrome %K Peripheral Arterial Disease %K Prevalence %K Risk Factors %K Vasculitis %X

Prior studies evaluating metabolic syndrome (MetS) and incident peripheral artery disease (PAD) have been limited by use of modified MetS criteria and restriction to clinical PAD end points. We investigated MetS and risk of developing a low ankle-brachial index (ABI) and clinical PAD in the Cardiovascular Health Study, a population-based cohort of adults aged ≥65 years. Participants with MetS met at least 3 of 5 Adult Treatment Panel III criteria. Baseline C-reactive protein-MetS or fibrinogen-MetS were defined as presence of 3 of 6 components, with elevated C-reactive protein (>3 mg/L) or fibrinogen (>341 mg/dL) as a sixth component. Incident low ABI, defined as ABI <0.9 and decline of ≥0.15, was assessed among a subset of 1899 individuals with 2 ABI measurements 6 years apart. Over a median follow-up of 13.7 years, 4632 individuals were followed up for clinical PAD, defined as revascularization or diagnosed claudication. Adult Treatment Panel III MetS was associated with both incident low ABI (risk ratio, 1.26; 95% confidence interval [CI], 1.00-1.58) and clinical PAD (hazard ratio, 1.47; 95% CI, 1.11-1.94). Incorporating C-reactive protein or fibrinogen into Adult Treatment Panel III criteria identified an additional 16% to 20% of individuals as having MetS, and both C-reactive protein-MetS and fibrinogen-MetS were associated with incident low ABI (risk ratio, 1.36; 95% CI, 1.07-1.72 and risk ratio, 1.43; 95% CI, 1.13-1.81, respectively) and clinical PAD (hazard ratio, 1.56; 95% CI, 1.17-2.08 and hazard ratio, 1.55; 95% CI, 1.17-2.07, respectively). Among Adult Treatment Panel III MetS criteria, risk of PAD was most strongly associated with hypertension.

%B Hypertension %V 63 %P 413-9 %8 2014 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24191289?dopt=Abstract %R 10.1161/HYPERTENSIONAHA.113.01925 %0 Journal Article %J Circ Cardiovasc Genet %D 2014 %T Multiancestral analysis of inflammation-related genetic variants and C-reactive protein in the population architecture using genomics and epidemiology study. %A Kocarnik, Jonathan M %A Pendergrass, Sarah A %A Carty, Cara L %A Pankow, James S %A Schumacher, Fredrick R %A Cheng, Iona %A Durda, Peter %A Ambite, Jose Luis %A Deelman, Ewa %A Cook, Nancy R %A Liu, Simin %A Wactawski-Wende, Jean %A Hutter, Carolyn %A Brown-Gentry, Kristin %A Wilson, Sarah %A Best, Lyle G %A Pankratz, Nathan %A Hong, Ching-Ping %A Cole, Shelley A %A Voruganti, V Saroja %A Bůzková, Petra %A Jorgensen, Neal W %A Jenny, Nancy S %A Wilkens, Lynne R %A Haiman, Christopher A %A Kolonel, Laurence N %A LaCroix, Andrea %A North, Kari %A Jackson, Rebecca %A Le Marchand, Loïc %A Hindorff, Lucia A %A Crawford, Dana C %A Gross, Myron %A Peters, Ulrike %K Adult %K African Continental Ancestry Group %K Aged %K Asian Continental Ancestry Group %K C-Reactive Protein %K Female %K Genetic Variation %K Genome-Wide Association Study %K Hispanic Americans %K Humans %K Indians, North American %K Inflammation %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K United States %K Young Adult %X

BACKGROUND: C-reactive protein (CRP) is a biomarker of inflammation. Genome-wide association studies (GWAS) have identified single-nucleotide polymorphisms (SNPs) associated with CRP concentrations and inflammation-related traits such as cardiovascular disease, type 2 diabetes mellitus, and obesity. We aimed to replicate previous CRP-SNP associations, assess whether these associations generalize to additional race/ethnicity groups, and evaluate inflammation-related SNPs for a potentially pleiotropic association with CRP.

METHODS AND RESULTS: We selected and analyzed 16 CRP-associated and 250 inflammation-related GWAS SNPs among 40 473 African American, American Indian, Asian/Pacific Islander, European American, and Hispanic participants from 7 studies collaborating in the Population Architecture using Genomics and Epidemiology (PAGE) study. Fixed-effect meta-analyses combined study-specific race/ethnicity-stratified linear regression estimates to evaluate the association between each SNP and high-sensitivity CRP. Overall, 18 SNPs in 8 loci were significantly associated with CRP (Bonferroni-corrected P<3.1×10(-3) for replication, P<2.0×10(-4) for pleiotropy): Seven of these were specific to European Americans, while 9 additionally generalized to African Americans (1), Hispanics (5), or both (3); 1 SNP was seen only in African Americans and Hispanics. Two SNPs in the CELSR2/PSRC1/SORT1 locus showed a potentially novel association with CRP: rs599839 (P=2.0×10(-6)) and rs646776 (P=3.1×10(-5)).

CONCLUSIONS: We replicated 16 SNP-CRP associations, 10 of which generalized to African Americans and/or Hispanics. We also identified potentially novel pleiotropic associations with CRP for two SNPs previously associated with coronary artery disease and/or low-density lipoprotein-cholesterol. These findings demonstrate the benefit of evaluating genotype-phenotype associations in multiple race/ethnicity groups and looking for pleiotropic relationships among SNPs previously associated with related phenotypes.

%B Circ Cardiovasc Genet %V 7 %P 178-88 %8 2014 Apr %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24622110?dopt=Abstract %R 10.1161/CIRCGENETICS.113.000173 %0 Journal Article %J Stroke %D 2014 %T Multilocus genetic risk score associates with ischemic stroke in case-control and prospective cohort studies. %A Malik, Rainer %A Bevan, Steve %A Nalls, Michael A %A Holliday, Elizabeth G %A Devan, William J %A Cheng, Yu-Ching %A Ibrahim-Verbaas, Carla A %A Verhaaren, Benjamin F J %A Bis, Joshua C %A Joon, Aron Y %A de Stefano, Anita L %A Fornage, Myriam %A Psaty, Bruce M %A Ikram, M Arfan %A Launer, Lenore J %A van Duijn, Cornelia M %A Sharma, Pankaj %A Mitchell, Braxton D %A Rosand, Jonathan %A Meschia, James F %A Levi, Christopher %A Rothwell, Peter M %A Sudlow, Cathie %A Markus, Hugh S %A Seshadri, Sudha %A Dichgans, Martin %K Adult %K Aged %K Aged, 80 and over %K Atrial Fibrillation %K Blood Pressure %K Brain Ischemia %K Case-Control Studies %K Cohort Studies %K Coronary Artery Disease %K Female %K Genetic Predisposition to Disease %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Hypertension %K Male %K Middle Aged %K Multilocus Sequence Typing %K Polymorphism, Single Nucleotide %K Population %K Prospective Studies %K Reproducibility of Results %K Risk Assessment %K Risk Factors %K Sex Factors %K Stroke %X

BACKGROUND AND PURPOSE: Genome-wide association studies have revealed multiple common variants associated with known risk factors for ischemic stroke (IS). However, their aggregate effect on risk is uncertain. We aimed to generate a multilocus genetic risk score (GRS) for IS based on genome-wide association studies data from clinical-based samples and to establish its external validity in prospective population-based cohorts.

METHODS: Three thousand five hundred forty-eight clinic-based IS cases and 6399 controls from the Wellcome Trust Case Control Consortium 2 were used for derivation of the GRS. Subjects from the METASTROKE consortium served as a replication sample. The validation sample consisted of 22 751 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. We selected variants that had reached genome-wide significance in previous association studies on established risk factors for IS.

RESULTS: A combined GRS for atrial fibrillation, coronary artery disease, hypertension, and systolic blood pressure significantly associated with IS both in the case-control samples and in the prospective population-based studies. Subjects in the top quintile of the combined GRS had >2-fold increased risk of IS compared with subjects in the lowest quintile. Addition of the combined GRS to a simple model based on sex significantly improved the prediction of IS in the combined clinic-based samples but not in the population-based studies, and there was no significant improvement in net reclassification.

CONCLUSIONS: A multilocus GRS based on common variants for established cardiovascular risk factors was significantly associated with IS both in clinic-based samples and in the general population. However, the improvement in clinical risk prediction was found to be small.

%B Stroke %V 45 %P 394-402 %8 2014 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24436234?dopt=Abstract %R 10.1161/STROKEAHA.113.002938 %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 Cytokine %D 2014 %T Novel gene variants predict serum levels of the cytokines IL-18 and IL-1ra in older adults. %A Matteini, A M %A Li, J %A Lange, E M %A Tanaka, T %A Lange, L A %A Tracy, R P %A Wang, Y %A Biggs, M L %A Arking, D E %A Fallin, M D %A Chakravarti, A %A Psaty, B M %A Bandinelli, S %A Ferrucci, L %A Reiner, A P %A Walston, J D %K Aged %K Aged, 80 and over %K Calcium-Binding Proteins %K CARD Signaling Adaptor Proteins %K Chromosomes, Human, Pair 2 %K Female %K Genetic Variation %K Genome-Wide Association Study %K Genotype %K Haplotypes %K Humans %K Inflammation %K Interleukin 1 Receptor Antagonist Protein %K Interleukin-18 %K Male %K Polymorphism, Single Nucleotide %X

Activation of inflammatory pathways measured by serum inflammatory markers such as interleukin-18 (IL-18) and interleukin-1 receptor antagonist (IL-1ra) is strongly associated with the progression of chronic disease states in older adults. Given that these serum cytokine levels are in part a heritable trait, genetic variation may predict increased serum levels. Using the Cardiovascular Health Study and InCHIANTI cohorts, a genome-wide association study was performed to identify genetic variants that influence IL-18 and IL-1ra serum levels among older adults. Multiple linear regression models characterized the association between each SNP and log-transformed cytokine values. Tests for multiple independent signals within statistically significant loci were performed using haplotype analysis and regression models conditional on lead SNP in each region. Multiple SNPs were associated with these cytokines with genome-wide significance, including SNPs in the IL-18-BCO gene region of chromosome 2 for IL-18 (top SNP rs2250417, P=1.9×10(-32)) and in the IL-1 gene family region of chromosome 2 for IL-1ra (rs6743376, P=2.3×10(-26)). Haplotype tests and conditional linear regression models showed evidence of multiple independent signals in these regions. Serum IL-18 levels were also associated with a region on chromosome 2 containing the NLRC4 gene (rs12989936, P=2.7×10(-19)). These data characterize multiple robust genetic signals that influence IL-18 and IL-1ra cytokine production. In particular, the signal for serum IL-18 located on chromosome two is novel and potentially important in inflammasome triggered chronic activation of inflammation in older adults. Replication in independent cohorts is an important next step, as well as molecular studies to better understand the role of NLRC4.

%B Cytokine %V 65 %P 10-6 %8 2014 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/24182552?dopt=Abstract %R 10.1016/j.cyto.2013.10.002 %0 Journal Article %J J Am Coll Cardiol %D 2014 %T Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese. %A Lubitz, Steven A %A Lunetta, Kathryn L %A Lin, Honghuang %A Arking, Dan E %A Trompet, Stella %A Li, Guo %A Krijthe, Bouwe P %A Chasman, Daniel I %A Barnard, John %A Kleber, Marcus E %A Dörr, Marcus %A Ozaki, Kouichi %A Smith, Albert V %A Müller-Nurasyid, Martina %A Walter, Stefan %A Agarwal, Sunil K %A Bis, Joshua C %A Brody, Jennifer A %A Chen, Lin Y %A Everett, Brendan M %A Ford, Ian %A Franco, Oscar H %A Harris, Tamara B %A Hofman, Albert %A Kääb, Stefan %A Mahida, Saagar %A Kathiresan, Sekar %A Kubo, Michiaki %A Launer, Lenore J %A Macfarlane, Peter W %A Magnani, Jared W %A McKnight, Barbara %A McManus, David D %A Peters, Annette %A Psaty, Bruce M %A Rose, Lynda M %A Rotter, Jerome I %A Silbernagel, Guenther %A Smith, Jonathan D %A Sotoodehnia, Nona %A Stott, David J %A Taylor, Kent D %A Tomaschitz, Andreas %A Tsunoda, Tatsuhiko %A Uitterlinden, André G %A Van Wagoner, David R %A Völker, Uwe %A Völzke, Henry %A Murabito, Joanne M %A Sinner, Moritz F %A Gudnason, Vilmundur %A Felix, Stephan B %A März, Winfried %A Chung, Mina %A Albert, Christine M %A Stricker, Bruno H %A Tanaka, Toshihiro %A Heckbert, Susan R %A Jukema, J Wouter %A Alonso, Alvaro %A Benjamin, Emelia J %A Ellinor, Patrick T %K Adult %K Aged %K Aged, 80 and over %K Asian Continental Ancestry Group %K Atrial Fibrillation %K Chromosome Mapping %K Chromosomes, Human, Pair 4 %K Europe %K European Continental Ancestry Group %K Female %K Genetic Markers %K Genetic Predisposition to Disease %K Homeodomain Proteins %K Humans %K Japan %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Transcription Factors %X

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

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

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

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

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

%B J Am Coll Cardiol %V 63 %P 1200-10 %8 2014 Apr 1 %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/24486271?dopt=Abstract %R 10.1016/j.jacc.2013.12.015 %0 Journal Article %J Nat Commun %D 2014 %T Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins. %A Postmus, Iris %A Trompet, Stella %A Deshmukh, Harshal A %A Barnes, Michael R %A Li, Xiaohui %A Warren, Helen R %A Chasman, Daniel I %A Zhou, Kaixin %A Arsenault, Benoit J %A Donnelly, Louise A %A Wiggins, Kerri L %A Avery, Christy L %A Griffin, Paula %A Feng, QiPing %A Taylor, Kent D %A Li, Guo %A Evans, Daniel S %A Smith, Albert V %A de Keyser, Catherine E %A Johnson, Andrew D %A de Craen, Anton J M %A Stott, David J %A Buckley, Brendan M %A Ford, Ian %A Westendorp, Rudi G J %A Slagboom, P Eline %A Sattar, Naveed %A Munroe, Patricia B %A Sever, Peter %A Poulter, Neil %A Stanton, Alice %A Shields, Denis C %A O'Brien, Eoin %A Shaw-Hawkins, Sue %A Chen, Y-D Ida %A Nickerson, Deborah A %A Smith, Joshua D %A Dubé, Marie Pierre %A Boekholdt, S Matthijs %A Hovingh, G Kees %A Kastelein, John J P %A McKeigue, Paul M %A Betteridge, John %A Neil, Andrew %A Durrington, Paul N %A Doney, Alex %A Carr, Fiona %A Morris, Andrew %A McCarthy, Mark I %A Groop, Leif %A Ahlqvist, Emma %A Bis, Joshua C %A Rice, Kenneth %A Smith, Nicholas L %A Lumley, Thomas %A Whitsel, Eric A %A Stürmer, Til %A Boerwinkle, Eric %A Ngwa, Julius S %A O'Donnell, Christopher J %A Vasan, Ramachandran S %A Wei, Wei-Qi %A Wilke, Russell A %A Liu, Ching-Ti %A Sun, Fangui %A Guo, Xiuqing %A Heckbert, Susan R %A Post, Wendy %A Sotoodehnia, Nona %A Arnold, Alice M %A Stafford, Jeanette M %A Ding, Jingzhong %A Herrington, David M %A Kritchevsky, Stephen B %A Eiriksdottir, Gudny %A Launer, Leonore J %A Harris, Tamara B %A Chu, Audrey Y %A Giulianini, Franco %A MacFadyen, Jean G %A Barratt, Bryan J %A Nyberg, Fredrik %A Stricker, Bruno H %A Uitterlinden, André G %A Hofman, Albert %A Rivadeneira, Fernando %A Emilsson, Valur %A Franco, Oscar H %A Ridker, Paul M %A Gudnason, Vilmundur %A Liu, Yongmei %A Denny, Joshua C %A Ballantyne, Christie M %A Rotter, Jerome I %A Adrienne Cupples, L %A Psaty, Bruce M %A Palmer, Colin N A %A Tardif, Jean-Claude %A Colhoun, Helen M %A Hitman, Graham %A Krauss, Ronald M %A Wouter Jukema, J %A Caulfield, Mark J %K Cholesterol, LDL %K Genome-Wide Association Study %K Humans %K Hydroxymethylglutaryl-CoA Reductase Inhibitors %K Pharmacogenetics %K Polymorphism, Single Nucleotide %X

Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.

%B Nat Commun %V 5 %P 5068 %8 2014 Oct 28 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/25350695?dopt=Abstract %R 10.1038/ncomms6068 %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 Stroke %D 2014 %T Predicting stroke through genetic risk functions: the CHARGE Risk Score Project. %A Ibrahim-Verbaas, Carla A %A Fornage, Myriam %A Bis, Joshua C %A Choi, Seung Hoan %A Psaty, Bruce M %A Meigs, James B %A Rao, Madhu %A Nalls, Mike %A Fontes, João D %A O'Donnell, Christopher J %A Kathiresan, Sekar %A Ehret, Georg B %A Fox, Caroline S %A Malik, Rainer %A Dichgans, Martin %A Schmidt, Helena %A Lahti, Jari %A Heckbert, Susan R %A Lumley, Thomas %A Rice, Kenneth %A Rotter, Jerome I %A Taylor, Kent D %A Folsom, Aaron R %A Boerwinkle, Eric %A Rosamond, Wayne D %A Shahar, Eyal %A Gottesman, Rebecca F %A Koudstaal, Peter J %A Amin, Najaf %A Wieberdink, Renske G %A Dehghan, Abbas %A Hofman, Albert %A Uitterlinden, André G %A DeStefano, Anita L %A Debette, Stephanie %A Xue, Luting %A Beiser, Alexa %A Wolf, Philip A %A DeCarli, Charles %A Ikram, M Arfan %A Seshadri, Sudha %A Mosley, Thomas H %A Longstreth, W T %A van Duijn, Cornelia M %A Launer, Lenore J %K Age Factors %K Aged %K Aged, 80 and over %K Area Under Curve %K Case-Control Studies %K Cohort Studies %K European Continental Ancestry Group %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Regression Analysis %K Risk Factors %K ROC Curve %K Sex Factors %K Stroke %X

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

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

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

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

%B Stroke %V 45 %P 403-12 %8 2014 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24436238?dopt=Abstract %R 10.1161/STROKEAHA.113.003044 %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2014 %T Prognostic implications of microvascular and macrovascular abnormalities in older adults: cardiovascular health study. %A Kim, Dae Hyun %A Grodstein, Francine %A Newman, Anne B %A Chaves, Paulo H M %A Odden, Michelle C %A Klein, Ronald %A Sarnak, Mark J %A Patel, Kushang V %A Lipsitz, Lewis A %K Aged %K Aged, 80 and over %K Aging %K Ankle Brachial Index %K Disability Evaluation %K Electrocardiography %K Female %K Follow-Up Studies %K Forecasting %K Humans %K Life Expectancy %K Magnetic Resonance Imaging %K Male %K Microcirculation %K Prognosis %K Prospective Studies %K Risk Factors %K Vascular Malformations %X

BACKGROUND: Microvascular and macrovascular abnormalities are frequently found on noninvasive tests performed in older adults. Their prognostic implications on disability and life expectancy have not been collectively assessed.

METHODS: This prospective study included 2,452 adults (mean age: 79.5 years) with available measures of microvascular (brain, retina, kidney) and macrovascular abnormalities (brain, carotid, coronary, peripheral artery) in the Cardiovascular Health Study. The burden of microvascular and macrovascular abnormalities was examined in relation to total, activity-of-daily-living disability-free, and severe disability-free life expectancies in the next 10 years (1999-2009).

RESULTS: At 75 years, individuals with low burden of both abnormalities lived, on average, 8.71 years (95% confidence interval: 8.29, 9.12) of which 7.67 years (7.16, 8.17) were without disability. In comparison, individuals with high burden of both abnormalities had shortest total life expectancy (6.95 years [6.52, 7.37]; p < .001) and disability-free life expectancy (5.60 years [5.10, 6.11]; p < .001). Although total life expectancy was similarly reduced for those with high burden of either type of abnormalities (microvascular: 7.96 years [7.50, 8.42] vs macrovascular: 8.25 years [7.80, 8.70]; p = .10), microvascular abnormalities seemed to have larger impact than macrovascular abnormalities on disability-free life expectancy (6.45 years [5.90, 6.99] vs 6.96 years [6.43, 7.48]; p = .016). These results were consistent for severe disability-free life expectancy and in individuals without clinical cardiovascular disease.

CONCLUSIONS: Considering both microvascular and macrovascular abnormalities from multiple noninvasive tests may provide additional prognostic information on how older adults spend their remaining life. Optimal clinical use of this information remains to be determined.

%B J Gerontol A Biol Sci Med Sci %V 69 %P 1495-502 %8 2014 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/24864308?dopt=Abstract %R 10.1093/gerona/glu074 %0 Journal Article %J Circulation %D 2014 %T Racial and regional differences in venous thromboembolism in the United States in 3 cohorts. %A Zakai, Neil A %A McClure, Leslie A %A Judd, Suzanne E %A Safford, Monika M %A Folsom, Aaron R %A Lutsey, Pamela L %A Cushman, Mary %K African Continental Ancestry Group %K Aged %K Cohort Studies %K European Continental Ancestry Group %K Female %K Humans %K Longitudinal Studies %K Male %K Middle Aged %K Prevalence %K Proportional Hazards Models %K Prospective Studies %K Residence Characteristics %K Risk Factors %K United States %K Venous Thromboembolism %X

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

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

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

%B Circulation %V 129 %P 1502-9 %8 2014 Apr 08 %G eng %N 14 %1 http://www.ncbi.nlm.nih.gov/pubmed/24508826?dopt=Abstract %R 10.1161/CIRCULATIONAHA.113.006472 %0 Journal Article %J J Clin Endocrinol Metab %D 2014 %T Ratio of urine albumin to creatinine attenuates the association of dementia with hip fracture risk. %A Bůzková, Petra %A Barzilay, Joshua I %A Fink, Howard A %A Robbins, John A %A Cauley, Jane A %A Fitzpatrick, Annette L %K Aged %K Aged, 80 and over %K Albuminuria %K Creatinine %K Dementia %K Female %K Hip Fractures %K Humans %K Incidence %K Magnetic Resonance Imaging %K Male %K Mild Cognitive Impairment %K Neuropsychological Tests %K Prospective Studies %K Risk %X

CONTEXT: Microvascular disease is a leading cause of cognitive impairment. Approximately 50% of people with a hip fracture have cognitive impairment.

OBJECTIVE: We tested the hypothesis that microvascular diseases of the brain (lacunar infarcts and white matter disease [WMD]), kidney (albuminuria [≥ 30 mg/g creatinine] and albumin creatinine ratio [ACR]), and eye (retinal vascular disorders) attenuate the association of cognitive impairment with hip fracture risk.

SETTING: The Cardiovascular Health Cognition Study.

PATIENTS: Three thousand, one-hundred six participants (mean age, ∼ 79 y; 8.84 y median follow-up) with cognitive testing. Subsets received ACR testing (n=2389), brain magnetic resonance imaging scans (n = 2094), and retinal photography (n = 1098).

MAIN OUTCOME MEASURE: Incident hip fracture.

RESULTS: There were 488 participants (16%) with mild cognitive impairment (MCI) and 564 (18%) with dementia. There were 337 incident hip fractures, of which 19% occurred in participants with MCI and 26% in participants with dementia. Adjusted hazard ratios (HR) and 95% confidence interval for hip fracture in participants with MCI were 2.45 (1.67-3.61) and for dementia 2.35 (1.57-3.52). With doubling of ACR, the HR for fracture was attenuated in participants with dementia compared with participants with normal cognition [interaction HR 0.70 (0.55-0.91)]. No such effect was found in participants with MCI. Albuminuria, lacunar infarcts, WMD, and retinal vascular disease (RVD) did not modify the association of dementia or MCI with hip fracture risk.

CONCLUSIONS: ACR attenuates part of the risk of hip fracture in people with dementia, suggesting that these disorders share a common pathogenesis.

%B J Clin Endocrinol Metab %V 99 %P 4116-23 %8 2014 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/25148233?dopt=Abstract %R 10.1210/jc.2014-2409 %0 Journal Article %J Kidney Int %D 2014 %T Relative risks of chronic kidney disease for mortality and end-stage renal disease across races are similar. %A Wen, Chi Pang %A Matsushita, Kunihiro %A Coresh, Josef %A Iseki, Kunitoshi %A Islam, Muhammad %A Katz, Ronit %A McClellan, William %A Peralta, Carmen A %A Wang, Haiyan %A de Zeeuw, Dick %A Astor, Brad C %A Gansevoort, Ron T %A Levey, Andrew S %A Levin, Adeera %K Adult %K African Continental Ancestry Group %K Aged %K Aged, 80 and over %K Albuminuria %K Asian Continental Ancestry Group %K Cardiovascular Diseases %K Cohort Studies %K Creatinine %K European Continental Ancestry Group %K Female %K Glomerular Filtration Rate %K Humans %K Kidney Failure, Chronic %K Male %K Middle Aged %K Odds Ratio %K Renal Insufficiency, Chronic %K Risk Factors %X

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

%B Kidney Int %V 86 %P 819-27 %8 2014 Oct %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/24522492?dopt=Abstract %R 10.1038/ki.2013.553 %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 PLoS One %D 2014 %T A self-report risk index to predict occurrence of dementia in three independent cohorts of older adults: the ANU-ADRI. %A Anstey, Kaarin J %A Cherbuin, Nicolas %A Herath, Pushpani M %A Qiu, Chengxuan %A Kuller, Lewis H %A Lopez, Oscar L %A Wilson, Robert S %A Fratiglioni, Laura %K Adult %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Dementia %K Female %K Humans %K Incidence %K Male %K Middle Aged %K Risk %K ROC Curve %K Self Report %X

BACKGROUND AND AIMS: The Australian National University AD Risk Index (ANU-ADRI, http://anuadri.anu.edu.au) is a self-report risk index developed using an evidence-based medicine approach to measure risk of Alzheimer's disease (AD). We aimed to evaluate the extent to which the ANU-ADRI can predict the risk of AD in older adults and to compare the ANU-ADRI to the dementia risk index developed from the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study for middle-aged cohorts.

METHODS: This study included three validation cohorts, i.e., the Rush Memory and Aging Study (MAP) (n = 903, age ≥53 years), the Kungsholmen Project (KP) (n = 905, age ≥75 years), and the Cardiovascular Health Cognition Study (CVHS) (n = 2496, age ≥65 years) that were each followed for dementia. Baseline data were collected on exposure to the 15 risk factors included in the ANU-ADRI of which MAP had 10, KP had 8 and CVHS had 9. Risk scores and C-statistics were computed for individual participants for the ANU-ADRI and the CAIDE index.

RESULTS: For the ANU-ADRI using available data, the MAP study c-statistic was 0·637 (95% CI 0·596-0·678), for the KP study it was 0·740 (0·712-0·768) and for the CVHS it was 0·733 (0·691-0·776) for predicting AD. When a common set of risk and protective factors were used c-statistics were 0.689 (95% CI 0.650-0.727), 0.666 (0.628-0.704) and 0.734 (0.707-0.761) for MAP, KP and CVHS respectively. Results for CAIDE ranged from c-statistics of 0.488 (0.427-0.554) to 0.595 (0.565-0.625).

CONCLUSION: A composite risk score derived from the ANU-ADRI weights including 8-10 risk or protective factors is a valid, self-report tool to identify those at risk of AD and dementia. The accuracy can be further improved in studies including more risk factors and younger cohorts with long-term follow-up.

%B PLoS One %V 9 %P e86141 %8 2014 %G eng %N 1 %R 10.1371/journal.pone.0086141 %0 Journal Article %J PLoS One %D 2014 %T Sequence analysis of six blood pressure candidate regions in 4,178 individuals: the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) targeted sequencing study. %A Morrison, Alanna C %A Bis, Joshua C %A Hwang, Shih-Jen %A Ehret, Georg B %A Lumley, Thomas %A Rice, Kenneth %A Muzny, Donna %A Gibbs, Richard A %A Boerwinkle, Eric %A Psaty, Bruce M %A Chakravarti, Aravinda %A Levy, Daniel %K Aging %K Blood Pressure %K Cohort Studies %K Heart %K Humans %K Sequence Analysis %X

BACKGROUND: Genome-wide association studies (GWAS) identified multiple loci for blood pressure (BP) and hypertension. Six genes--ATP2B1, CACNB2, CYP17A1, JAG1, PLEKHA7, and SH2B3--were evaluated for sequence variation with large effects on systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), and mean arterial pressure (MAP).

METHODS AND RESULTS: Targeted genomic sequence was determined in 4,178 European ancestry participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Common variants (≥50 minor allele copies) were evaluated individually and rare variants (minor allele frequency, MAF≤1%) were aggregated by locus. 464 common variants were identified across the 6 genes. An upstream CYP17A1 variant, rs11191416 (MAF = 0.09), was the most significant association for SBP (P = 0.0005); however the association was attenuated (P = 0.0469) after conditioning on the GWAS index single nucleotide polymorphism (SNP). A PLEKHA7 intronic variant was the strongest DBP association (rs12806040, MAF = 0.007, P = 0.0006) and was not in LD (r² = 0.01) with the GWAS SNP. A CACNB2 intronic SNP, rs1571787, was the most significant association with PP (MAF = 0.27, P = 0.0003), but was not independent from the GWAS SNP (r² = 0.34). Three variants (rs6163 and rs743572 in the CYP17A1 region and rs112467382 in PLEKHA7) were associated with BP traits (P<0.001). Rare variation, aggregately assessed in the 6 regions, was not significantly associated with BP measures.

CONCLUSION: Six targeted gene regions, previously identified by GWAS, did not harbor novel variation with large effects on BP in this sample.

%B PLoS One %V 9 %P e109155 %8 2014 %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/25275628?dopt=Abstract %R 10.1371/journal.pone.0109155 %0 Journal Article %J Circ Cardiovasc Genet %D 2014 %T Sequence variation in TMEM18 in association with body mass index: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. %A Liu, Ching-Ti %A Young, Kristin L %A Brody, Jennifer A %A Olden, Matthias %A Wojczynski, Mary K %A Heard-Costa, Nancy %A Li, Guo %A Morrison, Alanna C %A Muzny, Donna %A Gibbs, Richard A %A Reid, Jeffrey G %A Shao, Yaming %A Zhou, Yanhua %A Boerwinkle, Eric %A Heiss, Gerardo %A Wagenknecht, Lynne %A McKnight, Barbara %A Borecki, Ingrid B %A Fox, Caroline S %A North, Kari E %A Cupples, L Adrienne %K Adult %K Aged %K Aging %K Body Mass Index %K Cohort Studies %K Female %K Genetic Association Studies %K Genetic Variation %K Genome-Wide Association Study %K Genomics %K Heart Diseases %K Humans %K Male %K Membrane Proteins %K Middle Aged %K Polymorphism, Single Nucleotide %K Sequence Analysis, DNA %K Young Adult %X

BACKGROUND: Genome-wide association studies for body mass index (BMI) previously identified a locus near TMEM18. We conducted targeted sequencing of this region to investigate the role of common, low-frequency, and rare variants influencing BMI.

METHODS AND RESULTS: We sequenced TMEM18 and regions downstream of TMEM18 on chromosome 2 in 3976 individuals of European ancestry from 3 community-based cohorts (Atherosclerosis Risk in Communities, Cardiovascular Health Study, and Framingham Heart Study), including 200 adults selected for high BMI. We examined the association between BMI and variants identified in the region from nucleotide position 586 432 to 677 539 (hg18). Rare variants (minor allele frequency, <1%) were analyzed using a burden test and the sequence kernel association test. Results from the 3 cohort studies were meta-analyzed. We estimate that mean BMI is 0.43 kg/m(2) higher for each copy of the G allele of single-nucleotide polymorphism rs7596758 (minor allele frequency, 29%; P=3.46×10(-4)) using a Bonferroni threshold of P<4.6×10(-4). Analyses conditional on previous genome-wide association study single-nucleotide polymorphisms associated with BMI in the region led to attenuation of this signal and uncovered another independent (r(2)<0.2), statistically significant association, rs186019316 (P=2.11×10(-4)). Both rs186019316 and rs7596758 or proxies are located in transcription factor binding regions. No significant association with rare variants was found in either the exons of TMEM18 or the 3' genome-wide association study region.

CONCLUSIONS: Targeted sequencing around TMEM18 identified 2 novel BMI variants with possible regulatory function.

%B Circ Cardiovasc Genet %V 7 %P 344-9 %8 2014 Jun %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/24951660?dopt=Abstract %R 10.1161/CIRCGENETICS.13.000067 %0 Journal Article %J Circ Cardiovasc Genet %D 2014 %T Sequencing of 2 subclinical atherosclerosis candidate regions in 3669 individuals: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. %A Bis, Joshua C %A White, Charles C %A Franceschini, Nora %A Brody, Jennifer %A Zhang, Xiaoling %A Muzny, Donna %A Santibanez, Jireh %A Gibbs, Richard %A Liu, Xiaoming %A Lin, Honghuang %A Boerwinkle, Eric %A Psaty, Bruce M %A North, Kari E %A Cupples, L Adrienne %A O'Donnell, Christopher J %K Aged %K Aged, 80 and over %K Aging %K Atherosclerosis %K Class Ib Phosphatidylinositol 3-Kinase %K Cohort Studies %K European Continental Ancestry Group %K Female %K Genetic Variation %K Genome-Wide Association Study %K Genomics %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Sequence Analysis, DNA %K Sodium-Phosphate Cotransporter Proteins, Type I %X

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

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

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

%B Circ Cardiovasc Genet %V 7 %P 359-64 %8 2014 Jun %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/24951662?dopt=Abstract %R 10.1161/CIRCGENETICS.113.000116 %0 Journal Article %J Circ Cardiovasc Genet %D 2014 %T Sequencing of SCN5A identifies rare and common variants associated with cardiac conduction: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. %A Magnani, Jared W %A Brody, Jennifer A %A Prins, Bram P %A Arking, Dan E %A Lin, Honghuang %A Yin, Xiaoyan %A Liu, Ching-Ti %A Morrison, Alanna C %A Zhang, Feng %A Spector, Tim D %A Alonso, Alvaro %A Bis, Joshua C %A Heckbert, Susan R %A Lumley, Thomas %A Sitlani, Colleen M %A Cupples, L Adrienne %A Lubitz, Steven A %A Soliman, Elsayed Z %A Pulit, Sara L %A Newton-Cheh, Christopher %A O'Donnell, Christopher J %A Ellinor, Patrick T %A Benjamin, Emelia J %A Muzny, Donna M %A Gibbs, Richard A %A Santibanez, Jireh %A Taylor, Herman A %A Rotter, Jerome I %A Lange, Leslie A %A Psaty, Bruce M %A Jackson, Rebecca %A Rich, Stephen S %A Boerwinkle, Eric %A Jamshidi, Yalda %A Sotoodehnia, Nona %K Adult %K Aged %K Aged, 80 and over %K Aging %K Cohort Studies %K Female %K Genetic Variation %K Genome-Wide Association Study %K Genomics %K Heart Conduction System %K Heart Diseases %K Humans %K Male %K Middle Aged %K NAV1.5 Voltage-Gated Sodium Channel %K Polymorphism, Single Nucleotide %K Sequence Analysis, DNA %X

BACKGROUND: The cardiac sodium channel SCN5A regulates atrioventricular and ventricular conduction. Genetic variants in this gene are associated with PR and QRS intervals. We sought to characterize further the contribution of rare and common coding variation in SCN5A to cardiac conduction.

METHODS AND RESULTS: In Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study, we performed targeted exonic sequencing of SCN5A (n=3699, European ancestry individuals) and identified 4 common (minor allele frequency >1%) and 157 rare variants. Common and rare SCN5A coding variants were examined for association with PR and QRS intervals through meta-analysis of European ancestry participants from CHARGE, National Heart, Lung, and Blood Institute's Exome Sequencing Project (n=607), and the UK10K (n=1275) and by examining Exome Sequencing Project African ancestry participants (n=972). Rare coding SCN5A variants in aggregate were associated with PR interval in European and African ancestry participants (P=1.3×10(-3)). Three common variants were associated with PR and QRS interval duration among European ancestry participants and one among African ancestry participants. These included 2 well-known missense variants: rs1805124 (H558R) was associated with PR and QRS shortening in European ancestry participants (P=6.25×10(-4) and P=5.2×10(-3), respectively) and rs7626962 (S1102Y) was associated with PR shortening in those of African ancestry (P=2.82×10(-3)). Among European ancestry participants, 2 novel synonymous variants, rs1805126 and rs6599230, were associated with cardiac conduction. Our top signal, rs1805126 was associated with PR and QRS lengthening (P=3.35×10(-7) and P=2.69×10(-4), respectively) and rs6599230 was associated with PR shortening (P=2.67×10(-5)).

CONCLUSIONS: By sequencing SCN5A, we identified novel common and rare coding variants associated with cardiac conduction.

%B Circ Cardiovasc Genet %V 7 %P 365-73 %8 2014 Jun %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/24951663?dopt=Abstract %R 10.1161/CIRCGENETICS.113.000098 %0 Journal Article %J Stroke %D 2014 %T Shared genetic susceptibility to ischemic stroke and coronary artery disease: a genome-wide analysis of common variants. %A Dichgans, Martin %A Malik, Rainer %A König, Inke R %A Rosand, Jonathan %A Clarke, Robert %A Gretarsdottir, Solveig %A Thorleifsson, Gudmar %A Mitchell, Braxton D %A Assimes, Themistocles L %A Levi, Christopher %A O'Donnell, Christopher J %A Fornage, Myriam %A Thorsteinsdottir, Unnur %A Psaty, Bruce M %A Hengstenberg, Christian %A Seshadri, Sudha %A Erdmann, Jeanette %A Bis, Joshua C %A Peters, Annette %A Boncoraglio, Giorgio B %A März, Winfried %A Meschia, James F %A Kathiresan, Sekar %A Ikram, M Arfan %A McPherson, Ruth %A Stefansson, Kari %A Sudlow, Cathie %A Reilly, Muredach P %A Thompson, John R %A Sharma, Pankaj %A Hopewell, Jemma C %A Chambers, John C %A Watkins, Hugh %A Rothwell, Peter M %A Roberts, Robert %A Markus, Hugh S %A Samani, Nilesh J %A Farrall, Martin %A Schunkert, Heribert %K Brain Ischemia %K Coronary Artery Disease %K Data Interpretation, Statistical %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Phenotype %K Polymorphism, Single Nucleotide %K Reproducibility of Results %K Risk Factors %K Stroke %X

BACKGROUND AND PURPOSE: Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each has a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases.

METHODS: Genome-wide association data were obtained from the METASTROKE, Coronary Artery Disease Genome-wide Replication and Meta-analysis (CARDIoGRAM), and Coronary Artery Disease (C4D) Genetics consortia. We first analyzed common variants reaching a nominal threshold of significance (P<0.01) for CAD for their association with IS and vice versa. We then examined specific overlap across phenotypes for variants that reached a high threshold of significance. Finally, we conducted a joint meta-analysis on the combined phenotype of IS or CAD. Corresponding analyses were performed restricted to the 2167 individuals with the ischemic large artery stroke (LAS) subtype.

RESULTS: Common variants associated with CAD at P<0.01 were associated with a significant excess risk for IS and for LAS and vice versa. Among the 42 known genome-wide significant loci for CAD, 3 and 5 loci were significantly associated with IS and LAS, respectively. In the joint meta-analyses, 15 loci passed genome-wide significance (P<5×10(-8)) for the combined phenotype of IS or CAD and 17 loci passed genome-wide significance for LAS or CAD. Because these loci had prior evidence for genome-wide significance for CAD, we specifically analyzed the respective signals for IS and LAS and found evidence for association at chr12q24/SH2B3 (PIS=1.62×10(-7)) and ABO (PIS=2.6×10(-4)), as well as at HDAC9 (PLAS=2.32×10(-12)), 9p21 (PLAS=3.70×10(-6)), RAI1-PEMT-RASD1 (PLAS=2.69×10(-5)), EDNRA (PLAS=7.29×10(-4)), and CYP17A1-CNNM2-NT5C2 (PLAS=4.9×10(-4)).

CONCLUSIONS: Our results demonstrate substantial overlap in the genetic risk of IS and particularly the LAS subtype with CAD.

%B Stroke %V 45 %P 24-36 %8 2014 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/24262325?dopt=Abstract %R 10.1161/STROKEAHA.113.002707 %0 Journal Article %J Diabetologia %D 2014 %T Sleep duration does not mediate or modify association of common genetic variants with type 2 diabetes. %A Tare, Archana %A Lane, Jacqueline M %A Cade, Brian E %A Grant, Struan F A %A Chen, Ting-Hsu %A Punjabi, Naresh M %A Lauderdale, Diane S %A Zee, Phyllis C %A Gharib, Sina A %A Gottlieb, Daniel J %A Scheer, Frank A J L %A Redline, Susan %A Saxena, Richa %K Blood Glucose %K Body Composition %K Body Mass Index %K Cross-Sectional Studies %K Diabetes Mellitus, Type 2 %K European Continental Ancestry Group %K Fasting %K Female %K Genetic Predisposition to Disease %K Genetic Variation %K Genotype %K Glucose Intolerance %K Glycated Hemoglobin A %K Humans %K Insulin Resistance %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Risk Factors %K Sleep %K Surveys and Questionnaires %K Time Factors %K United States %X

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

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

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

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

%B Diabetologia %V 57 %P 339-46 %8 2014 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24280871?dopt=Abstract %R 10.1007/s00125-013-3110-y %0 Journal Article %J Circ Cardiovasc Genet %D 2014 %T Strategies to design and analyze targeted sequencing data: cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. %A Lin, Honghuang %A Wang, Min %A Brody, Jennifer A %A Bis, Joshua C %A Dupuis, Josée %A Lumley, Thomas %A McKnight, Barbara %A Rice, Kenneth M %A Sitlani, Colleen M %A Reid, Jeffrey G %A Bressler, Jan %A Liu, Xiaoming %A Davis, Brian C %A Johnson, Andrew D %A O'Donnell, Christopher J %A Kovar, Christie L %A Dinh, Huyen %A Wu, Yuanqing %A Newsham, Irene %A Chen, Han %A Broka, Andi %A DeStefano, Anita L %A Gupta, Mayetri %A Lunetta, Kathryn L %A Liu, Ching-Ti %A White, Charles C %A Xing, Chuanhua %A Zhou, Yanhua %A Benjamin, Emelia J %A Schnabel, Renate B %A Heckbert, Susan R %A Psaty, Bruce M %A Muzny, Donna M %A Cupples, L Adrienne %A Morrison, Alanna C %A Boerwinkle, Eric %K Adult %K Aged %K Aged, 80 and over %K Aging %K Cohort Studies %K Female %K Genetic Variation %K Genome-Wide Association Study %K Genomics %K Heart Diseases %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Research Design %K Sequence Analysis, DNA %X

BACKGROUND: Genome-wide association studies have identified thousands of genetic variants that influence a variety of diseases and health-related quantitative traits. However, the causal variants underlying the majority of genetic associations remain unknown. Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study aims to follow up genome-wide association study signals and identify novel associations of the allelic spectrum of identified variants with cardiovascular-related traits.

METHODS AND RESULTS: The study included 4231 participants from 3 CHARGE cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, and the Framingham Heart Study. We used a case-cohort design in which we selected both a random sample of participants and participants with extreme phenotypes for each of 14 traits. We sequenced and analyzed 77 genomic loci, which had previously been associated with ≥1 of 14 phenotypes. A total of 52 736 variants were characterized by sequencing and passed our stringent quality control criteria. For common variants (minor allele frequency ≥1%), we performed unweighted regression analyses to obtain P values for associations and weighted regression analyses to obtain effect estimates that accounted for the sampling design. For rare variants, we applied 2 approaches: collapsed aggregate statistics and joint analysis of variants using the sequence kernel association test.

CONCLUSIONS: We sequenced 77 genomic loci in participants from 3 cohorts. We established a set of filters to identify high-quality variants and implemented statistical and bioinformatics strategies to analyze the sequence data and identify potentially functional variants within genome-wide association study loci.

%B Circ Cardiovasc Genet %V 7 %P 335-43 %8 2014 Jun %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/24951659?dopt=Abstract %R 10.1161/CIRCGENETICS.113.000350 %0 Journal Article %J J Clin Endocrinol Metab %D 2014 %T Subclinical hypothyroidism, weight change, and body composition in the elderly: the Cardiovascular Health Study. %A Garin, Margaret C %A Arnold, Alice M %A Lee, Jennifer S %A Tracy, Russell P %A Cappola, Anne R %K Aged %K Aged, 80 and over %K Asymptomatic Diseases %K Body Composition %K Body Mass Index %K Cohort Studies %K Female %K Humans %K Hypothyroidism %K Male %K Thyroid Gland %K Weight Loss %X

BACKGROUND: Subclinical hypothyroidism is common in the elderly, yet its relationship with weight and body composition is unclear.

OBJECTIVE: We examined the relationship between subclinical hypothyroidism and weight change and body composition in older adults.

METHODS: A total of 427 subclinically hypothyroid and 2864 euthyroid U.S. individuals ≥65 years old enrolled in the Cardiovascular Health Study and not taking thyroid preparations were included. Analyses of 6-year weight change were performed, compared by thyroid status. A cross-sectional analysis of thyroid status and body composition was performed in a subset of 1276 participants who had dual-energy x-ray absorptiometry scans. Models were risk factor-adjusted and stratified by sex.

RESULTS: Overall, participants lost weight during follow-up (-0.38 kg/y in men, -0.37 kg/y in women). Subclinical hypothyroidism, when assessed at a single time point or persisting over 2 years, was not associated with a difference in weight change compared with euthyroidism. Subclinical hypothyroidism was also not associated with differences in lean mass, fat mass, or percent fat compared with euthyroidism. A TSH level 1 mU/L higher within the euthyroid or subclinical hypothyroid range was associated with a 0.51-kg higher baseline weight in women only (P < .001) but not with weight change in either sex. A 1 ng/dL higher free T4 level was associated with lower baseline weight and 0.32 kg/y greater weight loss in women only (P = .003). Baseline weight and weight change did not differ by T3 levels.

CONCLUSIONS: Our data do not support a clinically significant impact of subclinical hypothyroidism on weight status in the elderly.

%B J Clin Endocrinol Metab %V 99 %P 1220-6 %8 2014 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/24432998?dopt=Abstract %R 10.1210/jc.2013-3591 %0 Journal Article %J J Clin Endocrinol Metab %D 2014 %T Subclinical thyroid dysfunction and hip fracture and bone mineral density in older adults: the cardiovascular health study. %A Garin, Margaret C %A Arnold, Alice M %A Lee, Jennifer S %A Robbins, John %A Cappola, Anne R %K Absorptiometry, Photon %K Aged %K Aged, 80 and over %K Asymptomatic Diseases %K Bone Density %K Cardiovascular System %K Cohort Studies %K Cross-Sectional Studies %K Female %K Hip Fractures %K Humans %K Male %K Osteoporotic Fractures %K Risk Factors %K Sex Factors %K Thyroid Diseases %X

BACKGROUND: Subclinical thyroid dysfunction is common in the elderly, yet its relationship with hip fracture and bone mineral density (BMD) is unclear.

OBJECTIVE: We examined the association between endogenous subclinical hyper- and hypothyroidism and hip fracture and BMD in older adults.

METHODS: A total of 4936 US individuals 65 years old or older enrolled in the Cardiovascular Health Study and not taking thyroid preparations were included. Analyses of incident hip fracture were performed by thyroid status, over a median follow-up of 12 years. A cross-sectional analysis of thyroid status and BMD was performed in a subset of 1317 participants who had dual-energy x-ray absorptiometry scans. Models were adjusted for risk factors and stratified by sex.

RESULTS: No association was found between subclinical hypothyroidism and incident hip fracture compared with euthyroidism, when assessed at a single time point or persisting at two time points, in either women [hazard ratio (HR) 0.91, 95% confidence interval (CI) 0.69-1.20 for a single and HR 0.79, 95% CI 0.52-1.21 for two time points] or men (HR 1.27, 95% CI 0.82-1.95 for a single and HR 1.09, 95% CI 0.57-2.10 for two time points). Likewise, no association was found between subclinical hyperthyroidism and incident hip fracture in either sex (HR 1.11, 95% CI 0.55-2.25 in women and HR 1.78, 95% CI 0.56-5.66 in men). No association was found between subclinical thyroid dysfunction and BMD at the lumbar spine, total hip, or femoral neck sites.

CONCLUSIONS: Our data suggest no association between subclinical hypothyroidism or subclinical hyperthyroidism and hip fracture risk or BMD in older men and women. Additional data are needed to improve the precision of estimates for subclinical hyperthyroidism and in men.

%B J Clin Endocrinol Metab %V 99 %P 2657-64 %8 2014 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/24878045?dopt=Abstract %R 10.1210/jc.2014-1051 %0 Journal Article %J Heart Rhythm %D 2014 %T Targeted sequencing in candidate genes for atrial fibrillation: the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study. %A Lin, Honghuang %A Sinner, Moritz F %A Brody, Jennifer A %A Arking, Dan E %A Lunetta, Kathryn L %A Rienstra, Michiel %A Lubitz, Steven A %A Magnani, Jared W %A Sotoodehnia, Nona %A McKnight, Barbara %A McManus, David D %A Boerwinkle, Eric %A Psaty, Bruce M %A Rotter, Jerome I %A Bis, Joshua C %A Gibbs, Richard A %A Muzny, Donna %A Kovar, Christie L %A Morrison, Alanna C %A Gupta, Mayetri %A Folsom, Aaron R %A Kääb, Stefan %A Heckbert, Susan R %A Alonso, Alvaro %A Ellinor, Patrick T %A Benjamin, Emelia J %K Aged %K Atrial Fibrillation %K Female %K Genetic Predisposition to Disease %K Genetic Variation %K Genome-Wide Association Study %K Homeodomain Proteins %K Humans %K Linkage Disequilibrium %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Receptors, Interleukin-6 %X

BACKGROUND: Genome-wide association studies (GWAS) have identified common genetic variants that predispose to atrial fibrillation (AF). It is unclear whether rare and low-frequency variants in genes implicated by such GWAS confer additional risk of AF.

OBJECTIVE: To study the association of genetic variants with AF at GWAS top loci.

METHODS: In the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study, we selected and sequenced 77 target gene regions from GWAS loci of complex diseases or traits, including 4 genes hypothesized to be related to AF (PRRX1, CAV1, CAV2, and ZFHX3). Sequencing was performed in participants with (n = 948) and without (n = 3330) AF from the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Massachusetts General Hospital.

RESULTS: One common variant (rs11265611; P = 1.70 × 10(-6)) intronic to IL6R (interleukin-6 receptor gene) was significantly associated with AF after Bonferroni correction (odds ratio 0.70; 95% confidence interval 0.58-0.85). The variant was not genotyped or imputed by prior GWAS, but it is in linkage disequilibrium (r(2) = .69) with the single-nucleotide polymorphism, with the strongest association with AF so far at this locus (rs4845625). In the rare variant joint analysis, damaging variants within the PRRX1 region showed significant association with AF after Bonferroni correction (P = .01).

CONCLUSIONS: We identified 1 common single-nucleotide polymorphism and 1 gene region that were significantly associated with AF. Future sequencing efforts with larger sample sizes and more comprehensive genome coverage are anticipated to identify additional AF-related variants.

%B Heart Rhythm %V 11 %P 452-7 %8 2014 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/24239840?dopt=Abstract %R 10.1016/j.hrthm.2013.11.012 %0 Journal Article %J Clin Endocrinol (Oxf) %D 2014 %T Testosterone and dihydrotestosterone and incident ischaemic stroke in men in the Cardiovascular Health Study. %A Shores, Molly M %A Arnold, Alice M %A Biggs, Mary L %A Longstreth, W T %A Smith, Nicholas L %A Kizer, Jorge R %A Cappola, Anne R %A Hirsch, Calvin H %A Marck, Brett T %A Matsumoto, Alvin M %K Aged %K Aged, 80 and over %K Brain Ischemia %K Cardiovascular Physiological Phenomena %K Dihydrotestosterone %K Health %K Humans %K Incidence %K Longitudinal Studies %K Male %K Stroke %K Testosterone %X

OBJECTIVE: Ischaemic stroke is a major cause of morbidity and mortality in elderly men. Our main objective was to examine whether testosterone (T) or dihydrotestosterone (DHT) was associated with incident ischaemic stroke in elderly men.

DESIGN: Cohort study.

PARTICIPANTS: Elderly men in the Cardiovascular Health Study who had no history of stroke, heart disease or prostate cancer as of 1994 and were followed until December 2010.

MEASUREMENTS: Adjudicated ischaemic stroke.

RESULTS: Among 1032 men (mean age 76, range 66-97), followed for a median of 10 years, 114 had an incident ischaemic stroke. Total T and free T were not significantly associated with stroke risk, while DHT had a nonlinear association with incident stroke (P = 0·006) in analyses adjusted for stroke risk factors. The lowest risk of stroke was at DHT levels of 50-75 ng/dl, with greater risk of stroke at DHT levels above 75 ng/dl or below 50 ng/dl. Results were unchanged when SHBG was added to the model. Calculated free DHT had an inverse linear association with incident ischaemic stroke with HR 0·77 (95% CI, 0·61, 0·98) per standard deviation in analyses adjusted for stroke risk factors.

CONCLUSIONS: Dihydrotestosterone had a nonlinear association with stroke risk in which there was an optimal DHT level associated with the lowest stroke risk. Further studies are needed to confirm these results and to clarify whether there is an optimal androgen range associated with the least risk of adverse outcomes in elderly men.

%B Clin Endocrinol (Oxf) %V 81 %P 746-53 %8 2014 Nov %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/24645738?dopt=Abstract %R 10.1111/cen.12452 %0 Journal Article %J J Clin Endocrinol Metab %D 2014 %T Testosterone, dihydrotestosterone, and incident cardiovascular disease and mortality in the cardiovascular health study. %A Shores, Molly M %A Biggs, Mary L %A Arnold, Alice M %A Smith, Nicholas L %A Longstreth, W T %A Kizer, Jorge R %A Hirsch, Calvin H %A Cappola, Anne R %A Matsumoto, Alvin M %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Cause of Death %K Dihydrotestosterone %K Humans %K Incidence %K Longitudinal Studies %K Male %K Mortality %K Residence Characteristics %K Risk Factors %K Testosterone %X

CONTEXT: Low testosterone (T) is associated with prevalent cardiovascular disease (CVD) and mortality. DHT, a more potent androgen, may also be associated with CVD and mortality, but few studies have examined this.

OBJECTIVE: The study objective was to examine whether T and DHT are risk factors for incident CVD and mortality.

DESIGN: In a longitudinal cohort study, we evaluated whether total T, calculated free T (cFT), DHT, and calculated free DHT were associated with incident CVD and mortality in men in the Cardiovascular Health Study (mean age 76, range 66-97 years) who were free of CVD at the time of blood collection.

MAIN OUTCOME: The main outcomes were incident CVD and all-cause mortality.

RESULTS: Among 1032 men followed for a median of 9 years, 436 incident CVD events and 777 deaths occurred. In models adjusted for cardiovascular risk factors, total T and cFT were not associated with incident CVD or all-cause mortality, whereas DHT and calculated free DHT had curvilinear associations with incident CVD (P < .002 and P = .04, respectively) and all-cause mortality (P < .001 for both).

CONCLUSIONS: In a cohort of elderly men, DHT and calculated free DHT were associated with incident CVD and all-cause mortality. Further studies are needed to confirm these results and to clarify the underlying physiologic mechanisms.

%B J Clin Endocrinol Metab %V 99 %P 2061-8 %8 2014 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/24628549?dopt=Abstract %R 10.1210/jc.2013-3576 %0 Journal Article %J J Clin Endocrinol Metab %D 2014 %T Thyroid antibody status, subclinical hypothyroidism, and the risk of coronary heart disease: an individual participant data analysis. %A Collet, Tinh-Hai %A Bauer, Douglas C %A Cappola, Anne R %A Asvold, Bjørn O %A Weiler, Stefan %A Vittinghoff, Eric %A Gussekloo, Jacobijn %A Bremner, Alexandra %A den Elzen, Wendy P J %A Maciel, Rui M B %A Vanderpump, Mark P J %A Cornuz, Jacques %A Dörr, Marcus %A Wallaschofski, Henri %A Newman, Anne B %A Sgarbi, José A %A Razvi, Salman %A Völzke, Henry %A Walsh, John P %A Aujesky, Drahomir %A Rodondi, Nicolas %K Adult %K Aged %K Aged, 80 and over %K Autoantibodies %K Coronary Disease %K Female %K Humans %K Hypothyroidism %K Incidence %K Male %K Middle Aged %K Prevalence %K Prognosis %K Risk Factors %K Seroepidemiologic Studies %K Severity of Illness Index %K Young Adult %X

CONTEXT: Subclinical hypothyroidism has been associated with increased risk of coronary heart disease (CHD), particularly with thyrotropin levels of 10.0 mIU/L or greater. The measurement of thyroid antibodies helps predict the progression to overt hypothyroidism, but it is unclear whether thyroid autoimmunity independently affects CHD risk.

OBJECTIVE: The objective of the study was to compare the CHD risk of subclinical hypothyroidism with and without thyroid peroxidase antibodies (TPOAbs).

DATA SOURCES AND STUDY SELECTION: A MEDLINE and EMBASE search from 1950 to 2011 was conducted for prospective cohorts, reporting baseline thyroid function, antibodies, and CHD outcomes.

DATA EXTRACTION: Individual data of 38 274 participants from six cohorts for CHD mortality followed up for 460 333 person-years and 33 394 participants from four cohorts for CHD events.

DATA SYNTHESIS: Among 38 274 adults (median age 55 y, 63% women), 1691 (4.4%) had subclinical hypothyroidism, of whom 775 (45.8%) had positive TPOAbs. During follow-up, 1436 participants died of CHD and 3285 had CHD events. Compared with euthyroid individuals, age- and gender-adjusted risks of CHD mortality in subclinical hypothyroidism were similar among individuals with and without TPOAbs [hazard ratio (HR) 1.15, 95% confidence interval (CI) 0.87-1.53 vs HR 1.26, CI 1.01-1.58, P for interaction = .62], as were risks of CHD events (HR 1.16, CI 0.87-1.56 vs HR 1.26, CI 1.02-1.56, P for interaction = .65). Risks of CHD mortality and events increased with higher thyrotropin, but within each stratum, risks did not differ by TPOAb status.

CONCLUSIONS: CHD risk associated with subclinical hypothyroidism did not differ by TPOAb status, suggesting that biomarkers of thyroid autoimmunity do not add independent prognostic information for CHD outcomes.

%B J Clin Endocrinol Metab %V 99 %P 3353-62 %8 2014 Sep %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/24915118?dopt=Abstract %R 10.1210/jc.2014-1250 %0 Journal Article %J Hum Mol Genet %D 2014 %T Trans-ethnic meta-analysis of white blood cell phenotypes. %A Keller, Margaux F %A Reiner, Alexander P %A Okada, Yukinori %A van Rooij, Frank J A %A Johnson, Andrew D %A Chen, Ming-Huei %A Smith, Albert V %A Morris, Andrew P %A Tanaka, Toshiko %A Ferrucci, Luigi %A Zonderman, Alan B %A Lettre, Guillaume %A Harris, Tamara %A Garcia, Melissa %A Bandinelli, Stefania %A Qayyum, Rehan %A Yanek, Lisa R %A Becker, Diane M %A Becker, Lewis C %A Kooperberg, Charles %A Keating, Brendan %A Reis, Jared %A Tang, Hua %A Boerwinkle, Eric %A Kamatani, Yoichiro %A Matsuda, Koichi %A Kamatani, Naoyuki %A Nakamura, Yusuke %A Kubo, Michiaki %A Liu, Simin %A Dehghan, Abbas %A Felix, Janine F %A Hofman, Albert %A Uitterlinden, André G %A van Duijn, Cornelia M %A Franco, Oscar H %A Longo, Dan L %A Singleton, Andrew B %A Psaty, Bruce M %A Evans, Michelle K %A Cupples, L Adrienne %A Rotter, Jerome I %A O'Donnell, Christopher J %A Takahashi, Atsushi %A Wilson, James G %A Ganesh, Santhi K %A Nalls, Mike A %K African Americans %K Asian Continental Ancestry Group %K Bayes Theorem %K European Continental Ancestry Group %K Genome, Human %K Genome-Wide Association Study %K Genotype %K Humans %K Leukocyte Count %K Leukocytes %K Linkage Disequilibrium %K Phenotype %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %X

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

%B Hum Mol Genet %V 23 %P 6944-60 %8 2014 Dec 20 %G eng %N 25 %1 http://www.ncbi.nlm.nih.gov/pubmed/25096241?dopt=Abstract %R 10.1093/hmg/ddu401 %0 Journal Article %J Vasc Med %D 2014 %T Troponin T, NT-proBNP, and venous thromboembolism: the Longitudinal Investigation of Thromboembolism Etiology (LITE). %A Folsom, Aaron R %A Lutsey, Pamela L %A Nambi, Vijay %A deFilippi, Christopher R %A Heckbert, Susan R %A Cushman, Mary %A Ballantyne, Christie M %K Aged %K Aged, 80 and over %K Atherosclerosis %K Biomarkers %K Female %K Heart Failure %K Humans %K Incidence %K Longitudinal Studies %K Male %K Middle Aged %K Natriuretic Peptide, Brain %K Peptide Fragments %K Prospective Studies %K Risk Factors %K Troponin T %K Venous Thromboembolism %X

Increased levels of plasma troponins and natriuretic peptides are markers of cardiac dysfunction associated with increased risk of cardiovascular disease. Little information exists on cardiac dysfunction and occurrence of venous thromboembolism (VTE). In two prospective epidemiological cohorts, we tested the hypothesis that high-sensitivity troponin T (TnT) and N-terminal pro B-type natriuretic peptide (NT-proBNP) are associated positively with VTE occurrence. The Atherosclerosis Risk in Communities (ARIC) study and the Cardiovascular Health Study (CHS) measured plasma TnT and NT-proBNP in 13,719 men or women with no history of venous thrombosis, coronary heart disease, or heart failure and followed them for approximately 10 years for VTE occurrence (n = 348 VTEs). In both ARIC and CHS, TnT was associated positively with incidence of total VTE and provoked VTE, but not with unprovoked VTE: age, race, and sex-adjusted hazard ratios for total VTE in the pooled analysis were 1.00, 0.85, 1.36, 1.51, and 1.98 (p-trend <0.0001) across five categories of TnT. In contrast, the association of NT-proBNP with VTE was positive in ARIC (hazard ratios approximately 2.5-fold for the highest versus lowest NT-proBNP quintiles), but non-existent in CHS.

%B Vasc Med %V 19 %P 33-41 %8 2014 Feb %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/24558027?dopt=Abstract %R 10.1177/1358863X14520869 %0 Journal Article %J Neurology %D 2014 %T Vitamin D and the risk of dementia and Alzheimer disease. %A Littlejohns, Thomas J %A Henley, William E %A Lang, Iain A %A Annweiler, Cedric %A Beauchet, Olivier %A Chaves, Paulo H M %A Fried, Linda %A Kestenbaum, Bryan R %A Kuller, Lewis H %A Langa, Kenneth M %A Lopez, Oscar L %A Kos, Katarina %A Soni, Maya %A Llewellyn, David J %K Aged %K Alzheimer Disease %K Dementia %K Female %K Follow-Up Studies %K Humans %K Incidence %K Male %K Proportional Hazards Models %K Risk Factors %K United States %K Vitamin D %K Vitamin D Deficiency %X

OBJECTIVE: To determine whether low vitamin D concentrations are associated with an increased risk of incident all-cause dementia and Alzheimer disease.

METHODS: One thousand six hundred fifty-eight elderly ambulatory adults free from dementia, cardiovascular disease, and stroke who participated in the US population-based Cardiovascular Health Study between 1992-1993 and 1999 were included. Serum 25-hydroxyvitamin D (25(OH)D) concentrations were determined by liquid chromatography-tandem mass spectrometry from blood samples collected in 1992-1993. Incident all-cause dementia and Alzheimer disease status were assessed during follow-up using National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association criteria.

RESULTS: During a mean follow-up of 5.6 years, 171 participants developed all-cause dementia, including 102 cases of Alzheimer disease. Using Cox proportional hazards models, the multivariate adjusted hazard ratios (95% confidence interval [CI]) for incident all-cause dementia in participants who were severely 25(OH)D deficient (<25 nmol/L) and deficient (≥25 to <50 nmol/L) were 2.25 (95% CI: 1.23-4.13) and 1.53 (95% CI: 1.06-2.21) compared to participants with sufficient concentrations (≥50 nmol/L). The multivariate adjusted hazard ratios for incident Alzheimer disease in participants who were severely 25(OH)D deficient and deficient compared to participants with sufficient concentrations were 2.22 (95% CI: 1.02-4.83) and 1.69 (95% CI: 1.06-2.69). In multivariate adjusted penalized smoothing spline plots, the risk of all-cause dementia and Alzheimer disease markedly increased below a threshold of 50 nmol/L.

CONCLUSION: Our results confirm that vitamin D deficiency is associated with a substantially increased risk of all-cause dementia and Alzheimer disease. This adds to the ongoing debate about the role of vitamin D in nonskeletal conditions.

%B Neurology %V 83 %P 920-8 %8 2014 Sep 2 %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/25098535?dopt=Abstract %R 10.1212/WNL.0000000000000755 %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 JAMA %D 2015 %T Association between hospitalization for pneumonia and subsequent risk of cardiovascular disease. %A Corrales-Medina, Vicente F %A Alvarez, Karina N %A Weissfeld, Lisa A %A Angus, Derek C %A Chirinos, Julio A %A Chang, Chung-Chou H %A Newman, Anne %A Loehr, Laura %A Folsom, Aaron R %A Elkind, Mitchell S %A Lyles, Mary F %A Kronmal, Richard A %A Yende, Sachin %K Aged %K Atherosclerosis %K Cardiovascular Diseases %K Cohort Studies %K Comorbidity %K Female %K Hospitalization %K Humans %K Male %K Middle Aged %K Pneumonia %K Risk Factors %X

IMPORTANCE: The risk of cardiovascular disease (CVD) after infection is poorly understood.

OBJECTIVE: To determine whether hospitalization for pneumonia is associated with an increased short-term and long-term risk of CVD.

DESIGN, SETTINGS, AND PARTICIPANTS: We examined 2 community-based cohorts: the Cardiovascular Health Study (CHS, n = 5888; enrollment age, ≥65 years; enrollment period, 1989-1994) and the Atherosclerosis Risk in Communities study (ARIC, n = 15,792; enrollment age, 45-64 years; enrollment period, 1987-1989). Participants were followed up through December 31, 2010. We matched each participant hospitalized with pneumonia to 2 controls. Pneumonia cases and controls were followed for occurrence of CVD over 10 years after matching. We estimated hazard ratios (HRs) for CVD at different time intervals, adjusting for demographics, CVD risk factors, subclinical CVD, comorbidities, and functional status.

EXPOSURES: Hospitalization for pneumonia.

MAIN OUTCOMES AND MEASURES: Incident CVD (myocardial infarction, stroke, and fatal coronary heart disease).

RESULTS: Of 591 pneumonia cases in CHS, 206 had CVD events over 10 years after pneumonia hospitalization. CVD risk after pneumonia was highest in the first year. CVD occurred in 54 cases and 6 controls in the first 30 days (HR, 4.07; 95% CI, 2.86-5.27); 11 cases and 9 controls between 31 and 90 days (HR, 2.94; 95% CI, 2.18-3.70); and 22 cases and 55 controls between 91 days and 1 year (HR, 2.10; 95% CI, 1.59-2.60). Additional CVD risk remained elevated into the tenth year, when 4 cases and 12 controls developed CVD (HR, 1.86; 95% CI, 1.18-2.55). In ARIC, of 680 pneumonia cases, 112 had CVD over 10 years after hospitalization. CVD occurred in 4 cases and 3 controls in the first 30 days (HR, 2.38; 95% CI, 1.12-3.63); 4 cases and 0 controls between 31 and 90 days (HR, 2.40; 95% CI, 1.23-3.47); 11 cases and 8 controls between 91 days and 1 year (HR, 2.19; 95% CI, 1.20-3.19); and 8 cases and 7 controls during the second year (HR, 1.88; 95% CI, 1.10-2.66). After the second year, the HRs were no longer statistically significant.

CONCLUSIONS AND RELEVANCE: Hospitalization for pneumonia was associated with increased short-term and long-term risk of CVD, suggesting that pneumonia may be a risk factor for CVD.

%B JAMA %V 313 %P 264-74 %8 2015 Jan 20 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/25602997?dopt=Abstract %R 10.1001/jama.2014.18229 %0 Journal Article %J Respir Res %D 2015 %T Association of 25-Hydroxyvitamin D status and genetic variation in the vitamin D metabolic pathway with FEV1 in the Framingham Heart Study. %A Hansen, J G %A Gao, W %A Dupuis, J %A O'Connor, G T %A Tang, W %A Kowgier, M %A Sood, A %A Gharib, S A %A Palmer, L J %A Fornage, M %A Heckbert, S R %A Psaty, B M %A Booth, S L %A Cassano, Patricia A %K Adult %K Aged %K Cohort Studies %K Cross-Sectional Studies %K DNA-Binding Proteins %K Female %K Genetic Variation %K Humans %K Longitudinal Studies %K Male %K Massachusetts %K Metabolic Networks and Pathways %K Middle Aged %K Nuclear Proteins %K Polymorphism, Single Nucleotide %K Vitamin D %X

BACKGROUND: Vitamin D is associated with lung function in cross-sectional studies, and vitamin D inadequacy is hypothesized to play a role in the pathogenesis of chronic obstructive pulmonary disease. Further data are needed to clarify the relation between vitamin D status, genetic variation in vitamin D metabolic genes, and cross-sectional and longitudinal changes in lung function in healthy adults.

METHODS: We estimated the association between serum 25-hydroxyvitamin D [25(OH)D] and cross-sectional forced expiratory volume in the first second (FEV1) in Framingham Heart Study (FHS) Offspring and Third Generation participants and the association between serum 25(OH)D and longitudinal change in FEV1 in Third Generation participants using linear mixed-effects models. Using a gene-based approach, we investigated the association between 241 SNPs in 6 select vitamin D metabolic genes in relation to longitudinal change in FEV1 in Offspring participants and pursued replication of these findings in a meta-analyzed set of 4 independent cohorts.

RESULTS: We found a positive cross-sectional association between 25(OH)D and FEV1 in FHS Offspring and Third Generation participants (P=0.004). There was little or no association between 25(OH)D and longitudinal change in FEV1 in Third Generation participants (P=0.97). In Offspring participants, the CYP2R1 gene, hypothesized to influence usual serum 25(OH)D status, was associated with longitudinal change in FEV1 (gene-based P<0.05). The most significantly associated SNP from CYP2R1 had a consistent direction of association with FEV1 in the meta-analyzed set of replication cohorts, but the association did not reach statistical significance thresholds (P=0.09).

CONCLUSIONS: Serum 25(OH)D status was associated with cross-sectional FEV1, but not longitudinal change in FEV1. The inconsistent associations may be driven by differences in the groups studied. CYP2R1 demonstrated a gene-based association with longitudinal change in FEV1 and is a promising candidate gene for further studies.

%B Respir Res %V 16 %P 81 %8 2015 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/26122139?dopt=Abstract %R 10.1186/s12931-015-0238-y %0 Journal Article %J Neurobiol Aging %D 2015 %T Association of Alzheimer's disease GWAS loci with MRI markers of brain aging. %A Chauhan, Ganesh %A Adams, Hieab H H %A Bis, Joshua C %A Weinstein, Galit %A Yu, Lei %A Töglhofer, Anna Maria %A Smith, Albert Vernon %A van der Lee, Sven J %A Gottesman, Rebecca F %A Thomson, Russell %A Wang, Jing %A Yang, Qiong %A Niessen, Wiro J %A Lopez, Oscar L %A Becker, James T %A Phan, Thanh G %A Beare, Richard J %A Arfanakis, Konstantinos %A Fleischman, Debra %A Vernooij, Meike W %A Mazoyer, Bernard %A Schmidt, Helena %A Srikanth, Velandai %A Knopman, David S %A Jack, Clifford R %A Amouyel, Philippe %A Hofman, Albert %A DeCarli, Charles %A Tzourio, Christophe %A van Duijn, Cornelia M %A Bennett, David A %A Schmidt, Reinhold %A Longstreth, William T %A Mosley, Thomas H %A Fornage, Myriam %A Launer, Lenore J %A Seshadri, Sudha %A Ikram, M Arfan %A Debette, Stephanie %K Aging %K Alleles %K Alzheimer Disease %K Apolipoproteins E %K Brain %K Female %K Genome-Wide Association Study %K Hippocampus %K Humans %K Magnetic Resonance Imaging %K Male %K Organ Size %K Polymorphism, Single Nucleotide %K Risk %K Sialic Acid Binding Ig-like Lectin 3 %X

Whether novel risk variants of Alzheimer's disease (AD) identified through genome-wide association studies also influence magnetic resonance imaging-based intermediate phenotypes of AD in the general population is unclear. We studied association of 24 AD risk loci with intracranial volume, total brain volume, hippocampal volume (HV), white matter hyperintensity burden, and brain infarcts in a meta-analysis of genetic association studies from large population-based samples (N = 8175-11,550). In single-SNP based tests, AD risk allele of APOE (rs2075650) was associated with smaller HV (p = 0.0054) and CD33 (rs3865444) with smaller intracranial volume (p = 0.0058). In gene-based tests, there was associations of HLA-DRB1 with total brain volume (p = 0.0006) and BIN1 with HV (p = 0.00089). A weighted AD genetic risk score was associated with smaller HV (beta ± SE = -0.047 ± 0.013, p = 0.00041), even after excluding the APOE locus (p = 0.029). However, only association of AD genetic risk score with HV, including APOE, was significant after multiple testing correction (including number of independent phenotypes tested). These results suggest that novel AD genetic risk variants may contribute to structural brain aging in nondemented older community persons.

%B Neurobiol Aging %V 36 %P 1765.e7-16 %8 2015 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/25670335?dopt=Abstract %R 10.1016/j.neurobiolaging.2014.12.028 %0 Journal Article %J JAMA %D 2015 %T Association of Cardiometabolic Multimorbidity With Mortality. %A Di Angelantonio, Emanuele %A Kaptoge, Stephen %A Wormser, David %A Willeit, Peter %A Butterworth, Adam S %A Bansal, Narinder %A O'Keeffe, Linda M %A Gao, Pei %A Wood, Angela M %A Burgess, Stephen %A Freitag, Daniel F %A Pennells, Lisa %A Peters, Sanne A %A Hart, Carole L %A Håheim, Lise Lund %A Gillum, Richard F %A Nordestgaard, Børge G %A Psaty, Bruce M %A Yeap, Bu B %A Knuiman, Matthew W %A Nietert, Paul J %A Kauhanen, Jussi %A Salonen, Jukka T %A Kuller, Lewis H %A Simons, Leon A %A van der Schouw, Yvonne T %A Barrett-Connor, Elizabeth %A Selmer, Randi %A Crespo, Carlos J %A Rodriguez, Beatriz %A Verschuren, W M Monique %A Salomaa, Veikko %A Svärdsudd, Kurt %A van der Harst, Pim %A Björkelund, Cecilia %A Wilhelmsen, Lars %A Wallace, Robert B %A Brenner, Hermann %A Amouyel, Philippe %A Barr, Elizabeth L M %A Iso, Hiroyasu %A Onat, Altan %A Trevisan, Maurizio %A D'Agostino, Ralph B %A Cooper, Cyrus %A Kavousi, Maryam %A Welin, Lennart %A Roussel, Ronan %A Hu, Frank B %A Sato, Shinichi %A Davidson, Karina W %A Howard, Barbara V %A Leening, Maarten J G %A Leening, Maarten %A Rosengren, Annika %A Dörr, Marcus %A Deeg, Dorly J H %A Kiechl, Stefan %A Stehouwer, Coen D A %A Nissinen, Aulikki %A Giampaoli, Simona %A Donfrancesco, Chiara %A Kromhout, Daan %A Price, Jackie F %A Peters, Annette %A Meade, Tom W %A Casiglia, Edoardo %A Lawlor, Debbie A %A Gallacher, John %A Nagel, Dorothea %A Franco, Oscar H %A Assmann, Gerd %A Dagenais, Gilles R %A Jukema, J Wouter %A Sundström, Johan %A Woodward, Mark %A Brunner, Eric J %A Khaw, Kay-Tee %A Wareham, Nicholas J %A Whitsel, Eric A %A Njølstad, Inger %A Hedblad, Bo %A Wassertheil-Smoller, Sylvia %A Engström, Gunnar %A Rosamond, Wayne D %A Selvin, Elizabeth %A Sattar, Naveed %A Thompson, Simon G %A Danesh, John %K Adult %K Aged %K Comorbidity %K Diabetes Mellitus %K Female %K Humans %K Life Expectancy %K Male %K Middle Aged %K Mortality %K Myocardial Infarction %K Risk Factors %K Stroke %X

IMPORTANCE: The prevalence of cardiometabolic multimorbidity is increasing.

OBJECTIVE: To estimate reductions in life expectancy associated with cardiometabolic multimorbidity.

DESIGN, SETTING, AND PARTICIPANTS: Age- and sex-adjusted mortality rates and hazard ratios (HRs) were calculated using individual participant data from the Emerging Risk Factors Collaboration (689,300 participants; 91 cohorts; years of baseline surveys: 1960-2007; latest mortality follow-up: April 2013; 128,843 deaths). The HRs from the Emerging Risk Factors Collaboration were compared with those from the UK Biobank (499,808 participants; years of baseline surveys: 2006-2010; latest mortality follow-up: November 2013; 7995 deaths). Cumulative survival was estimated by applying calculated age-specific HRs for mortality to contemporary US age-specific death rates.

EXPOSURES: A history of 2 or more of the following: diabetes mellitus, stroke, myocardial infarction (MI).

MAIN OUTCOMES AND MEASURES: All-cause mortality and estimated reductions in life expectancy.

RESULTS: In participants in the Emerging Risk Factors Collaboration without a history of diabetes, stroke, or MI at baseline (reference group), the all-cause mortality rate adjusted to the age of 60 years was 6.8 per 1000 person-years. Mortality rates per 1000 person-years were 15.6 in participants with a history of diabetes, 16.1 in those with stroke, 16.8 in those with MI, 32.0 in those with both diabetes and MI, 32.5 in those with both diabetes and stroke, 32.8 in those with both stroke and MI, and 59.5 in those with diabetes, stroke, and MI. Compared with the reference group, the HRs for all-cause mortality were 1.9 (95% CI, 1.8-2.0) in participants with a history of diabetes, 2.1 (95% CI, 2.0-2.2) in those with stroke, 2.0 (95% CI, 1.9-2.2) in those with MI, 3.7 (95% CI, 3.3-4.1) in those with both diabetes and MI, 3.8 (95% CI, 3.5-4.2) in those with both diabetes and stroke, 3.5 (95% CI, 3.1-4.0) in those with both stroke and MI, and 6.9 (95% CI, 5.7-8.3) in those with diabetes, stroke, and MI. The HRs from the Emerging Risk Factors Collaboration were similar to those from the more recently recruited UK Biobank. The HRs were little changed after further adjustment for markers of established intermediate pathways (eg, levels of lipids and blood pressure) and lifestyle factors (eg, smoking, diet). At the age of 60 years, a history of any 2 of these conditions was associated with 12 years of reduced life expectancy and a history of all 3 of these conditions was associated with 15 years of reduced life expectancy.

CONCLUSIONS AND RELEVANCE: Mortality associated with a history of diabetes, stroke, or MI was similar for each condition. Because any combination of these conditions was associated with multiplicative mortality risk, life expectancy was substantially lower in people with multimorbidity.

%B JAMA %V 314 %P 52-60 %8 2015 Jul 7 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26151266?dopt=Abstract %R 10.1001/jama.2015.7008 %0 Journal Article %J Hum Mol Genet %D 2015 %T Association of exome sequences with plasma C-reactive protein levels in >9000 participants. %A Schick, Ursula M %A Auer, Paul L %A Bis, Joshua C %A Lin, Honghuang %A Wei, Peng %A Pankratz, Nathan %A Lange, Leslie A %A Brody, Jennifer %A Stitziel, Nathan O %A Kim, Daniel S %A Carlson, Christopher S %A Fornage, Myriam %A Haessler, Jeffery %A Hsu, Li %A Jackson, Rebecca D %A Kooperberg, Charles %A Leal, Suzanne M %A Psaty, Bruce M %A Boerwinkle, Eric %A Tracy, Russell %A Ardissino, Diego %A Shah, Svati %A Willer, Cristen %A Loos, Ruth %A Melander, Olle %A McPherson, Ruth %A Hovingh, Kees %A Reilly, Muredach %A Watkins, Hugh %A Girelli, Domenico %A Fontanillas, Pierre %A Chasman, Daniel I %A Gabriel, Stacey B %A Gibbs, Richard %A Nickerson, Deborah A %A Kathiresan, Sekar %A Peters, Ulrike %A Dupuis, Josée %A Wilson, James G %A Rich, Stephen S %A Morrison, Alanna C %A Benjamin, Emelia J %A Gross, Myron D %A Reiner, Alex P %K Adult %K African Americans %K C-Reactive Protein %K Cardiovascular Diseases %K Cohort Studies %K European Continental Ancestry Group %K Exome %K Female %K Gene Frequency %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Hepatocyte Nuclear Factor 1-alpha %K Humans %K Male %K Plasma %K Polymorphism, Single Nucleotide %K Receptors, Interleukin-6 %K Risk Factors %X

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

%B Hum Mol Genet %V 24 %P 559-71 %8 2015 Jan 15 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/25187575?dopt=Abstract %R 10.1093/hmg/ddu450 %0 Journal Article %J J Bone Miner Res %D 2015 %T Association of Fetuin-A With Incident Fractures in Community-Dwelling Older Adults: The Cardiovascular Health Study. %A Fink, Howard A %A Bůzková, Petra %A Garimella, Pranav S %A Mukamal, Kenneth J %A Cauley, Jane A %A Kizer, Jorge R %A Barzilay, Joshua I %A Jalal, Diana I %A Ix, Joachim H %K Adult %K Aged %K Aged, 80 and over %K alpha-2-HS-Glycoprotein %K Bone Density %K Cross-Sectional Studies %K Female %K Follow-Up Studies %K Fractures, Bone %K Humans %K Incidence %K Male %K Models, Biological %X

Fetuin-A, a serum protein that regulates calcium mineralization, has been associated with bone mineral density (BMD) in several cross-sectional human studies, suggesting a possible beneficial effect on clinically important measures of bone health. Fetuin-A and incidence of subsequent fracture was assessed in 4714 men and women ≥65 years of age. Proportional hazards models were used to estimate risk of incident hip (hospital discharge ICD-9 codes) and composite fracture (hip, pelvis, humerus, or proximal forearm; hospital discharge ICD-9 codes and Medicare claims data). A total of 576 participants had an incident hip fracture (median follow-up 11.2 years) and 768 had an incident composite fracture (median follow-up 6.9 years). In unadjusted analyses, there was no association between fetuin-A (per SD increase) and risk of hip fracture (hazard ratio [HR], 0.96; 95% CI, 0.88 to 1.05) or composite fracture (HR, 0.99; 95% CI, 0.92 to 1.06). Results were not significantly changed after adjustment for potential confounding variables. Analyses modeling fetuin-A in quartiles or within a subset with available BMD measures also showed no statistically significant association with risk of hip or composite fracture. Though fetuin-A was positively associated with areal BMD in partially adjusted models (total hip: β, 0.013 g/cm(2) ; 95% CI, 0.005 to 0.021; femoral neck: β, 0.011 g/cm(2) ; 95% CI, 0.004 to 0.018; and lumbar spine: β, 0.007 g/cm(2) ; 95% CI, 0.001 to 0.028), these associations were no longer significant after further adjustment for BMI and in final multivariate models. In this large sample of community-dwelling older adults, a small positive association between fetuin-A and areal BMD appeared attributable to confounding variables and we found no evidence of an association between fetuin-A and risk of clinical fracture.

%B J Bone Miner Res %V 30 %P 1394-402 %8 2015 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/25656814?dopt=Abstract %R 10.1002/jbmr.2475 %0 Journal Article %J J Mol Med (Berl) %D 2015 %T Association of mitochondrial DNA levels with frailty and all-cause mortality. %A Ashar, Foram N %A Moes, Anna %A Moore, Ann Z %A Grove, Megan L %A Chaves, Paulo H M %A Coresh, Josef %A Newman, Anne B %A Matteini, Amy M %A Bandeen-Roche, Karen %A Boerwinkle, Eric %A Walston, Jeremy D %A Arking, Dan E %K African Americans %K Aged %K Aged, 80 and over %K Aging %K DNA, Mitochondrial %K European Continental Ancestry Group %K Female %K Follow-Up Studies %K Gene Dosage %K Geriatric Assessment %K Humans %K Kaplan-Meier Estimate %K Male %K Mortality %K Odds Ratio %K Population Surveillance %K Prospective Studies %K Surveys and Questionnaires %K United States %X

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

%B J Mol Med (Berl) %V 93 %P 177-186 %8 2015 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/25471480?dopt=Abstract %R 10.1007/s00109-014-1233-3 %0 Journal Article %J JACC Heart Fail %D 2015 %T Burden of Comorbidities and Functional and Cognitive Impairments in Elderly Patients at the Initial Diagnosis of Heart Failure and Their Impact on Total Mortality: The Cardiovascular Health Study. %A Murad, Khalil %A Goff, David C %A Morgan, Timothy M %A Burke, Gregory L %A Bartz, Traci M %A Kizer, Jorge R %A Chaudhry, Sarwat I %A Gottdiener, John S %A Kitzman, Dalane W %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Atrial Fibrillation %K Cognition Disorders %K Cohort Studies %K Comorbidity %K Coronary Disease %K Female %K Heart Failure %K Humans %K Hypertension %K Incidence %K Longitudinal Studies %K Male %K Peripheral Arterial Disease %K Physical Fitness %K Prevalence %K Proportional Hazards Models %K Pulmonary Disease, Chronic Obstructive %X

OBJECTIVES: The purpose of this study was to determine the prevalence of clinically relevant comorbidities and measures of physical and cognitive impairment in elderly persons with incident heart failure (HF).

BACKGROUND: Comorbidities and functional and cognitive impairments are common in the elderly and often associated with greater mortality risk.

METHODS: We examined the prevalence of 9 comorbidities and 4 measures of functional and cognitive impairments in 558 participants from the Cardiovascular Health Study who developed incident HF between 1990 and 2002. Participants were followed prospectively until mid-2008 to determine their mortality risk.

RESULTS: Mean age of participants was 79.2 ± 6.3 years with 52% being men. Sixty percent of participants had ≥3 comorbidities, and only 2.5% had none. Twenty-two percent and 44% of participants had ≥1 activity of daily living (ADL) and ≥1 instrumental activity of daily living (IADL) impaired respectively. Seventeen percent of participants had cognitive impairment (modified mini-mental state exam score <80, scores range between 0 and 100). During follow up, 504 participants died, with 1-, 5-, and 10-year mortality rates of 19%, 56%, and 83%, respectively. In a multivariable-adjusted model, the following were significantly associated with greater total mortality risk: diabetes mellitus (hazard ratio [HR]: 1.64; 95% confidence interval [CI]: 1.33 to 2.03), chronic kidney disease (HR: 1.32; 95% CI: 1.07 to 1.62 for moderate disease; HR: 3.00; 95% CI: 1.82 to 4.95 for severe), cerebrovascular disease (HR: 1.53; 95% CI: 1.22 to 1.92), depression (HR: 1.44; 95% CI: 1.09 to 1.90), functional impairment (HR: 1.30; 95% CI: 1.04 to 1.63 for 1 IADL impaired; HR: 1.49; 95% CI: 1.07 to 2.04 for ≥2 IADL impaired), and cognitive impairment (HR: 1.33; 95% CI: 1.02 to 1.73). Other comorbidities (hypertension, coronary heart disease, peripheral arterial disease, atrial fibrillation, and obstructive airway disease) and measures of functional impairments (ADLs and 15-ft walk time) were not associated with mortality.

CONCLUSIONS: Elderly patients with incident HF have a high burden of comorbidities and functional and cognitive impairments. Some of these conditions are associated with greater mortality risk.

%B JACC Heart Fail %V 3 %P 542-50 %8 2015 Jul %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/26160370?dopt=Abstract %R 10.1016/j.jchf.2015.03.004 %0 Journal Article %J J Am Heart Assoc %D 2015 %T Cardiovascular and Mortality Outcomes in the Elderly With Impaired Cardiac and Pulmonary Function: The Cardiovascular Health Study (CHS). %A Waheed, Salman %A Chaves, Paulo H M %A Gardin, Julius M %A Cao, Jie Jane %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Female %K Heart Diseases %K Heart Failure %K Hospitalization %K Humans %K Kaplan-Meier Estimate %K Lung Diseases %K Male %K Mortality %K Prospective Studies %K Respiratory Function Tests %K Risk Assessment %K Risk Factors %K Stroke Volume %K United States %K Ventricular Dysfunction, Left %X

BACKGROUND: Impaired pulmonary function (IPF) and left ventricular systolic dysfunction (LVSD) are prevalent in the elderly and are associated with significant morbidity and mortality. The main objectives of this study were to examine the relative impact and joint association of IPF and LVSD with heart failure, cardiovascular mortality and all-cause mortality, and their impact on risk classification using a continuous net reclassification index.

METHODS AND RESULTS: We followed 2342 adults without prevalent cardiovascular disease (mean age, 76 years) from the Cardiovascular Health Study for a median of 12.6 years. LVSD was defined as LV ejection fraction <55%. IPF was defined as: forced expiratory volume in 1 second:forced vital capacity <70%, and predicted forced expiratory volume in 1 second <80%. Outcomes included heart failure hospitalization, cardiovascular mortality, all-cause mortality, and composite outcome. LVSD was detected in 128 subjects (6%), IPF in 441 (19%) and both in 38 (2%). Compared to those without LVSD or IPF, there was a significantly increased cardiovascular risk for groups of LVSD only, IPF only, and LVSD plus IPF, adjusted hazard ratio (95% CI) 2.1 (1.5-3.0), 1.7 (1.4-2.1), and 3.2 (2.0-5.1) for HF; 1.8 (1.2-2.6), 1.4 (1.1-1.8), and 2.8 (1.7-4.7) for cardiovascular mortality; 1.3 (1.0-1.8), 1.7 (1.4-1.9), and 2.1 (1.5-3.0) for all-cause mortality, and 1.6 (1.3-2.1), 1.7 (1.5-1.9), and 2.4 (1.7-3.3) for composite outcome, respectively. Risk classification improved significantly for all outcomes when IPF was added to the adjusted model with LVSD or LVSD to IPF.

CONCLUSIONS: While risk of cardiovascular outcomes was the highest among elderly with both LVSD and IPF, risk was comparable between subjects with IPF alone and those with LVSD alone. This observation, combined with improved risk classification by adding IPF to LVSD or LVSD to IPF, underscore the importance of comprehensive heart and lung evaluation in cardiovascular outcome assessment.

%B J Am Heart Assoc %V 4 %8 2015 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/26645833?dopt=Abstract %R 10.1161/JAHA.115.002308 %0 Journal Article %J J Thromb Haemost %D 2015 %T Coagulation factor XII genetic variation, ex vivo thrombin generation, and stroke risk in the elderly: results from the Cardiovascular Health Study. %A Olson, N C %A Butenas, S %A Lange, L A %A Lange, E M %A Cushman, M %A Jenny, N S %A Walston, J %A Souto, J C %A Soria, J M %A Chauhan, G %A Debette, S %A Longstreth, W T %A Seshadri, S %A Reiner, A P %A Tracy, R P %K African Americans %K Age Factors %K Aged %K Blood Coagulation %K Brain Ischemia %K European Continental Ancestry Group %K Factor XII %K Female %K Gene Frequency %K Genetic Predisposition to Disease %K Humans %K Incidence %K Male %K Phenotype %K Polymorphism, Single Nucleotide %K Prospective Studies %K Risk Assessment %K Risk Factors %K Stroke %K Thrombin %K Time Factors %K United States %X

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

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

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

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

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

%B J Thromb Haemost %V 13 %P 1867-77 %8 2015 Oct %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/26286125?dopt=Abstract %R 10.1111/jth.13111 %0 Journal Article %J Neurology %D 2015 %T Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. %A Rannikmae, Kristiina %A Davies, Gail %A Thomson, Pippa A %A Bevan, Steve %A Devan, William J %A Falcone, Guido J %A Traylor, Matthew %A Anderson, Christopher D %A Battey, Thomas W K %A Radmanesh, Farid %A Deka, Ranjan %A Woo, Jessica G %A Martin, Lisa J %A Jimenez-Conde, Jordi %A Selim, Magdy %A Brown, Devin L %A Silliman, Scott L %A Kidwell, Chelsea S %A Montaner, Joan %A Langefeld, Carl D %A Slowik, Agnieszka %A Hansen, Bjorn M %A Lindgren, Arne G %A Meschia, James F %A Fornage, Myriam %A Bis, Joshua C %A Debette, Stephanie %A Ikram, Mohammad A %A Longstreth, Will T %A Schmidt, Reinhold %A Zhang, Cathy R %A Yang, Qiong %A Sharma, Pankaj %A Kittner, Steven J %A Mitchell, Braxton D %A Holliday, Elizabeth G %A Levi, Christopher R %A Attia, John %A Rothwell, Peter M %A Poole, Deborah L %A Boncoraglio, Giorgio B %A Psaty, Bruce M %A Malik, Rainer %A Rost, Natalia %A Worrall, Bradford B %A Dichgans, Martin %A Van Agtmael, Tom %A Woo, Daniel %A Markus, Hugh S %A Seshadri, Sudha %A Rosand, Jonathan %A Sudlow, Cathie L M %K Cerebral Small Vessel Diseases %K Collagen Type IV %K Genetic Association Studies %K Genetic Variation %K Humans %K Polymorphism, Single Nucleotide %X

OBJECTIVES: We hypothesized that common variants in the collagen genes COL4A1/COL4A2 are associated with sporadic forms of cerebral small vessel disease.

METHODS: We conducted meta-analyses of existing genotype data among individuals of European ancestry to determine associations of 1,070 common single nucleotide polymorphisms (SNPs) in the COL4A1/COL4A2 genomic region with the following: intracerebral hemorrhage and its subtypes (deep, lobar) (1,545 cases, 1,485 controls); ischemic stroke and its subtypes (cardioembolic, large vessel disease, lacunar) (12,389 cases, 62,004 controls); and white matter hyperintensities (2,733 individuals with ischemic stroke and 9,361 from population-based cohorts with brain MRI data). We calculated a statistical significance threshold that accounted for multiple testing and linkage disequilibrium between SNPs (p < 0.000084).

RESULTS: Three intronic SNPs in COL4A2 were significantly associated with deep intracerebral hemorrhage (lead SNP odds ratio [OR] 1.29, 95% confidence interval [CI] 1.14-1.46, p = 0.00003; r(2) > 0.9 between SNPs). Although SNPs associated with deep intracerebral hemorrhage did not reach our significance threshold for association with lacunar ischemic stroke (lead SNP OR 1.10, 95% CI 1.03-1.18, p = 0.0073), and with white matter hyperintensity volume in symptomatic ischemic stroke patients (lead SNP OR 1.07, 95% CI 1.01-1.13, p = 0.016), the direction of association was the same. There was no convincing evidence of association with white matter hyperintensities in population-based studies or with non-small vessel disease cerebrovascular phenotypes.

CONCLUSIONS: Our results indicate an association between common variation in the COL4A2 gene and symptomatic small vessel disease, particularly deep intracerebral hemorrhage. These findings merit replication studies, including in ethnic groups of non-European ancestry.

%B Neurology %V 84 %P 918-26 %8 2015 Mar 3 %G ENG %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/25653287?dopt=Abstract %R 10.1212/WNL.0000000000001309 %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 J Med Genet %D 2015 %T DCAF4, a novel gene associated with leucocyte telomere length. %A Mangino, Massimo %A Christiansen, Lene %A Stone, Rivka %A Hunt, Steven C %A Horvath, Kent %A Eisenberg, Dan T A %A Kimura, Masayuki %A Petersen, Inge %A Kark, Jeremy D %A Herbig, Utz %A Reiner, Alex P %A Benetos, Athanase %A Codd, Veryan %A Nyholt, Dale R %A Sinnreich, Ronit %A Christensen, Kaare %A Nassar, Hisham %A Hwang, Shih-Jen %A Levy, Daniel %A Bataille, Veronique %A Fitzpatrick, Annette L %A Chen, Wei %A Berenson, Gerald S %A Samani, Nilesh J %A Martin, Nicholas G %A Tishkoff, Sarah %A Schork, Nicholas J %A Kyvik, Kirsten Ohm %A Dalgård, Christine %A Spector, Timothy D %A Aviv, Abraham %K Alleles %K Carrier Proteins %K Gene Expression Regulation %K Genome-Wide Association Study %K Humans %K Leukocytes %K Melanoma %K Risk Factors %K Telomere %K Telomere Homeostasis %X

BACKGROUND: Leucocyte telomere length (LTL), which is fashioned by multiple genes, has been linked to a host of human diseases, including sporadic melanoma. A number of genes associated with LTL have already been identified through genome-wide association studies. The main aim of this study was to establish whether DCAF4 (DDB1 and CUL4-associated factor 4) is associated with LTL. In addition, using ingenuity pathway analysis (IPA), we examined whether LTL-associated genes in the general population might partially explain the inherently longer LTL in patients with sporadic melanoma, the risk for which is increased with ultraviolet radiation (UVR).

RESULTS: Genome-wide association (GWA) meta-analysis and de novo genotyping of 20 022 individuals revealed a novel association (p=6.4×10(-10)) between LTL and rs2535913, which lies within DCAF4. Notably, eQTL analysis showed that rs2535913 is associated with decline in DCAF4 expressions in both lymphoblastoid cells and sun-exposed skin (p=4.1×10(-3) and 2×10(-3), respectively). Moreover, IPA revealed that LTL-associated genes, derived from GWA meta-analysis (N=9190), are over-represented among genes engaged in melanoma pathways. Meeting increasingly stringent p value thresholds (p<0.05, <0.01, <0.005, <0.001) in the LTL-GWA meta-analysis, these genes were jointly over-represented for melanoma at p values ranging from 1.97×10(-169) to 3.42×10(-24).

CONCLUSIONS: We uncovered a new locus associated with LTL in the general population. We also provided preliminary findings that suggest a link of LTL through genetic mechanisms with UVR and melanoma in the general population.

%B J Med Genet %V 52 %P 157-62 %8 2015 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/25624462?dopt=Abstract %R 10.1136/jmedgenet-2014-102681 %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 PLoS One %D 2015 %T Drug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium. %A Bis, Joshua C %A Sitlani, Colleen %A Irvin, Ryan %A Avery, Christy L %A Smith, Albert Vernon %A Sun, Fangui %A Evans, Daniel S %A Musani, Solomon K %A Li, Xiaohui %A Trompet, Stella %A Krijthe, Bouwe P %A Harris, Tamara B %A Quibrera, P Miguel %A Brody, Jennifer A %A Demissie, Serkalem %A Davis, Barry R %A Wiggins, Kerri L %A Tranah, Gregory J %A Lange, Leslie A %A Sotoodehnia, Nona %A Stott, David J %A Franco, Oscar H %A Launer, Lenore J %A Stürmer, Til %A Taylor, Kent D %A Cupples, L Adrienne %A Eckfeldt, John H %A Smith, Nicholas L %A Liu, Yongmei %A Wilson, James G %A Heckbert, Susan R %A Buckley, Brendan M %A Ikram, M Arfan %A Boerwinkle, Eric %A Chen, Yii-Der Ida %A de Craen, Anton J M %A Uitterlinden, André G %A Rotter, Jerome I %A Ford, Ian %A Hofman, Albert %A Sattar, Naveed %A Slagboom, P Eline %A Westendorp, Rudi G J %A Gudnason, Vilmundur %A Vasan, Ramachandran S %A Lumley, Thomas %A Cummings, Steven R %A Taylor, Herman A %A Post, Wendy %A Jukema, J Wouter %A Stricker, Bruno H %A Whitsel, Eric A %A Psaty, Bruce M %A Arnett, Donna %K African Americans %K Aged %K Antihypertensive Agents %K Cardiovascular Diseases %K European Continental Ancestry Group %K Female %K Genome-Wide Association Study %K Humans %K Hypertension %K Incidence %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Treatment Outcome %X

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

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

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

%B PLoS One %V 10 %P e0140496 %8 2015 %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/26516778?dopt=Abstract %R 10.1371/journal.pone.0140496 %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 Am J Kidney Dis %D 2015 %T Fibroblast growth factor 23 and sudden versus non-sudden cardiac death: the Cardiovascular Health Study. %A Deo, Rajat %A Katz, Ronit %A de Boer, Ian H %A Sotoodehnia, Nona %A Kestenbaum, Bryan %A Mukamal, Kenneth J %A Chonchol, Michel %A Sarnak, Mark J %A Siscovick, David %A Shlipak, Michael G %A Ix, Joachim H %K Aged %K Aged, 80 and over %K Biomarkers %K Comorbidity %K Death, Sudden, Cardiac %K Electrocardiography %K Female %K Fibroblast Growth Factors %K Follow-Up Studies %K Heart Arrest %K Heart Diseases %K Humans %K Kaplan-Meier Estimate %K Male %K Prospective Studies %K Renal Insufficiency, Chronic %K Risk Factors %K Sympathetic Nervous System %K United States %X

BACKGROUND: Elevated fibroblast growth factor 23 (FGF-23) concentrations are associated with greater risk of cardiovascular events and mortality, especially among people with chronic kidney disease (CKD). Because individuals with CKD are at an increased risk of sudden cardiac death (SCD), we sought to understand whether FGF-23 level is a stronger risk factor for SCD versus non-SCD.

STUDY DESIGN: Cohort study.

SETTING & PARTICIPANTS: 3,244 participants 65 years or older in the community-based Cardiovascular Health Study.

PREDICTOR: Plasma FGF-23 concentrations.

OUTCOMES: We assessed SCD and non-SCD in these analyses. SCD was adjudicated rigorously and was defined as a sudden pulseless condition of cardiac origin in a previously stable person occurring out of hospital or in the emergency department.

MEASUREMENTS: We estimated associations of baseline FGF-23 concentrations with SCD and non-SCD using Cox proportional hazards models after adjustment for demographics, cardiovascular risk factors, comorbid conditions, and kidney function. We also tested whether associations differed by CKD status.

RESULTS: During a median follow-up of 8.1 years, there were 118 adjudicated SCD and 570 non-SCD events. After multivariable adjustment for demographics, cardiovascular risk factors, comorbid conditions, and parameters of kidney function, higher FGF-23 concentrations were an independent risk factor for non-SCD (HR [per doubling], 1.17; 95% CI, 1.06-1.30). However, elevated FGF-23 concentrations were not associated independently with SCD (HR [per doubling], 1.07; 95% CI, 0.85-1.35). In stratified analysis by CKD status (36.5% of cohort), doubling of FGF-23 concentrations was associated independently with non-SCD (adjusted HR, 1.26; 95% CI, 1.10-1.45). A similar magnitude of association was observed between FGF-23 level and SCD in the CKD subgroup; however, it was not significant (HR, 1.20; 95% CI, 0.89-1.62).

LIMITATIONS: Limited power to detect moderate-sized effects between FGF-23 level and SCD in both the primary and stratified analyses.

CONCLUSIONS: In this population-based study, FGF-23 level elevations were associated independently with non-SCD. Among individuals with CKD, the associations between FGF-23 level and SCD and non-SCD were similar.

%B Am J Kidney Dis %V 66 %P 40-6 %8 2015 Jul %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/25572028?dopt=Abstract %R 10.1053/j.ajkd.2014.10.025 %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 Am J Hematol %D 2015 %T Gene-centric approach identifies new and known loci for FVIII activity and VWF antigen levels in European Americans and African Americans. %A Tang, Weihong %A Cushman, Mary %A Green, David %A Rich, Stephen S %A Lange, Leslie A %A Yang, Qiong %A Tracy, Russell P %A Tofler, Geoffrey H %A Basu, Saonli %A Wilson, James G %A Keating, Brendan J %A Weng, Lu-Chen %A Taylor, Herman A %A Jacobs, David R %A Delaney, Joseph A %A Palmer, Cameron D %A Young, Taylor %A Pankow, James S %A O'Donnell, Christopher J %A Smith, Nicholas L %A Reiner, Alexander P %A Folsom, Aaron R %K Adult %K African Americans %K Aged %K European Continental Ancestry Group %K Factor VIII %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Male %K Methionine Adenosyltransferase %K Middle Aged %K Polymorphism, Single Nucleotide %K Venous Thromboembolism %K von Willebrand Factor %X

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

%B Am J Hematol %V 90 %P 534-40 %8 2015 Jun %G eng %N 6 %R 10.1002/ajh.24005 %0 Journal Article %J Diabetes Care %D 2015 %T Gene-Environment Interactions of Circadian-Related Genes for Cardiometabolic Traits. %A Dashti, Hassan S %A Follis, Jack L %A Smith, Caren E %A Tanaka, Toshiko %A Garaulet, Marta %A Gottlieb, Daniel J %A Hruby, Adela %A Jacques, Paul F %A Kiefte-de Jong, Jessica C %A Lamon-Fava, Stefania %A Scheer, Frank A J L %A Bartz, Traci M %A Kovanen, Leena %A Wojczynski, Mary K %A Frazier-Wood, Alexis C %A Ahluwalia, Tarunveer S %A Perälä, Mia-Maria %A Jonsson, Anna %A Muka, Taulant %A Kalafati, Ioanna P %A Mikkilä, Vera %A Ordovas, Jose M %K Adult %K Alleles %K Blood Glucose %K Circadian Rhythm Signaling Peptides and Proteins %K Cohort Studies %K Diabetes Mellitus, Type 2 %K Diet, Fat-Restricted %K European Continental Ancestry Group %K Fasting %K Female %K Gene-Environment Interaction %K Humans %K Insulin Resistance %K Male %K Middle Aged %K Multicenter Studies as Topic %K Observational Studies as Topic %K Phenotype %K Polymorphism, Single Nucleotide %K Sleep %K Waist Circumference %X

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

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

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

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

%B Diabetes Care %V 38 %P 1456-66 %8 2015 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/26084345?dopt=Abstract %R 10.2337/dc14-2709 %0 Journal Article %J Stat Med %D 2015 %T Generalized estimating equations for genome-wide association studies using longitudinal phenotype data. %A Sitlani, Colleen M %A Rice, Kenneth M %A Lumley, Thomas %A McKnight, Barbara %A Cupples, L Adrienne %A Avery, Christy L %A Noordam, Raymond %A Stricker, Bruno H C %A Whitsel, Eric A %A Psaty, Bruce M %K Aged %K Aging %K Cardiovascular Diseases %K Cohort Studies %K Computer Simulation %K Cross-Sectional Studies %K Epidemiologic Research Design %K Gene-Environment Interaction %K Genetic Variation %K Genome, Human %K Genome-Wide Association Study %K Humans %K Longitudinal Studies %K Meta-Analysis as Topic %K Models, Genetic %K Pharmacogenetics %K Risk Assessment %K United States %X

Many longitudinal cohort studies have both genome-wide measures of genetic variation and repeated measures of phenotypes and environmental exposures. Genome-wide association study analyses have typically used only cross-sectional data to evaluate quantitative phenotypes and binary traits. Incorporation of repeated measures may increase power to detect associations, but also requires specialized analysis methods. Here, we discuss one such method-generalized estimating equations (GEE)-in the contexts of analysis of main effects of rare genetic variants and analysis of gene-environment interactions. We illustrate the potential for increased power using GEE analyses instead of cross-sectional analyses. We also address challenges that arise, such as the need for small-sample corrections when the minor allele frequency of a genetic variant and/or the prevalence of an environmental exposure is low. To illustrate methods for detection of gene-drug interactions on a genome-wide scale, using repeated measures data, we conduct single-study analyses and meta-analyses across studies in three large cohort studies participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium-the Atherosclerosis Risk in Communities study, the Cardiovascular Health Study, and the Rotterdam Study.

%B Stat Med %V 34 %P 118-30 %8 2015 Jan 15 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/25297442?dopt=Abstract %R 10.1002/sim.6323 %0 Journal Article %J Mol Psychiatry %D 2015 %T Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949). %A Davies, G %A Armstrong, N %A Bis, J C %A Bressler, J %A Chouraki, V %A Giddaluru, S %A Hofer, E %A Ibrahim-Verbaas, C A %A Kirin, M %A Lahti, J %A van der Lee, S J %A Le Hellard, S %A Liu, T %A Marioni, R E %A Oldmeadow, C %A Postmus, I %A Smith, A V %A Smith, J A %A Thalamuthu, A %A Thomson, R %A Vitart, V %A Wang, J %A Yu, L %A Zgaga, L %A Zhao, W %A Boxall, R %A Harris, S E %A Hill, W D %A Liewald, D C %A Luciano, M %A Adams, H %A Ames, D %A Amin, N %A Amouyel, P %A Assareh, A A %A Au, R %A Becker, J T %A Beiser, A %A Berr, C %A Bertram, L %A Boerwinkle, E %A Buckley, B M %A Campbell, H %A Corley, J %A De Jager, P L %A Dufouil, C %A Eriksson, J G %A Espeseth, T %A Faul, J D %A Ford, I %A Gottesman, R F %A Griswold, M E %A Gudnason, V %A Harris, T B %A Heiss, G %A Hofman, A %A Holliday, E G %A Huffman, J %A Kardia, S L R %A Kochan, N %A Knopman, D S %A Kwok, J B %A Lambert, J-C %A Lee, T %A Li, G %A Li, S-C %A Loitfelder, M %A Lopez, O L %A Lundervold, A J %A Lundqvist, A %A Mather, K A %A Mirza, S S %A Nyberg, L %A Oostra, B A %A Palotie, A %A Papenberg, G %A Pattie, A %A Petrovic, K %A Polasek, O %A Psaty, B M %A Redmond, P %A Reppermund, S %A Rotter, J I %A Schmidt, H %A Schuur, M %A Schofield, P W %A Scott, R J %A Steen, V M %A Stott, D J %A van Swieten, J C %A Taylor, K D %A Trollor, J %A Trompet, S %A Uitterlinden, A G %A Weinstein, G %A Widen, E %A Windham, B G %A Jukema, J W %A Wright, A F %A Wright, M J %A Yang, Q %A Amieva, H %A Attia, J R %A Bennett, D A %A Brodaty, H %A de Craen, A J M %A Hayward, C %A Ikram, M A %A Lindenberger, U %A Nilsson, L-G %A Porteous, D J %A Räikkönen, K %A Reinvang, I %A Rudan, I %A Sachdev, P S %A Schmidt, R %A Schofield, P R %A Srikanth, V %A Starr, J M %A Turner, S T %A Weir, D R %A Wilson, J F %A van Duijn, C %A Launer, L %A Fitzpatrick, A L %A Seshadri, S %A Mosley, T H %A Deary, I J %K Aged %K Aged, 80 and over %K Atherosclerosis %K Cognition %K Cognition Disorders %K Cohort Studies %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K HMGN1 Protein %K Humans %K Male %K Middle Aged %K Neuropsychological Tests %K Phenotype %K Polymorphism, Single Nucleotide %K Scotland %X

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53,949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10(-9), MIR2113; rs17522122, P=2.55 × 10(-8), AKAP6; rs10119, P=5.67 × 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.

%B Mol Psychiatry %V 20 %P 183-92 %8 2015 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/25644384?dopt=Abstract %R 10.1038/mp.2014.188 %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 Stroke %D 2015 %T Genetic overlap between diagnostic subtypes of ischemic stroke. %A Holliday, Elizabeth G %A Traylor, Matthew %A Malik, Rainer %A Bevan, Steve %A Falcone, Guido %A Hopewell, Jemma C %A Cheng, Yu-Ching %A Cotlarciuc, Ioana %A Bis, Joshua C %A Boerwinkle, Eric %A Boncoraglio, Giorgio B %A Clarke, Robert %A Cole, John W %A Fornage, Myriam %A Furie, Karen L %A Ikram, M Arfan %A Jannes, Jim %A Kittner, Steven J %A Lincz, Lisa F %A Maguire, Jane M %A Meschia, James F %A Mosley, Thomas H %A Nalls, Mike A %A Oldmeadow, Christopher %A Parati, Eugenio A %A Psaty, Bruce M %A Rothwell, Peter M %A Seshadri, Sudha %A Scott, Rodney J %A Sharma, Pankaj %A Sudlow, Cathie %A Wiggins, Kerri L %A Worrall, Bradford B %A Rosand, Jonathan %A Mitchell, Braxton D %A Dichgans, Martin %A Markus, Hugh S %A Levi, Christopher %A Attia, John %A Wray, Naomi R %K Alleles %K Atherosclerosis %K Cerebral Small Vessel Diseases %K Cohort Studies %K Data Interpretation, Statistical %K Embolism %K Genome-Wide Association Study %K Genotype %K Humans %K Ischemia %K Linear Models %K Meta-Analysis as Topic %K Phenotype %K Polymorphism, Single Nucleotide %K Stroke %X

BACKGROUND AND PURPOSE: Despite moderate heritability, the phenotypic heterogeneity of ischemic stroke has hampered gene discovery, motivating analyses of diagnostic subtypes with reduced sample sizes. We assessed evidence for a shared genetic basis among the 3 major subtypes: large artery atherosclerosis (LAA), cardioembolism, and small vessel disease (SVD), to inform potential cross-subtype analyses.

METHODS: Analyses used genome-wide summary data for 12 389 ischemic stroke cases (including 2167 LAA, 2405 cardioembolism, and 1854 SVD) and 62 004 controls from the Metastroke consortium. For 4561 cases and 7094 controls, individual-level genotype data were also available. Genetic correlations between subtypes were estimated using linear mixed models and polygenic profile scores. Meta-analysis of a combined LAA-SVD phenotype (4021 cases and 51 976 controls) was performed to identify shared risk alleles.

RESULTS: High genetic correlation was identified between LAA and SVD using linear mixed models (rg=0.96, SE=0.47, P=9×10(-4)) and profile scores (rg=0.72; 95% confidence interval, 0.52-0.93). Between LAA and cardioembolism and SVD and cardioembolism, correlation was moderate using linear mixed models but not significantly different from zero for profile scoring. Joint meta-analysis of LAA and SVD identified strong association (P=1×10(-7)) for single nucleotide polymorphisms near the opioid receptor μ1 (OPRM1) gene.

CONCLUSIONS: Our results suggest that LAA and SVD, which have been hitherto treated as genetically distinct, may share a substantial genetic component. Combined analyses of LAA and SVD may increase power to identify small-effect alleles influencing shared pathophysiological processes.

%B Stroke %V 46 %P 615-9 %8 2015 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/25613305?dopt=Abstract %R 10.1161/STROKEAHA.114.007930 %0 Journal Article %J Nat Commun %D 2015 %T Genome of The Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels. %A van Leeuwen, Elisabeth M %A Karssen, Lennart C %A Deelen, Joris %A Isaacs, Aaron %A Medina-Gómez, Carolina %A Mbarek, Hamdi %A Kanterakis, Alexandros %A Trompet, Stella %A Postmus, Iris %A Verweij, Niek %A van Enckevort, David J %A Huffman, Jennifer E %A White, Charles C %A Feitosa, Mary F %A Bartz, Traci M %A Manichaikul, Ani %A Joshi, Peter K %A Peloso, Gina M %A Deelen, Patrick %A van Dijk, Freerk %A Willemsen, Gonneke %A de Geus, Eco J %A Milaneschi, Yuri %A Penninx, Brenda W J H %A Francioli, Laurent C %A Menelaou, Androniki %A Pulit, Sara L %A Rivadeneira, Fernando %A Hofman, Albert %A Oostra, Ben A %A Franco, Oscar H %A Mateo Leach, Irene %A Beekman, Marian %A de Craen, Anton J M %A Uh, Hae-Won %A Trochet, Holly %A Hocking, Lynne J %A Porteous, David J %A Sattar, Naveed %A Packard, Chris J %A Buckley, Brendan M %A Brody, Jennifer A %A Bis, Joshua C %A Rotter, Jerome I %A Mychaleckyj, Josyf C %A Campbell, Harry %A Duan, Qing %A Lange, Leslie A %A Wilson, James F %A Hayward, Caroline %A Polasek, Ozren %A Vitart, Veronique %A Rudan, Igor %A Wright, Alan F %A Rich, Stephen S %A Psaty, Bruce M %A Borecki, Ingrid B %A Kearney, Patricia M %A Stott, David J %A Adrienne Cupples, L %A Jukema, J Wouter %A van der Harst, Pim %A Sijbrands, Eric J %A Hottenga, Jouke-Jan %A Uitterlinden, André G %A Swertz, Morris A %A van Ommen, Gert-Jan B %A de Bakker, Paul I W %A Eline Slagboom, P %A Boomsma, Dorret I %A Wijmenga, Cisca %A van Duijn, Cornelia M %K ATP-Binding Cassette Transporters %K Cholesterol %K Gene Frequency %K Genetic Association Studies %K Humans %K Mutation, Missense %K Netherlands %X

Variants associated with blood lipid levels may be population-specific. To identify low-frequency variants associated with this phenotype, population-specific reference panels may be used. Here we impute nine large Dutch biobanks (~35,000 samples) with the population-specific reference panel created by the Genome of The Netherlands Project and perform association testing with blood lipid levels. We report the discovery of five novel associations at four loci (P value <6.61 × 10(-4)), including a rare missense variant in ABCA6 (rs77542162, p.Cys1359Arg, frequency 0.034), which is predicted to be deleterious. The frequency of this ABCA6 variant is 3.65-fold increased in the Dutch and its effect (βLDL-C=0.135, βTC=0.140) is estimated to be very similar to those observed for single variants in well-known lipid genes, such as LDLR.

%B Nat Commun %V 6 %P 6065 %8 2015 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/25751400?dopt=Abstract %R 10.1038/ncomms7065 %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2015 %T Genome-Wide Association Study and Linkage Analysis of the Healthy Aging Index. %A Minster, Ryan L %A Sanders, Jason L %A Singh, Jatinder %A Kammerer, Candace M %A Barmada, M Michael %A Matteini, Amy M %A Zhang, Qunyuan %A Wojczynski, Mary K %A Daw, E Warwick %A Brody, Jennifer A %A Arnold, Alice M %A Lunetta, Kathryn L %A Murabito, Joanne M %A Christensen, Kaare %A Perls, Thomas T %A Province, Michael A %A Newman, Anne B %K Aging %K Apolipoproteins E %K Forkhead Transcription Factors %K Genetic Linkage %K Genome-Wide Association Study %K Humans %K Longevity %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %X

BACKGROUND: The Healthy Aging Index (HAI) is a tool for measuring the extent of health and disease across multiple systems.

METHODS: We conducted a genome-wide association study and a genome-wide linkage analysis to map quantitative trait loci associated with the HAI and a modified HAI weighted for mortality risk in 3,140 individuals selected for familial longevity from the Long Life Family Study. The genome-wide association study used the Long Life Family Study as the discovery cohort and individuals from the Cardiovascular Health Study and the Framingham Heart Study as replication cohorts.

RESULTS: There were no genome-wide significant findings from the genome-wide association study; however, several single-nucleotide polymorphisms near ZNF704 on chromosome 8q21.13 were suggestively associated with the HAI in the Long Life Family Study (p < 10(-) (6)) and nominally replicated in the Cardiovascular Health Study and Framingham Heart Study. Linkage results revealed significant evidence (log-odds score = 3.36) for a quantitative trait locus for mortality-optimized HAI in women on chromosome 9p24-p23. However, results of fine-mapping studies did not implicate any specific candidate genes within this region of interest.

CONCLUSIONS: ZNF704 may be a potential candidate gene for studies of the genetic underpinnings of longevity.

%B J Gerontol A Biol Sci Med Sci %V 70 %P 1003-8 %8 2015 Aug %G ENG %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/25758594?dopt=Abstract %R 10.1093/gerona/glv006 %0 Journal Article %J Mol Psychiatry %D 2015 %T Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption. %A Cornelis, M C %A Byrne, E M %A Esko, T %A Nalls, M A %A Ganna, A %A Paynter, N %A Monda, K L %A Amin, N %A Fischer, K %A Renstrom, F %A Ngwa, J S %A Huikari, V %A Cavadino, A %A Nolte, I M %A Teumer, A %A Yu, K %A Marques-Vidal, P %A Rawal, R %A Manichaikul, A %A Wojczynski, M K %A Vink, J M %A Zhao, J H %A Burlutsky, G %A Lahti, J %A Mikkilä, V %A Lemaitre, R N %A Eriksson, J %A Musani, S K %A Tanaka, T %A Geller, F %A Luan, J %A Hui, J %A Mägi, R %A Dimitriou, M %A Garcia, M E %A Ho, W-K %A Wright, M J %A Rose, L M %A Magnusson, P K E %A Pedersen, N L %A Couper, D %A Oostra, B A %A Hofman, A %A Ikram, M A %A Tiemeier, H W %A Uitterlinden, A G %A van Rooij, F J A %A Barroso, I %A Johansson, I %A Xue, L %A Kaakinen, M %A Milani, L %A Power, C %A Snieder, H %A Stolk, R P %A Baumeister, S E %A Biffar, R %A Gu, F %A Bastardot, F %A Kutalik, Z %A Jacobs, D R %A Forouhi, N G %A Mihailov, E %A Lind, L %A Lindgren, C %A Michaëlsson, K %A Morris, A %A Jensen, M %A Khaw, K-T %A Luben, R N %A Wang, J J %A Männistö, S %A Perälä, M-M %A Kähönen, M %A Lehtimäki, T %A Viikari, J %A Mozaffarian, D %A Mukamal, K %A Psaty, B M %A Döring, A %A Heath, A C %A Montgomery, G W %A Dahmen, N %A Carithers, T %A Tucker, K L %A Ferrucci, L %A Boyd, H A %A Melbye, M %A Treur, J L %A Mellström, D %A Hottenga, J J %A Prokopenko, I %A Tönjes, A %A Deloukas, P %A Kanoni, S %A Lorentzon, M %A Houston, D K %A Liu, Y %A Danesh, J %A Rasheed, A %A Mason, M A %A Zonderman, A B %A Franke, L %A Kristal, B S %A Karjalainen, J %A Reed, D R %A Westra, H-J %A Evans, M K %A Saleheen, D %A Harris, T B %A Dedoussis, G %A Curhan, G %A Stumvoll, M %A Beilby, J %A Pasquale, L R %A Feenstra, B %A Bandinelli, S %A Ordovás, J M %A Chan, A T %A Peters, U %A Ohlsson, C %A Gieger, C %A Martin, N G %A Waldenberger, M %A Siscovick, D S %A Raitakari, O %A Eriksson, J G %A Mitchell, P %A Hunter, D J %A Kraft, P %A Rimm, E B %A Boomsma, D I %A Borecki, I B %A Loos, R J F %A Wareham, N J %A Vollenweider, P %A Caporaso, N %A Grabe, H J %A Neuhouser, M L %A Wolffenbuttel, B H R %A Hu, F B %A Hypponen, E %A Järvelin, M-R %A Cupples, L A %A Franks, P W %A Ridker, P M %A van Duijn, C M %A Heiss, G %A Metspalu, A %A North, K E %A Ingelsson, E %A Nettleton, J A %A van Dam, R M %A Chasman, D I %K Adaptor Proteins, Signal Transducing %K Basic Helix-Loop-Helix Leucine Zipper Transcription Factors %K Brain-Derived Neurotrophic Factor %K Coffea %K Cytochrome P-450 CYP1A2 %K Food Habits %K Genome-Wide Association Study %K Humans %K Phenotype %K Polymorphism, Single Nucleotide %X

Coffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to 91,462 coffee consumers of European ancestry with top single-nucleotide polymorphisms (SNPs) followed-up in ~30 062 and 7964 coffee consumers of European and African-American ancestry, respectively. Studies from both stages were combined in a trans-ethnic meta-analysis. Confirmed loci were examined for putative functional and biological relevance. Eight loci, including six novel loci, met GW significance (log10Bayes factor (BF)>5.64) with per-allele effect sizes of 0.03-0.14 cups per day. Six are located in or near genes potentially involved in pharmacokinetics (ABCG2, AHR, POR and CYP1A2) and pharmacodynamics (BDNF and SLC6A4) of caffeine. Two map to GCKR and MLXIPL genes related to metabolic traits but lacking known roles in coffee consumption. Enhancer and promoter histone marks populate the regions of many confirmed loci and several potential regulatory SNPs are highly correlated with the lead SNP of each. SNP alleles near GCKR, MLXIPL, BDNF and CYP1A2 that were associated with higher coffee consumption have previously been associated with smoking initiation, higher adiposity and fasting insulin and glucose but lower blood pressure and favorable lipid, inflammatory and liver enzyme profiles (P<5 × 10(-8)).Our genetic findings among European and African-American adults reinforce the role of caffeine in mediating habitual coffee consumption and may point to molecular mechanisms underlying inter-individual variability in pharmacological and health effects of coffee.

%B Mol Psychiatry %V 20 %P 647-56 %8 2015 May %G ENG %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/25288136?dopt=Abstract %R 10.1038/mp.2014.107 %0 Journal Article %J Biol Psychiatry %D 2015 %T Genome-wide studies of verbal declarative memory in nondemented older people: the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. %A Debette, Stephanie %A Ibrahim Verbaas, Carla A %A Bressler, Jan %A Schuur, Maaike %A Smith, Albert %A Bis, Joshua C %A Davies, Gail %A Wolf, Christiane %A Gudnason, Vilmundur %A Chibnik, Lori B %A Yang, Qiong %A DeStefano, Anita L %A de Quervain, Dominique J F %A Srikanth, Velandai %A Lahti, Jari %A Grabe, Hans J %A Smith, Jennifer A %A Priebe, Lutz %A Yu, Lei %A Karbalai, Nazanin %A Hayward, Caroline %A Wilson, James F %A Campbell, Harry %A Petrovic, Katja %A Fornage, Myriam %A Chauhan, Ganesh %A Yeo, Robin %A Boxall, Ruth %A Becker, James %A Stegle, Oliver %A Mather, Karen A %A Chouraki, Vincent %A Sun, Qi %A Rose, Lynda M %A Resnick, Susan %A Oldmeadow, Christopher %A Kirin, Mirna %A Wright, Alan F %A Jonsdottir, Maria K %A Au, Rhoda %A Becker, Albert %A Amin, Najaf %A Nalls, Mike A %A Turner, Stephen T %A Kardia, Sharon L R %A Oostra, Ben %A Windham, Gwen %A Coker, Laura H %A Zhao, Wei %A Knopman, David S %A Heiss, Gerardo %A Griswold, Michael E %A Gottesman, Rebecca F %A Vitart, Veronique %A Hastie, Nicholas D %A Zgaga, Lina %A Rudan, Igor %A Polasek, Ozren %A Holliday, Elizabeth G %A Schofield, Peter %A Choi, Seung Hoan %A Tanaka, Toshiko %A An, Yang %A Perry, Rodney T %A Kennedy, Richard E %A Sale, Michèle M %A Wang, Jing %A Wadley, Virginia G %A Liewald, David C %A Ridker, Paul M %A Gow, Alan J %A Pattie, Alison %A Starr, John M %A Porteous, David %A Liu, Xuan %A Thomson, Russell %A Armstrong, Nicola J %A Eiriksdottir, Gudny %A Assareh, Arezoo A %A Kochan, Nicole A %A Widen, Elisabeth %A Palotie, Aarno %A Hsieh, Yi-Chen %A Eriksson, Johan G %A Vogler, Christian %A van Swieten, John C %A Shulman, Joshua M %A Beiser, Alexa %A Rotter, Jerome %A Schmidt, Carsten O %A Hoffmann, Wolfgang %A Nöthen, Markus M %A Ferrucci, Luigi %A Attia, John %A Uitterlinden, André G %A Amouyel, Philippe %A Dartigues, Jean-François %A Amieva, Hélène %A Räikkönen, Katri %A Garcia, Melissa %A Wolf, Philip A %A Hofman, Albert %A Longstreth, W T %A Psaty, Bruce M %A Boerwinkle, Eric %A DeJager, Philip L %A Sachdev, Perminder S %A Schmidt, Reinhold %A Breteler, Monique M B %A Teumer, Alexander %A Lopez, Oscar L %A Cichon, Sven %A Chasman, Daniel I %A Grodstein, Francine %A Müller-Myhsok, Bertram %A Tzourio, Christophe %A Papassotiropoulos, Andreas %A Bennett, David A %A Ikram, M Arfan %A Deary, Ian J %A van Duijn, Cornelia M %A Launer, Lenore %A Fitzpatrick, Annette L %A Seshadri, Sudha %A Mosley, Thomas H %K Aged %K Aged, 80 and over %K Aging %K Apolipoproteins E %K Claudin-5 %K Cohort Studies %K Female %K Genome-Wide Association Study %K Genotype %K Humans %K Male %K Memory Disorders %K Middle Aged %K Polymorphism, Single Nucleotide %K Proteins %K Proteoglycans %K Regression Analysis %K Sulfotransferases %K Verbal Learning %X

BACKGROUND: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting.

METHODS: We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10(-6)) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults.

RESULTS: rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10(-10)) and replication cohorts (p = 5.65 × 10(-8)). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10(-8), and rs6813517 [SPOCK3], p = 2.58 × 10(-8)) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism.

CONCLUSIONS: This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.

%B Biol Psychiatry %V 77 %P 749-63 %8 2015 Apr 15 %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/25648963?dopt=Abstract %R 10.1016/j.biopsych.2014.08.027 %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 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 Ann Behav Med %D 2015 %T Husbands' and Wives' Physical Activity and Depressive Symptoms: Longitudinal Findings from the Cardiovascular Health Study. %A Monin, Joan K %A Levy, Becca %A Chen, Baibing %A Fried, Terri %A Stahl, Sarah T %A Schulz, Richard %A Doyle, Margaret %A Kershaw, Trace %K Aged %K Cardiovascular System %K Depression %K Female %K Health Surveys %K Humans %K Longitudinal Studies %K Male %K Motor Activity %K Sex Characteristics %K Spouses %X

BACKGROUND: When examining older adults' health behaviors and psychological health, it is important to consider the social context.

PURPOSE: The purpose of this study was to examine in older adult marriages whether each spouse's physical activity predicted changes in their own (actor effects) and their partner's (partner effects) depressive symptoms. Gender differences were also examined.

METHOD: Each spouse within 1260 married couples (at baseline) in the Cardiovascular Health Study completed self-report measures at wave 1 (1989-1990), wave 3 (1992-1993), and wave 7 (1996-1997). Dyadic path analyses were performed.

RESULTS: Husbands' physical activity significantly predicted own decreased depressive symptoms (actor effect). For both spouses, own physical activity did not significantly predict the spouse's depressive symptoms (partner effects). However, husbands' physical activity and depressive symptoms predicted wives' physical activity and depressive symptoms (partner effects), respectively. Depressive symptoms did not predict physical activity.

CONCLUSION: Findings suggest that husbands' physical activity is particularly influential for older married couples' psychological health.

%B Ann Behav Med %V 49 %P 704-14 %8 2015 Oct %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/25868508?dopt=Abstract %R 10.1007/s12160-015-9705-4 %0 Journal Article %J Hum Mol Genet %D 2015 %T Integrative pathway genomics of lung function and airflow obstruction. %A Gharib, Sina A %A Loth, Daan W %A Soler Artigas, Maria %A Birkland, Timothy P %A Wilk, Jemma B %A Wain, Louise V %A Brody, Jennifer A %A Obeidat, Ma'en %A Hancock, Dana B %A Tang, Wenbo %A Rawal, Rajesh %A Boezen, H Marike %A Imboden, Medea %A Huffman, Jennifer E %A Lahousse, Lies %A Alves, Alexessander C %A Manichaikul, Ani %A Hui, Jennie %A Morrison, Alanna C %A Ramasamy, Adaikalavan %A Smith, Albert Vernon %A Gudnason, Vilmundur %A Surakka, Ida %A Vitart, Veronique %A Evans, David M %A Strachan, David P %A Deary, Ian J %A Hofman, Albert %A Gläser, Sven %A Wilson, James F %A North, Kari E %A Zhao, Jing Hua %A Heckbert, Susan R %A Jarvis, Deborah L %A Probst-Hensch, Nicole %A Schulz, Holger %A Barr, R Graham %A Jarvelin, Marjo-Riitta %A O'Connor, George T %A Kähönen, Mika %A Cassano, Patricia A %A Hysi, Pirro G %A Dupuis, Josée %A Hayward, Caroline %A Psaty, Bruce M %A Hall, Ian P %A Parks, William C %A Tobin, Martin D %A London, Stephanie J %K Airway Obstruction %K Animals %K Cell Proliferation %K European Continental Ancestry Group %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genomics %K Humans %K Immune System %K Lung %K Male %K Metabolic Networks and Pathways %K Mice %K Phenotype %K Polymorphism, Single Nucleotide %K Signal Transduction %X

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

%B Hum Mol Genet %V 24 %P 6836-48 %8 2015 Dec 1 %G eng %N 23 %1 http://www.ncbi.nlm.nih.gov/pubmed/26395457?dopt=Abstract %R 10.1093/hmg/ddv378 %0 Journal Article %J Am Heart J %D 2015 %T Intermediate and long-term risk of new-onset heart failure after hospitalization for pneumonia in elderly adults. %A Corrales-Medina, Vicente F %A Taljaard, Monica %A Yende, Sachin %A Kronmal, Richard %A Dwivedi, Girish %A Newman, Anne B %A Elkind, Mitchell S V %A Lyles, Mary F %A Chirinos, Julio A %K Aged %K Disease Progression %K Female %K Follow-Up Studies %K Forecasting %K Heart Failure %K Hospitalization %K Humans %K Incidence %K Inpatients %K Male %K Patient Readmission %K Pneumonia %K Proportional Hazards Models %K Retrospective Studies %K Risk Assessment %K Risk Factors %K Time Factors %X

BACKGROUND: Pneumonia is associated with high risk of heart failure (HF) in the short term (30 days) postinfection. Whether this association persists beyond this period is unknown.

METHODS: We studied 5,613 elderly (≥65 years) adults enrolled in the Cardiovascular Health Study between 1989 and 1994 at 4 US communities. Participants had no clinical diagnosis of HF at enrollment, and they were followed up through December 2010. Hospitalizations for pneumonia were identified using validated International Classification of Disease Ninth Revision codes. A centralized committee adjudicated new-onset HF events. Using Cox regression, we estimated adjusted hazard ratios (HRs) of new-onset HF at different time intervals after hospitalization for pneumonia.

RESULTS: A total of 652 participants hospitalized for pneumonia during follow-up were still alive and free of clinical diagnosis of HF by day 30 posthospitalization. Relative to the time of their hospitalization, new-onset HF occurred in 22 cases between 31 and 90 days (HR 6.9, 95% CI 4.46-10.63, P < .001), 14 cases between 91 days and 6 months (HR 3.2, 95% CI 1.88-5.50, P < .001), 20 cases between 6 months and 1 year (HR 2.6, 95% CI 1.64-4.04, P < .001), 76 cases between 1 and 5 years (HR 1.7, 95% CI 1.30-2.12, P < .001), and 71 cases after 5 years (HR 2.0, 95% CI 1.56-2.58, P < .001). Results were robust to sensitivity analyses using stringent definitions of pneumonia and extreme assumptions for potential informative censoring.

CONCLUSION: Hospitalization for pneumonia is associated with increased risk of new-onset HF in the intermediate and long term. Studies should characterize the mechanisms of this association in order to prevent HF in elderly pneumonia survivors.

%B Am Heart J %V 170 %P 306-12 %8 2015 Aug %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26299228?dopt=Abstract %R 10.1016/j.ahj.2015.04.028 %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 JACC Cardiovasc Imaging %D 2015 %T LV Mass as a Predictor of CVD Events in Older Adults With and Without Metabolic Syndrome and Diabetes. %A Hoang, Khiet %A Zhao, Yanglu %A Gardin, Julius M %A Carnethon, Mercedes %A Mukamal, Ken %A Yanez, David %A Wong, Nathan D %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Comorbidity %K Diabetes Mellitus %K Female %K Heart Ventricles %K Humans %K Hypertrophy, Left Ventricular %K Logistic Models %K Male %K Metabolic Syndrome X %K Prognosis %K Proportional Hazards Models %K Prospective Studies %K Risk Assessment %K Risk Factors %K Time Factors %K United States %X

OBJECTIVES: The purpose of this study was to examine the prognostic significance of left ventricular (LV) mass for cardiovascular disease (CVD) events in older adults with and without metabolic syndrome (MetS) and diabetes mellitus (DM).

BACKGROUND: MetS and DM are associated with increased CVD risk, but it is unclear in these groups whether subclinical CVD as shown by increased LV mass improves risk prediction compared to standard risk factors in older individuals.

METHODS: We studied 3,724 adults (mean 72.4 ± 5.4 years of age, 61.0% female, 4.4% African-American) from the Cardiovascular Health Study who had MetS but not DM or had DM alone or had neither condition. Cox regression was used to examine the association of LV mass, (alone and indexed by height and body surface area [BSA]) as determined by echocardiography, with CVD events, including coronary heart disease (CHD), stroke, heart failure (HF), and CVD death, as well as total mortality. We also assessed the added prediction, discriminative value, and net reclassification improvement (NRI) for clinical utility of LV mass compared to standard risk factors.

RESULTS: Over a mean follow-up of 14.2 ± 6.3 years, 2,180 subjects experienced CVD events, including 986 CVD deaths. After adjustment for age, sex and standard risk factors, LV mass was positively associated with CVD events in those with MetS (hazard ratio [HR]: 1.4, p < 0.001) and without MetS (HR: 1.4, p < 0.001), but not DM (HR: 1.0, p = 0.62), with similar findings for LV mass indexed for height or BSA. Adding LV mass to standard risk factors moderately improved the prediction accuracy in the overall sample and MetS group from changes in C-statistics (p < 0.05). Categorical-free net reclassification improvement increased significantly by 17% to 19% in those with MetS. Findings were comparable for CHD, CVD mortality, and total mortality.

CONCLUSIONS: LV mass is associated with increased CVD risk and provides modest added prediction and clinical utility compared to standard risk factors in older persons with and without MetS but not with DM.

%B JACC Cardiovasc Imaging %V 8 %P 1007-15 %8 2015 Sep %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/26319502?dopt=Abstract %R 10.1016/j.jcmg.2015.04.019 %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 Hum Genet %D 2015 %T Meta-analysis of 65,734 individuals identifies TSPAN15 and SLC44A2 as two susceptibility loci for venous thromboembolism. %A Germain, Marine %A Chasman, Daniel I %A de Haan, Hugoline %A Tang, Weihong %A Lindström, Sara %A Weng, Lu-Chen %A de Andrade, Mariza %A de Visser, Marieke C H %A Wiggins, Kerri L %A Suchon, Pierre %A Saut, Noémie %A Smadja, David M %A Le Gal, Grégoire %A van Hylckama Vlieg, Astrid %A Di Narzo, Antonio %A Hao, Ke %A Nelson, Christopher P %A Rocanin-Arjo, Ares %A Folkersen, Lasse %A Monajemi, Ramin %A Rose, Lynda M %A Brody, Jennifer A %A Slagboom, Eline %A Aïssi, Dylan %A Gagnon, France %A Deleuze, Jean-Francois %A Deloukas, Panos %A Tzourio, Christophe %A Dartigues, Jean-François %A Berr, Claudine %A Taylor, Kent D %A Civelek, Mete %A Eriksson, Per %A Psaty, Bruce M %A Houwing-Duitermaat, Jeanine %A Goodall, Alison H %A Cambien, Francois %A Kraft, Peter %A Amouyel, Philippe %A Samani, Nilesh J %A Basu, Saonli %A Ridker, Paul M %A Rosendaal, Frits R %A Kabrhel, Christopher %A Folsom, Aaron R %A Heit, John %A Reitsma, Pieter H %A Trégouët, David-Alexandre %A Smith, Nicholas L %A Morange, Pierre-Emmanuel %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Membrane Glycoproteins %K Membrane Transport Proteins %K Odds Ratio %K Tetraspanins %K Venous Thromboembolism %X

Venous thromboembolism (VTE), the third leading cause of cardiovascular mortality, is a complex thrombotic disorder with environmental and genetic determinants. Although several genetic variants have been found associated with VTE, they explain a minor proportion of VTE risk in cases. We undertook a meta-analysis of genome-wide association studies (GWASs) to identify additional VTE susceptibility genes. Twelve GWASs totaling 7,507 VTE case subjects and 52,632 control subjects formed our discovery stage where 6,751,884 SNPs were tested for association with VTE. Nine loci reached the genome-wide significance level of 5 × 10(-8) including six already known to associate with VTE (ABO, F2, F5, F11, FGG, and PROCR) and three unsuspected loci. SNPs mapping to these latter were selected for replication in three independent case-control studies totaling 3,009 VTE-affected individuals and 2,586 control subjects. This strategy led to the identification and replication of two VTE-associated loci, TSPAN15 and SLC44A2, with lead risk alleles associated with odds ratio for disease of 1.31 (p = 1.67 × 10(-16)) and 1.21 (p = 2.75 × 10(-15)), respectively. The lead SNP at the TSPAN15 locus is the intronic rs78707713 and the lead SLC44A2 SNP is the non-synonymous rs2288904 previously shown to associate with transfusion-related acute lung injury. We further showed that these two variants did not associate with known hemostatic plasma markers. TSPAN15 and SLC44A2 do not belong to conventional pathways for thrombosis and have not been associated to other cardiovascular diseases nor related quantitative biomarkers. Our findings uncovered unexpected actors of VTE etiology and pave the way for novel mechanistic concepts of VTE pathophysiology.

%B Am J Hum Genet %V 96 %P 532-42 %8 2015 Apr 2 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/25772935?dopt=Abstract %R 10.1016/j.ajhg.2015.01.019 %0 Journal Article %J Stroke %D 2015 %T Meta-Analysis of Genome-Wide Association Studies Identifies Genetic Risk Factors for Stroke in African Americans. %A Carty, Cara L %A Keene, Keith L %A Cheng, Yu-Ching %A Meschia, James F %A Chen, Wei-Min %A Nalls, Mike %A Bis, Joshua C %A Kittner, Steven J %A Rich, Stephen S %A Tajuddin, Salman %A Zonderman, Alan B %A Evans, Michele K %A Langefeld, Carl D %A Gottesman, Rebecca %A Mosley, Thomas H %A Shahar, Eyal %A Woo, Daniel %A Yaffe, Kristine %A Liu, Yongmei %A Sale, Michèle M %A Dichgans, Martin %A Malik, Rainer %A Longstreth, W T %A Mitchell, Braxton D %A Psaty, Bruce M %A Kooperberg, Charles %A Reiner, Alexander %A Worrall, Bradford B %A Fornage, Myriam %K African Americans %K Case-Control Studies %K Cohort Studies %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Polymorphism, Single Nucleotide %K Risk Factors %K Stroke %X

BACKGROUND AND PURPOSE: The majority of genome-wide association studies (GWAS) of stroke have focused on European-ancestry populations; however, none has been conducted in African Americans, despite the disproportionately high burden of stroke in this population. The Consortium of Minority Population Genome-Wide Association Studies of Stroke (COMPASS) was established to identify stroke susceptibility loci in minority populations.

METHODS: Using METAL, we conducted meta-analyses of GWAS in 14 746 African Americans (1365 ischemic and 1592 total stroke cases) from COMPASS, and tested genetic variants with P<10(-6) for validation in METASTROKE, a consortium of ischemic stroke genetic studies in European-ancestry populations. We also evaluated stroke loci previously identified in European-ancestry populations.

RESULTS: The 15q21.3 locus linked with lipid levels and hypertension was associated with total stroke (rs4471613; P=3.9×10(-8)) in African Americans. Nominal associations (P<10(-6)) for total or ischemic stroke were observed for 18 variants in or near genes implicated in cell cycle/mRNA presplicing (PTPRG, CDC5L), platelet function (HPS4), blood-brain barrier permeability (CLDN17), immune response (ELTD1, WDFY4, and IL1F10-IL1RN), and histone modification (HDAC9). Two of these loci achieved nominal significance in METASTROKE: 5q35.2 (P=0.03), and 1p31.1 (P=0.018). Four of 7 previously reported ischemic stroke loci (PITX2, HDAC9, CDKN2A/CDKN2B, and ZFHX3) were nominally associated (P<0.05) with stroke in COMPASS.

CONCLUSIONS: We identified a novel genetic variant associated with total stroke in African Americans and found that ischemic stroke loci identified in European-ancestry populations may also be relevant for African Americans. Our findings support investigation of diverse populations to identify and characterize genetic risk factors, and the importance of shared genetic risk across populations.

%B Stroke %V 46 %P 2063-8 %8 2015 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/26089329?dopt=Abstract %R 10.1161/STROKEAHA.115.009044 %0 Journal Article %J Am J Kidney Dis %D 2015 %T A Meta-analysis of the Association of Estimated GFR, Albuminuria, Age, Race, and Sex With Acute Kidney Injury. %A Grams, Morgan E %A Sang, Yingying %A Ballew, Shoshana H %A Gansevoort, Ron T %A Kimm, Heejin %A Kovesdy, Csaba P %A Naimark, David %A Oien, Cecilia %A Smith, David H %A Coresh, Josef %A Sarnak, Mark J %A Stengel, Bénédicte %A Tonelli, Marcello %K Acute Kidney Injury %K Adolescent %K Adult %K African Americans %K Age Distribution %K Aged %K Albuminuria %K Continental Population Groups %K European Continental Ancestry Group %K Female %K Glomerular Filtration Rate %K Humans %K Incidence %K Male %K Middle Aged %K Predictive Value of Tests %K Prognosis %K Severity of Illness Index %K Sex Distribution %K Young Adult %X

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

STUDY DESIGN: Collaborative meta-analysis.

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

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

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

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

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

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

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

%B Am J Kidney Dis %V 66 %P 591-601 %8 2015 Oct %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/25943717?dopt=Abstract %R 10.1053/j.ajkd.2015.02.337 %0 Journal Article %J Am J Kidney Dis %D 2015 %T A Meta-analysis of the Association of Estimated GFR, Albuminuria, Diabetes Mellitus, and Hypertension With Acute Kidney Injury. %A James, Matthew T %A Grams, Morgan E %A Woodward, Mark %A Elley, C Raina %A Green, Jamie A %A Wheeler, David C %A de Jong, Paul %A Gansevoort, Ron T %A Levey, Andrew S %A Warnock, David G %A Sarnak, Mark J %K Acute Kidney Injury %K Adult %K Aged %K Comorbidity %K Diabetes Mellitus %K Disease Progression %K Female %K Glomerular Filtration Rate %K Humans %K Hypertension %K Incidence %K Kidney Failure, Chronic %K Male %K Middle Aged %K Prognosis %K Renal Insufficiency, Chronic %X

BACKGROUND: Diabetes mellitus and hypertension are risk factors for acute kidney injury (AKI). Whether estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (ACR) remain risk factors for AKI in the presence and absence of these conditions is uncertain.

STUDY DESIGN: Meta-analysis of cohort studies.

SETTING & POPULATION: 8 general-population (1,285,045 participants) and 5 chronic kidney disease (CKD; 79,519 participants) cohorts.

SELECTION CRITERIA FOR STUDIES: Cohorts participating in the CKD Prognosis Consortium.

PREDICTORS: Diabetes and hypertension status, eGFR by the 2009 CKD Epidemiology Collaboration creatinine equation, urine ACR, and interactions.

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

RESULTS: During a mean follow-up of 4 years, there were 16,480 episodes of AKI in the general-population and 2,087 episodes in the CKD cohorts. Low eGFRs and high ACRs were associated with higher risks of AKI in individuals with or without diabetes and with or without hypertension. When compared to a common reference of eGFR of 80mL/min/1.73m(2) in nondiabetic patients, HRs for AKI were generally higher in diabetic patients at any level of eGFR. The same was true for diabetic patients at all levels of ACR compared with nondiabetic patients. The risk gradient for AKI with lower eGFRs was greater in those without diabetes than with diabetes, but similar with higher ACRs in those without versus with diabetes. Those with hypertension had a higher risk of AKI at eGFRs>60mL/min/1.73m(2) than those without hypertension. However, risk gradients for AKI with both lower eGFRs and higher ACRs were greater for those without than with hypertension.

LIMITATIONS: AKI identified by diagnostic code.

CONCLUSIONS: Lower eGFRs and higher ACRs are associated with higher risks of AKI among individuals with or without either diabetes or hypertension.

%B Am J Kidney Dis %V 66 %P 602-12 %8 2015 Oct %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/25975964?dopt=Abstract %R 10.1053/j.ajkd.2015.02.338 %0 Journal Article %J J Am Geriatr Soc %D 2015 %T Microvascular and Macrovascular Abnormalities and Cognitive and Physical Function in Older Adults: Cardiovascular Health Study. %A Kim, Dae Hyun %A Grodstein, Francine %A Newman, Anne B %A Chaves, Paulo H M %A Odden, Michelle C %A Klein, Ronald %A Sarnak, Mark J %A Lipsitz, Lewis A %K Aged %K Aged, 80 and over %K Cognition %K Cross-Sectional Studies %K Female %K Humans %K Male %K Neuropsychological Tests %K Vascular Malformations %X

OBJECTIVES: To evaluate and compare the associations between microvascular and macrovascular abnormalities and cognitive and physical function

DESIGN: Cross-sectional analysis of the Cardiovascular Health Study (1998-1999).

SETTING: Community.

PARTICIPANTS: Individuals with available data on three or more of five microvascular abnormalities (brain, retina, kidney) and three or more of six macrovascular abnormalities (brain, carotid artery, heart, peripheral artery) (N = 2,452; mean age 79.5).

MEASUREMENTS: Standardized composite scores derived from three cognitive tests (Modified Mini-Mental State Examination, Digit-Symbol Substitution Test, Trail-Making Test (TMT)) and three physical tests (gait speed, grip strength, 5-time sit to stand)

RESULTS: Participants with high microvascular and macrovascular burden had worse cognitive (mean score difference = -0.30, 95% confidence interval (CI) = -0.37 to -0.24) and physical (mean score difference = -0.32, 95% CI = -0.38 to -0.26) function than those with low microvascular and macrovascular burden. Individuals with high microvascular burden alone had similarly lower scores than those with high macrovascular burden alone (cognitive function: -0.16, 95% CI = -0.24 to -0.08 vs -0.13, 95% CI = -0.20 to -0.06; physical function: -0.15, 95% CI = -0.22 to -0.08 vs -0.12, 95% CI = -0.18 to -0.06). Psychomotor speed and working memory, assessed using the TMT, were only impaired in the presence of high microvascular burden. Of the 11 vascular abnormalities considered, white matter hyperintensity, cystatin C-based glomerular filtration rate, large brain infarct, and ankle-arm index were independently associated with cognitive and physical function.

CONCLUSION: Microvascular and macrovascular abnormalities assessed using noninvasive tests of the brain, kidney, and peripheral artery were independently associated with poor cognitive and physical function in older adults. Future research should evaluate the usefulness of these tests in prognostication.

%B J Am Geriatr Soc %V 63 %P 1886-93 %8 2015 Sep %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/26338279?dopt=Abstract %R 10.1111/jgs.13594 %0 Journal Article %J Circ Cardiovasc Genet %D 2015 %T Multiethnic genome-wide association study of cerebral white matter hyperintensities on MRI. %A Verhaaren, Benjamin F J %A Debette, Stephanie %A Bis, Joshua C %A Smith, Jennifer A %A Ikram, M Kamran %A Adams, Hieab H %A Beecham, Ashley H %A Rajan, Kumar B %A Lopez, Lorna M %A Barral, Sandra %A van Buchem, Mark A %A van der Grond, Jeroen %A Smith, Albert V %A Hegenscheid, Katrin %A Aggarwal, Neelum T %A de Andrade, Mariza %A Atkinson, Elizabeth J %A Beekman, Marian %A Beiser, Alexa S %A Blanton, Susan H %A Boerwinkle, Eric %A Brickman, Adam M %A Bryan, R Nick %A Chauhan, Ganesh %A Chen, Christopher P L H %A Chouraki, Vincent %A de Craen, Anton J M %A Crivello, Fabrice %A Deary, Ian J %A Deelen, Joris %A De Jager, Philip L %A Dufouil, Carole %A Elkind, Mitchell S V %A Evans, Denis A %A Freudenberger, Paul %A Gottesman, Rebecca F %A Guðnason, Vilmundur %A Habes, Mohamad %A Heckbert, Susan R %A Heiss, Gerardo %A Hilal, Saima %A Hofer, Edith %A Hofman, Albert %A Ibrahim-Verbaas, Carla A %A Knopman, David S %A Lewis, Cora E %A Liao, Jiemin %A Liewald, David C M %A Luciano, Michelle %A van der Lugt, Aad %A Martinez, Oliver O %A Mayeux, Richard %A Mazoyer, Bernard %A Nalls, Mike %A Nauck, Matthias %A Niessen, Wiro J %A Oostra, Ben A %A Psaty, Bruce M %A Rice, Kenneth M %A Rotter, Jerome I %A von Sarnowski, Bettina %A Schmidt, Helena %A Schreiner, Pamela J %A Schuur, Maaike %A Sidney, Stephen S %A Sigurdsson, Sigurdur %A Slagboom, P Eline %A Stott, David J M %A van Swieten, John C %A Teumer, Alexander %A Töglhofer, Anna Maria %A Traylor, Matthew %A Trompet, Stella %A Turner, Stephen T %A Tzourio, Christophe %A Uh, Hae-Won %A Uitterlinden, André G %A Vernooij, Meike W %A Wang, Jing J %A Wong, Tien Y %A Wardlaw, Joanna M %A Windham, B Gwen %A Wittfeld, Katharina %A Wolf, Christiane %A Wright, Clinton B %A Yang, Qiong %A Zhao, Wei %A Zijdenbos, Alex %A Jukema, J Wouter %A Sacco, Ralph L %A Kardia, Sharon L R %A Amouyel, Philippe %A Mosley, Thomas H %A Longstreth, W T %A DeCarli, Charles C %A van Duijn, Cornelia M %A Schmidt, Reinhold %A Launer, Lenore J %A Grabe, Hans J %A Seshadri, Sudha S %A Ikram, M Arfan %A Fornage, Myriam %K Aged %K Aged, 80 and over %K Chromosomes, Human %K Continental Population Groups %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Male %K Meta-Analysis as Topic %K Middle Aged %K Models, Genetic %K Stroke %K White Matter %X

BACKGROUND: The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies.

METHODS AND RESULTS: We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7×10(-19)) and identified novel loci on chr10q24 (P=1.6×10(-9)) and chr2p21 (P=4.4×10(-8)). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0×10(-8)) and chr2p16 (P=1.5×10(-8)). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16).

CONCLUSIONS: We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.

%B Circ Cardiovasc Genet %V 8 %P 398-409 %8 2015 Apr %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/25663218?dopt=Abstract %R 10.1161/CIRCGENETICS.114.000858 %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2015 %T Multisystem physiologic impairments and changes in gait speed of older adults. %A Rosso, Andrea L %A Sanders, Jason L %A Arnold, Alice M %A Boudreau, Robert M %A Hirsch, Calvin H %A Carlson, Michelle C %A Rosano, Caterina %A Kritchevsky, Stephen B %A Newman, Anne B %K Age Factors %K Aged %K Aged, 80 and over %K Brain %K Cardiovascular Physiological Phenomena %K Cohort Studies %K Female %K Gait %K Geriatric Assessment %K Glucose %K Health Status Indicators %K Humans %K Kidney %K Lung %K Male %K Sensitivity and Specificity %K Time Factors %X

BACKGROUND: Slowed gait is an important health indicator in older adults but a single identifiable cause is often lacking. We assessed whether a summary index measuring impairments across multiple physiologic systems was associated with slowed gait in older individuals.

METHODS: Data from the Cardiovascular Health Study (n = 3,010) were used to assess associations between baseline physiologic index (measuring vasculature, brain, kidneys, lungs, and glucose metabolism; range 0-10 with 0-2 points/system and lower score indicating higher function) and annual gait speed (m/s) over 6 years. Participants with complete data on the physiologic index and at least two gait speed measures were included. Mean gait speed and 95% confidence intervals (CI) by category of index were calculated using mixed effects models.

RESULTS: Those with scores of three or higher on the index had significantly slower gait speed at baseline compared to those with scores of 0-2 (7-10: mean speed = 0.83 m/s, 95% CI: 0.80, 0.84; 0-2: mean speed = 1.01 m/s, 95% CI: 0.99, 1.03). Those with higher indices also had faster decline in gait speed compared to those with lower scores after adjustment for demographic and health characteristics (7-10: change in speed = -0.020 m/s/year, 95% CI: -0.024, -0.016; 0-2: change in speed= -0.010 m/s/year, 95% CI: -0.014, -0.006).

CONCLUSIONS: Greater impairment across five organ systems was associated with slower gait speed and greater declines in gait speed over 6 years. Impairments accumulated over multiple physiologic systems may make older adults more vulnerable to slow gait speed.

%B J Gerontol A Biol Sci Med Sci %V 70 %P 319-24 %8 2015 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/25380599?dopt=Abstract %R 10.1093/gerona/glu176 %0 Journal Article %J Mol Psychiatry %D 2015 %T Novel loci associated with usual sleep duration: the CHARGE Consortium Genome-Wide Association Study. %A Gottlieb, D J %A Hek, K %A Chen, T-H %A Watson, N F %A Eiriksdottir, G %A Byrne, E M %A Cornelis, M %A Warby, S C %A Bandinelli, S %A Cherkas, L %A Evans, D S %A Grabe, H J %A Lahti, J %A Li, M %A Lehtimäki, T %A Lumley, T %A Marciante, K D %A Pérusse, L %A Psaty, B M %A Robbins, J %A Tranah, G J %A Vink, J M %A Wilk, J B %A Stafford, J M %A Bellis, C %A Biffar, R %A Bouchard, C %A Cade, B %A Curhan, G C %A Eriksson, J G %A Ewert, R %A Ferrucci, L %A Fülöp, T %A Gehrman, P R %A Goodloe, R %A Harris, T B %A Heath, A C %A Hernandez, D %A Hofman, A %A Hottenga, J-J %A Hunter, D J %A Jensen, M K %A Johnson, A D %A Kähönen, M %A Kao, L %A Kraft, P %A Larkin, E K %A Lauderdale, D S %A Luik, A I %A Medici, M %A Montgomery, G W %A Palotie, A %A Patel, S R %A Pistis, G %A Porcu, E %A Quaye, L %A Raitakari, O %A Redline, S %A Rimm, E B %A Rotter, J I %A Smith, A V %A Spector, T D %A Teumer, A %A Uitterlinden, A G %A Vohl, M-C %A Widen, E %A Willemsen, G %A Young, T %A Zhang, X %A Liu, Y %A Blangero, J %A Boomsma, D I %A Gudnason, V %A Hu, F %A Mangino, M %A Martin, N G %A O'Connor, G T %A Stone, K L %A Tanaka, T %A Viikari, J %A Gharib, S A %A Punjabi, N M %A Räikkönen, K %A Völzke, H %A Mignot, E %A Tiemeier, H %K Adult %K African Americans %K Aged %K Dyssomnias %K European Continental Ancestry Group %K Female %K Genetic Association Studies %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Self Report %K Sleep %X

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

%B Mol Psychiatry %V 20 %P 1232-9 %8 2015 Oct %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/25469926?dopt=Abstract %R 10.1038/mp.2014.133 %0 Journal Article %J JACC Heart Fail %D 2015 %T Older Adults, "Malignant" Left Ventricular Hypertrophy, and Associated Cardiac-Specific Biomarker Phenotypes to Identify the Differential Risk of New-Onset Reduced Versus Preserved Ejection Fraction Heart Failure: CHS (Cardiovascular Health Study). %A Seliger, Stephen L %A de Lemos, James %A Neeland, Ian J %A Christenson, Robert %A Gottdiener, John %A Drazner, Mark H %A Berry, Jarett %A Sorkin, John %A DeFilippi, Christopher %K Aged %K Biomarkers %K Echocardiography %K Female %K Heart Failure %K Humans %K Hypertrophy, Left Ventricular %K Male %K Natriuretic Peptide, Brain %K Peptide Fragments %K Phenotype %K Prospective Studies %K Risk Factors %K Troponin T %X

OBJECTIVES: This study hypothesized that biomarkers of subclinical myocardial injury (high-sensitivity cardiac troponin T [hs-cTnT]) and hemodynamic stress (N-terminal pro-B-type natriuretic peptide [NT-proBNP]) would differentiate heart failure (HF) risk among older adults with left ventricular hypertrophy (LVH).

BACKGROUND: The natural history of LVH, an important risk factor for HF, is heterogeneous.

METHODS: NT-proBNP and hs-cTnT were measured at baseline and after 2 to 3 years in older adults without prior HF or myocardial infarction in the CHS (Cardiovascular Health Study). LVH and left ventricular ejection fraction were determined by echocardiography. HF events were adjudicated over a median of 13.1 years and classified as preserved or reduced left ventricular ejection fraction (heart failure with preserved ejection fraction or heart failure with reduced ejection fraction [HFrEF]). Adjusted risk of HF by LVH and biomarker tertiles, and by LVH and longitudinal increase in each biomarker was estimated using Cox regression.

RESULTS: Prevalence of LVH was 12.5% among 2,347 participants with complete measures. Adjusted risk of HF (N = 643 events) was approximately 3.8-fold higher among participants with LVH and in the highest biomarker tertile, compared with those with low biomarker levels without LVH (NT-proBNP, hazard ratio [HR]: 3.78; 95% confidence interval [CI]: 2.78 to 5.15 and hs-cTnT, HR: 3.86; 95% CI: 2.84 to 5.26). The adjusted risk of HFrEF was 7.8 times higher among those with the highest tertile of hs-cTnT and LVH (HR: 7.83; 95% CI: 4.43 to 13.83). Those with LVH and longitudinal increases in hs-cTnT or NT-proBNP were approximately 3-fold more likely to develop HF, primarily HFrEF, compared with those without LVH and with stable biomarkers.

CONCLUSIONS: The combination of LVH with greater hs-cTnT or NT-proBNP levels, and their longitudinal increase, identifies older adults at highest risk for symptomatic HF, especially HFrEF. These biomarkers may characterize sub-phenotypes in the transition from LVH to HF and suggest modifiable targets for prevention.

%B JACC Heart Fail %V 3 %P 445-55 %8 2015 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/25982111?dopt=Abstract %R 10.1016/j.jchf.2014.12.018 %0 Journal Article %J Neurobiol Aging %D 2015 %T Physical activity, body mass index, and brain atrophy in Alzheimer's disease. %A Boyle, Christina P %A Raji, Cyrus A %A Erickson, Kirk I %A Lopez, Oscar L %A Becker, James T %A Gach, H Michael %A Longstreth, W T %A Teverovskiy, Leonid %A Kuller, Lewis H %A Carmichael, Owen T %A Thompson, Paul M %K Aged %K Aged, 80 and over %K Aging %K Alzheimer Disease %K Atrophy %K Biomarkers %K Body Mass Index %K Brain %K Cognitive Dysfunction %K Cross-Sectional Studies %K Diffusion Magnetic Resonance Imaging %K Female %K Humans %K Magnetic Resonance Imaging %K Male %K Motor Activity %K Neuroimaging %X

The purpose of this study was to use a novel imaging biomarker to assess associations between physical activity (PA), body mass index (BMI), and brain structure in normal aging, mild cognitive impairment, and Alzheimer's dementia. We studied 963 participants (mean age: 74.1 ± 4.4 years) from the multisite Cardiovascular Health Study including healthy controls (n = 724), Alzheimer's dementia patients (n = 104), and people with mild cognitive impairment (n = 135). Volumetric brain images were processed using tensor-based morphometry to analyze regional brain volumes. We regressed the local brain tissue volume on reported PA and computed BMI, and performed conjunction analyses using both variables. Covariates included age, sex, and study site. PA was independently associated with greater whole brain and regional brain volumes and reduced ventricular dilation. People with higher BMI had lower whole brain and regional brain volumes. A PA-BMI conjunction analysis showed brain preservation with PA and volume loss with increased BMI in overlapping brain regions. In one of the largest voxel-based cross-sectional studies to date, PA and lower BMI may be beneficial to the brain across the spectrum of aging and neurodegeneration.

%B Neurobiol Aging %V 36 Suppl 1 %P S194-S202 %8 2015 Jan %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/25248607?dopt=Abstract %R 10.1016/j.neurobiolaging.2014.05.036 %0 Journal Article %J Arterioscler Thromb Vasc Biol %D 2015 %T Plasma Levels of Soluble Interleukin-2 Receptor α: Associations With Clinical Cardiovascular Events and Genome-Wide Association Scan. %A Durda, Peter %A Sabourin, Jeremy %A Lange, Ethan M %A Nalls, Mike A %A Mychaleckyj, Josyf C %A Jenny, Nancy Swords %A Li, Jin %A Walston, Jeremy %A Harris, Tamara B %A Psaty, Bruce M %A Valdar, William %A Liu, Yongmei %A Cushman, Mary %A Reiner, Alex P %A Tracy, Russell P %A Lange, Leslie A %K Adult %K African Americans %K Age Distribution %K Aged %K Cardiovascular Diseases %K Cohort Studies %K Coronary Artery Disease %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Incidence %K Interleukin-2 Receptor alpha Subunit %K Kaplan-Meier Estimate %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Proportional Hazards Models %K Prospective Studies %K Risk Assessment %K Sex Distribution %K Survival Analysis %X

OBJECTIVE: Interleukin (IL) -2 receptor subunit α regulates lymphocyte activation, which plays an important role in atherosclerosis. Associations between soluble IL-2Rα (sIL-2Rα) and cardiovascular disease (CVD) have not been widely studied and little is known about the genetic determinants of sIL-2Rα levels.

APPROACH AND RESULTS: We measured baseline levels of sIL-2Rα in 4408 European American (EA) and 766 African American (AA) adults from the Cardiovascular Health Study (CHS) and examined associations with baseline CVD risk factors, subclinical CVD, and incident CVD events. We also performed a genome-wide association study for sIL-2Rα in CHS (2964 EAs and 683 AAs) and further combined CHS EA results with those from two other EA cohorts in a meta-analysis (n=4464 EAs). In age, sex- and race- adjusted models, sIL-2Rα was positively associated with current smoking, type 2 diabetes mellitus, hypertension, insulin, waist circumference, C-reactive protein, IL-6, fibrinogen, internal carotid wall thickness, all-cause mortality, CVD mortality, and incident CVD, stroke, and heart failure. When adjusted for baseline CVD risk factors and subclinical CVD, associations with all-cause mortality, CVD mortality, and heart failure remained significant in both EAs and AAs. In the EA genome-wide association study analysis, we observed 52 single-nucleotide polymorphisms in the chromosome 10p15-14 region, which contains IL2RA, IL15RA, and RMB17, that reached genome-wide significance (P<5×10(-8)). The most significant single-nucleotide polymorphism was rs7911500 (P=1.31×10(-75)). The EA meta-analysis results were highly consistent with CHS-only results. No single-nucleotide polymorphisms reached statistical significance in the AAs.

CONCLUSIONS: These results support a role for sIL-2Rα in atherosclerosis and provide evidence for multiple-associated single-nucleotide polymorphisms at chromosome 10p15-14.

%B Arterioscler Thromb Vasc Biol %V 35 %P 2246-53 %8 2015 Oct %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/26293465?dopt=Abstract %R 10.1161/ATVBAHA.115.305289 %0 Journal Article %J PLoS One %D 2015 %T Population genomic analysis of 962 whole genome sequences of humans reveals natural selection in non-coding regions. %A Yu, Fuli %A Lu, Jian %A Liu, Xiaoming %A Gazave, Elodie %A Chang, Diana %A Raj, Srilakshmi %A Hunter-Zinck, Haley %A Blekhman, Ran %A Arbiza, Leonardo %A Van Hout, Cris %A Morrison, Alanna %A Johnson, Andrew D %A Bis, Joshua %A Cupples, L Adrienne %A Psaty, Bruce M %A Muzny, Donna %A Yu, Jin %A Gibbs, Richard A %A Keinan, Alon %A Clark, Andrew G %A Boerwinkle, Eric %K DNA, Intergenic %K Genetic Loci %K Humans %K Metagenomics %K Open Reading Frames %K Polymorphism, Single Nucleotide %X

Whole genome analysis in large samples from a single population is needed to provide adequate power to assess relative strengths of natural selection across different functional components of the genome. In this study, we analyzed next-generation sequencing data from 962 European Americans, and found that as expected approximately 60% of the top 1% of positive selection signals lie in intergenic regions, 33% in intronic regions, and slightly over 1% in coding regions. Several detailed functional annotation categories in intergenic regions showed statistically significant enrichment in positively selected loci when compared to the null distribution of the genomic span of ENCODE categories. There was a significant enrichment of purifying selection signals detected in enhancers, transcription factor binding sites, microRNAs and target sites, but not on lincRNA or piRNAs, suggesting different evolutionary constraints for these domains. Loci in "repressed or low activity regions" and loci near or overlapping the transcription start site were the most significantly over-represented annotations among the top 1% of signals for positive selection.

%B PLoS One %V 10 %P e0121644 %8 2015 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/25807536?dopt=Abstract %R 10.1371/journal.pone.0121644 %0 Journal Article %J BMC Musculoskelet Disord %D 2015 %T Positive association of tomato consumption with serum urate: support for tomato consumption as an anecdotal trigger of gout flares. %A Flynn, Tanya J %A Cadzow, Murray %A Dalbeth, Nicola %A Jones, Peter B %A Stamp, Lisa K %A Hindmarsh, Jennie Harré %A Todd, Alwyn S %A Walker, Robert J %A Topless, Ruth %A Merriman, Tony R %K Adolescent %K Adult %K Aged %K European Continental Ancestry Group %K Female %K Gout %K Humans %K Hyperuricemia %K Lycopersicon esculentum %K Male %K Middle Aged %K New Zealand %K Oceanic Ancestry Group %K Surveys and Questionnaires %K Uric Acid %K Young Adult %X

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

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

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

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

%B BMC Musculoskelet Disord %V 16 %P 196 %8 2015 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/26286027?dopt=Abstract %R 10.1186/s12891-015-0661-8 %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 Clin Chem %D 2015 %T Prognostic Significance of High-Sensitivity Cardiac Troponin T Concentrations between the Limit of Blank and Limit of Detection in Community-Dwelling Adults: A Metaanalysis. %A Parikh, Ravi H %A Seliger, Stephen L %A de Lemos, James %A Nambi, Vijay %A Christenson, Robert %A Ayers, Colby %A Sun, Wensheng %A Gottdiener, John S %A Kuller, Lewis H %A Ballantyne, Christie %A deFilippi, Christopher R %K Aged %K Atherosclerosis %K Biomarkers %K Cross-Sectional Studies %K Female %K Heart Failure %K Humans %K Independent Living %K Limit of Detection %K Longitudinal Studies %K Male %K Middle Aged %K Myocardial Infarction %K Prognosis %K Risk Assessment %K Risk Factors %K Sex Factors %K Troponin T %X

BACKGROUND: There is controversy regarding whether to report concentrations of high-sensitivity cardiac troponin T (hs-cTnT) to the limit of blank (LOB) (3 ng/L) or the limit of detection (LOD) (5 ng/L) of the assay in community-based cohorts. We hypothesized that hs-cTnT concentrations between the LOB and LOD would be associated with poorer cardiovascular outcomes compared to concentrations below the LOB.

METHODS: hs-cTnT was analyzed in a total of 10 723 participants from the Cardiovascular Health Study (CHS), Atherosclerosis Risk in Communities (ARIC) study, and Dallas Heart Study (DHS). Participants were divided into 2 groups, those with hs-cTnT concentrations below the limit of blank (LOB) (<3 ng/L) and those with hs-cTnT between the LOB and limit of detection (LOD) (3-4.99 ng/L). Cross-sectional associations with traditional cardiovascular risk factors and cardiac structural measurements, and longitudinal associations with long-term cardiovascular outcomes of incident heart failure and cardiovascular death, were determined.

RESULTS: Participants with hs-cTnT between the LOB and LOD for all 3 cohorts were older, more likely to be male, and have a higher burden of cardiovascular risk factors and structural pathology. A metaanalysis of the 3 cohorts showed participants with hs-cTnT between the LOB and LOD were at increased risk of new-onset heart failure (hazard ratio, 1.18; 95% CI, 1.02-1.38) and cardiovascular mortality (hazard ratio, 1.29; 95% CI, 1.06-1.57).

CONCLUSIONS: hs-cTnT concentrations between the LOB and LOD (3-4.99 ng/L) are associated with a higher prevalence of traditional risk factors, more cardiac pathology, and worse outcomes than concentrations below the LOB (<3 ng/L).

%B Clin Chem %V 61 %P 1524-31 %8 2015 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/26506994?dopt=Abstract %R 10.1373/clinchem.2015.244160 %0 Journal Article %J Am J Hematol %D 2015 %T Prospective study of circulating factor XI and incident venous thromboembolism: The Longitudinal Investigation of Thromboembolism Etiology (LITE). %A Folsom, Aaron R %A Tang, Weihong %A Roetker, Nicholas S %A Heckbert, Susan R %A Cushman, Mary %A Pankow, James S %K African Americans %K Aged %K Alleles %K European Continental Ancestry Group %K Factor XI %K Female %K Gene Expression %K Humans %K Incidence %K Longitudinal Studies %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Proportional Hazards Models %K Prospective Studies %K Risk Factors %K United States %K Venous Thromboembolism %X

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

%B Am J Hematol %V 90 %P 1047-51 %8 2015 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/26260105?dopt=Abstract %R 10.1002/ajh.24168 %0 Journal Article %J JAMA Neurol %D 2015 %T Rare and Coding Region Genetic Variants Associated With Risk of Ischemic Stroke: The NHLBI Exome Sequence Project. %A Auer, Paul L %A Nalls, Mike %A Meschia, James F %A Worrall, Bradford B %A Longstreth, W T %A Seshadri, Sudha %A Kooperberg, Charles %A Burger, Kathleen M %A Carlson, Christopher S %A Carty, Cara L %A Chen, Wei-Min %A Cupples, L Adrienne %A DeStefano, Anita L %A Fornage, Myriam %A Hardy, John %A Hsu, Li %A Jackson, Rebecca D %A Jarvik, Gail P %A Kim, Daniel S %A Lakshminarayan, Kamakshi %A Lange, Leslie A %A Manichaikul, Ani %A Quinlan, Aaron R %A Singleton, Andrew B %A Thornton, Timothy A %A Nickerson, Deborah A %A Peters, Ulrike %A Rich, Stephen S %K Aged %K Brain Ischemia %K Exome %K Female %K Genetic Predisposition to Disease %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Muscle Proteins %K National Heart, Lung, and Blood Institute (U.S.) %K Nuclear Proteins %K Open Reading Frames %K Palmitoyl-CoA Hydrolase %K Stroke %K United States %X

IMPORTANCE: Stroke is the second leading cause of death and the third leading cause of years of life lost. Genetic factors contribute to stroke prevalence, and candidate gene and genome-wide association studies (GWAS) have identified variants associated with ischemic stroke risk. These variants often have small effects without obvious biological significance. Exome sequencing may discover predicted protein-altering variants with a potentially large effect on ischemic stroke risk.

OBJECTIVE: To investigate the contribution of rare and common genetic variants to ischemic stroke risk by targeting the protein-coding regions of the human genome.

DESIGN, SETTING, AND PARTICIPANTS: The National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP) analyzed approximately 6000 participants from numerous cohorts of European and African ancestry. For discovery, 365 cases of ischemic stroke (small-vessel and large-vessel subtypes) and 809 European ancestry controls were sequenced; for replication, 47 affected sibpairs concordant for stroke subtype and an African American case-control series were sequenced, with 1672 cases and 4509 European ancestry controls genotyped. The ESP's exome sequencing and genotyping started on January 1, 2010, and continued through June 30, 2012. Analyses were conducted on the full data set between July 12, 2012, and July 13, 2013.

MAIN OUTCOMES AND MEASURES: Discovery of new variants or genes contributing to ischemic stroke risk and subtype (primary analysis) and determination of support for protein-coding variants contributing to risk in previously published candidate genes (secondary analysis).

RESULTS: We identified 2 novel genes associated with an increased risk of ischemic stroke: a protein-coding variant in PDE4DIP (rs1778155; odds ratio, 2.15; P = 2.63 × 10(-8)) with an intracellular signal transduction mechanism and in ACOT4 (rs35724886; odds ratio, 2.04; P = 1.24 × 10(-7)) with a fatty acid metabolism; confirmation of PDE4DIP was observed in affected sibpair families with large-vessel stroke subtype and in African Americans. Replication of protein-coding variants in candidate genes was observed for 2 previously reported GWAS associations: ZFHX3 (cardioembolic stroke) and ABCA1 (large-vessel stroke).

CONCLUSIONS AND RELEVANCE: Exome sequencing discovered 2 novel genes and mechanisms, PDE4DIP and ACOT4, associated with increased risk for ischemic stroke. In addition, ZFHX3 and ABCA1 were discovered to have protein-coding variants associated with ischemic stroke. These results suggest that genetic variation in novel pathways contributes to ischemic stroke risk and serves as a target for prediction, prevention, and therapy.

%B JAMA Neurol %V 72 %P 781-8 %8 2015 Jul %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/25961151?dopt=Abstract %R 10.1001/jamaneurol.2015.0582 %0 Journal Article %J Blood %D 2015 %T Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF. %A Huffman, Jennifer E %A de Vries, Paul S %A Morrison, Alanna C %A Sabater-Lleal, Maria %A Kacprowski, Tim %A Auer, Paul L %A Brody, Jennifer A %A Chasman, Daniel I %A Chen, Ming-Huei %A Guo, Xiuqing %A Lin, Li-An %A Marioni, Riccardo E %A Müller-Nurasyid, Martina %A Yanek, Lisa R %A Pankratz, Nathan %A Grove, Megan L %A de Maat, Moniek P M %A Cushman, Mary %A Wiggins, Kerri L %A Qi, Lihong %A Sennblad, Bengt %A Harris, Sarah E %A Polasek, Ozren %A Riess, Helene %A Rivadeneira, Fernando %A Rose, Lynda M %A Goel, Anuj %A Taylor, Kent D %A Teumer, Alexander %A Uitterlinden, André G %A Vaidya, Dhananjay %A Yao, Jie %A Tang, Weihong %A Levy, Daniel %A Waldenberger, Melanie %A Becker, Diane M %A Folsom, Aaron R %A Giulianini, Franco %A Greinacher, Andreas %A Hofman, Albert %A Huang, Chiang-Ching %A Kooperberg, Charles %A Silveira, Angela %A Starr, John M %A Strauch, Konstantin %A Strawbridge, Rona J %A Wright, Alan F %A McKnight, Barbara %A Franco, Oscar H %A Zakai, Neil %A Mathias, Rasika A %A Psaty, Bruce M %A Ridker, Paul M %A Tofler, Geoffrey H %A Völker, Uwe %A Watkins, Hugh %A Fornage, Myriam %A Hamsten, Anders %A Deary, Ian J %A Boerwinkle, Eric %A Koenig, Wolfgang %A Rotter, Jerome I %A Hayward, Caroline %A Dehghan, Abbas %A Reiner, Alex P %A O'Donnell, Christopher J %A Smith, Nicholas L %K Cohort Studies %K Factor VII %K Factor VIII %K Fibrinogen %K Gene Frequency %K Genetic Association Studies %K Genetic Variation %K Humans %K Nerve Tissue Proteins %K Polymorphism, Single Nucleotide %K Potassium Channels %K von Willebrand Factor %X

Fibrinogen, coagulation factor VII (FVII), and factor VIII (FVIII) and its carrier von Willebrand factor (vWF) play key roles in hemostasis. Previously identified common variants explain only a small fraction of the trait heritabilities, and additional variations may be explained by associations with rarer variants with larger effects. The aim of this study was to identify low-frequency (minor allele frequency [MAF] ≥0.01 and <0.05) and rare (MAF <0.01) variants that influence plasma concentrations of these 4 hemostatic factors by meta-analyzing exome chip data from up to 76,000 participants of 4 ancestries. We identified 12 novel associations of low-frequency (n = 2) and rare (n = 10) variants across the fibrinogen, FVII, FVIII, and vWF traits that were independent of previously identified associations. Novel loci were found within previously reported genes and had effect sizes much larger than and independent of previously identified common variants. In addition, associations at KCNT1, HID1, and KATNB1 identified new candidate genes related to hemostasis for follow-up replication and functional genomic analysis. Newly identified low-frequency and rare-variant associations accounted for modest amounts of trait variance and therefore are unlikely to increase predicted trait heritability but provide new information for understanding individual variation in hemostasis pathways.

%B Blood %V 126 %P e19-29 %8 2015 Sep 10 %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/26105150?dopt=Abstract %R 10.1182/blood-2015-02-624551 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Relationship between Systemic and Cerebral Vascular Disease and Brain Structure Integrity in Normal Elderly Individuals. %A Riverol, Mario %A Becker, James T %A Lopez, Oscar L %A Raji, Cyrus A %A Thompson, Paul M %A Carmichael, Owen T %A Gach, H Michael %A Longstreth, William T %A Fried, Linda %A Tracy, Russell P %A Kuller, Lewis H %K Aged %K Aged, 80 and over %K Analysis of Variance %K Brain %K Cerebrovascular Disorders %K Female %K Humans %K Image Processing, Computer-Assisted %K Logistic Models %K Magnetic Resonance Imaging %K Male %K Neuropsychological Tests %K Peripheral Vascular Diseases %K Predictive Value of Tests %K Retrospective Studies %K White Matter %X

Cerebral white matter lesions (WMLs) are considered a reflection of cerebral and systemic small vessel disease (SVD), and are associated with reductions in brain volume. Like the brain, the kidney is also sensitive to factors that affect vasculature. Glomerular dysfunction due to renal vascular damage can be measured with different biochemical parameters, such as creatinine or cystatin C, although cystatin C is considered to be more accurate than creatinine in the elderly. The purpose of the study was to determine whether manifestations of SVD in the kidney can predict SVD-based damage to the brain. We examined the relationship between glomerular dysfunction as a measure of SVD on WMLs, gray matter (GM) volume, and cognition in 735 cognitively normal participants from the Cardiovascular Health Study Cognition Study. The multivariate analyses controlled for demographic characteristics, hypertension, heart disease, diabetes, Apolipoprotein 4 allele, C reactive protein, lipids, physical activity, smoking, and body mass index (BMI). Elevated cystatin C levels were associated with lower neuropsychological test scores, the presence of MRI-identified brain infarcts, the severity of WMLs, and GM atrophy five years later. In adjusted models, GM volume was significantly associated with cystatin-C only until BMI and severity of WMLs were added to the model, meaning that the effect of SVD on GM volume is mediated by these two variables. These findings suggest that age-related SVD is a process that leads to altered brain structure, and creates a vulnerability state for cognitive decline.

%B J Alzheimers Dis %V 44 %P 319-28 %8 2015 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/25213770?dopt=Abstract %R 10.3233/JAD-141077 %0 Journal Article %J Heart Rhythm %D 2015 %T Serial measures of cardiac troponin T levels by a highly sensitive assay and incident atrial fibrillation in a prospective cohort of ambulatory older adults. %A Hussein, Ayman A %A Bartz, Traci M %A Gottdiener, John S %A Sotoodehnia, Nona %A Heckbert, Susan R %A Lloyd-Jones, Donald %A Kizer, Jorge R %A Christenson, Robert %A Wazni, Oussama %A DeFilippi, Christopher %K Aged %K Atrial Fibrillation %K Biomarkers %K Electrocardiography %K Female %K Heart Failure %K Humans %K Incidence %K Longitudinal Studies %K Male %K Outpatients %K Risk Assessment %K Risk Factors %K Statistics as Topic %K Troponin T %K United States %X

BACKGROUND: Various mechanisms in cardiac remodeling related to atrial fibrillation (AF) lead to elevated circulating cardiac troponin levels, but little is known about such elevations upstream to AF onset.

OBJECTIVE: The purpose of this study was to study the association between circulating troponin levels as assessed by a highly sensitive cardiac troponin T (hs-cTnT) assay and incident atrial fibrillation (AF).

METHODS: In a large prospective cohort of ambulatory older adults [the Cardiovascular Health Study (CHS)], hs-cTnT levels were measured in sera that were collected at enrollment from 4262 participants without AF (2871 with follow-up measurements). Incident AF was identified by electrocardiograms during CHS visits, hospital discharge diagnoses, and Medicare files, including outpatient and physician claims diagnoses.

RESULTS: Over median follow-up of 11.2 years (interquartile range 6.1-16.5), 1363 participants (32.0%) developed AF. Higher baseline levels of hs-cTnT were associated with incident AF in covariate-adjusted analyses accounting for demographics, traditional risk factors, and incident heart failure in time-dependent analyzes (hazard ratio for 3rd tertile vs undetectable 1.75, 95% confidence interval 1.48-2.08). This association was statistically significant in analyses that additionally adjusted for biomarkers of inflammation and hemodynamic strain (hazard ratio for 3rd tertile vs undetectable 1.38, 95% confidence interval 1.16-1.65). Significant associations were also found when hs-cTnT levels were treated as a continuous variable and when examining change from baseline of hs-cTnT levels and incident AF.

CONCLUSION: The findings show a significant association of circulating troponin levels in ambulatory older adults with incident AF beyond that of traditional risk factors, incident heart failure, and biomarkers of inflammation and hemodynamic strain.

%B Heart Rhythm %V 12 %P 879-85 %8 2015 May %G ENG %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/25602173?dopt=Abstract %R 10.1016/j.hrthm.2015.01.020 %0 Journal Article %J Metabolism %D 2015 %T Serum urate levels and the risk of hip fractures: data from the Cardiovascular Health Study. %A Mehta, Tapan %A Bůzková, Petra %A Sarnak, Mark J %A Chonchol, Michel %A Cauley, Jane A %A Wallace, Erin %A Fink, Howard A %A Robbins, John %A Jalal, Diana %K Aged %K Aged, 80 and over %K Body Mass Index %K Cohort Studies %K Estrogen Replacement Therapy %K Female %K Health Surveys %K Hip Fractures %K Humans %K Kaplan-Meier Estimate %K Male %K Prospective Studies %K Risk %K Sex Factors %K United States %K Uric Acid %X

PURPOSE: Uric acid inhibits vitamin D activation experimentally and higher serum urate levels are associated with higher parathyroid hormone levels in humans suggesting a link between uric acid and bone health. We hypothesized that hyperuricemia may increase the risk of fractures in older adults.

METHODS: 1963 men and 2729 women ≥65 years of age who participated in the Cardiovascular Health Study and had baseline serum urate levels were included in the study. The primary outcome was incident hip fracture, assessed prospectively through June, 2008 by inpatient and outpatient records. The analysis was stratified by sex a priori.

RESULTS: There was a U-shaped relationship between serum urate levels and hip fractures in men. Men in the lowest and the highest urate quartiles (<4.88 and ≥6.88 mg/dL respectively) had a significantly higher rate of fractures in unadjusted analysis. However, upon multivariate adjustment, only the HR for hip fracture in highest quartile versus the reference remained significant (HR 1.9; 95% C.I. 1.1, 3.1; p value 0.02). High serum urate levels were not associated with hip fractures in women.

CONCLUSION: In this large prospective cohort of community-dwelling older adults, increased serum urate levels were associated with an increased risk of hip fractures in men. Further studies are needed to confirm these findings and to understand the mechanisms that underlie them.

%B Metabolism %V 64 %P 438-46 %8 2015 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/25491429?dopt=Abstract %R 10.1016/j.metabol.2014.11.006 %0 Journal Article %J Neurology %D 2015 %T Shared genetic basis for migraine and ischemic stroke: A genome-wide analysis of common variants. %A Malik, Rainer %A Freilinger, Tobias %A Winsvold, Bendik S %A Anttila, Verneri %A Vander Heiden, Jason %A Traylor, Matthew %A de Vries, Boukje %A Holliday, Elizabeth G %A Terwindt, Gisela M %A Sturm, Jonathan %A Bis, Joshua C %A Hopewell, Jemma C %A Ferrari, Michel D %A Rannikmae, Kristiina %A Wessman, Maija %A Kallela, Mikko %A Kubisch, Christian %A Fornage, Myriam %A Meschia, James F %A Lehtimäki, Terho %A Sudlow, Cathie %A Clarke, Robert %A Chasman, Daniel I %A Mitchell, Braxton D %A Maguire, Jane %A Kaprio, Jaakko %A Farrall, Martin %A Raitakari, Olli T %A Kurth, Tobias %A Ikram, M Arfan %A Reiner, Alex P %A Longstreth, W T %A Rothwell, Peter M %A Strachan, David P %A Sharma, Pankaj %A Seshadri, Sudha %A Quaye, Lydia %A Cherkas, Lynn %A Schürks, Markus %A Rosand, Jonathan %A Ligthart, Lannie %A Boncoraglio, Giorgio B %A Davey Smith, George %A van Duijn, Cornelia M %A Stefansson, Kari %A Worrall, Bradford B %A Nyholt, Dale R %A Markus, Hugh S %A van den Maagdenberg, Arn M J M %A Cotsapas, Chris %A Zwart, John A %A Palotie, Aarno %A Dichgans, Martin %K Brain Ischemia %K Genome-Wide Association Study %K Humans %K Migraine with Aura %K Migraine without Aura %K Stroke %X

OBJECTIVE: To quantify genetic overlap between migraine and ischemic stroke (IS) with respect to common genetic variation.

METHODS: We applied 4 different approaches to large-scale meta-analyses of genome-wide data on migraine (23,285 cases and 95,425 controls) and IS (12,389 cases and 62,004 controls). First, we queried known genome-wide significant loci for both disorders, looking for potential overlap of signals. We then analyzed the overall shared genetic load using polygenic scores and estimated the genetic correlation between disease subtypes using data derived from these models. We further interrogated genomic regions of shared risk using analysis of covariance patterns between the 2 phenotypes using cross-phenotype spatial mapping.

RESULTS: We found substantial genetic overlap between migraine and IS using all 4 approaches. Migraine without aura (MO) showed much stronger overlap with IS and its subtypes than migraine with aura (MA). The strongest overlap existed between MO and large artery stroke (LAS; p = 6.4 × 10(-28) for the LAS polygenic score in MO) and between MO and cardioembolic stroke (CE; p = 2.7 × 10(-20) for the CE score in MO).

CONCLUSIONS: Our findings indicate shared genetic susceptibility to migraine and IS, with a particularly strong overlap between MO and both LAS and CE pointing towards shared mechanisms. Our observations on MA are consistent with a limited role of common genetic variants in this subtype.

%B Neurology %V 84 %P 2132-45 %8 2015 May 26 %G eng %N 21 %1 http://www.ncbi.nlm.nih.gov/pubmed/25934857?dopt=Abstract %R 10.1212/WNL.0000000000001606 %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 J Clin Endocrinol Metab %D 2015 %T Subclinical Hypothyroidism and the Risk of Stroke Events and Fatal Stroke: An Individual Participant Data Analysis. %A Chaker, Layal %A Baumgartner, Christine %A den Elzen, Wendy P J %A Ikram, M Arfan %A Blum, Manuel R %A Collet, Tinh-Hai %A Bakker, Stephan J L %A Dehghan, Abbas %A Drechsler, Christiane %A Luben, Robert N %A Hofman, Albert %A Portegies, Marileen L P %A Medici, Marco %A Iervasi, Giorgio %A Stott, David J %A Ford, Ian %A Bremner, Alexandra %A Wanner, Christoph %A Ferrucci, Luigi %A Newman, Anne B %A Dullaart, Robin P %A Sgarbi, José A %A Ceresini, Graziano %A Maciel, Rui M B %A Westendorp, Rudi G %A Jukema, J Wouter %A Imaizumi, Misa %A Franklyn, Jayne A %A Bauer, Douglas C %A Walsh, John P %A Razvi, Salman %A Khaw, Kay-Tee %A Cappola, Anne R %A Völzke, Henry %A Franco, Oscar H %A Gussekloo, Jacobijn %A Rodondi, Nicolas %A Peeters, Robin P %K Adult %K Asymptomatic Diseases %K Female %K Humans %K Hypothyroidism %K Incidence %K Male %K Risk Factors %K Stroke %K Thyrotropin %X

OBJECTIVE: The objective was to determine the risk of stroke associated with subclinical hypothyroidism.

DATA SOURCES AND STUDY SELECTION: Published prospective cohort studies were identified through a systematic search through November 2013 without restrictions in several databases. Unpublished studies were identified through the Thyroid Studies Collaboration. We collected individual participant data on thyroid function and stroke outcome. Euthyroidism was defined as TSH levels of 0.45-4.49 mIU/L, and subclinical hypothyroidism was defined as TSH levels of 4.5-19.9 mIU/L with normal T4 levels.

DATA EXTRACTION AND SYNTHESIS: We collected individual participant data on 47 573 adults (3451 subclinical hypothyroidism) from 17 cohorts and followed up from 1972-2014 (489 192 person-years). Age- and sex-adjusted pooled hazard ratios (HRs) for participants with subclinical hypothyroidism compared to euthyroidism were 1.05 (95% confidence interval [CI], 0.91-1.21) for stroke events (combined fatal and nonfatal stroke) and 1.07 (95% CI, 0.80-1.42) for fatal stroke. Stratified by age, the HR for stroke events was 3.32 (95% CI, 1.25-8.80) for individuals aged 18-49 years. There was an increased risk of fatal stroke in the age groups 18-49 and 50-64 years, with a HR of 4.22 (95% CI, 1.08-16.55) and 2.86 (95% CI, 1.31-6.26), respectively (p trend 0.04). We found no increased risk for those 65-79 years old (HR, 1.00; 95% CI, 0.86-1.18) or ≥ 80 years old (HR, 1.31; 95% CI, 0.79-2.18). There was a pattern of increased risk of fatal stroke with higher TSH concentrations.

CONCLUSIONS: Although no overall effect of subclinical hypothyroidism on stroke could be demonstrated, an increased risk in subjects younger than 65 years and those with higher TSH concentrations was observed.

%B J Clin Endocrinol Metab %V 100 %P 2181-91 %8 2015 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/25856213?dopt=Abstract %R 10.1210/jc.2015-1438 %0 Journal Article %J JAMA %D 2015 %T Subclinical thyroid dysfunction and fracture risk: a meta-analysis. %A Blum, Manuel R %A Bauer, Douglas C %A Collet, Tinh-Hai %A Fink, Howard A %A Cappola, Anne R %A da Costa, Bruno R %A Wirth, Christina D %A Peeters, Robin P %A Asvold, Bjørn O %A den Elzen, Wendy P J %A Luben, Robert N %A Imaizumi, Misa %A Bremner, Alexandra P %A Gogakos, Apostolos %A Eastell, Richard %A Kearney, Patricia M %A Strotmeyer, Elsa S %A Wallace, Erin R %A Hoff, Mari %A Ceresini, Graziano %A Rivadeneira, Fernando %A Uitterlinden, André G %A Stott, David J %A Westendorp, Rudi G J %A Khaw, Kay-Tee %A Langhammer, Arnuf %A Ferrucci, Luigi %A Gussekloo, Jacobijn %A Williams, Graham R %A Walsh, John P %A Jüni, Peter %A Aujesky, Drahomir %A Rodondi, Nicolas %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Female %K Fractures, Bone %K Hip Fractures %K Humans %K Hyperthyroidism %K Hypothyroidism %K Male %K Middle Aged %K Risk Factors %K Spinal Fractures %K Thyrotropin %K Young Adult %X

IMPORTANCE: Associations between subclinical thyroid dysfunction and fractures are unclear and clinical trials are lacking.

OBJECTIVE: To assess the association of subclinical thyroid dysfunction with hip, nonspine, spine, or any fractures.

DATA SOURCES AND STUDY SELECTION: The databases of MEDLINE and EMBASE (inception to March 26, 2015) were searched without language restrictions for prospective cohort studies with thyroid function data and subsequent fractures.

DATA EXTRACTION: Individual participant data were obtained from 13 prospective cohorts in the United States, Europe, Australia, and Japan. Levels of thyroid function were defined as euthyroidism (thyroid-stimulating hormone [TSH], 0.45-4.49 mIU/L), subclinical hyperthyroidism (TSH <0.45 mIU/L), and subclinical hypothyroidism (TSH ≥4.50-19.99 mIU/L) with normal thyroxine concentrations.

MAIN OUTCOME AND MEASURES: The primary outcome was hip fracture. Any fractures, nonspine fractures, and clinical spine fractures were secondary outcomes.

RESULTS: Among 70,298 participants, 4092 (5.8%) had subclinical hypothyroidism and 2219 (3.2%) had subclinical hyperthyroidism. During 762,401 person-years of follow-up, hip fracture occurred in 2975 participants (4.6%; 12 studies), any fracture in 2528 participants (9.0%; 8 studies), nonspine fracture in 2018 participants (8.4%; 8 studies), and spine fracture in 296 participants (1.3%; 6 studies). In age- and sex-adjusted analyses, the hazard ratio (HR) for subclinical hyperthyroidism vs euthyroidism was 1.36 for hip fracture (95% CI, 1.13-1.64; 146 events in 2082 participants vs 2534 in 56,471); for any fracture, HR was 1.28 (95% CI, 1.06-1.53; 121 events in 888 participants vs 2203 in 25,901); for nonspine fracture, HR was 1.16 (95% CI, 0.95-1.41; 107 events in 946 participants vs 1745 in 21,722); and for spine fracture, HR was 1.51 (95% CI, 0.93-2.45; 17 events in 732 participants vs 255 in 20,328). Lower TSH was associated with higher fracture rates: for TSH of less than 0.10 mIU/L, HR was 1.61 for hip fracture (95% CI, 1.21-2.15; 47 events in 510 participants); for any fracture, HR was 1.98 (95% CI, 1.41-2.78; 44 events in 212 participants); for nonspine fracture, HR was 1.61 (95% CI, 0.96-2.71; 32 events in 185 participants); and for spine fracture, HR was 3.57 (95% CI, 1.88-6.78; 8 events in 162 participants). Risks were similar after adjustment for other fracture risk factors. Endogenous subclinical hyperthyroidism (excluding thyroid medication users) was associated with HRs of 1.52 (95% CI, 1.19-1.93) for hip fracture, 1.42 (95% CI, 1.16-1.74) for any fracture, and 1.74 (95% CI, 1.01-2.99) for spine fracture. No association was found between subclinical hypothyroidism and fracture risk.

CONCLUSIONS AND RELEVANCE: Subclinical hyperthyroidism was associated with an increased risk of hip and other fractures, particularly among those with TSH levels of less than 0.10 mIU/L and those with endogenous subclinical hyperthyroidism. Further study is needed to determine whether treating subclinical hyperthyroidism can prevent fractures.

%B JAMA %V 313 %P 2055-65 %8 2015 May 26 %G eng %N 20 %1 http://www.ncbi.nlm.nih.gov/pubmed/26010634?dopt=Abstract %R 10.1001/jama.2015.5161 %0 Journal Article %J J Clin Endocrinol Metab %D 2015 %T Thyroid function in the euthyroid range and adverse outcomes in older adults. %A Cappola, Anne R %A Arnold, Alice M %A Wulczyn, Kendra %A Carlson, Michelle %A Robbins, John %A Psaty, Bruce M %K Aged %K Aged, 80 and over %K Aging %K Atrial Fibrillation %K Cause of Death %K Coronary Disease %K Dementia %K Female %K Heart Failure %K Hip Fractures %K Humans %K Incidence %K Male %K Prognosis %K Reference Values %K Survival Analysis %K Thyroid Function Tests %K Thyroid Gland %X

CONTEXT: The appropriateness of current reference ranges for thyroid function testing in older adults has been questioned.

OBJECTIVE: This study aimed to determine the relationship between thyroid function tests within the euthyroid range and adverse outcomes in older adults not taking thyroid medication.

DESIGN, SETTING, AND PARTICIPANTS: US community-dwelling adults years of older (n = 2843) enrolled onto the Cardiovascular Health Study with TSH, free T4 (FT4), and total T3 concentrations in the euthyroid range.

MAIN OUTCOME MEASURES: Incidence of atrial fibrillation, coronary heart disease, heart failure, hip fracture, dementia, and all-cause death were measured.

RESULTS: No departures from linearity were detected. Higher TSH was negatively associated (P = .03) and higher FT4 was positively associated (P = .007) with mortality. Higher FT4 was associated with atrial fibrillation (P < .001) and heart failure (P = .004). Compared with the first quartile, individuals with TSH in the fourth quartile had a 9.6 per 1000 person-year lower incidence of dementia (P < .05) and those with FT4 in the fourth quartile had higher incidences of atrial fibrillation, coronary heart disease, heart failure, and mortality (11.0, 8.0, 7.8, and 14.3 per 1000 person-years, respectively, all P < .05). Total T3 was not associated with any outcome.

CONCLUSIONS: Higher TSH and lower FT4 concentrations within the euthyroid range are associated with lower risk of multiple adverse events in older people, including mortality. This suggests tolerance for lower thyroid hormone levels in this age group. Clinical trials are needed to evaluate the risk-benefit profile of new thresholds for initiating treatment and optimal target concentrations for thyroid hormone replacement in older people.

%B J Clin Endocrinol Metab %V 100 %P 1088-96 %8 2015 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/25514105?dopt=Abstract %R 10.1210/jc.2014-3586 %0 Journal Article %J JAMA Intern Med %D 2015 %T Thyroid function within the normal range and risk of coronary heart disease: an individual participant data analysis of 14 cohorts. %A Asvold, Bjørn O %A Vatten, Lars J %A Bjøro, Trine %A Bauer, Douglas C %A Bremner, Alexandra %A Cappola, Anne R %A Ceresini, Graziano %A den Elzen, Wendy P J %A Ferrucci, Luigi %A Franco, Oscar H %A Franklyn, Jayne A %A Gussekloo, Jacobijn %A Iervasi, Giorgio %A Imaizumi, Misa %A Kearney, Patricia M %A Khaw, Kay-Tee %A Maciel, Rui M B %A Newman, Anne B %A Peeters, Robin P %A Psaty, Bruce M %A Razvi, Salman %A Sgarbi, José A %A Stott, David J %A Trompet, Stella %A Vanderpump, Mark P J %A Völzke, Henry %A Walsh, John P %A Westendorp, Rudi G J %A Rodondi, Nicolas %K Cohort Studies %K Coronary Disease %K Humans %K Hypothyroidism %K Thyrotropin %X

IMPORTANCE: Some experts suggest that serum thyrotropin levels in the upper part of the current reference range should be considered abnormal, an approach that would reclassify many individuals as having mild hypothyroidism. Health hazards associated with such thyrotropin levels are poorly documented, but conflicting evidence suggests that thyrotropin levels in the upper part of the reference range may be associated with an increased risk of coronary heart disease (CHD).

OBJECTIVE: To assess the association between differences in thyroid function within the reference range and CHD risk.

DESIGN, SETTING, AND PARTICIPANTS: Individual participant data analysis of 14 cohorts with baseline examinations between July 1972 and April 2002 and with median follow-up ranging from 3.3 to 20.0 years. Participants included 55,412 individuals with serum thyrotropin levels of 0.45 to 4.49 mIU/L and no previously known thyroid or cardiovascular disease at baseline.

EXPOSURES: Thyroid function as expressed by serum thyrotropin levels at baseline.

MAIN OUTCOMES AND MEASURES: Hazard ratios (HRs) of CHD mortality and CHD events according to thyrotropin levels after adjustment for age, sex, and smoking status.

RESULTS: Among 55,412 individuals, 1813 people (3.3%) died of CHD during 643,183 person-years of follow-up. In 10 cohorts with information on both nonfatal and fatal CHD events, 4666 of 48,875 individuals (9.5%) experienced a first-time CHD event during 533,408 person-years of follow-up. For each 1-mIU/L higher thyrotropin level, the HR was 0.97 (95% CI, 0.90-1.04) for CHD mortality and 1.00 (95% CI, 0.97-1.03) for a first-time CHD event. Similarly, in analyses by categories of thyrotropin, the HRs of CHD mortality (0.94 [95% CI, 0.74-1.20]) and CHD events (0.97 [95% CI, 0.83-1.13]) were similar among participants with the highest (3.50-4.49 mIU/L) compared with the lowest (0.45-1.49 mIU/L) thyrotropin levels. Subgroup analyses by sex and age group yielded similar results.

CONCLUSIONS AND RELEVANCE: Thyrotropin levels within the reference range are not associated with risk of CHD events or CHD mortality. This finding suggests that differences in thyroid function within the population reference range do not influence the risk of CHD. Increased CHD risk does not appear to be a reason for lowering the upper thyrotropin reference limit.

%B JAMA Intern Med %V 175 %P 1037-47 %8 2015 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/25893284?dopt=Abstract %R 10.1001/jamainternmed.2015.0930 %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 J Am Soc Nephrol %D 2015 %T Urine Collagen Fragments and CKD Progression-The Cardiovascular Health Study. %A Ix, Joachim H %A Biggs, Mary L %A Mukamal, Kenneth %A Djoussé, Luc %A Siscovick, David %A Tracy, Russell %A Katz, Ronit %A Delaney, Joseph A %A Chaves, Paulo %A Rifkin, Dena E %A Hughes-Austin, Jan M %A Garimella, Pranav S %A Sarnak, Mark J %A Shlipak, Michael G %A Kizer, Jorge R %K Aged %K Cardiovascular Diseases %K Case-Control Studies %K Disease Progression %K Female %K Heart Failure %K Humans %K Kidney Failure, Chronic %K Male %K Peptide Fragments %K Procollagen %K Prospective Studies %K Renal Insufficiency, Chronic %X

Tubulointerstitial fibrosis is common with ageing and strongly prognostic for ESRD but is poorly captured by eGFR or urine albumin to creatinine ratio (ACR). Higher urine levels of procollagen type III N-terminal propeptide (PIIINP) mark the severity of tubulointerstitial fibrosis in biopsy studies, but the association of urine PIIINP with CKD progression is unknown. Among community-living persons aged ≥65 years, we measured PIIINP in spot urine specimens from the 1996 to 1997 Cardiovascular Health Study visit among individuals with CKD progression (30% decline in eGFR over 9 years, n=192) or incident ESRD (n=54) during follow-up, and in 958 randomly selected participants. We evaluated associations of urine PIIINP with CKD progression and incident ESRD. Associations of urine PIIINP with cardiovascular disease, heart failure, and death were evaluated as secondary end points. At baseline, mean age (±SD) was 78±5 years, mean eGFR was 63±18 ml/min per 1.73 m(2), and median urine PIIINP was 2.6 (interquartile range, 1.4-4.2) μg/L. In a case-control study (192 participants, 231 controls), each doubling of urine PIIINP associated with 22% higher odds of CKD progression (adjusted odds ratio, 1.22; 95% confidence interval, 1.00 to 1.49). Higher urine PIIINP level was also associated with incident ESRD, but results were not significant in fully adjusted models. In a prospective study among the 958 randomly selected participants, higher urine PIIINP was significantly associated with death, but not with incident cardiovascular disease or heart failure. These data suggest higher urine PIIINP levels associate with CKD progression independently of eGFR and ACR in older individuals.

%B J Am Soc Nephrol %V 26 %P 2494-503 %8 2015 Oct %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/25655067?dopt=Abstract %R 10.1681/ASN.2014070696 %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 Stroke %D 2015 %T White Matter Lesion Progression: Genome-Wide Search for Genetic Influences. %A Hofer, Edith %A Cavalieri, Margherita %A Bis, Joshua C %A DeCarli, Charles %A Fornage, Myriam %A Sigurdsson, Sigurdur %A Srikanth, Velandai %A Trompet, Stella %A Verhaaren, Benjamin F J %A Wolf, Christiane %A Yang, Qiong %A Adams, Hieab H H %A Amouyel, Philippe %A Beiser, Alexa %A Buckley, Brendan M %A Callisaya, Michele %A Chauhan, Ganesh %A de Craen, Anton J M %A Dufouil, Carole %A van Duijn, Cornelia M %A Ford, Ian %A Freudenberger, Paul %A Gottesman, Rebecca F %A Gudnason, Vilmundur %A Heiss, Gerardo %A Hofman, Albert %A Lumley, Thomas %A Martinez, Oliver %A Mazoyer, Bernard %A Moran, Chris %A Niessen, Wiro J %A Phan, Thanh %A Psaty, Bruce M %A Satizabal, Claudia L %A Sattar, Naveed %A Schilling, Sabrina %A Shibata, Dean K %A Slagboom, P Eline %A Smith, Albert %A Stott, David J %A Taylor, Kent D %A Thomson, Russell %A Töglhofer, Anna M %A Tzourio, Christophe %A van Buchem, Mark %A Wang, Jing %A Westendorp, Rudi G J %A Windham, B Gwen %A Vernooij, Meike W %A Zijdenbos, Alex %A Beare, Richard %A Debette, Stephanie %A Ikram, M Arfan %A Jukema, J Wouter %A Launer, Lenore J %A Longstreth, W T %A Mosley, Thomas H %A Seshadri, Sudha %A Schmidt, Helena %A Schmidt, Reinhold %K Adult %K Aged %K Cohort Studies %K Disease Progression %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Leukoencephalopathies %K Male %K Middle Aged %K Prospective Studies %K White Matter %X

BACKGROUND AND PURPOSE: White matter lesion (WML) progression on magnetic resonance imaging is related to cognitive decline and stroke, but its determinants besides baseline WML burden are largely unknown. Here, we estimated heritability of WML progression, and sought common genetic variants associated with WML progression in elderly participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.

METHODS: Heritability of WML progression was calculated in the Framingham Heart Study. The genome-wide association study included 7773 elderly participants from 10 cohorts. To assess the relative contribution of genetic factors to progression of WML, we compared in 7 cohorts risk models including demographics, vascular risk factors plus single-nucleotide polymorphisms that have been shown to be associated cross-sectionally with WML in the current and previous association studies.

RESULTS: A total of 1085 subjects showed WML progression. The heritability estimate for WML progression was low at 6.5%, and no single-nucleotide polymorphisms achieved genome-wide significance (P<5×10(-8)). Four loci were suggestive (P<1×10(-5)) of an association with WML progression: 10q24.32 (rs10883817, P=1.46×10(-6)); 12q13.13 (rs4761974, P=8.71×10(-7)); 20p12.1 (rs6135309, P=3.69×10(-6)); and 4p15.31 (rs7664442, P=2.26×10(-6)). Variants that have been previously related to WML explained only 0.8% to 11.7% more of the variance in WML progression than age, vascular risk factors, and baseline WML burden.

CONCLUSIONS: Common genetic factors contribute little to the progression of age-related WML in middle-aged and older adults. Future research on determinants of WML progression should focus more on environmental, lifestyle, or host-related biological factors.

%B Stroke %V 46 %P 3048-57 %8 2015 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/26451028?dopt=Abstract %R 10.1161/STROKEAHA.115.009252 %0 Journal Article %J JAMA Intern Med %D 2016 %T -3 Polyunsaturated Fatty Acid Biomarkers and Coronary Heart Disease: Pooling Project of 19 Cohort Studies %A Del Gobbo, L. C. %A Imamura, F. %A Aslibekyan, S. %A Marklund, M. %A Virtanen, J. K. %A Wennberg, M. %A Yakoob, M. Y. %A Chiuve, S. E. %A Dela Cruz, L. %A Frazier-Wood, A. C. %A Fretts, A. M. %A Guallar, E. %A Matsumoto, C. %A Prem, K. %A Tanaka, T. %A Wu, J. H. %A Zhou, X. %A Helmer, C. %A Ingelsson, E. %A Yuan, J. M. %A Barberger-Gateau, P. %A Campos, H. %A Chaves, P. H. %A é, L. %A Giles, G. G. %A mez-Aracena, J. %A Hodge, A. M. %A Hu, F. B. %A Jansson, J. H. %A Johansson, I. %A Khaw, K. T. %A Koh, W. P. %A Lemaitre, R. N. %A Lind, L. %A Luben, R. N. %A Rimm, E. B. %A rus, U. %A Samieri, C. %A Franks, P. W. %A Siscovick, D. S. %A Stampfer, M. %A Steffen, L. M. %A Steffen, B. T. %A Tsai, M. Y. %A van Dam, R. M. %A Voutilainen, S. %A Willett, W. C. %A Woodward, M. %A Mozaffarian, D. %X -3 polyunsaturated fatty acids for primary prevention of coronary heart disease (CHD) remains controversial. Most prior longitudinal studies evaluated self-reported consumption rather than biomarkers.\ -3) for incident CHD.\ A global consortium of 19 studies identified by November 2014.\ -3 biomarkers and ascertained CHD.\ -6 levels, and FADS desaturase genes.\ Incident total CHD, fatal CHD, and nonfatal myocardial infarction (MI).\ -3 biomarkers ALA, DPA, and DHA were associated with a lower risk of fatal CHD, with relative risks (RRs) of 0.91 (95% CI, 0.84-0.98) for ALA, 0.90 (95% CI, 0.85-0.96) for DPA, and 0.90 (95% CI, 0.84-0.96) for DHA. Although DPA was associated with a lower risk of total CHD (RR, 0.94; 95% CI, 0.90-0.99), ALA (RR, 1.00; 95% CI, 0.95-1.05), EPA (RR, 0.94; 95% CI, 0.87-1.02), and DHA (RR, 0.95; 95% CI, 0.91-1.00) were not. Significant associations with nonfatal MI were not evident. Associations appeared generally stronger in phospholipids and total plasma. Restricted cubic splines did not identify evidence of nonlinearity in dose responses.\ -3 fatty acids are associated with a modestly lower incidence of fatal CHD. %B JAMA Intern Med %V 176 %P 1155–1166 %8 Aug %G eng %0 Journal Article %J J Am Coll Cardiol %D 2016 %T 52 Genetic Loci Influencing Myocardial Mass. %A van der Harst, Pim %A van Setten, Jessica %A Verweij, Niek %A Vogler, Georg %A Franke, Lude %A Maurano, Matthew T %A Wang, Xinchen %A Mateo Leach, Irene %A Eijgelsheim, Mark %A Sotoodehnia, Nona %A Hayward, Caroline %A Sorice, Rossella %A Meirelles, Osorio %A Lyytikäinen, Leo-Pekka %A Polasek, Ozren %A Tanaka, Toshiko %A Arking, Dan E %A Ulivi, Sheila %A Trompet, Stella %A Müller-Nurasyid, Martina %A Smith, Albert V %A Dörr, Marcus %A Kerr, Kathleen F %A Magnani, Jared W %A del Greco M, Fabiola %A Zhang, Weihua %A Nolte, Ilja M %A Silva, Claudia T %A Padmanabhan, Sandosh %A Tragante, Vinicius %A Esko, Tõnu %A Abecasis, Goncalo R %A Adriaens, Michiel E %A Andersen, Karl %A Barnett, Phil %A Bis, Joshua C %A Bodmer, Rolf %A Buckley, Brendan M %A Campbell, Harry %A Cannon, Megan V %A Chakravarti, Aravinda %A Chen, Lin Y %A Delitala, Alessandro %A Devereux, Richard B %A Doevendans, Pieter A %A Dominiczak, Anna F %A Ferrucci, Luigi %A Ford, Ian %A Gieger, Christian %A Harris, Tamara B %A Haugen, Eric %A Heinig, Matthias %A Hernandez, Dena G %A Hillege, Hans L %A Hirschhorn, Joel N %A Hofman, Albert %A Hubner, Norbert %A Hwang, Shih-Jen %A Iorio, Annamaria %A Kähönen, Mika %A Kellis, Manolis %A Kolcic, Ivana %A Kooner, Ishminder K %A Kooner, Jaspal S %A Kors, Jan A %A Lakatta, Edward G %A Lage, Kasper %A Launer, Lenore J %A Levy, Daniel %A Lundby, Alicia %A Macfarlane, Peter W %A May, Dalit %A Meitinger, Thomas %A Metspalu, Andres %A Nappo, Stefania %A Naitza, Silvia %A Neph, Shane %A Nord, Alex S %A Nutile, Teresa %A Okin, Peter M %A Olsen, Jesper V %A Oostra, Ben A %A Penninger, Josef M %A Pennacchio, Len A %A Pers, Tune H %A Perz, Siegfried %A Peters, Annette %A Pinto, Yigal M %A Pfeufer, Arne %A Pilia, Maria Grazia %A Pramstaller, Peter P %A Prins, Bram P %A Raitakari, Olli T %A Raychaudhuri, Soumya %A Rice, Ken M %A Rossin, Elizabeth J %A Rotter, Jerome I %A Schafer, Sebastian %A Schlessinger, David %A Schmidt, Carsten O %A Sehmi, Jobanpreet %A Silljé, Herman H W %A Sinagra, Gianfranco %A Sinner, Moritz F %A Slowikowski, Kamil %A Soliman, Elsayed Z %A Spector, Timothy D %A Spiering, Wilko %A Stamatoyannopoulos, John A %A Stolk, Ronald P %A Strauch, Konstantin %A Tan, Sian-Tsung %A Tarasov, Kirill V %A Trinh, Bosco %A Uitterlinden, André G %A van den Boogaard, Malou %A van Duijn, Cornelia M %A van Gilst, Wiek H %A Viikari, Jorma S %A Visscher, Peter M %A Vitart, Veronique %A Völker, Uwe %A Waldenberger, Melanie %A Weichenberger, Christian X %A Westra, Harm-Jan %A Wijmenga, Cisca %A Wolffenbuttel, Bruce H %A Yang, Jian %A Bezzina, Connie R %A Munroe, Patricia B %A Snieder, Harold %A Wright, Alan F %A Rudan, Igor %A Boyer, Laurie A %A Asselbergs, Folkert W %A van Veldhuisen, Dirk J %A Stricker, Bruno H %A Psaty, Bruce M %A Ciullo, Marina %A Sanna, Serena %A Lehtimäki, Terho %A Wilson, James F %A Bandinelli, Stefania %A Alonso, Alvaro %A Gasparini, Paolo %A Jukema, J Wouter %A Kääb, Stefan %A Gudnason, Vilmundur %A Felix, Stephan B %A Heckbert, Susan R %A de Boer, Rudolf A %A Newton-Cheh, Christopher %A Hicks, Andrew A %A Chambers, John C %A Jamshidi, Yalda %A Visel, Axel %A Christoffels, Vincent M %A Isaacs, Aaron %A Samani, Nilesh J %A de Bakker, Paul I W %X

BACKGROUND: Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death.

OBJECTIVES: This meta-analysis sought to gain insights into the genetic determinants of myocardial mass.

METHODS: We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment.

RESULTS: We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p < 1 × 10(-8). These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus. We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in vitro and in vivo.

CONCLUSIONS: Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets.

%B J Am Coll Cardiol %V 68 %P 1435-48 %8 2016 Sep 27 %G eng %N 13 %R 10.1016/j.jacc.2016.07.729 %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 PLoS One %D 2016 %T Association of Smoking, Alcohol, and Obesity with Cardiovascular Death and Ischemic Stroke in Atrial Fibrillation: The Atherosclerosis Risk in Communities (ARIC) Study and Cardiovascular Health Study (CHS). %A Kwon, Younghoon %A Norby, Faye L %A Jensen, Paul N %A Agarwal, Sunil K %A Soliman, Elsayed Z %A Lip, Gregory Y H %A Longstreth, W T %A Alonso, Alvaro %A Heckbert, Susan R %A Chen, Lin Y %K Aged %K Alcohol Drinking %K Atrial Fibrillation %K Cardiovascular Diseases %K Female %K Humans %K Male %K Middle Aged %K Obesity %K Smoking %K Stroke %X

Atrial fibrillation (AF) is associated with an increased risk of ischemic stroke and cardiovascular (CV) death. Whether modifiable lifestyle risk factors are associated with these CV outcomes in AF is unknown. Among Atherosclerosis Risk in Communities (ARIC) study and Cardiovascular Health Study (CHS) participants with incident AF, we estimated the risk of composite endpoint of ischemic stroke or CV death associated with candidate modifiable risk factor (smoking, heavy alcohol consumption, or high body mass index [BMI]), and computed the C-statistic, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) of incorporating each factor into the CHA2DS2-VASc. Among 1222 ARIC (mean age: 63.4) and 756 CHS (mean age: 79.1) participants with incident AF, during mean follow-up of 6.9 years and 5.7 years, there were 332 and 335 composite events respectively. Compared with never smokers, current smokers had a higher incidence of the composite endpoint in ARIC [HR: 1.65 (1.21-2.26)] but not in CHS [HR: 1.05 (0.69-1.61)]. In ARIC, the addition of current smoking did not improve risk prediction over and above the CHA2DS2-VASc. No significant associations were observed with alcohol consumption or BMI with CVD outcomes in AF patients from either cohort. Smoking is associated with an increased risk of ischemic stroke or CV death in ARIC, which comprised mostly middle-aged to young-old (65-74 years), but not in CHS, which comprised mostly middle-old or oldest-old (≥75 years) adults with AF. However, addition of smoking to the CHA2DS2-VASc score did not improve risk prediction of these outcomes.

%B PLoS One %V 11 %P e0147065 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26756465?dopt=Abstract %R 10.1371/journal.pone.0147065 %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 Thromb Res %D 2016 %T Body size measures, hemostatic and inflammatory markers and risk of venous thrombosis: The Longitudinal Investigation of Thromboembolism Etiology. %A Cushman, Mary %A O'Meara, Ellen S %A Heckbert, Susan R %A Zakai, Neil A %A Rosamond, Wayne %A Folsom, Aaron R %X

OBJECTIVE: Obesity is an important venous thrombosis (VT) risk factor but the reasons for this are unclear.

MATERIALS AND METHODS: In a cohort of 20,914 individuals aged 45 and older without prior VT, we calculated the relative risk (RR) of VT over 12.6years follow-up according to baseline body size measures, and studied whether associations were mediated by biomarkers of hemostasis and inflammation that are related to adiposity.

RESULTS: Greater levels of all body size measures (weight, height, waist, hip circumference, calf circumference, body-mass index, waist-hip ratio, fat mass and fat-free mass) were associated with increased risk of VT, with 4th versus 1st quartile RRs of 1.5-3.0. There were no multiplicative interactions of biomarkers with obesity status. Adjustment for biomarkers associated with VT risk and body size (factors VII and VIII, von Willebrand factor, partial thromboplastin time, D-dimer, C-reactive protein and factor XI) only marginally lowered, or did not impact, the RRs associated with body size measures.

CONCLUSIONS: Greater body size, by multiple measures, is a risk factor for VT. Associations were not mediated by circulating levels of studied biomarkers suggesting that body size relates to VT because of physical factors associated with blood flow, not the hypercoagulability or inflammation associated with adiposity.

%B Thromb Res %V 144 %P 127-32 %8 2016 Aug %G eng %R 10.1016/j.thromres.2016.06.012 %0 Journal Article %J J Am Geriatr Soc %D 2016 %T Can a Healthy Lifestyle Compress the Disabled Period in Older Adults? %A Jacob, Mini E %A Yee, Laura M %A Diehr, Paula H %A Arnold, Alice M %A Thielke, Stephen M %A Chaves, Paulo H M %A Gobbo, Liana Del %A Hirsch, Calvin %A Siscovick, David %A Newman, Anne B %X

OBJECTIVES: To determine whether lifestyle factors, measured late in life, could compress the disabled period toward the end of life.

DESIGN: Community-based cohort study of older adults followed from 1989 to 2015.

SETTING: Four U.S. communities.

PARTICIPANTS: Community-living men and women aged 65 and older (N = 5,248, mean age 72.7 ± 5.5, 57% female, 15.2% minority) who were not wheelchair dependent and were able to give informed consent at baseline.

MEASUREMENTS: Multiple lifestyle factors, including smoking, alcohol consumption, physical activity, diet, body mass index (BMI), social networks, and social support, were measured at baseline. Activities of daily living (ADLs) were assessed at baseline and throughout follow-up. Years of life (YoL) was defined as years until death. Years of able life (YAL) was defined as years without any ADL difficulty. YAL/YoL%, the proportion of life lived able, was used to indicate the relative compression or expansion of the disabled period.

RESULTS: The average duration of disabled years was 4.5 (out of 15.4 mean YoL) for women and 2.9 (out of 12.4 mean YoL) for men. In a multivariable model, obesity was associated with 7.3 percentage points (95% confidence interval (CI) = 5.4-9.2) lower YAL/YoL% than normal weight. Scores in the lowest quintile of the Alternate Healthy Eating Index were associated with a 3.7% (95% CI = 1.6-5.9) lower YAL/YoL% than scores in the highest quintile. Every 25 blocks walked in a week was associated with 0.5 percentage points (95% CI = 0.3-0.8) higher YAL/YoL%.

CONCLUSION: The effects of healthy lifestyle factors on the proportion of future life lived free of disability indicate that the disabled period can be compressed, given the right combination of these factors.

%B J Am Geriatr Soc %V 64 %P 1952-1961 %8 2016 Oct %G eng %N 10 %R 10.1111/jgs.14314 %0 Journal Article %J Hum Mol Genet %D 2016 %T Common variants in DRD2 are associated with sleep duration: the CARe consortium. %A Cade, Brian E %A Gottlieb, Daniel J %A Lauderdale, Diane S %A Bennett, David A %A Buchman, Aron S %A Buxbaum, Sarah G %A De Jager, Philip L %A Evans, Daniel S %A Fulop, Tibor %A Gharib, Sina A %A Johnson, W Craig %A Kim, Hyun %A Larkin, Emma K %A Lee, Seung Ku %A Lim, Andrew S %A Punjabi, Naresh M %A Shin, Chol %A Stone, Katie L %A Tranah, Gregory J %A Weng, Jia %A Yaffe, Kristine %A Zee, Phyllis C %A Patel, Sanjay R %A Zhu, Xiaofeng %A Redline, Susan %A Saxena, Richa %K Cohort Studies %K Ethnic Groups %K Humans %K Polymorphism, Single Nucleotide %K Polysomnography %K Receptors, Dopamine D2 %K Sleep %K Time Factors %X

Sleep duration is implicated in the etiologies of chronic diseases and premature mortality. However, the genetic basis for sleep duration is poorly defined. We sought to identify novel genetic components influencing sleep duration in a multi-ethnic sample. Meta-analyses were conducted of genetic associations with self-reported, habitual sleep duration from seven Candidate Gene Association Resource (CARe) cohorts of over 25 000 individuals of African, Asian, European and Hispanic American ancestry. All individuals were genotyped for ∼50 000 SNPs from 2000 candidate heart, lung, blood and sleep genes. African-Americans had additional genome-wide genotypes. Four cohorts provided replication. A SNP (rs17601612) in the dopamine D2 receptor gene (DRD2) was significantly associated with sleep duration (P = 9.8 × 10(-7)). Conditional analysis identified a second DRD2 signal with opposite effects on sleep duration. In exploratory analysis, suggestive association was observed for rs17601612 with polysomnographically determined sleep latency (P = 0.002). The lead DRD2 signal was recently identified in a schizophrenia GWAS, and a genetic risk score of 11 additional schizophrenia GWAS loci genotyped on the IBC array was also associated with longer sleep duration (P = 0.03). These findings support a role for DRD2 in influencing sleep duration. Our work motivates future pharmocogenetics research on alerting agents such as caffeine and modafinil that interact with the dopaminergic pathway and further investigation of genetic overlap between sleep and neuro-psychiatric traits.

%B Hum Mol Genet %V 25 %P 167-79 %8 2016 Jan 1 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26464489?dopt=Abstract %R 10.1093/hmg/ddv434 %0 Journal Article %J Circulation %D 2016 %T Development and Validation of a Sudden Cardiac Death Prediction Model for the General Population. %A Deo, Rajat %A Norby, Faye L %A Katz, Ronit %A Sotoodehnia, Nona %A Adabag, Selcuk %A deFilippi, Christopher R %A Kestenbaum, Bryan %A Chen, Lin Y %A Heckbert, Susan R %A Folsom, Aaron R %A Kronmal, Richard A %A Konety, Suma %A Patton, Kristen K %A Siscovick, David %A Shlipak, Michael G %A Alonso, Alvaro %X

BACKGROUND: Most sudden cardiac death (SCD) events occur in the general population among persons who do not have any prior history of clinical heart disease. We sought to develop a predictive model of SCD among US adults.

METHODS: We evaluated a series of demographic, clinical, laboratory, electrocardiographic, and echocardiographic measures in participants in the ARIC study (Atherosclerosis Risk in Communities) (n=13 677) and the CHS (Cardiovascular Health Study) (n=4207) who were free of baseline cardiovascular disease. Our initial objective was to derive a SCD prediction model using the ARIC cohort and validate it in CHS. Independent risk factors for SCD were first identified in the ARIC cohort to derive a 10-year risk model of SCD. We compared the prediction of SCD with non-SCD and all-cause mortality in both the derivation and validation cohorts. Furthermore, we evaluated whether the SCD prediction equation was better at predicting SCD than the 2013 American College of Cardiology/American Heart Association Cardiovascular Disease Pooled Cohort risk equation.

RESULTS: There were a total of 345 adjudicated SCD events in our analyses, and the 12 independent risk factors in the ARIC study included age, male sex, black race, current smoking, systolic blood pressure, use of antihypertensive medication, diabetes mellitus, serum potassium, serum albumin, high-density lipoprotein, estimated glomerular filtration rate, and QTc interval. During a 10-year follow-up period, a model combining these risk factors showed good to excellent discrimination for SCD risk (c-statistic 0.820 in ARIC and 0.745 in CHS). The SCD prediction model was slightly better in predicting SCD than the 2013 American College of Cardiology/American Heart Association Pooled Cohort risk equations (c-statistic 0.808 in ARIC and 0.743 in CHS). Only the SCD prediction model, however, demonstrated similar and accurate prediction for SCD using both the original, uncalibrated score and the recalibrated equation. Finally, in the echocardiographic subcohort, a left ventricular ejection fraction <50% was present in only 1.1% of participants and did not enhance SCD prediction.

CONCLUSIONS: Our study is the first to derive and validate a generalizable risk score that provides well-calibrated, absolute risk estimates across different risk strata in an adult population of white and black participants without a clinical diagnosis of cardiovascular disease.

%B Circulation %V 134 %P 806-16 %8 2016 Sep 13 %G eng %N 11 %R 10.1161/CIRCULATIONAHA.116.023042 %0 Journal Article %J Diabetes Res Clin Pract %D 2016 %T Diabetes mellitus and venous thromboembolism: A systematic review and meta-analysis. %A Bell, Elizabeth J %A Folsom, Aaron R %A Lutsey, Pamela L %A Selvin, Elizabeth %A Zakai, Neil A %A Cushman, Mary %A Alonso, Alvaro %X

UNLABELLED: Diabetes mellitus (DM) may be a risk factor for venous thromboembolism (VTE) but results are inconsistent.

AIM: We conducted a systematic review and meta-analysis of epidemiologic studies to quantify the association between DM and VTE.

METHODS AND RESULTS: We included studies identified in PubMed, Web of Science, and CINAHL through 07/31/2014. We identified 19 studies that met our selection criteria. We pooled RRs using a random-effects model: the pooled RR for the association of DM with VTE was 1.10 (95% CI: 0.94-1.29). Between-study heterogeneity was explored with a forest plot, funnel plot, meta-regression, and a stratified analysis. Between-study heterogeneity was observed and not explained by study design, method of DM assessment, or degree of adjustment for confounding. Sensitivity analyses omitted one study at a time to assess the influence of any single study on the pooled estimate. These analyses indicated that one large study was highly influential; when this study was excluded, the pooled estimate increased and just reached statistical significance: 1.16 (95% CI: 1.01-1.34).

CONCLUSIONS: This meta-analysis suggests either no association or a modest positive one between DM and VTE in the general population. DM is unlikely to play a major role in VTE development.

%B Diabetes Res Clin Pract %V 111 %P 10-8 %8 2016 Jan %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/26612139?dopt=Abstract %R 10.1016/j.diabres.2015.10.019 %0 Journal Article %J J Am Coll Cardiol %D 2016 %T Diagnostic Yield and Clinical Utility of Sequencing Familial Hypercholesterolemia Genes in Patients With Severe Hypercholesterolemia. %A Khera, Amit V %A Won, Hong-Hee %A Peloso, Gina M %A Lawson, Kim S %A Bartz, Traci M %A Deng, Xuan %A van Leeuwen, Elisabeth M %A Natarajan, Pradeep %A Emdin, Connor A %A Bick, Alexander G %A Morrison, Alanna C %A Brody, Jennifer A %A Gupta, Namrata %A Nomura, Akihiro %A Kessler, Thorsten %A Duga, Stefano %A Bis, Joshua C %A van Duijn, Cornelia M %A Cupples, L Adrienne %A Psaty, Bruce %A Rader, Daniel J %A Danesh, John %A Schunkert, Heribert %A McPherson, Ruth %A Farrall, Martin %A Watkins, Hugh %A Lander, Eric %A Wilson, James G %A Correa, Adolfo %A Boerwinkle, Eric %A Merlini, Piera Angelica %A Ardissino, Diego %A Saleheen, Danish %A Gabriel, Stacey %A Kathiresan, Sekar %X

BACKGROUND: Approximately 7% of American adults have severe hypercholesterolemia (untreated low-density lipoprotein [LDL] cholesterol ≥190 mg/dl), which may be due to familial hypercholesterolemia (FH). Lifelong LDL cholesterol elevations in FH mutation carriers may confer coronary artery disease (CAD) risk beyond that captured by a single LDL cholesterol measurement.

OBJECTIVES: This study assessed the prevalence of an FH mutation among those with severe hypercholesterolemia and determined whether CAD risk varies according to mutation status beyond the observed LDL cholesterol level.

METHODS: Three genes causative for FH (LDLR, APOB, and PCSK9) were sequenced in 26,025 participants from 7 case-control studies (5,540 CAD case subjects, 8,577 CAD-free control subjects) and 5 prospective cohort studies (11,908 participants). FH mutations included loss-of-function variants in LDLR, missense mutations in LDLR predicted to be damaging, and variants linked to FH in ClinVar, a clinical genetics database.

RESULTS: Among 20,485 CAD-free control and prospective cohort participants, 1,386 (6.7%) had LDL cholesterol ≥190 mg/dl; of these, only 24 (1.7%) carried an FH mutation. Within any stratum of observed LDL cholesterol, risk of CAD was higher among FH mutation carriers than noncarriers. Compared with a reference group with LDL cholesterol <130 mg/dl and no mutation, participants with LDL cholesterol ≥190 mg/dl and no FH mutation had a 6-fold higher risk for CAD (odds ratio: 6.0; 95% confidence interval: 5.2 to 6.9), whereas those with both LDL cholesterol ≥190 mg/dl and an FH mutation demonstrated a 22-fold increased risk (odds ratio: 22.3; 95% confidence interval: 10.7 to 53.2). In an analysis of participants with serial lipid measurements over many years, FH mutation carriers had higher cumulative exposure to LDL cholesterol than noncarriers.

CONCLUSIONS: Among participants with LDL cholesterol ≥190 mg/dl, gene sequencing identified an FH mutation in <2%. However, for any observed LDL cholesterol, FH mutation carriers had substantially increased risk for CAD.

%B J Am Coll Cardiol %V 67 %P 2578-89 %8 2016 Jun 7 %G eng %N 22 %1 http://www.ncbi.nlm.nih.gov/pubmed/27050191?dopt=Abstract %R 10.1016/j.jacc.2016.03.520 %0 Journal Article %J PLoS Genet %D 2016 %T Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure. %A Smith, J Gustav %A Felix, Janine F %A Morrison, Alanna C %A Kalogeropoulos, Andreas %A Trompet, Stella %A Wilk, Jemma B %A Gidlöf, Olof %A Wang, Xinchen %A Morley, Michael %A Mendelson, Michael %A Joehanes, Roby %A Ligthart, Symen %A Shan, Xiaoyin %A Bis, Joshua C %A Wang, Ying A %A Sjögren, Marketa %A Ngwa, Julius %A Brandimarto, Jeffrey %A Stott, David J %A Aguilar, David %A Rice, Kenneth M %A Sesso, Howard D %A Demissie, Serkalem %A Buckley, Brendan M %A Taylor, Kent D %A Ford, Ian %A Yao, Chen %A Liu, Chunyu %A Sotoodehnia, Nona %A van der Harst, Pim %A Stricker, Bruno H Ch %A Kritchevsky, Stephen B %A Liu, Yongmei %A Gaziano, J Michael %A Hofman, Albert %A Moravec, Christine S %A Uitterlinden, André G %A Kellis, Manolis %A van Meurs, Joyce B %A Margulies, Kenneth B %A Dehghan, Abbas %A Levy, Daniel %A Olde, Björn %A Psaty, Bruce M %A Cupples, L Adrienne %A Jukema, J Wouter %A Djoussé, Luc %A Franco, Oscar H %A Boerwinkle, Eric %A Boyer, Laurie A %A Newton-Cheh, Christopher %A Butler, Javed %A Vasan, Ramachandran S %A Cappola, Thomas P %A Smith, Nicholas L %X

Failure of the human heart to maintain sufficient output of blood for the demands of the body, heart failure, is a common condition with high mortality even with modern therapeutic alternatives. To identify molecular determinants of mortality in patients with new-onset heart failure, we performed a meta-analysis of genome-wide association studies and follow-up genotyping in independent populations. We identified and replicated an association for a genetic variant on chromosome 5q22 with 36% increased risk of death in subjects with heart failure (rs9885413, P = 2.7x10-9). We provide evidence from reporter gene assays, computational predictions and epigenomic marks that this polymorphism increases activity of an enhancer region active in multiple human tissues. The polymorphism was further reproducibly associated with a DNA methylation signature in whole blood (P = 4.5x10-40) that also associated with allergic sensitization and expression in blood of the cytokine TSLP (P = 1.1x10-4). Knockdown of the transcription factor predicted to bind the enhancer region (NHLH1) in a human cell line (HEK293) expressing NHLH1 resulted in lower TSLP expression. In addition, we observed evidence of recent positive selection acting on the risk allele in populations of African descent. Our findings provide novel genetic leads to factors that influence mortality in patients with heart failure.

%B PLoS Genet %V 12 %P e1006034 %8 2016 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/27149122?dopt=Abstract %R 10.1371/journal.pgen.1006034 %0 Journal Article %J Mol Psychiatry %D 2016 %T A DNA methylation biomarker of alcohol consumption. %A Liu, C %A Marioni, R E %A Hedman, Å K %A Pfeiffer, L %A Tsai, P-C %A Reynolds, L M %A Just, A C %A Duan, Q %A Boer, C G %A Tanaka, T %A Elks, C E %A Aslibekyan, S %A Brody, J A %A Kühnel, B %A Herder, C %A Almli, L M %A Zhi, D %A Wang, Y %A Huan, T %A Yao, C %A Mendelson, M M %A Joehanes, R %A Liang, L %A Love, S-A %A Guan, W %A Shah, S %A McRae, A F %A Kretschmer, A %A Prokisch, H %A Strauch, K %A Peters, A %A Visscher, P M %A Wray, N R %A Guo, X %A Wiggins, K L %A Smith, A K %A Binder, E B %A Ressler, K J %A Irvin, M R %A Absher, D M %A Hernandez, D %A Ferrucci, L %A Bandinelli, S %A Lohman, K %A Ding, J %A Trevisi, L %A Gustafsson, S %A Sandling, J H %A Stolk, L %A Uitterlinden, A G %A Yet, I %A Castillo-Fernandez, J E %A Spector, T D %A Schwartz, J D %A Vokonas, P %A Lind, L %A Li, Y %A Fornage, M %A Arnett, D K %A Wareham, N J %A Sotoodehnia, N %A Ong, K K %A van Meurs, J B J %A Conneely, K N %A Baccarelli, A A %A Deary, I J %A Bell, J T %A North, K E %A Liu, Y %A Waldenberger, M %A London, S J %A Ingelsson, E %A Levy, D %X

The lack of reliable measures of alcohol intake is a major obstacle to the diagnosis and treatment of alcohol-related diseases. Epigenetic modifications such as DNA methylation may provide novel biomarkers of alcohol use. To examine this possibility, we performed an epigenome-wide association study of methylation of cytosine-phosphate-guanine dinucleotide (CpG) sites in relation to alcohol intake in 13 population-based cohorts (ntotal=13 317; 54% women; mean age across cohorts 42-76 years) using whole blood (9643 European and 2423 African ancestries) or monocyte-derived DNA (588 European, 263 African and 400 Hispanic ancestry) samples. We performed meta-analysis and variable selection in whole-blood samples of people of European ancestry (n=6926) and identified 144 CpGs that provided substantial discrimination (area under the curve=0.90-0.99) for current heavy alcohol intake (⩾42 g per day in men and ⩾28 g per day in women) in four replication cohorts. The ancestry-stratified meta-analysis in whole blood identified 328 (9643 European ancestry samples) and 165 (2423 African ancestry samples) alcohol-related CpGs at Bonferroni-adjusted P<1 × 10(-7). Analysis of the monocyte-derived DNA (n=1251) identified 62 alcohol-related CpGs at P<1 × 10(-7). In whole-blood samples of people of European ancestry, we detected differential methylation in two neurotransmitter receptor genes, the γ-Aminobutyric acid-A receptor delta and γ-aminobutyric acid B receptor subunit 1; their differential methylation was associated with expression levels of a number of genes involved in immune function. In conclusion, we have identified a robust alcohol-related DNA methylation signature and shown the potential utility of DNA methylation as a clinically useful diagnostic test to detect current heavy alcohol consumption.Molecular Psychiatry advance online publication, 15 November 2016; doi:10.1038/mp.2016.192.

%B Mol Psychiatry %8 2016 Nov 15 %G eng %R 10.1038/mp.2016.192 %0 Journal Article %J Genome Biol %D 2016 %T DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases. %A Ligthart, Symen %A Marzi, Carola %A Aslibekyan, Stella %A Mendelson, Michael M %A Conneely, Karen N %A Tanaka, Toshiko %A Colicino, Elena %A Waite, Lindsay L %A Joehanes, Roby %A Guan, Weihua %A Brody, Jennifer A %A Elks, Cathy %A Marioni, Riccardo %A Jhun, Min A %A Agha, Golareh %A Bressler, Jan %A Ward-Caviness, Cavin K %A Chen, Brian H %A Huan, Tianxiao %A Bakulski, Kelly %A Salfati, Elias L %A Fiorito, Giovanni %A Wahl, Simone %A Schramm, Katharina %A Sha, Jin %A Hernandez, Dena G %A Just, Allan C %A Smith, Jennifer A %A Sotoodehnia, Nona %A Pilling, Luke C %A Pankow, James S %A Tsao, Phil S %A Liu, Chunyu %A Zhao, Wei %A Guarrera, Simonetta %A Michopoulos, Vasiliki J %A Smith, Alicia K %A Peters, Marjolein J %A Melzer, David %A Vokonas, Pantel %A Fornage, Myriam %A Prokisch, Holger %A Bis, Joshua C %A Chu, Audrey Y %A Herder, Christian %A Grallert, Harald %A Yao, Chen %A Shah, Sonia %A McRae, Allan F %A Lin, Honghuang %A Horvath, Steve %A Fallin, Daniele %A Hofman, Albert %A Wareham, Nicholas J %A Wiggins, Kerri L %A Feinberg, Andrew P %A Starr, John M %A Visscher, Peter M %A Murabito, Joanne M %A Kardia, Sharon L R %A Absher, Devin M %A Binder, Elisabeth B %A Singleton, Andrew B %A Bandinelli, Stefania %A Peters, Annette %A Waldenberger, Melanie %A Matullo, Giuseppe %A Schwartz, Joel D %A Demerath, Ellen W %A Uitterlinden, André G %A van Meurs, Joyce B J %A Franco, Oscar H %A Chen, Yii-Der Ida %A Levy, Daniel %A Turner, Stephen T %A Deary, Ian J %A Ressler, Kerry J %A Dupuis, Josée %A Ferrucci, Luigi %A Ong, Ken K %A Assimes, Themistocles L %A Boerwinkle, Eric %A Koenig, Wolfgang %A Arnett, Donna K %A Baccarelli, Andrea A %A Benjamin, Emelia J %A Dehghan, Abbas %X

BACKGROUND: Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation.

RESULTS: We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P < 1.15 × 10(-7)) in the discovery panel of European ancestry and replicated (P < 2.29 × 10(-4)) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associated with whole blood gene expression in cis (P < 8.47 × 10(-5)), ten (17%) CpG sites were associated with a nearby genetic variant (P < 2.50 × 10(-3)), and 51 (88%) were also associated with at least one related cardiometabolic entity (P < 9.58 × 10(-5)). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants.

CONCLUSION: We have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation.

%B Genome Biol %V 17 %P 255 %8 2016 Dec 12 %G eng %N 1 %R 10.1186/s13059-016-1119-5 %0 Journal Article %J Circ Cardiovasc Imaging %D 2016 %T Echocardiographic Predictors of Sudden Cardiac Death: The Atherosclerosis Risk in Communities Study and Cardiovascular Health Study. %A Konety, Suma H %A Koene, Ryan J %A Norby, Faye L %A Wilsdon, Tony %A Alonso, Alvaro %A Siscovick, David %A Sotoodehnia, Nona %A Gottdiener, John %A Fox, Ervin R %A Chen, Lin Y %A Adabag, Selcuk %A Folsom, Aaron R %X

BACKGROUND: This study assessed the echocardiographic predictors of sudden cardiac death (SCD) within 2 population-based cohorts.

METHODS AND RESULTS: Echocardiograms were obtained on 2383 participants (1993-1995) from the ARIC study (Atherosclerosis Risk in Communities; 100% black) and 5366 participants (1987-1989 and 1994-1995) from the CHS (Cardiovascular Health Study). The main outcome was physician-adjudicated SCD. We used Cox proportional-hazards models with incident coronary heart disease and heart failure as time-dependent covariates to assess the association between echocardiographic variables and SCD, adjusting for Framingham risk score variables, coronary heart disease, and renal function. Cohort-specific results were meta-analyzed. During a median follow-up of 7.3 and 13.1 years, 44 ARIC study participants and 275 CHS participants had SCD, respectively. In the meta-analyzed results, the adjusted hazard ratios (95% confidence intervals) for predictors of SCD were 3.07 (2.29-4.11) for reduced left ventricular ejection fraction; 1.85 (1.36-2.52) for mitral annular calcification; 1.64 (1.07-2.51) for mitral E/A >1.5, and 1.52 (1.14-2.02) for mitral E/A <0.7 (versus mitral E/A 0.7-1.5); 1.30 (1.15-1.48) per 1 SD increase in left ventricular mass; and 1.15 (1.02-1.30) per 1 SD increase in left atrial diameter. A receiver-operating characteristic model for prediction of SCD using Framingham risk score variables had a C statistic of 0.61 for ARIC study and 0.67 for CHS; the full multivariable model including all echocardiographic variables had a C statistic of 0.76 for ARIC study and 0.74 for CHS.

CONCLUSIONS: In addition to reduced left ventricular ejection fraction, we identified other echocardiographic-derived variables predictive for SCD that provided incremental value compared with clinical risk factors.

%B Circ Cardiovasc Imaging %V 9 %8 2016 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/27496550?dopt=Abstract %R 10.1161/CIRCIMAGING.115.004431 %0 Journal Article %J Genet Epidemiol %D 2016 %T An Empirical Comparison of Joint and Stratified Frameworks for Studying G × E Interactions: Systolic Blood Pressure and Smoking in the CHARGE Gene-Lifestyle Interactions Working Group. %A Sung, Yun Ju %A Winkler, Thomas W %A Manning, Alisa K %A Aschard, Hugues %A Gudnason, Vilmundur %A Harris, Tamara B %A Smith, Albert V %A Boerwinkle, Eric %A Brown, Michael R %A Morrison, Alanna C %A Fornage, Myriam %A Lin, Li-An %A Richard, Melissa %A Bartz, Traci M %A Psaty, Bruce M %A Hayward, Caroline %A Polasek, Ozren %A Marten, Jonathan %A Rudan, Igor %A Feitosa, Mary F %A Kraja, Aldi T %A Province, Michael A %A Deng, Xuan %A Fisher, Virginia A %A Zhou, Yanhua %A Bielak, Lawrence F %A Smith, Jennifer %A Huffman, Jennifer E %A Padmanabhan, Sandosh %A Smith, Blair H %A Ding, Jingzhong %A Liu, Yongmei %A Lohman, Kurt %A Bouchard, Claude %A Rankinen, Tuomo %A Rice, Treva K %A Arnett, Donna %A Schwander, Karen %A Guo, Xiuqing %A Palmas, Walter %A Rotter, Jerome I %A Alfred, Tamuno %A Bottinger, Erwin P %A Loos, Ruth J F %A Amin, Najaf %A Franco, Oscar H %A van Duijn, Cornelia M %A Vojinovic, Dina %A Chasman, Daniel I %A Ridker, Paul M %A Rose, Lynda M %A Kardia, Sharon %A Zhu, Xiaofeng %A Rice, Kenneth %A Borecki, Ingrid B %A Rao, Dabeeru C %A Gauderman, W James %A Cupples, L Adrienne %X

Studying gene-environment (G × E) interactions is important, as they extend our knowledge of the genetic architecture of complex traits and may help to identify novel variants not detected via analysis of main effects alone. The main statistical framework for studying G × E interactions uses a single regression model that includes both the genetic main and G × E interaction effects (the "joint" framework). The alternative "stratified" framework combines results from genetic main-effect analyses carried out separately within the exposed and unexposed groups. Although there have been several investigations using theory and simulation, an empirical comparison of the two frameworks is lacking. Here, we compare the two frameworks using results from genome-wide association studies of systolic blood pressure for 3.2 million low frequency and 6.5 million common variants across 20 cohorts of European ancestry, comprising 79,731 individuals. Our cohorts have sample sizes ranging from 456 to 22,983 and include both family-based and population-based samples. In cohort-specific analyses, the two frameworks provided similar inference for population-based cohorts. The agreement was reduced for family-based cohorts. In meta-analyses, agreement between the two frameworks was less than that observed in cohort-specific analyses, despite the increased sample size. In meta-analyses, agreement depended on (1) the minor allele frequency, (2) inclusion of family-based cohorts in meta-analysis, and (3) filtering scheme. The stratified framework appears to approximate the joint framework well only for common variants in population-based cohorts. We conclude that the joint framework is the preferred approach and should be used to control false positives when dealing with low-frequency variants and/or family-based cohorts.

%B Genet Epidemiol %V 40 %P 404-15 %8 2016 Jul %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/27230302?dopt=Abstract %R 10.1002/gepi.21978 %0 Journal Article %J Circ Cardiovasc Genet %D 2016 %T Epigenetic Signatures of Cigarette Smoking. %A Joehanes, Roby %A Just, Allan C %A Marioni, Riccardo E %A Pilling, Luke C %A Reynolds, Lindsay M %A Mandaviya, Pooja R %A Guan, Weihua %A Xu, Tao %A Elks, Cathy E %A Aslibekyan, Stella %A Moreno-Macias, Hortensia %A Smith, Jennifer A %A Brody, Jennifer A %A Dhingra, Radhika %A Yousefi, Paul %A Pankow, James S %A Kunze, Sonja %A Shah, Sonia H %A McRae, Allan F %A Lohman, Kurt %A Sha, Jin %A Absher, Devin M %A Ferrucci, Luigi %A Zhao, Wei %A Demerath, Ellen W %A Bressler, Jan %A Grove, Megan L %A Huan, Tianxiao %A Liu, Chunyu %A Mendelson, Michael M %A Yao, Chen %A Kiel, Douglas P %A Peters, Annette %A Wang-Sattler, Rui %A Visscher, Peter M %A Wray, Naomi R %A Starr, John M %A Ding, Jingzhong %A Rodriguez, Carlos J %A Wareham, Nicholas J %A Irvin, Marguerite R %A Zhi, Degui %A Barrdahl, Myrto %A Vineis, Paolo %A Ambatipudi, Srikant %A Uitterlinden, André G %A Hofman, Albert %A Schwartz, Joel %A Colicino, Elena %A Hou, Lifang %A Vokonas, Pantel S %A Hernandez, Dena G %A Singleton, Andrew B %A Bandinelli, Stefania %A Turner, Stephen T %A Ware, Erin B %A Smith, Alicia K %A Klengel, Torsten %A Binder, Elisabeth B %A Psaty, Bruce M %A Taylor, Kent D %A Gharib, Sina A %A Swenson, Brenton R %A Liang, Liming %A DeMeo, Dawn L %A O'Connor, George T %A Herceg, Zdenko %A Ressler, Kerry J %A Conneely, Karen N %A Sotoodehnia, Nona %A Kardia, Sharon L R %A Melzer, David %A Baccarelli, Andrea A %A van Meurs, Joyce B J %A Romieu, Isabelle %A Arnett, Donna K %A Ong, Ken K %A Liu, Yongmei %A Waldenberger, Melanie %A Deary, Ian J %A Fornage, Myriam %A Levy, Daniel %A London, Stephanie J %X

BACKGROUND: DNA methylation leaves a long-term signature of smoking exposure and is one potential mechanism by which tobacco exposure predisposes to adverse health outcomes, such as cancers, osteoporosis, lung, and cardiovascular disorders.

METHODS AND RESULTS: To comprehensively determine the association between cigarette smoking and DNA methylation, we conducted a meta-analysis of genome-wide DNA methylation assessed using the Illumina BeadChip 450K array on 15 907 blood-derived DNA samples from participants in 16 cohorts (including 2433 current, 6518 former, and 6956 never smokers). Comparing current versus never smokers, 2623 cytosine-phosphate-guanine sites (CpGs), annotated to 1405 genes, were statistically significantly differentially methylated at Bonferroni threshold of P<1×10(-7) (18 760 CpGs at false discovery rate <0.05). Genes annotated to these CpGs were enriched for associations with several smoking-related traits in genome-wide studies including pulmonary function, cancers, inflammatory diseases, and heart disease. Comparing former versus never smokers, 185 of the CpGs that differed between current and never smokers were significant P<1×10(-7) (2623 CpGs at false discovery rate <0.05), indicating a pattern of persistent altered methylation, with attenuation, after smoking cessation. Transcriptomic integration identified effects on gene expression at many differentially methylated CpGs.

CONCLUSIONS: Cigarette smoking has a broad impact on genome-wide methylation that, at many loci, persists many years after smoking cessation. Many of the differentially methylated genes were novel genes with respect to biological effects of smoking and might represent therapeutic targets for prevention or treatment of tobacco-related diseases. Methylation at these sites could also serve as sensitive and stable biomarkers of lifetime exposure to tobacco smoke.

%B Circ Cardiovasc Genet %V 9 %P 436-447 %8 2016 Oct %G eng %N 5 %R 10.1161/CIRCGENETICS.116.001506 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Evaluation of a Genetic Risk Score to Improve Risk Prediction for Alzheimer's Disease. %A Chouraki, Vincent %A Reitz, Christiane %A Maury, Fleur %A Bis, Joshua C %A Bellenguez, Céline %A Yu, Lei %A Jakobsdottir, Johanna %A Mukherjee, Shubhabrata %A Adams, Hieab H %A Choi, Seung Hoan %A Larson, Eric B %A Fitzpatrick, Annette %A Uitterlinden, André G %A De Jager, Philip L %A Hofman, Albert %A Gudnason, Vilmundur %A Vardarajan, Badri %A Ibrahim-Verbaas, Carla %A van der Lee, Sven J %A Lopez, Oscar %A Dartigues, Jean-François %A Berr, Claudine %A Amouyel, Philippe %A Bennett, David A %A van Duijn, Cornelia %A DeStefano, Anita L %A Launer, Lenore J %A Ikram, M Arfan %A Crane, Paul K %A Lambert, Jean-Charles %A Mayeux, Richard %A Seshadri, Sudha %X

Effective prevention of Alzheimer's disease (AD) requires the development of risk prediction tools permitting preclinical intervention. We constructed a genetic risk score (GRS) comprising common genetic variants associated with AD, evaluated its association with incident AD and assessed its capacity to improve risk prediction over traditional models based on age, sex, education, and APOEɛ4. In eight prospective cohorts included in the International Genomics of Alzheimer's Project (IGAP), we derived weighted sum of risk alleles from the 19 top SNPs reported by the IGAP GWAS in participants aged 65 and older without prevalent dementia. Hazard ratios (HR) of incident AD were estimated in Cox models. Improvement in risk prediction was measured by the difference in C-index (Δ-C), the integrated discrimination improvement (IDI) and continuous net reclassification improvement (NRI>0). Overall, 19,687 participants at risk were included, of whom 2,782 developed AD. The GRS was associated with a 17% increase in AD risk (pooled HR = 1.17; 95% CI =   [1.13-1.21] per standard deviation increase in GRS; p-value =  2.86×10-16). This association was stronger among persons with at least one APOEɛ4 allele (HRGRS = 1.24; 95% CI =   [1.15-1.34]) than in others (HRGRS = 1.13; 95% CI =   [1.08-1.18]; pinteraction = 3.45×10-2). Risk prediction after seven years of follow-up showed a small improvement when adding the GRS to age, sex, APOEɛ4, and education (Δ-Cindex =  0.0043 [0.0019-0.0067]). Similar patterns were observed for IDI and NRI>0. In conclusion, a risk score incorporating common genetic variation outside the APOEɛ4 locus improved AD risk prediction and may facilitate risk stratification for prevention trials.

%B J Alzheimers Dis %V 53 %P 921-32 %8 2016 Jun 18 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27340842?dopt=Abstract %R 10.3233/JAD-150749 %0 Journal Article %J Am J Hum Genet %D 2016 %T Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits. %A Chami, Nathalie %A Chen, Ming-Huei %A Slater, Andrew J %A Eicher, John D %A Evangelou, Evangelos %A Tajuddin, Salman M %A Love-Gregory, Latisha %A Kacprowski, Tim %A Schick, Ursula M %A Nomura, Akihiro %A Giri, Ayush %A Lessard, Samuel %A Brody, Jennifer A %A Schurmann, Claudia %A Pankratz, Nathan %A Yanek, Lisa R %A Manichaikul, Ani %A Pazoki, Raha %A Mihailov, Evelin %A Hill, W David %A Raffield, Laura M %A Burt, Amber %A Bartz, Traci M %A Becker, Diane M %A Becker, Lewis C %A Boerwinkle, Eric %A Bork-Jensen, Jette %A Bottinger, Erwin P %A O'Donoghue, Michelle L %A Crosslin, David R %A de Denus, Simon %A Dubé, Marie-Pierre %A Elliott, Paul %A Engström, Gunnar %A Evans, Michele K %A Floyd, James S %A Fornage, Myriam %A Gao, He %A Greinacher, Andreas %A Gudnason, Vilmundur %A Hansen, Torben %A Harris, Tamara B %A Hayward, Caroline %A Hernesniemi, Jussi %A Highland, Heather M %A Hirschhorn, Joel N %A Hofman, Albert %A Irvin, Marguerite R %A Kähönen, Mika %A Lange, Ethan %A Launer, Lenore J %A Lehtimäki, Terho %A Li, Jin %A Liewald, David C M %A Linneberg, Allan %A Liu, Yongmei %A Lu, Yingchang %A Lyytikäinen, Leo-Pekka %A Mägi, Reedik %A Mathias, Rasika A %A Melander, Olle %A Metspalu, Andres %A Mononen, Nina %A Nalls, Mike A %A Nickerson, Deborah A %A Nikus, Kjell %A O'Donnell, Chris J %A Orho-Melander, Marju %A Pedersen, Oluf %A Petersmann, Astrid %A Polfus, Linda %A Psaty, Bruce M %A Raitakari, Olli T %A Raitoharju, Emma %A Richard, Melissa %A Rice, Kenneth M %A Rivadeneira, Fernando %A Rotter, Jerome I %A Schmidt, Frank %A Smith, Albert Vernon %A Starr, John M %A Taylor, Kent D %A Teumer, Alexander %A Thuesen, Betina H %A Torstenson, Eric S %A Tracy, Russell P %A Tzoulaki, Ioanna %A Zakai, Neil A %A Vacchi-Suzzi, Caterina %A van Duijn, Cornelia M %A van Rooij, Frank J A %A Cushman, Mary %A Deary, Ian J %A Velez Edwards, Digna R %A Vergnaud, Anne-Claire %A Wallentin, Lars %A Waterworth, Dawn M %A White, Harvey D %A Wilson, James G %A Zonderman, Alan B %A Kathiresan, Sekar %A Grarup, Niels %A Esko, Tõnu %A Loos, Ruth J F %A Lange, Leslie A %A Faraday, Nauder %A Abumrad, Nada A %A Edwards, Todd L %A Ganesh, Santhi K %A Auer, Paul L %A Johnson, Andrew D %A Reiner, Alexander P %A Lettre, Guillaume %X

Red blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2 × 10(-10) for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p < 3 × 10(-8) for hematocrit [HCT] and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribution width (rs3211938, MAF = 8.7%, p = 7 × 10(-11)) and showed that it is associated with lower CD36 expression and strong allelic imbalance in ex vivo differentiated human erythroblasts. We also identified a rare missense variant in ALAS2 (rs201062903, MAF = 0.2%) associated with lower mean corpuscular volume and mean corpuscular hemoglobin (p < 8 × 10(-9)). Mendelian mutations in ALAS2 are a cause of sideroblastic anemia and erythropoietic protoporphyria. Gene-based testing highlighted three rare missense variants in PKLR, a gene mutated in Mendelian non-spherocytic hemolytic anemia, associated with HGB and HCT (SKAT p < 8 × 10(-7)). These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits. Our association results and functional annotation suggest the involvement of new genes in human erythropoiesis. We also confirm that rare and low-frequency variants play a role in the architecture of complex human traits, although their phenotypic effect is generally smaller than originally anticipated.

%B Am J Hum Genet %V 99 %P 8-21 %8 2016 Jul 7 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27346685?dopt=Abstract %R 10.1016/j.ajhg.2016.05.007 %0 Journal Article %J J Am Geriatr Soc %D 2016 %T Fibroblast Growth Factor-23 and Frailty in Elderly Community-Dwelling Individuals: The Cardiovascular Health Study. %A Beben, Tomasz %A Ix, Joachim H %A Shlipak, Michael G %A Sarnak, Mark J %A Fried, Linda F %A Hoofnagle, Andrew N %A Chonchol, Michel %A Kestenbaum, Bryan R %A de Boer, Ian H %A Rifkin, Dena E %K Aged %K Anthropometry %K Biomarkers %K Cardiovascular Diseases %K Cross-Sectional Studies %K Enzyme-Linked Immunosorbent Assay %K Female %K Fibroblast Growth Factors %K Frail Elderly %K Glomerular Filtration Rate %K Humans %K Independent Living %K Longitudinal Studies %K Male %K Phenotype %K Risk Factors %K Surveys and Questionnaires %X

OBJECTIVES: To evaluate whether fibroblast growth factor 23 (FGF-23) is related to frailty and to characterize the nature of their joint association with mortality.

DESIGN: Cross-sectional analysis for frailty and longitudinal cohort analysis for mortality.

SETTING: Cardiovascular Health Study.

PARTICIPANTS: Community-dwelling individuals (N = 2,977; mean age 77.9 ± 4.7, 40% male, 83% white).

MEASUREMENTS: The predictor was serum FGF-23 concentration (C-terminal enzyme-linked immunosorbent assay), and the outcomes were frailty status (determined according to frailty phenotype criteria of weight loss, weakness, exhaustion, slowness, and low physical activity) and mortality. Multinomial logistic regression was used to assess the cross-sectional association between FGF-23 and frailty and prefrailty, adjusting for demographic characteristics, cardiovascular disease and risk factors, and kidney markers. Proportional hazards Cox proportional hazards regression was used to assess the association between FGF-23, frailty, and all-cause mortality.

RESULTS: Mean estimated glomerular filtration rate (eGFR) was 64 ± 17 mL/min per 1.73 m(2) . Median FGF-23 was 70.3 RU/mL (interquartile range 53.4-99.2); 52% were prefrail, and 13% were frail. After multivariate adjustment, each doubling in FGF-23 concentration was associated with 38% (95% confidence interval (CI) = 17-62%) higher odds of frailty than of nonfrailty and 16% (95% CI = 3-30%) higher odds of prefrailty. FGF-23 (hazard ratio (HR) = 1.16, 95% CI = 1.10-1.23) and frailty (HR = 1.82, 95% CI = 1.57-2.12) were independently associated with mortality, but neither association was meaningfully attenuated when adjusted for the other.

CONCLUSION: In a large cohort of older adults, higher FGF-23 was independently associated with prevalent frailty and prefrailty. FGF-23 and frailty were independent and additive risk factors for mortality. FGF-23 may be a marker for functional outcomes.

%B J Am Geriatr Soc %V 64 %P 270-6 %8 2016 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26889836?dopt=Abstract %R 10.1111/jgs.13951 %0 Journal Article %J Osteoporos Int %D 2016 %T Fibrosis markers, hip fracture risk, and bone density in older adults. %A Barzilay, J I %A Bůžková, P %A Kizer, J R %A Djoussé, L %A Ix, J H %A Fink, H A %A Siscovick, D S %A Cauley, J A %A Mukamal, K J %X

UNLABELLED: We examined whether blood levels of two markers of fibrosis (transforming growth factor beta one (TGF-β1) and procollagen type III N-terminal propeptide (PIIINP)) are related to hip fracture risk and to bone mineral density (BMD). TGF-β1 levels were associated with lower hip fracture risk in women and with lower BMD in men. PIIINP levels were not associated with either outcome.

INTRODUCTION: TGF-β1 serves several roles in bone formation and resorption. A consequence of TGF-β1 activation is the production of PIIINP, a marker of collagen III deposition. Here, we explore whether these two biomarkers are related to incident hip fracture and bone mineral density (BMD) and whether their associations are modified by systemic inflammation, as measured by C-reactive protein (CRP) levels.

METHODS: Participants were from the Cardiovascular Health Study (mean age 78 years; mean follow-up 8.3 years). We included 1681 persons with measured levels of TGF-β1 (149 hip fractures) and 3226 persons with measured levels of PIIINP (310 hip fractures).

RESULTS: Among women, higher TGF-β1 levels were associated with lower hip fracture risk (HR, per doubling, 0.78 [95 % CI 0.61, 0.91]). Among men, TGF-β1 levels were associated with hip fracture risk in a non-linear manner, but among those with elevated CRP levels, doubling was associated with increased risk of fracture (HR 2.22 [1.20, 4.08]) (p = 0.02, interaction between low and high CRP and TGF-β1 on fracture risk). TGF-β1 levels had no significant association with total hip or total body BMD in women but were significantly associated with lower BMD in men. There were no associations of PIIINP levels with hip fracture risk or BMD in men or women.

CONCLUSIONS: TGF-β1 levels appear to be associated with bone-related phenotypes in a sex-specific manner. The reasons for these differences between men and women regarding TGF-β1 levels and hip fracture risk and bone density require further investigation.

%B Osteoporos Int %V 27 %P 815-20 %8 2016 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26267013?dopt=Abstract %R 10.1007/s00198-015-3269-9 %0 Journal Article %J Hum Mol Genet %D 2016 %T Fine-mapping, novel loci identification, and SNP association transferability in a genome-wide association study of QRS duration in African Americans. %A Evans, Daniel S %A Avery, Christy L %A Nalls, Mike A %A Li, Guo %A Barnard, John %A Smith, Erin N %A Tanaka, Toshiko %A Butler, Anne M %A Buxbaum, Sarah G %A Alonso, Alvaro %A Arking, Dan E %A Berenson, Gerald S %A Bis, Joshua C %A Buyske, Steven %A Carty, Cara L %A Chen, Wei %A Chung, Mina K %A Cummings, Steven R %A Deo, Rajat %A Eaton, Charles B %A Fox, Ervin R %A Heckbert, Susan R %A Heiss, Gerardo %A Hindorff, Lucia A %A Hsueh, Wen-Chi %A Isaacs, Aaron %A Jamshidi, Yalda %A Kerr, Kathleen F %A Liu, Felix %A Liu, Yongmei %A Lohman, Kurt K %A Magnani, Jared W %A Maher, Joseph F %A Mehra, Reena %A Meng, Yan A %A Musani, Solomon K %A Newton-Cheh, Christopher %A North, Kari E %A Psaty, Bruce M %A Redline, Susan %A Rotter, Jerome I %A Schnabel, Renate B %A Schork, Nicholas J %A Shohet, Ralph V %A Singleton, Andrew B %A Smith, Jonathan D %A Soliman, Elsayed Z %A Srinivasan, Sathanur R %A Taylor, Herman A %A Van Wagoner, David R %A Wilson, James G %A Young, Taylor %A Zhang, Zhu-Ming %A Zonderman, Alan B %A Evans, Michele K %A Ferrucci, Luigi %A Murray, Sarah S %A Tranah, Gregory J %A Whitsel, Eric A %A Reiner, Alex P %A Sotoodehnia, Nona %X

The electrocardiographic QRS duration, a measure of ventricular depolarization and conduction, is associated with cardiovascular mortality. While single nucleotide polymorphisms (SNPs) associated with QRS duration have been identified at 22 loci in populations of European descent, the genetic architecture of QRS duration in non-European populations is largely unknown. We therefore performed a genome-wide association study (GWAS) meta-analysis of QRS duration in 13,031 African Americans from ten cohorts and a transethnic GWAS meta-analysis with additional results from populations of European descent. In the African American GWAS, a single genome-wide significant SNP association was identified (rs3922844, P = 4 × 10(-14)) in intron 16 of SCN5A, a voltage-gated cardiac sodium channel gene. The QRS-prolonging rs3922844 C allele was also associated with decreased SCN5A RNA expression in human atrial tissue (P = 1.1 × 10(-4)). High density genotyping revealed that the SCN5A association region in African Americans was confined to intron 16. Transethnic GWAS meta-analysis identified novel SNP associations on chromosome 18 in MYL12A (rs1662342, P = 4.9 × 10(-8)) and chromosome 1 near CD1E and SPTA1 (rs7547997, P = 7.9 × 10(-9)). The 22 QRS loci previously identified in populations of European descent were enriched for significant SNP associations with QRS duration in African Americans (P = 9.9 × 10(-7)), and index SNP associations in or near SCN5A, SCN10A, CDKN1A, NFIA, HAND1, TBX5 and SETBP1 replicated in African Americans. In summary, rs3922844 was associated with QRS duration and SCN5A expression, two novel QRS loci were identified using transethnic meta-analysis, and a significant proportion of QRS-SNP associations discovered in populations of European descent were transferable to African Americans when adequate power was achieved.

%B Hum Mol Genet %8 2016 Aug 29 %G eng %R 10.1093/hmg/ddw284 %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2016 %T Gait Speed Predicts Incident Disability: A Pooled Analysis. %A Perera, Subashan %A Patel, Kushang V %A Rosano, Caterina %A Rubin, Susan M %A Satterfield, Suzanne %A Harris, Tamara %A Ensrud, Kristine %A Orwoll, Eric %A Lee, Christine G %A Chandler, Julie M %A Newman, Anne B %A Cauley, Jane A %A Guralnik, Jack M %A Ferrucci, Luigi %A Studenski, Stephanie A %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Aging %K Cohort Studies %K Disability Evaluation %K Disabled Persons %K Female %K Gait %K Geriatric Assessment %K Humans %K Independent Living %K Male %K Mobility Limitation %K Predictive Value of Tests %K Prognosis %K Psychomotor Performance %K Risk Assessment %K Risk Factors %K ROC Curve %K Survival Analysis %K United States %X

BACKGROUND: Functional independence with aging is an important goal for individuals and society. Simple prognostic indicators can inform health promotion and care planning, but evidence is limited by heterogeneity in measures of function.

METHODS: We performed a pooled analysis of data from seven studies of 27,220 community-dwelling older adults aged 65 or older with baseline gait speed, followed for disability and mortality. Outcomes were incident inability or dependence on another person in bathing or dressing; and difficulty walking ¼ - ½ mile or climbing 10 steps within 3 years.

RESULTS: Participants with faster baseline gait had lower rates of incident disability. In subgroups (defined by 0.2 m/s-wide intervals from <0.4 to ≥ 1.4 m/s) with increasingly greater gait speed, 3-year rates of bathing or dressing dependence trended from 10% to 1% in men, and from 15% to 1% in women, while mobility difficulty trended from 47% to 4% in men and 40% to 6% in women. The age-adjusted relative risk ratio per 0.1 m/s greater speed for bathing or dressing dependence in men was 0.68 (0.57-0.81) and in women: 0.74 (0.66-0.82); for mobility difficulty, men: 0.75 (0.68-0.82), women: 0.73 (0.67-0.80). Results were similar for combined disability and mortality. Effects were largely consistent across subgroups based on age, gender, race, body mass index, prior hospitalization, and selected chronic conditions. In the presence of multiple other risk factors for disability, gait speed significantly increased the area under the receiver operator characteristic curve.

CONCLUSION: In older adults, gait speed predicts 3 year incidence of bathing or dressing dependence, mobility difficulty, and a composite outcome of disability and mortality.

%B J Gerontol A Biol Sci Med Sci %V 71 %P 63-71 %8 2016 Jan %G ENG %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26297942?dopt=Abstract %R 10.1093/gerona/glv126 %0 Journal Article %J Am J Kidney Dis %D 2016 %T Galectin-3 and Soluble ST2 and Kidney Function Decline in Older Adults: The Cardiovascular Health Study (CHS). %A Bansal, Nisha %A Katz, Ronit %A Seliger, Stephen %A DeFilippi, Christopher %A Sarnak, Mark J %A Delaney, Joseph A %A Christenson, Robert %A de Boer, Ian H %A Kestenbaum, Bryan %A Robinson-Cohen, Cassianne %A Ix, Joachim H %A Shlipak, Michael G %K Aged %K Cohort Studies %K Creatinine %K Cystatin C %K Female %K Galectin 3 %K Glomerular Filtration Rate %K Humans %K Interleukin-1 Receptor-Like 1 Protein %K Logistic Models %K Longitudinal Studies %K Male %K Prognosis %K Renal Insufficiency, Chronic %B Am J Kidney Dis %V 67 %P 994-6 %8 2016 06 %G eng %N 6 %R 10.1053/j.ajkd.2015.12.022 %0 Journal Article %J Sci Rep %D 2016 %T {Gene-gene Interaction Analyses for Atrial Fibrillation %A Lin, H. %A Mueller-Nurasyid, M. %A Smith, A. V. %A Arking, D. E. %A Barnard, J. %A Bartz, T. M. %A Lunetta, K. L. %A Lohman, K. %A Kleber, M. E. %A Lubitz, S. A. %A Geelhoed, B. %A Trompet, S. %A Niemeijer, M. N. %A Kacprowski, T. %A Chasman, D. I. %A Klarin, D. %A Sinner, M. F. %A Waldenberger, M. %A Meitinger, T. %A Harris, T. B. %A Launer, L. J. %A Soliman, E. Z. %A Chen, L. Y. %A Smith, J. D. %A Van Wagoner, D. R. %A Rotter, J. I. %A Psaty, B. M. %A Xie, Z. %A Hendricks, A. E. %A Ding, J. %A Delgado, G. E. %A Verweij, N. %A van der Harst, P. %A Macfarlane, P. W. %A Ford, I. %A Hofman, A. %A Uitterlinden, A. %A Heeringa, J. %A Franco, O. H. %A Kors, J. A. %A Weiss, S. %A V?lzke, H. %A Rose, L. M. %A Natarajan, P. %A Kathiresan, S. %A K??b, S. %A Gudnason, V. %A Alonso, A. %A Chung, M. K. %A Heckbert, S. R. %A Benjamin, E. J. %A Liu, Y. %A M?rz, W. %A Rienstra, M. %A Jukema, J. W. %A Stricker, B. H. %A D?rr, M. %A Albert, C. M. %A Ellinor, P. T. %X {Atrial fibrillation (AF) is a heritable disease that affects more than thirty million individuals worldwide. Extensive efforts have been devoted to the study of genetic determinants of AF. The objective of our study is to examine the effect of gene-gene interaction on AF susceptibility. We performed a large-scale association analysis of gene-gene interactions with AF in 8,173 AF cases, and 65,237 AF-free referents collected from 15 studies for discovery. We examined putative interactions between genome-wide SNPs and 17 known AF-related SNPs. The top interactions were then tested for association in an independent cohort for replication, which included more than 2,363 AF cases and 114,746 AF-free referents. One interaction, between rs7164883 at the HCN4 locus and rs4980345 at the SLC28A1 locus, was found to be significantly associated with AF in the discovery cohorts (interaction OR = 1.44, 95% CI: 1.27-1.65 %B Sci Rep %V 6 %P 35371 %8 11 %G eng %0 Journal Article %J Genet Epidemiol %D 2016 %T General Framework for Meta-Analysis of Haplotype Association Tests. %A Wang, Shuai %A Zhao, Jing Hua %A An, Ping %A Guo, Xiuqing %A Jensen, Richard A %A Marten, Jonathan %A Huffman, Jennifer E %A Meidtner, Karina %A Boeing, Heiner %A Campbell, Archie %A Rice, Kenneth M %A Scott, Robert A %A Yao, Jie %A Schulze, Matthias B %A Wareham, Nicholas J %A Borecki, Ingrid B %A Province, Michael A %A Rotter, Jerome I %A Hayward, Caroline %A Goodarzi, Mark O %A Meigs, James B %A Dupuis, Josée %X

For complex traits, most associated single nucleotide variants (SNV) discovered to date have a small effect, and detection of association is only possible with large sample sizes. Because of patient confidentiality concerns, it is often not possible to pool genetic data from multiple cohorts, and meta-analysis has emerged as the method of choice to combine results from multiple studies. Many meta-analysis methods are available for single SNV analyses. As new approaches allow the capture of low frequency and rare genetic variation, it is of interest to jointly consider multiple variants to improve power. However, for the analysis of haplotypes formed by multiple SNVs, meta-analysis remains a challenge, because different haplotypes may be observed across studies. We propose a two-stage meta-analysis approach to combine haplotype analysis results. In the first stage, each cohort estimate haplotype effect sizes in a regression framework, accounting for relatedness among observations if appropriate. For the second stage, we use a multivariate generalized least square meta-analysis approach to combine haplotype effect estimates from multiple cohorts. Haplotype-specific association tests and a global test of independence between haplotypes and traits are obtained within our framework. We demonstrate through simulation studies that we control the type-I error rate, and our approach is more powerful than inverse variance weighted meta-analysis of single SNV analysis when haplotype effects are present. We replicate a published haplotype association between fasting glucose-associated locus (G6PC2) and fasting glucose in seven studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and we provide more precise haplotype effect estimates.

%B Genet Epidemiol %V 40 %P 244-52 %8 2016 Apr %G eng %N 3 %R 10.1002/gepi.21959 %0 Journal Article %J Nat Commun %D 2016 %T {Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function %A Pattaro, C. %A Teumer, A. %A Gorski, M. %A Chu, A. Y. %A Li, M. %A Mijatovic, V. %A Garnaas, M. %A Tin, A. %A Sorice, R. %A Li, Y. %A Taliun, D. %A Olden, M. %A Foster, M. %A Yang, Q. %A Chen, M. H. %A Pers, T. H. %A Johnson, A. D. %A Ko, Y. A. %A Fuchsberger, C. %A Tayo, B. %A Nalls, M. %A Feitosa, M. F. %A Isaacs, A. %A Dehghan, A. %A d'Adamo, P. %A Adeyemo, A. %A Dieffenbach, A. K. %A Zonderman, A. B. %A Nolte, I. M. %A van der Most, P. J. %A Wright, A. F. %A Shuldiner, A. R. %A Morrison, A. C. %A Hofman, A. %A Smith, A. V. %A Dreisbach, A. W. %A Franke, A. %A Uitterlinden, A. G. %A Metspalu, A. %A Tonjes, A. %A Lupo, A. %A Robino, A. %A Johansson, ?. %A Demirkan, A. %A Kollerits, B. %A Freedman, B. I. %A Ponte, B. %A Oostra, B. A. %A Paulweber, B. %A Kr?mer, B. K. %A Mitchell, B. D. %A Buckley, B. M. %A Peralta, C. A. %A Hayward, C. %A Helmer, C. %A Rotimi, C. N. %A Shaffer, C. M. %A M?ller, C. %A Sala, C. %A van Duijn, C. M. %A Saint-Pierre, A. %A Ackermann, D. %A Shriner, D. %A Ruggiero, D. %A Toniolo, D. %A Lu, Y. %A Cusi, D. %A Czamara, D. %A Ellinghaus, D. %A Siscovick, D. S. %A Ruderfer, D. %A Gieger, C. %A Grallert, H. %A Rochtchina, E. %A Atkinson, E. J. %A Holliday, E. G. %A Boerwinkle, E. %A Salvi, E. %A Bottinger, E. P. %A Murgia, F. %A Rivadeneira, F. %A Ernst, F. %A Kronenberg, F. %A Hu, F. B. %A Navis, G. J. %A Curhan, G. C. %A Ehret, G. B. %A Homuth, G. %A Coassin, S. %A Thun, G. A. %A Pistis, G. %A Gambaro, G. %A Malerba, G. %A Montgomery, G. W. %A Eiriksdottir, G. %A Jacobs, G. %A Li, G. %A Wichmann, H. E. %A Campbell, H. %A Schmidt, H. %A Wallaschofski, H. %A V?lzke, H. %A Brenner, H. %A Kroemer, H. K. %A Kramer, H. %A Lin, H. %A Leach, I. M. %A Ford, I. %A Guessous, I. %A Rudan, I. %A Prokopenko, I. %A Borecki, I. %A Heid, I. M. %A Kolcic, I. %A Persico, I. %A Jukema, J. W. %A Wilson, J. F. %A Felix, J. F. %A Divers, J. %A Lambert, J. C. %A Stafford, J. M. %A Gaspoz, J. M. %A Smith, J. A. %A Faul, J. D. %A Wang, J. J. %A Ding, J. %A Hirschhorn, J. N. %A Attia, J. %A Whitfield, J. B. %A Chalmers, J. %A Viikari, J. %A Coresh, J. %A Denny, J. C. %A Karjalainen, J. %A Fernandes, J. K. %A Endlich, K. %A Butterbach, K. %A Keene, K. L. %A Lohman, K. %A Portas, L. %A Launer, L. J. %A Lyytik?inen, L. P. %A Yengo, L. %A Franke, L. %A Ferrucci, L. %A Rose, L. M. %A Kedenko, L. %A Rao, M. %A Struchalin, M. %A Kleber, M. E. %A Cavalieri, M. %A Haun, M. %A Cornelis, M. C. %A Ciullo, M. %A Pirastu, M. %A de Andrade, M. %A McEvoy, M. A. %A Woodward, M. %A Adam, M. %A Cocca, M. %A Nauck, M. %A Imboden, M. %A Waldenberger, M. %A Pruijm, M. %A Metzger, M. %A Stumvoll, M. %A Evans, M. K. %A Sale, M. M. %A K?h?nen, M. %A Boban, M. %A Bochud, M. %A Rheinberger, M. %A Verweij, N. %A Bouatia-Naji, N. %A Martin, N. G. %A Hastie, N. %A Probst-Hensch, N. %A Soranzo, N. %A Devuyst, O. %A Raitakari, O. %A Gottesman, O. %A Franco, O. H. %A Polasek, O. %A Gasparini, P. %A Munroe, P. B. %A Ridker, P. M. %A Mitchell, P. %A Muntner, P. %A Meisinger, C. %A Smit, J. H. %A Kovacs, P. %A Wild, P. S. %A Froguel, P. %A Rettig, R. %A M?gi, R. %A Biffar, R. %A Schmidt, R. %A Middelberg, R. P. %A Carroll, R. J. %A Penninx, B. W. %A Scott, R. J. %A Katz, R. %A Sedaghat, S. %A Wild, S. H. %A Kardia, S. L. %A Ulivi, S. %A Hwang, S. J. %A Enroth, S. %A Kloiber, S. %A Trompet, S. %A Stengel, B. %A Hancock, S. J. %A Turner, S. T. %A Rosas, S. E. %A Stracke, S. %A Harris, T. B. %A Zeller, T. %A Zemunik, T. %A Lehtim?ki, T. %A Illig, T. %A Aspelund, T. %A Nikopensius, T. %A Esko, T. %A Tanaka, T. %A Gyllensten, U. %A V?lker, U. %A Emilsson, V. %A Vitart, V. %A Aalto, V. %A Gudnason, V. %A Chouraki, V. %A Chen, W. M. %A Igl, W. %A M?rz, W. %A Koenig, W. %A Lieb, W. %A Loos, R. J. %A Liu, Y. %A Snieder, H. %A Pramstaller, P. P. %A Parsa, A. %A O'Connell, J. R. %A Susztak, K. %A Hamet, P. %A Tremblay, J. %A De Boer, I. H. %A B?ger, C. A. %A Goessling, W. %A Chasman, D. I. %A K?ttgen, A. %A Kao, W. H. %A Fox, C. S. %A Abecasis, G. R. %A Adair, L. S. %A Alexander, M. %A Altshuler, D. %A Amin, N. %A Arking, D. E. %A Arora, P. %A Aulchenko, Y. %A Bakker, S. J. %A Bandinelli, S. %A Barroso, I. %A Beckmann, J. S. %A Beilby, J. P. %A Bergman, R. N. %A Bergmann, S. %A Bis, J. C. %A Boehnke, M. %A Bonnycastle, L. L. %A Bornstein, S. R. %A Bots, M. L. %A Bragg-Gresham, J. L. %A Brand, S. M. %A Brand, E. %A Braund, P. S. %A Brown, M. J. %A Burton, P. R. %A Casas, J. P. %A Caulfield, M. J. %A Chakravarti, A. %A Chambers, J. C. %A Chandak, G. R. %A Chang, Y. P. %A Charchar, F. J. %A Chaturvedi, N. %A Shin Cho, Y. %A Clarke, R. %A Collins, F. S. %A Collins, R. %A Connell, J. M. %A Cooper, J. A. %A Cooper, M. N. %A Cooper, R. S. %A Corsi, A. M. %A D?rr, M. %A Dahgam, S. %A Danesh, J. %A Davey Smith, G. %A Day, I. N. %A Deloukas, P. %A Denniff, M. %A Dominiczak, A. F. %A Dong, Y. %A Doumatey, A. %A Elliott, P. %A Elosua, R. %A Erdmann, J. %A Eyheramendy, S. %A Farrall, M. %A Fava, C. %A Forrester, T. %A Fowkes, F. G. %A Fox, E. R. %A Frayling, T. M. %A Galan, P. %A Ganesh, S. K. %A Garcia, M. %A Gaunt, T. R. %A Glazer, N. L. %A Go, M. J. %A Goel, A. %A Gr?ssler, J. %A Grobbee, D. E. %A Groop, L. %A Guarrera, S. %A Guo, X. %A Hadley, D. %A Hamsten, A. %A Han, B. G. %A Hardy, R. %A Hartikainen, A. L. %A Heath, S. %A Heckbert, S. R. %A Hedblad, B. %A Hercberg, S. %A Hernandez, D. %A Hicks, A. A. %A Hilton, G. %A Hingorani, A. D. %A Bolton, J. A. %A Hopewell, J. C. %A Howard, P. %A Humphries, S. E. %A Hunt, S. C. %A Hveem, K. %A Ikram, M. A. %A Islam, M. %A Iwai, N. %A Jarvelin, M. R. %A Jackson, A. U. %A Jafar, T. H. %A Janipalli, C. S. %A Johnson, T. %A Kathiresan, S. %A Khaw, K. T. %A Kim, H. L. %A Kinra, S. %A Kita, Y. %A Kivimaki, M. %A Kooner, J. S. %A Kumar, M. J. %A Kuh, D. %A Kulkarni, S. R. %A Kumari, M. %A Kuusisto, J. %A Kuznetsova, T. %A Laakso, M. %A Laan, M. %A Laitinen, J. %A Lakatta, E. G. %A Langefeld, C. D. %A Larson, M. G. %A Lathrop, M. %A Lawlor, D. A. %A Lawrence, R. W. %A Lee, J. Y. %A Lee, N. R. %A Levy, D. %A Li, Y. %A Longstreth, W. T. %A Luan, J. %A Lucas, G. %A Ludwig, B. %A Mangino, M. %A Mani, K. R. %A Marmot, M. G. %A Mattace-Raso, F. U. %A Matullo, G. %A McArdle, W. L. %A McKenzie, C. A. %A Meitinger, T. %A Melander, O. %A Meneton, P. %A Meschia, J. F. %A Miki, T. %A Milaneschi, Y. %A Mohlke, K. L. %A Mooser, V. %A Morken, M. A. %A Morris, R. W. %A Mosley, T. H. %A Najjar, S. %A Narisu, N. %A Newton-Cheh, C. %A Nguyen, K. D. %A Nilsson, P. %A Nyberg, F. %A O'Donnell, C. J. %A Ogihara, T. %A Ohkubo, T. %A Okamura, T. %A Ong, R. T. %A Ongen, H. %A Onland-Moret, N. C. %A O'Reilly, P. F. %A Org, E. %A Orru, M. %A Palmas, W. %A Palmen, J. %A Palmer, L. J. %A Palmer, N. D. %A Parker, A. N. %A Peden, J. F. %A Peltonen, L. %A Perola, M. %A Pihur, V. %A Platou, C. G. %A Plump, A. %A Prabhakaran, D. %A Psaty, B. M. %A Raffel, L. J. %A Rao, D. C. %A Rasheed, A. %A Ricceri, F. %A Rice, K. M. %A Rosengren, A. %A Rotter, J. I. %A Rudock, M. E. %A S?ber, S. %A Salako, T. %A Saleheen, D. %A Salomaa, V. %A Samani, N. J. %A Schwartz, S. M. %A Schwarz, P. E. %A Scott, L. J. %A Scott, J. %A Scuteri, A. %A Sehmi, J. S. %A Seielstad, M. %A Seshadri, S. %A Sharma, P. %A Shaw-Hawkins, S. %A Shi, G. %A Shrine, N. R. %A Sijbrands, E. J. %A Sim, X. %A Singleton, A. %A Sj?gren, M. %A Smith, N. L. %A Soler Artigas, M. %A Spector, T. D. %A Staessen, J. A. %A Stancakova, A. %A Steinle, N. I. %A Strachan, D. P. %A Stringham, H. M. %A Sun, Y. V. %A Swift, A. J. %A Tabara, Y. %A Tai, E. S. %A Talmud, P. J. %A Taylor, A. %A Terzic, J. %A Thelle, D. S. %A Tobin, M. D. %A Tomaszewski, M. %A Tripathy, V. %A Tuomilehto, J. %A Tzoulaki, I. %A Uda, M. %A Ueshima, H. %A Uiterwaal, C. S. %A Umemura, S. %A van der Harst, P. %A van der Schouw, Y. T. %A van Gilst, W. H. %A Vartiainen, E. %A Vasan, R. S. %A Veldre, G. %A Verwoert, G. C. %A Viigimaa, M. %A Vinay, D. G. %A Vineis, P. %A Voight, B. F. %A Vollenweider, P. %A Wagenknecht, L. E. %A Wain, L. V. %A Wang, X. %A Wang, T. J. %A Wareham, N. J. %A Watkins, H. %A Weder, A. B. %A Whincup, P. H. %A Wiggins, K. L. %A Witteman, J. C. %A Wong, A. %A Wu, Y. %A Yajnik, C. S. %A Yao, J. %A Young, J. H. %A Zelenika, D. %A Zhai, G. %A Zhang, W. %A Zhang, F. %A Zhao, J. H. %A Zhu, H. %A Zhu, X. %A Zitting, P. %A Zukowska-Szczechowska, E. %A Okada, Y. %A Wu, J. Y. %A Gu, D. %A Takeuchi, F. %A Takahashi, A. %A Maeda, S. %A Tsunoda, T. %A Chen, P. %A Lim, S. C. %A Wong, T. Y. %A Liu, J. %A Young, T. L. %A Aung, T. %A Teo, Y. Y. %A Kim, Y. J. %A Kang, D. %A Chen, C. H. %A Tsai, F. J. %A Chang, L. C. %A Fann, S. J. %A Mei, H. %A Hixson, J. E. %A Chen, S. %A Katsuya, T. %A Isono, M. %A Albrecht, E. %A Yamamoto, K. %A Kubo, M. %A Nakamura, Y. %A Kamatani, N. %A Kato, N. %A He, J. %A Chen, Y. T. %A Tanaka, T. %A Reilly, M. P. %A Schunkert, H. %A Assimes, T. L. %A Hall, A. %A Hengstenberg, C. %A K?nig, I. R. %A Laaksonen, R. %A McPherson, R. %A Thompson, J. R. %A Thorsteinsdottir, U. %A Ziegler, A. %A Absher, D. %A Chen, L. %A Cupples, L. A. %A Halperin, E. %A Li, M. %A Musunuru, K. %A Preuss, M. %A Schillert, A. %A Thorleifsson, G. %A Wells, G. A. %A Holm, H. %A Roberts, R. %A Stewart, A. F. %A Fortmann, S. %A Go, A. %A Hlatky, M. %A Iribarren, C. %A Knowles, J. %A Myers, R. %A Quertermous, T. %A Sidney, S. %A Risch, N. %A Tang, H. %A Blankenberg, S. %A Schnabel, R. %A Sinning, C. %A Lackner, K. J. %A Tiret, L. %A Nicaud, V. %A Cambien, F. %A Bickel, C. %A Rupprecht, H. J. %A Perret, C. %A Proust, C. %A M?nzel, T. F. %A Barbalic, M. %A Chen, I. Y. %A Demissie-Banjaw, S. %A Folsom, A. %A Lumley, T. %A Marciante, K. %A Taylor, K. D. %A Volcik, K. %A Gretarsdottir, S. %A Gulcher, J. R. %A Kong, A. %A Stefansson, K. %A Thorgeirsson, G. %A Andersen, K. %A Fischer, M. %A Grosshennig, A. %A Linsel-Nitschke, P. %A Stark, K. %A Schreiber, S. %A Aherrahrou, Z. %A Bruse, P. %A Doering, A. %A Klopp, N. %A Diemert, P. %A Loley, C. %A Medack, A. %A Nahrstedt, J. %A Peters, A. %A Wagner, A. K. %A Willenborg, C. %A B?hm, B. O. %A Dobnig, H. %A Grammer, T. B. %A Hoffmann, M. M. %A Meinitzer, A. %A Winkelmann, B. R. %A Pilz, S. %A Renner, W. %A Scharnagl, H. %A Stojakovic, T. %A Tomaschitz, A. %A Winkler, K. %A Guiducci, C. %A Burtt, N. %A Gabriel, S. B. %A Dandona, S. %A Jarinova, O. %A Qu, L. %A Wilensky, R. %A Matthai, W. %A Hakonarson, H. H. %A Devaney, J. %A Burnett, M. S. %A Pichard, A. D. %A Kent, K. M. %A Satler, L. %A Lindsay, J. M. %A Waksman, R. %A Knouff, C. W. %A Waterworth, D. M. %A Walker, M. C. %A Epstein, S. E. %A Rader, D. J. %A Nelson, C. P. %A Wright, B. J. %A Balmforth, A. J. %A Ball, S. G. %A Loehr, L. R. %A Rosamond, W. D. %A Benjamin, E. %A Haritunians, T. %A Couper, D. %A Murabito, J. %A Wang, Y. A. %A Stricker, B. H. %A Chang, P. P. %A Willerson, J. T. %A Felix, S. B. %A Watzinger, N. %A Aragam, J. %A Zweiker, R. %A Lind, L. %A Rodeheffer, R. J. %A Greiser, K. H. %A Deckers, J. W. %A Stritzke, J. %A Ingelsson, E. %A Kullo, I. %A Haerting, J. %A Reffelmann, T. %A Redfield, M. M. %A Werdan, K. %A Mitchell, G. F. %A Arnett, D. K. %A Gottdiener, J. S. %A Blettner, M. %A Friedrich, N. %X Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. %B Nat Commun %V 7 %P 10023 %8 Jan %G eng %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 Eur J Hum Genet %D 2016 %T Genetic variants in RBFOX3 are associated with sleep latency. %A Amin, Najaf %A Allebrandt, Karla V %A van der Spek, Ashley %A Müller-Myhsok, Bertram %A Hek, Karin %A Teder-Laving, Maris %A Hayward, Caroline %A Esko, Tõnu %A van Mill, Josine G %A Mbarek, Hamdi %A Watson, Nathaniel F %A Melville, Scott A %A Del Greco, Fabiola M %A Byrne, Enda M %A Oole, Edwin %A Kolcic, Ivana %A Chen, Ting-Hsu %A Evans, Daniel S %A Coresh, Josef %A Vogelzangs, Nicole %A Karjalainen, Juha %A Willemsen, Gonneke %A Gharib, Sina A %A Zgaga, Lina %A Mihailov, Evelin %A Stone, Katie L %A Campbell, Harry %A Brouwer, Rutger Ww %A Demirkan, Ayse %A Isaacs, Aaron %A Dogas, Zoran %A Marciante, Kristin D %A Campbell, Susan %A Borovecki, Fran %A Luik, Annemarie I %A Li, Man %A Hottenga, Jouke Jan %A Huffman, Jennifer E %A van den Hout, Mirjam Cgn %A Cummings, Steven R %A Aulchenko, Yurii S %A Gehrman, Philip R %A Uitterlinden, André G %A Wichmann, Heinz-Erich %A Müller-Nurasyid, Martina %A Fehrmann, Rudolf Sn %A Montgomery, Grant W %A Hofman, Albert %A Kao, Wen Hong Linda %A Oostra, Ben A %A Wright, Alan F %A Vink, Jacqueline M %A Wilson, James F %A Pramstaller, Peter P %A Hicks, Andrew A %A Polasek, Ozren %A Punjabi, Naresh M %A Redline, Susan %A Psaty, Bruce M %A Heath, Andrew C %A Merrow, Martha %A Tranah, Gregory J %A Gottlieb, Daniel J %A Boomsma, Dorret I %A Martin, Nicholas G %A Rudan, Igor %A Tiemeier, Henning %A van IJcken, Wilfred Fj %A Penninx, Brenda W %A Metspalu, Andres %A Meitinger, Thomas %A Franke, Lude %A Roenneberg, Till %A van Duijn, Cornelia M %X

Time to fall asleep (sleep latency) is a major determinant of sleep quality. Chronic, long sleep latency is a major characteristic of sleep-onset insomnia and/or delayed sleep phase syndrome. In this study we aimed to discover common polymorphisms that contribute to the genetics of sleep latency. We performed a meta-analysis of genome-wide association studies (GWAS) including 2 572 737 single nucleotide polymorphisms (SNPs) established in seven European cohorts including 4242 individuals. We found a cluster of three highly correlated variants (rs9900428, rs9907432 and rs7211029) in the RNA-binding protein fox-1 homolog 3 gene (RBFOX3) associated with sleep latency (P-values=5.77 × 10(-08), 6.59 × 10(-)(08) and 9.17 × 10(-)(08)). These SNPs were replicated in up to 12 independent populations including 30 377 individuals (P-values=1.5 × 10(-)(02), 7.0 × 10(-)(03) and 2.5 × 10(-)(03); combined meta-analysis P-values=5.5 × 10(-07), 5.4 × 10(-07) and 1.0 × 10(-07)). A functional prediction of RBFOX3 based on co-expression with other genes shows that this gene is predominantly expressed in brain (P-value=1.4 × 10(-316)) and the central nervous system (P-value=7.5 × 10(-)(321)). The predicted function of RBFOX3 based on co-expression analysis with other genes shows that this gene is significantly involved in the release cycle of neurotransmitters including gamma-aminobutyric acid and various monoamines (P-values<2.9 × 10(-11)) that are crucial in triggering the onset of sleep. To conclude, in this first large-scale GWAS of sleep latency we report a novel association of variants in RBFOX3 gene. Further, a functional prediction of RBFOX3 supports the involvement of RBFOX3 with sleep latency.

%B Eur J Hum Genet %V 24 %P 1488-95 %8 2016 Oct %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/27142678?dopt=Abstract %R 10.1038/ejhg.2016.31 %0 Journal Article %J Nat Genet %D 2016 %T {The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals %A Ehret, G. B. %A Ferreira, T. %A Chasman, D. I. %A Jackson, A. U. %A Schmidt, E. M. %A Johnson, T. %A Thorleifsson, G. %A Luan, J. %A Donnelly, L. A. %A Kanoni, S. %A Petersen, A. K. %A Pihur, V. %A Strawbridge, R. J. %A Shungin, D. %A Hughes, M. F. %A Meirelles, O. %A Kaakinen, M. %A Bouatia-Naji, N. %A Kristiansson, K. %A Shah, S. %A Kleber, M. E. %A Guo, X. %A Lyytik?inen, L. P. %A Fava, C. %A Eriksson, N. %A Nolte, I. M. %A Magnusson, P. K. %A Salfati, E. L. %A Rallidis, L. S. %A Theusch, E. %A Smith, A. J. P. %A Folkersen, L. %A Witkowska, K. %A Pers, T. H. %A Joehanes, R. %A Kim, S. K. %A Lataniotis, L. %A Jansen, R. %A Johnson, A. D. %A Warren, H. %A Kim, Y. J. %A Zhao, W. %A Wu, Y. %A Tayo, B. O. %A Bochud, M. %A Absher, D. %A Adair, L. S. %A Amin, N. %A Arking, D. E. %A Axelsson, T. %A Baldassarre, D. %A Balkau, B. %A Bandinelli, S. %A Barnes, M. R. %A Barroso, I. %A Bevan, S. %A Bis, J. C. %A Bjornsdottir, G. %A Boehnke, M. %A Boerwinkle, E. %A Bonnycastle, L. L. %A Boomsma, D. I. %A Bornstein, S. R. %A Brown, M. J. %A Burnier, M. %A Cabrera, C. P. %A Chambers, J. C. %A Chang, I. S. %A Cheng, C. Y. %A Chines, P. S. %A Chung, R. H. %A Collins, F. S. %A Connell, J. M. %A D?ring, A. %A Dallongeville, J. %A Danesh, J. %A de Faire, U. %A Delgado, G. %A Dominiczak, A. F. %A Doney, A. S. F. %A Drenos, F. %A Edkins, S. %A Eicher, J. D. %A Elosua, R. %A Enroth, S. %A Erdmann, J. %A Eriksson, P. %A Esko, T. %A Evangelou, E. %A Evans, A. %A Fall, T. %A Farrall, M. %A Felix, J. F. %A Ferri?res, J. %A Ferrucci, L. %A Fornage, M. %A Forrester, T. %A Franceschini, N. %A Duran, O. H. F. %A Franco-Cereceda, A. %A Fraser, R. M. %A Ganesh, S. K. %A Gao, H. %A Gertow, K. %A Gianfagna, F. %A Gigante, B. %A Giulianini, F. %A Goel, A. %A Goodall, A. H. %A Goodarzi, M. O. %A Gorski, M. %A Gr??ler, J. %A Groves, C. %A Gudnason, V. %A Gyllensten, U. %A Hallmans, G. %A Hartikainen, A. L. %A Hassinen, M. %A Havulinna, A. S. %A Hayward, C. %A Hercberg, S. %A Herzig, K. H. %A Hicks, A. A. %A Hingorani, A. D. %A Hirschhorn, J. N. %A Hofman, A. %A Holmen, J. %A Holmen, O. L. %A Hottenga, J. J. %A Howard, P. %A Hsiung, C. A. %A Hunt, S. C. %A Ikram, M. A. %A Illig, T. %A Iribarren, C. %A Jensen, R. A. %A K?h?nen, M. %A Kang, H. %A Kathiresan, S. %A Keating, B. J. %A Khaw, K. T. %A Kim, Y. K. %A Kim, E. %A Kivimaki, M. %A Klopp, N. %A Kolovou, G. %A Komulainen, P. %A Kooner, J. S. %A Kosova, G. %A Krauss, R. M. %A Kuh, D. %A Kutalik, Z. %A Kuusisto, J. %A Kval?y, K. %A Lakka, T. A. %A Lee, N. R. %A Lee, I. T. %A Lee, W. J. %A Levy, D. %A Li, X. %A Liang, K. W. %A Lin, H. %A Lin, L. %A Lindstr?m, J. %A Lobbens, S. %A M?nnist?, S. %A M?ller, G. %A M?ller-Nurasyid, M. %A Mach, F. %A Markus, H. S. %A Marouli, E. %A McCarthy, M. I. %A McKenzie, C. A. %A Meneton, P. %A Menni, C. %A Metspalu, A. %A Mijatovic, V. %A Moilanen, L. %A Montasser, M. E. %A Morris, A. D. %A Morrison, A. C. %A Mulas, A. %A Nagaraja, R. %A Narisu, N. %A Nikus, K. %A O'Donnell, C. J. %A O'Reilly, P. F. %A Ong, K. K. %A Paccaud, F. %A Palmer, C. D. %A Parsa, A. %A Pedersen, N. L. %A Penninx, B. W. %A Perola, M. %A Peters, A. %A Poulter, N. %A Pramstaller, P. P. %A Psaty, B. M. %A Quertermous, T. %A Rao, D. C. %A Rasheed, A. %A Rayner, N. W. N. W. R. %A Renstr?m, F. %A Rettig, R. %A Rice, K. M. %A Roberts, R. %A Rose, L. M. %A Rossouw, J. %A Samani, N. J. %A Sanna, S. %A Saramies, J. %A Schunkert, H. %A Sebert, S. %A Sheu, W. H. %A Shin, Y. A. %A Sim, X. %A Smit, J. H. %A Smith, A. V. %A Sosa, M. X. %A Spector, T. D. %A Stan??kov?, A. %A Stanton, A. %A Stirrups, K. E. %A Stringham, H. M. %A Sundstrom, J. %A Swift, A. J. %A Syv?nen, A. C. %A Tai, E. S. %A Tanaka, T. %A Tarasov, K. V. %A Teumer, A. %A Thorsteinsdottir, U. %A Tobin, M. D. %A Tremoli, E. %A Uitterlinden, A. G. %A Uusitupa, M. %A Vaez, A. %A Vaidya, D. %A van Duijn, C. M. %A van Iperen, E. P. A. %A Vasan, R. S. %A Verwoert, G. C. %A Virtamo, J. %A Vitart, V. %A Voight, B. F. %A Vollenweider, P. %A Wagner, A. %A Wain, L. V. %A Wareham, N. J. %A Watkins, H. %A Weder, A. B. %A Westra, H. J. %A Wilks, R. %A Wilsgaard, T. %A Wilson, J. F. %A Wong, T. Y. %A Yang, T. P. %A Yao, J. %A Yengo, L. %A Zhang, W. %A Zhao, J. H. %A Zhu, X. %A Bovet, P. %A Cooper, R. S. %A Mohlke, K. L. %A Saleheen, D. %A Lee, J. Y. %A Elliott, P. %A Gierman, H. J. %A Willer, C. J. %A Franke, L. %A Hovingh, G. K. %A Taylor, K. D. %A Dedoussis, G. %A Sever, P. %A Wong, A. %A Lind, L. %A Assimes, T. L. %A Nj?lstad, I. %A Schwarz, P. E. %A Langenberg, C. %A Snieder, H. %A Caulfield, M. J. %A Melander, O. %A Laakso, M. %A Saltevo, J. %A Rauramaa, R. %A Tuomilehto, J. %A Ingelsson, E. %A Lehtim?ki, T. %A Hveem, K. %A Palmas, W. %A M?rz, W. %A Kumari, M. %A Salomaa, V. %A Chen, Y. I. %A Rotter, J. I. %A Froguel, P. %A Jarvelin, M. R. %A Lakatta, E. G. %A Kuulasmaa, K. %A Franks, P. W. %A Hamsten, A. %A Wichmann, H. E. %A Palmer, C. N. A. %A Stefansson, K. %A Ridker, P. M. %A Loos, R. J. F. %A Chakravarti, A. %A Deloukas, P. %A Morris, A. P. %A Newton-Cheh, C. %A Munroe, P. B. %X To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure-related pathways and highlight tissues beyond the classical renal system in blood pressure regulation. %B Nat Genet %V 48 %P 1171–1184 %8 10 %G eng %0 Journal Article %J Stroke %D 2016 %T Genome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2. %A Cheng, Yu-Ching %A Stanne, Tara M %A Giese, Anne-Katrin %A Ho, Weang Kee %A Traylor, Matthew %A Amouyel, Philippe %A Holliday, Elizabeth G %A Malik, Rainer %A Xu, Huichun %A Kittner, Steven J %A Cole, John W %A O'Connell, Jeffrey R %A Danesh, John %A Rasheed, Asif %A Zhao, Wei %A Engelter, Stefan %A Grond-Ginsbach, Caspar %A Kamatani, Yoichiro %A Lathrop, Mark %A Leys, Didier %A Thijs, Vincent %A Metso, Tiina M %A Tatlisumak, Turgut %A Pezzini, Alessandro %A Parati, Eugenio A %A Norrving, Bo %A Bevan, Steve %A Rothwell, Peter M %A Sudlow, Cathie %A Slowik, Agnieszka %A Lindgren, Arne %A Walters, Matthew R %A Jannes, Jim %A Shen, Jess %A Crosslin, David %A Doheny, Kimberly %A Laurie, Cathy C %A Kanse, Sandip M %A Bis, Joshua C %A Fornage, Myriam %A Mosley, Thomas H %A Hopewell, Jemma C %A Strauch, Konstantin %A Müller-Nurasyid, Martina %A Gieger, Christian %A Waldenberger, Melanie %A Peters, Annette %A Meisinger, Christine %A Ikram, M Arfan %A Longstreth, W T %A Meschia, James F %A Seshadri, Sudha %A Sharma, Pankaj %A Worrall, Bradford %A Jern, Christina %A Levi, Christopher %A Dichgans, Martin %A Boncoraglio, Giorgio B %A Markus, Hugh S %A Debette, Stephanie %A Rolfs, Arndt %A Saleheen, Danish %A Mitchell, Braxton D %K Adult %K African Continental Ancestry Group %K Age of Onset %K Aged %K Asian Continental Ancestry Group %K Brain Ischemia %K Chromosomes, Human, Pair 10 %K Computer Simulation %K DNA, Intergenic %K European Continental Ancestry Group %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Odds Ratio %K Polymorphism, Single Nucleotide %K Serine Endopeptidases %K Stroke %X

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

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

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

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

%B Stroke %V 47 %P 307-16 %8 2016 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26732560?dopt=Abstract %R 10.1161/STROKEAHA.115.011328 %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 Bone Rep %D 2016 %T A genome-wide association study meta-analysis of clinical fracture in 10,012 African American women. %A Taylor, Kira C %A Evans, Daniel S %A Edwards, Digna R Velez %A Edwards, Todd L %A Sofer, Tamar %A Li, Guo %A Liu, Youfang %A Franceschini, Nora %A Jackson, Rebecca D %A Giri, Ayush %A Donneyong, Macarius %A Psaty, Bruce %A Rotter, Jerome I %A LaCroix, Andrea Z %A Jordan, Joanne M %A Robbins, John A %A Lewis, Beth %A Stefanick, Marcia L %A Liu, Yongmei %A Garcia, Melissa %A Harris, Tamara %A Cauley, Jane A %A North, Kari E %X

BACKGROUND: Osteoporosis is a major public health problem associated with excess disability and mortality. It is estimated that 50-70% of the variation in osteoporotic fracture risk is attributable to genetic factors. The purpose of this hypothesis-generating study was to identify possible genetic determinants of fracture among African American (AA) women in a GWAS meta-analysis.

METHODS: Data on clinical fractures (all fractures except fingers, toes, face, skull or sternum) were analyzed among AA female participants in the Women's Health Initiative (WHI) (N = 8155), Cardiovascular Health Study (CHS) (N = 504), BioVU (N = 704), Health ABC (N = 651), and the Johnston County Osteoarthritis Project (JoCoOA) (N = 291). Affymetrix (WHI) and Illumina (Health ABC, JoCoOA, BioVU, CHS) GWAS panels were used for genotyping, and a 1:1 ratio of YRI:CEU HapMap haplotypes was used as an imputation reference panel. We used Cox proportional hazard models or logistic regression to evaluate the association of ~ 2.5 million SNPs with fracture risk, adjusting for ancestry, age, and geographic region where applicable. We conducted a fixed-effects, inverse variance-weighted meta-analysis. Genome-wide significance was set at P < 5 × 10- 8.

RESULTS: One SNP, rs12775980 in an intron of SVIL on chromosome 10p11.2, reached genome-wide significance (P = 4.0 × 10- 8). Although this SNP has a low minor allele frequency (0.03), there was no evidence for heterogeneity of effects across the studies (I2 = 0). This locus was not reported in any previous osteoporosis-related GWA studies. We also interrogated previously reported GWA-significant loci associated with fracture or bone mineral density in our data. One locus (SMOC1) generalized, but overall there was not substantial evidence of generalization. Possible reasons for the lack of generalization are discussed.

CONCLUSION: This GWAS meta-analysis of fractures in African American women identified a potentially novel locus in the supervillin gene, which encodes a platelet-associated factor and was previously associated with platelet thrombus formation in African Americans. If validated in other populations of African descent, these findings suggest potential new mechanisms involved in fracture that may be particularly important among African Americans.

%B Bone Rep %V 5 %P 233-242 %8 2016 Dec %G eng %R 10.1016/j.bonr.2016.08.005 %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 Aging Cell %D 2016 %T Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits. %A Teumer, Alexander %A Qi, Qibin %A Nethander, Maria %A Aschard, Hugues %A Bandinelli, Stefania %A Beekman, Marian %A Berndt, Sonja I %A Bidlingmaier, Martin %A Broer, Linda %A Cappola, Anne %A Ceda, Gian Paolo %A Chanock, Stephen %A Chen, Ming-Huei %A Chen, Tai C %A Chen, Yii-Der Ida %A Chung, Jonathan %A Del Greco Miglianico, Fabiola %A Eriksson, Joel %A Ferrucci, Luigi %A Friedrich, Nele %A Gnewuch, Carsten %A Goodarzi, Mark O %A Grarup, Niels %A Guo, Tingwei %A Hammer, Elke %A Hayes, Richard B %A Hicks, Andrew A %A Hofman, Albert %A Houwing-Duistermaat, Jeanine J %A Hu, Frank %A Hunter, David J %A Husemoen, Lise L %A Isaacs, Aaron %A Jacobs, Kevin B %A Janssen, Joop A M J L %A Jansson, John-Olov %A Jehmlich, Nico %A Johnson, Simon %A Juul, Anders %A Karlsson, Magnus %A Kilpeläinen, Tuomas O %A Kovacs, Peter %A Kraft, Peter %A Li, Chao %A Linneberg, Allan %A Liu, Yongmei %A Loos, Ruth J F %A Lorentzon, Mattias %A Lu, Yingchang %A Maggio, Marcello %A Mägi, Reedik %A Meigs, James %A Mellström, Dan %A Nauck, Matthias %A Newman, Anne B %A Pollak, Michael N %A Pramstaller, Peter P %A Prokopenko, Inga %A Psaty, Bruce M %A Reincke, Martin %A Rimm, Eric B %A Rotter, Jerome I %A Saint Pierre, Aude %A Schurmann, Claudia %A Seshadri, Sudha %A Sjögren, Klara %A Slagboom, P Eline %A Strickler, Howard D %A Stumvoll, Michael %A Suh, Yousin %A Sun, Qi %A Zhang, Cuilin %A Svensson, Johan %A Tanaka, Toshiko %A Tare, Archana %A Tönjes, Anke %A Uh, Hae-Won %A van Duijn, Cornelia M %A van Heemst, Diana %A Vandenput, Liesbeth %A Vasan, Ramachandran S %A Völker, Uwe %A Willems, Sara M %A Ohlsson, Claes %A Wallaschofski, Henri %A Kaplan, Robert C %X

The growth hormone/insulin-like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through genomewide association study of up to 30 884 adults of European ancestry from 21 studies, we confirmed and extended the list of previously identified loci associated with circulating IGF-I and IGFBP-3 concentrations (IGF1, IGFBP3, GCKR, TNS3, GHSR, FOXO3, ASXL2, NUBP2/IGFALS, SORCS2, and CELSR2). Significant sex interactions, which were characterized by different genotype-phenotype associations between men and women, were found only for associations of IGFBP-3 concentrations with SNPs at the loci IGFBP3 and SORCS2. Analyses of SNPs, gene expression, and protein levels suggested that interplay between IGFBP3 and genes within the NUBP2 locus (IGFALS and HAGH) may affect circulating IGF-I and IGFBP-3 concentrations. The IGF-I-decreasing allele of SNP rs934073, which is an eQTL of ASXL2, was associated with lower adiposity and higher likelihood of survival beyond 90 years. The known longevity-associated variant rs2153960 (FOXO3) was observed to be a genomewide significant SNP for IGF-I concentrations. Bioinformatics analysis suggested enrichment of putative regulatory elements among these IGF-I- and IGFBP-3-associated loci, particularly of rs646776 at CELSR2. In conclusion, this study identified several loci associated with circulating IGF-I and IGFBP-3 concentrations and provides clues to the potential role of the IGF axis in mediating effects of known (FOXO3) and novel (ASXL2) longevity-associated loci.

%B Aging Cell %V 15 %P 811-24 %8 2016 Oct %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/27329260?dopt=Abstract %R 10.1111/acel.12490 %0 Journal Article %J Aging Cell %D 2016 %T GWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium. %A Matteini, Amy M %A Tanaka, Toshiko %A Karasik, David %A Atzmon, Gil %A Chou, Wen-Chi %A Eicher, John D %A Johnson, Andrew D %A Arnold, Alice M %A Callisaya, Michele L %A Davies, Gail %A Evans, Daniel S %A Holtfreter, Birte %A Lohman, Kurt %A Lunetta, Kathryn L %A Mangino, Massimo %A Smith, Albert V %A Smith, Jennifer A %A Teumer, Alexander %A Yu, Lei %A Arking, Dan E %A Buchman, Aron S %A Chibinik, Lori B %A De Jager, Philip L %A Evans, Denis A %A Faul, Jessica D %A Garcia, Melissa E %A Gillham-Nasenya, Irina %A Gudnason, Vilmundur %A Hofman, Albert %A Hsu, Yi-Hsiang %A Ittermann, Till %A Lahousse, Lies %A Liewald, David C %A Liu, Yongmei %A Lopez, Lorna %A Rivadeneira, Fernando %A Rotter, Jerome I %A Siggeirsdottir, Kristin %A Starr, John M %A Thomson, Russell %A Tranah, Gregory J %A Uitterlinden, André G %A Völker, Uwe %A Völzke, Henry %A Weir, David R %A Yaffe, Kristine %A Zhao, Wei %A Zhuang, Wei Vivian %A Zmuda, Joseph M %A Bennett, David A %A Cummings, Steven R %A Deary, Ian J %A Ferrucci, Luigi %A Harris, Tamara B %A Kardia, Sharon L R %A Kocher, Thomas %A Kritchevsky, Stephen B %A Psaty, Bruce M %A Seshadri, Sudha %A Spector, Timothy D %A Srikanth, Velandai K %A Windham, B Gwen %A Zillikens, M Carola %A Newman, Anne B %A Walston, Jeremy D %A Kiel, Douglas P %A Murabito, Joanne M %X

Decline in muscle strength with aging is an important predictor of health trajectory in the elderly. Several factors, including genetics, are proposed contributors to variability in muscle strength. To identify genetic contributors to muscle strength, a meta-analysis of genomewide association studies of handgrip was conducted. Grip strength was measured using a handheld dynamometer in 27 581 individuals of European descent over 65 years of age from 14 cohort studies. Genomewide association analysis was conducted on ~2.7 million imputed and genotyped variants (SNPs). Replication of the most significant findings was conducted using data from 6393 individuals from three cohorts. GWAS of lower body strength was also characterized in a subset of cohorts. Two genomewide significant (P-value< 5 × 10(-8) ) and 39 suggestive (P-value< 5 × 10(-5) ) associations were observed from meta-analysis of the discovery cohorts. After meta-analysis with replication cohorts, genomewide significant association was observed for rs752045 on chromosome 8 (β = 0.47, SE = 0.08, P-value = 5.20 × 10(-10) ). This SNP is mapped to an intergenic region and is located within an accessible chromatin region (DNase hypersensitivity site) in skeletal muscle myotubes differentiated from the human skeletal muscle myoblasts cell line. This locus alters a binding motif of the CCAAT/enhancer-binding protein-β (CEBPB) that is implicated in muscle repair mechanisms. GWAS of lower body strength did not yield significant results. A common genetic variant in a chromosomal region that regulates myotube differentiation and muscle repair may contribute to variability in grip strength in the elderly. Further studies are needed to uncover the mechanisms that link this genetic variant with muscle strength.

%B Aging Cell %V 15 %P 792-800 %8 2016 Oct %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/27325353?dopt=Abstract %R 10.1111/acel.12468 %0 Journal Article %J Mol Psychiatry %D 2016 %T GWAS for executive function and processing speed suggests involvement of the CADM2 gene. %A Ibrahim-Verbaas, C A %A Bressler, J %A Debette, S %A Schuur, M %A Smith, A V %A Bis, J C %A Davies, G %A Trompet, S %A Smith, J A %A Wolf, C %A Chibnik, L B %A Liu, Y %A Vitart, V %A Kirin, M %A Petrovic, K %A Polasek, O %A Zgaga, L %A Fawns-Ritchie, C %A Hoffmann, P %A Karjalainen, J %A Lahti, J %A Llewellyn, D J %A Schmidt, C O %A Mather, K A %A Chouraki, V %A Sun, Q %A Resnick, S M %A Rose, L M %A Oldmeadow, C %A Stewart, M %A Smith, B H %A Gudnason, V %A Yang, Q %A Mirza, S S %A Jukema, J W %A deJager, P L %A Harris, T B %A Liewald, D C %A Amin, N %A Coker, L H %A Stegle, O %A Lopez, O L %A Schmidt, R %A Teumer, A %A Ford, I %A Karbalai, N %A Becker, J T %A Jonsdottir, M K %A Au, R %A Fehrmann, R S N %A Herms, S %A Nalls, M %A Zhao, W %A Turner, S T %A Yaffe, K %A Lohman, K %A van Swieten, J C %A Kardia, S L R %A Knopman, D S %A Meeks, W M %A Heiss, G %A Holliday, E G %A Schofield, P W %A Tanaka, T %A Stott, D J %A Wang, J %A Ridker, P %A Gow, A J %A Pattie, A %A Starr, J M %A Hocking, L J %A Armstrong, N J %A McLachlan, S %A Shulman, J M %A Pilling, L C %A Eiriksdottir, G %A Scott, R J %A Kochan, N A %A Palotie, A %A Hsieh, Y-C %A Eriksson, J G %A Penman, A %A Gottesman, R F %A Oostra, B A %A Yu, L %A DeStefano, A L %A Beiser, A %A Garcia, M %A Rotter, J I %A Nöthen, M M %A Hofman, A %A Slagboom, P E %A Westendorp, R G J %A Buckley, B M %A Wolf, P A %A Uitterlinden, A G %A Psaty, B M %A Grabe, H J %A Bandinelli, S %A Chasman, D I %A Grodstein, F %A Räikkönen, K %A Lambert, J-C %A Porteous, D J %A Price, J F %A Sachdev, P S %A Ferrucci, L %A Attia, J R %A Rudan, I %A Hayward, C %A Wright, A F %A Wilson, J F %A Cichon, S %A Franke, L %A Schmidt, H %A Ding, J %A de Craen, A J M %A Fornage, M %A Bennett, D A %A Deary, I J %A Ikram, M A %A Launer, L J %A Fitzpatrick, A L %A Seshadri, S %A van Duijn, C M %A Mosley, T H %X

To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32,070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.

%B Mol Psychiatry %V 21 %P 189-97 %8 2016 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/25869804?dopt=Abstract %R 10.1038/mp.2015.37 %0 Journal Article %J BMC Bioinformatics %D 2016 %T A hybrid computational strategy to address WGS variant analysis in >5000 samples. %A Huang, Zhuoyi %A Rustagi, Navin %A Veeraraghavan, Narayanan %A Carroll, Andrew %A Gibbs, Richard %A Boerwinkle, Eric %A Venkata, Manjunath Gorentla %A Yu, Fuli %K Databases, Genetic %K Genome, Human %K Genomics %K High-Throughput Nucleotide Sequencing %K Humans %X

BACKGROUND: The decreasing costs of sequencing are driving the need for cost effective and real time variant calling of whole genome sequencing data. The scale of these projects are far beyond the capacity of typical computing resources available with most research labs. Other infrastructures like the cloud AWS environment and supercomputers also have limitations due to which large scale joint variant calling becomes infeasible, and infrastructure specific variant calling strategies either fail to scale up to large datasets or abandon joint calling strategies.

RESULTS: We present a high throughput framework including multiple variant callers for single nucleotide variant (SNV) calling, which leverages hybrid computing infrastructure consisting of cloud AWS, supercomputers and local high performance computing infrastructures. We present a novel binning approach for large scale joint variant calling and imputation which can scale up to over 10,000 samples while producing SNV callsets with high sensitivity and specificity. As a proof of principle, we present results of analysis on Cohorts for Heart And Aging Research in Genomic Epidemiology (CHARGE) WGS freeze 3 dataset in which joint calling, imputation and phasing of over 5300 whole genome samples was produced in under 6 weeks using four state-of-the-art callers. The callers used were SNPTools, GATK-HaplotypeCaller, GATK-UnifiedGenotyper and GotCloud. We used Amazon AWS, a 4000-core in-house cluster at Baylor College of Medicine, IBM power PC Blue BioU at Rice and Rhea at Oak Ridge National Laboratory (ORNL) for the computation. AWS was used for joint calling of 180 TB of BAM files, and ORNL and Rice supercomputers were used for the imputation and phasing step. All other steps were carried out on the local compute cluster. The entire operation used 5.2 million core hours and only transferred a total of 6 TB of data across the platforms.

CONCLUSIONS: Even with increasing sizes of whole genome datasets, ensemble joint calling of SNVs for low coverage data can be accomplished in a scalable, cost effective and fast manner by using heterogeneous computing platforms without compromising on the quality of variants.

%B BMC Bioinformatics %V 17 %P 361 %8 2016 Sep 10 %G eng %N 1 %R 10.1186/s12859-016-1211-6 %0 Journal Article %J Am Heart J %D 2016 %T Impact of genetic variants on the upstream efficacy of renin-angiotensin system inhibitors for the prevention of atrial fibrillation. %A Roberts, Jason D %A Dewland, Thomas A %A Glidden, David V %A Hoffmann, Thomas J %A Arking, Dan E %A Chen, Lin Y %A Psaty, Bruce M %A Olgin, Jeffrey E %A Alonso, Alvaro %A Heckbert, Susan R %A Marcus, Gregory M %X

BACKGROUND: Renin-angiotensin system (RAS) inhibition via angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers may reduce the risk of developing atrial fibrillation (AF) in certain populations, but the evidence is conflicting. Recent genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) associated with AF, potentially identifying clinically relevant subtypes of the disease. We sought to investigate the impact of carrier status of 9 AF-associated SNPs on the efficacy of RAS inhibition for the primary prevention of AF.

METHODS: We performed SNP-RAS inhibitor interaction testing with unadjusted and adjusted Cox proportional hazards models using a discovery (Cardiovascular Health Study) and a replication (Atherosclerosis Risk in Communities) cohort. Additive genetic models were used for the SNP analyses, and 2-tailed P values <.05 were considered statistically significant.

RESULTS: Among 2,796 Cardiovascular Health Study participants, none of the 9 a priori identified candidate SNPs exhibited a significant SNP-drug interaction. Two of the 9 SNPs, rs2106261 (16q22) and rs6666258 (1q21), revealed interaction relationships that neared statistical significance (with point estimates in the same direction for angiotensin-converting enzyme inhibitor only and angiotensin II receptor blocker only analyses), but neither association could be replicated among 8,604 participants in Atherosclerosis Risk in Communities.

CONCLUSIONS: Our study failed to identify AF-associated SNP genetic subtypes of AF that derive increased benefit from upstream RAS inhibition for AF prevention. Future studies should continue to investigate the impact of genotype on the response to AF treatment strategies in an effort to develop personalized approaches to therapy and prevention.

%B Am Heart J %V 175 %P 9-17 %8 2016 May %G eng %R 10.1016/j.ahj.2016.02.002 %0 Journal Article %J Eur J Prev Cardiol %D 2016 %T Inflammatory markers and extent and progression of early atherosclerosis: Meta-analysis of individual-participant-data from 20 prospective studies of the PROG-IMT collaboration. %A Willeit, Peter %A Thompson, Simon G %A Agewall, Stefan %A Bergström, Göran %A Bickel, Horst %A Catapano, Alberico L %A Chien, Kuo-Liong %A de Groot, Eric %A Empana, Jean-Philippe %A Etgen, Thorleif %A Franco, Oscar H %A Iglseder, Bernhard %A Johnsen, Stein H %A Kavousi, Maryam %A Lind, Lars %A Liu, Jing %A Mathiesen, Ellisiv B %A Norata, Giuseppe D %A Olsen, Michael H %A Papagianni, Aikaterini %A Poppert, Holger %A Price, Jackie F %A Sacco, Ralph L %A Yanez, David N %A Zhao, Dong %A Schminke, Ulf %A Bülbül, Alpaslan %A Polak, Joseph F %A Sitzer, Matthias %A Hofman, Albert %A Grigore, Liliana %A Dörr, Marcus %A Su, Ta-Chen %A Ducimetiere, Pierre %A Xie, Wuxiang %A Ronkainen, Kimmo %A Kiechl, Stefan %A Rundek, Tatjana %A Robertson, Christine %A Fagerberg, Björn %A Bokemark, Lena %A Steinmetz, Helmuth %A Ikram, M Arfan %A Völzke, Henry %A Lin, Hung-Ju %A Plichart, Matthieu %A Tuomainen, Tomi-Pekka %A Desvarieux, Moïse %A McLachlan, Stela %A Schmidt, Caroline %A Kauhanen, Jussi %A Willeit, Johann %A Lorenz, Matthias W %A Sander, Dirk %X

BACKGROUND: Large-scale epidemiological evidence on the role of inflammation in early atherosclerosis, assessed by carotid ultrasound, is lacking. We aimed to quantify cross-sectional and longitudinal associations of inflammatory markers with common-carotid-artery intima-media thickness (CCA-IMT) in the general population.

METHODS: Information on high-sensitivity C-reactive protein, fibrinogen, leucocyte count and CCA-IMT was available in 20 prospective cohort studies of the PROG-IMT collaboration involving 49,097 participants free of pre-existing cardiovascular disease. Estimates of associations were calculated within each study and then combined using random-effects meta-analyses.

RESULTS: Mean baseline CCA-IMT amounted to 0.74 mm (SD = 0.18) and mean CCA-IMT progression over a mean of 3.9 years to 0.011 mm/year (SD = 0.039). Cross-sectional analyses showed positive linear associations between inflammatory markers and baseline CCA-IMT. After adjustment for traditional cardiovascular risk factors, mean differences in baseline CCA-IMT per one-SD higher inflammatory marker were: 0.0082 mm for high-sensitivity C-reactive protein (p < 0.001); 0.0072 mm for fibrinogen (p < 0.001); and 0.0025 mm for leucocyte count (p = 0.033). 'Inflammatory load', defined as the number of elevated inflammatory markers (i.e. in upper two quintiles), showed a positive linear association with baseline CCA-IMT (p < 0.001). Longitudinal associations of baseline inflammatory markers and changes therein with CCA-IMT progression were null or at most weak. Participants with the highest 'inflammatory load' had a greater CCA-IMT progression (p = 0.015).

CONCLUSION: Inflammation was independently associated with CCA-IMT cross-sectionally. The lack of clear associations with CCA-IMT progression may be explained by imprecision in its assessment within a limited time period. Our findings for 'inflammatory load' suggest important combined effects of the three inflammatory markers on early atherosclerosis.

%B Eur J Prev Cardiol %V 23 %P 194-205 %8 2016 Jan %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/25416041?dopt=Abstract %R 10.1177/2047487314560664 %0 Journal Article %J J Clin Endocrinol Metab %D 2016 %T Insulinlike growth factor binding protein-1 and ghrelin predict health outcomes among older adults: CHS cohort. %A Kaplan, Robert C %A Strizich, Garrett %A Aneke-Nash, Chino %A Dominguez-Islas, Clara %A Bůzková, Petra %A Strickler, Howard %A Rohan, Thomas %A Pollak, Michael %A Kuller, Lewis %A Kizer, Jorge R %A Cappola, Anne %A Li, Christopher I %A Psaty, Bruce M %A Newman, Anne %X

CONTEXT: Multiple diseases may explain the association of the growth hormone / insulinlike growth factor-I (GH/IGF-I) axis with longevity.

OBJECTIVE: To relate circulating GH/IGF-I system protein levels with major health events.

DESIGN: Cohort study Setting: Four US communities Participants: Adults (n=2268) 65 years and older free of diabetes and cardiovascular disease.

MEASUREMENTS: We assessed insulinlike growth factor binding protein-1 (IGFBP-1) and ghrelin in fasting and 2-hour oral glucose tolerance test (OGTT) blood samples, as well as fasting IGF-I and IGFBP-3. Hazard ratios for mortality and a composite outcome for first incident myocardial infarction, stroke, heart failure, hip fracture, or death were adjusted for sociodemographic, behavioral, and physiologic covariates.

RESULTS: During 13,930 person-years of follow-up, 48.1% individuals sustained one or more components of the composite outcome and 31.8% died. Versus the lowest quartiles, the highest quartiles of fasting and 2-h ghrelin were associated with a 27% higher (95% CI: 6%, 53%) and 39% higher (95% CI: 14%, 71%) risks of the composite outcome, respectively. The highest quartile of 2-h IGFBP-1 was associated with 35% higher (95% CI: 1%, 52%) risk of the composite endpoint. Similarly, higher mortality was significantly associated with higher fasting and 2-h ghrelin level, and with 2-h IGFBP-1 level. When examined together, 2-h post-OGTT levels of IGFBP-1 and ghrelin tended to predict outcomes better than fasting levels.

CONCLUSIONS: Circulating IGFBP-1 and ghrelin measured during an OGTT predict major health events and death in older adults, which may explain the influence of the GH-IGF-axis on lifespan and health.

%B J Clin Endocrinol Metab %P jc20162779 %8 2016 Nov 07 %G eng %R 10.1210/jc.2016-2779 %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 Proc Natl Acad Sci U S A %D 2016 %T KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference. %A Schumann, Gunter %A Liu, Chunyu %A O'Reilly, Paul %A Gao, He %A Song, Parkyong %A Xu, Bing %A Ruggeri, Barbara %A Amin, Najaf %A Jia, Tianye %A Preis, Sarah %A Segura Lepe, Marcelo %A Akira, Shizuo %A Barbieri, Caterina %A Baumeister, Sebastian %A Cauchi, Stephane %A Clarke, Toni-Kim %A Enroth, Stefan %A Fischer, Krista %A Hällfors, Jenni %A Harris, Sarah E %A Hieber, Saskia %A Hofer, Edith %A Hottenga, Jouke-Jan %A Johansson, Asa %A Joshi, Peter K %A Kaartinen, Niina %A Laitinen, Jaana %A Lemaitre, Rozenn %A Loukola, Anu %A Luan, Jian'an %A Lyytikäinen, Leo-Pekka %A Mangino, Massimo %A Manichaikul, Ani %A Mbarek, Hamdi %A Milaneschi, Yuri %A Moayyeri, Alireza %A Mukamal, Kenneth %A Nelson, Christopher %A Nettleton, Jennifer %A Partinen, Eemil %A Rawal, Rajesh %A Robino, Antonietta %A Rose, Lynda %A Sala, Cinzia %A Satoh, Takashi %A Schmidt, Reinhold %A Schraut, Katharina %A Scott, Robert %A Smith, Albert Vernon %A Starr, John M %A Teumer, Alexander %A Trompet, Stella %A Uitterlinden, André G %A Venturini, Cristina %A Vergnaud, Anne-Claire %A Verweij, Niek %A Vitart, Veronique %A Vuckovic, Dragana %A Wedenoja, Juho %A Yengo, Loic %A Yu, Bing %A Zhang, Weihua %A Zhao, Jing Hua %A Boomsma, Dorret I %A Chambers, John %A Chasman, Daniel I %A Daniela, Toniolo %A de Geus, Eco %A Deary, Ian %A Eriksson, Johan G %A Esko, Tõnu %A Eulenburg, Volker %A Franco, Oscar H %A Froguel, Philippe %A Gieger, Christian %A Grabe, Hans J %A Gudnason, Vilmundur %A Gyllensten, Ulf %A Harris, Tamara B %A Hartikainen, Anna-Liisa %A Heath, Andrew C %A Hocking, Lynne %A Hofman, Albert %A Huth, Cornelia %A Jarvelin, Marjo-Riitta %A Jukema, J Wouter %A Kaprio, Jaakko %A Kooner, Jaspal S %A Kutalik, Zoltán %A Lahti, Jari %A Langenberg, Claudia %A Lehtimäki, Terho %A Liu, Yongmei %A Madden, Pamela A F %A Martin, Nicholas %A Morrison, Alanna %A Penninx, Brenda %A Pirastu, Nicola %A Psaty, Bruce %A Raitakari, Olli %A Ridker, Paul %A Rose, Richard %A Rotter, Jerome I %A Samani, Nilesh J %A Schmidt, Helena %A Spector, Tim D %A Stott, David %A Strachan, David %A Tzoulaki, Ioanna %A van der Harst, Pim %A van Duijn, Cornelia M %A Marques-Vidal, Pedro %A Vollenweider, Peter %A Wareham, Nicholas J %A Whitfield, John B %A Wilson, James %A Wolffenbuttel, Bruce %A Bakalkin, Georgy %A Evangelou, Evangelos %A Liu, Yun %A Rice, Kenneth M %A Desrivières, Sylvane %A Kliewer, Steven A %A Mangelsdorf, David J %A Müller, Christian P %A Levy, Daniel %A Elliott, Paul %X

Excessive alcohol consumption is a major public health problem worldwide. Although drinking habits are known to be inherited, few genes have been identified that are robustly linked to alcohol drinking. We conducted a genome-wide association metaanalysis and replication study among >105,000 individuals of European ancestry and identified β-Klotho (KLB) as a locus associated with alcohol consumption (rs11940694; P = 9.2 × 10(-12)). β-Klotho is an obligate coreceptor for the hormone FGF21, which is secreted from the liver and implicated in macronutrient preference in humans. We show that brain-specific β-Klotho KO mice have an increased alcohol preference and that FGF21 inhibits alcohol drinking by acting on the brain. These data suggest that a liver-brain endocrine axis may play an important role in the regulation of alcohol drinking behavior and provide a unique pharmacologic target for reducing alcohol consumption.

%B Proc Natl Acad Sci U S A %V 113 %P 14372-14377 %8 2016 Dec 13 %G eng %N 50 %R 10.1073/pnas.1611243113 %0 Journal Article %J Thromb Res %D 2016 %T Lack of association of plasma gamma prime (γ') fibrinogen with incident cardiovascular disease. %A Appiah, Duke %A Heckbert, Susan R %A Cushman, Mary %A Psaty, Bruce M %A Folsom, Aaron R %X

INTRODUCTION: The association of gamma prime (γ') fibrinogen; a fibrinogen γ chain variant generated via alternative mRNA processing, with cardiovascular disease (CVD) remains equivocal. We prospectively examine the association of plasma γ' fibrinogen with the incidence of multiple cardiovascular disease (CVD) endpoints, independent of established CVD risk factors and total fibrinogen.

MATERIALS AND METHODS: We measured plasma γ' fibrinogen on plasma samples collected in 1992-1993 from adults ≥65years (n=3219) enrolled in the Cardiovascular Health Study, who were followed through 2013 for incident CVD events.

RESULTS AND CONCLUSIONS: In multivariable Cox models adjusted for traditional CVD risk factors and total fibrinogen, the hazard ratio per 1 standard deviation (10.7mg/dl) increment of γ' fibrinogen was 1.02 (95%CI: 0.95-1.10) for coronary heart disease; 0.88 (0.77-1.00) for ischemic stroke; 1.07 (0.87-1.32) for peripheral artery disease; 1.00 (0.92-1.08) for heart failure and 1.01 (0.92-1.10) for CVD mortality. Likewise, we failed to show a statistically significant association of γ'/total fibrinogen ratio with any CVD endpoint. These results suggest that among the elderly, γ' fibrinogen does not add much to CVD prediction beyond traditional risk factors and total fibrinogen level.

%B Thromb Res %V 143 %P 50-2 %8 2016 Jul %G eng %R 10.1016/j.thromres.2016.04.023 %0 Journal Article %J Am J Hum Genet %D 2016 %T Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases. %A Tajuddin, Salman M %A Schick, Ursula M %A Eicher, John D %A Chami, Nathalie %A Giri, Ayush %A Brody, Jennifer A %A Hill, W David %A Kacprowski, Tim %A Li, Jin %A Lyytikäinen, Leo-Pekka %A Manichaikul, Ani %A Mihailov, Evelin %A O'Donoghue, Michelle L %A Pankratz, Nathan %A Pazoki, Raha %A Polfus, Linda M %A Smith, Albert Vernon %A Schurmann, Claudia %A Vacchi-Suzzi, Caterina %A Waterworth, Dawn M %A Evangelou, Evangelos %A Yanek, Lisa R %A Burt, Amber %A Chen, Ming-Huei %A van Rooij, Frank J A %A Floyd, James S %A Greinacher, Andreas %A Harris, Tamara B %A Highland, Heather M %A Lange, Leslie A %A Liu, Yongmei %A Mägi, Reedik %A Nalls, Mike A %A Mathias, Rasika A %A Nickerson, Deborah A %A Nikus, Kjell %A Starr, John M %A Tardif, Jean-Claude %A Tzoulaki, Ioanna %A Velez Edwards, Digna R %A Wallentin, Lars %A Bartz, Traci M %A Becker, Lewis C %A Denny, Joshua C %A Raffield, Laura M %A Rioux, John D %A Friedrich, Nele %A Fornage, Myriam %A Gao, He %A Hirschhorn, Joel N %A Liewald, David C M %A Rich, Stephen S %A Uitterlinden, Andre %A Bastarache, Lisa %A Becker, Diane M %A Boerwinkle, Eric %A de Denus, Simon %A Bottinger, Erwin P %A Hayward, Caroline %A Hofman, Albert %A Homuth, Georg %A Lange, Ethan %A Launer, Lenore J %A Lehtimäki, Terho %A Lu, Yingchang %A Metspalu, Andres %A O'Donnell, Chris J %A Quarells, Rakale C %A Richard, Melissa %A Torstenson, Eric S %A Taylor, Kent D %A Vergnaud, Anne-Claire %A Zonderman, Alan B %A Crosslin, David R %A Deary, Ian J %A Dörr, Marcus %A Elliott, Paul %A Evans, Michele K %A Gudnason, Vilmundur %A Kähönen, Mika %A Psaty, Bruce M %A Rotter, Jerome I %A Slater, Andrew J %A Dehghan, Abbas %A White, Harvey D %A Ganesh, Santhi K %A Loos, Ruth J F %A Esko, Tõnu %A Faraday, Nauder %A Wilson, James G %A Cushman, Mary %A Johnson, Andrew D %A Edwards, Todd L %A Zakai, Neil A %A Lettre, Guillaume %A Reiner, Alex P %A Auer, Paul L %X

White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of ∼157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3' UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases.

%B Am J Hum Genet %V 99 %P 22-39 %8 2016 Jul 7 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27346689?dopt=Abstract %R 10.1016/j.ajhg.2016.05.003 %0 Journal Article %J Pharmacogenomics J %D 2016 %T Large-scale pharmacogenomic study of sulfonylureas and the QT, JT and QRS intervals: CHARGE Pharmacogenomics Working Group. %A Floyd, J S %A Sitlani, C M %A Avery, C L %A Noordam, R %A Li, X %A Smith, A V %A Gogarten, S M %A Li, J %A Broer, L %A Evans, D S %A Trompet, S %A Brody, J A %A Stewart, J D %A Eicher, J D %A Seyerle, A A %A Roach, J %A Lange, L A %A Lin, H J %A Kors, J A %A Harris, T B %A Li-Gao, R %A Sattar, N %A Cummings, S R %A Wiggins, K L %A Napier, M D %A Stürmer, T %A Bis, J C %A Kerr, K F %A Uitterlinden, A G %A Taylor, K D %A Stott, D J %A de Mutsert, R %A Launer, L J %A Busch, E L %A Méndez-Giráldez, R %A Sotoodehnia, N %A Soliman, E Z %A Li, Y %A Duan, Q %A Rosendaal, F R %A Slagboom, P E %A Wilhelmsen, K C %A Reiner, A P %A Chen, Y-DI %A Heckbert, S R %A Kaplan, R C %A Rice, K M %A Jukema, J W %A Johnson, A D %A Liu, Y %A Mook-Kanamori, D O %A Gudnason, V %A Wilson, J G %A Rotter, J I %A Laurie, C C %A Psaty, B M %A Whitsel, E A %A Cupples, L A %A Stricker, B H %X

Sulfonylureas, a commonly used class of medication used to treat type 2 diabetes, have been associated with an increased risk of cardiovascular disease. Their effects on QT interval duration and related electrocardiographic phenotypes are potential mechanisms for this adverse effect. In 11 ethnically diverse cohorts that included 71 857 European, African-American and Hispanic/Latino ancestry individuals with repeated measures of medication use and electrocardiogram (ECG) measurements, we conducted a pharmacogenomic genome-wide association study of sulfonylurea use and three ECG phenotypes: QT, JT and QRS intervals. In ancestry-specific meta-analyses, eight novel pharmacogenomic loci met the threshold for genome-wide significance (P<5 × 10(-8)), and a pharmacokinetic variant in CYP2C9 (rs1057910) that has been associated with sulfonylurea-related treatment effects and other adverse drug reactions in previous studies was replicated. Additional research is needed to replicate the novel findings and to understand their biological basis.The Pharmacogenomics Journal advance online publication, 13 December 2016; doi:10.1038/tpj.2016.90.

%B Pharmacogenomics J %8 2016 Dec 13 %G eng %R 10.1038/tpj.2016.90 %0 Journal Article %J Am J Med %D 2016 %T Lifetime Risk of Venous Thromboembolism in Two Cohort Studies. %A Bell, Elizabeth J %A Lutsey, Pamela L %A Basu, Saonli %A Cushman, Mary %A Heckbert, Susan R %A Lloyd-Jones, Donald M %A Folsom, Aaron R %K African Continental Ancestry Group %K Aged %K Anemia, Sickle Cell %K Cohort Studies %K Factor V %K Follow-Up Studies %K Heterozygote %K Humans %K Kaplan-Meier Estimate %K Middle Aged %K Obesity %K Risk %K Sickle Cell Trait %K United States %K Venous Thromboembolism %X

BACKGROUND: Greater public awareness of venous thromboembolism may be an important next step for optimizing venous thromboembolism prevention and treatment. "Lifetime risk" is an easily interpretable way of presenting risk information. Therefore, we sought to calculate the lifetime risk of venous thromboembolism (deep vein thrombosis or pulmonary embolism) using data from 2 large, prospective cohort studies: the Cardiovascular Health Study (CHS) and the Atherosclerosis Risk in Communities (ARIC) study.

METHODS: We followed participants aged 45-64 years in ARIC (n = 14,185) and ≥65 in CHS (n = 5414) at baseline visits (1987-1989 in ARIC, 1989-1990 and 1992-1993 in CHS) for incident venous thromboembolism (n = 728 in ARIC through 2011 and n = 172 in CHS through 2001). We estimated lifetime risks and 95% confidence intervals of incident venous thromboembolism using a modified Kaplan-Meier method, accounting for the competing risk of death from other causes.

RESULTS: At age 45 years, the remaining lifetime risk of venous thromboembolism in ARIC was 8.1% (95% confidence interval, 7.1-8.7). High-risk groups were African Americans (11.5% lifetime risk), those with obesity (10.9%), heterozygous for the factor V Leiden (17.1%), or with sickle cell trait or disease (18.2%). Lifetime risk estimates differed by cohort; these differences were explained by differences in time period of venous thromboembolism ascertainment.

CONCLUSIONS: At least 1 in 12 middle-aged adults will develop venous thromboembolism in their remaining lifetime. This estimate of lifetime risk may be useful to promote awareness of venous thromboembolism and guide decisions at both clinical and policy levels.

%B Am J Med %V 129 %P 339.e19-26 %8 2016 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26597668?dopt=Abstract %R 10.1016/j.amjmed.2015.10.014 %0 Journal Article %J Arterioscler Thromb Vasc Biol %D 2016 %T Lipoprotein-Associated Phospholipase A2 and Incident Peripheral Arterial Disease in Older Adults: The Cardiovascular Health Study. %A Garg, Parveen K %A Arnold, Alice M %A Hinckley Stukovsky, Karen D %A Koro, Carol %A Jenny, Nancy S %A Mukamal, Kenneth J %A Criqui, Michael H %A Furberg, Curt D %A Newman, Anne B %A Cushman, Mary %K 1-Alkyl-2-acetylglycerophosphocholine Esterase %K Age Factors %K Aged %K Aging %K Ankle Brachial Index %K Biomarkers %K Chi-Square Distribution %K Female %K Humans %K Incidence %K Inflammation Mediators %K Logistic Models %K Male %K Odds Ratio %K Peripheral Arterial Disease %K Prognosis %K Proportional Hazards Models %K Risk Assessment %K Risk Factors %K Time Factors %K United States %K Up-Regulation %X

OBJECTIVE: Although prior studies report a relationship between elevated lipoprotein-associated phospholipase A2 (Lp-PLA2) and incident cardiovascular disease, the prospective association of Lp-PLA2 with incident peripheral arterial disease (PAD) has not been studied. We investigated the association between Lp-PLA2 mass and activity and the risk of developing clinical PAD and low ankle-brachial index (ABI).

APPROACH AND RESULTS: Among Cardiovascular Health Study participants, a population-based cohort of 5888 adults aged ≥65 years enrolled in 1989 to 1990, Lp-PLA2 mass and activity were measured in 4537 individuals without baseline PAD. Clinical PAD, defined as leg artery revascularization or diagnosed claudication, was ascertained through 2011. Incident low ABI, defined as ABI <0.9 and decline of ≥0.15, was assessed among 3537 individuals who had an ABI >0.9 at baseline and a second ABI measurement 3 or 6 years later. Analyses were adjusted for demographics, cholesterol, smoking, comorbidities, and C-reactive protein. Each standard deviation increment in Lp-PLA2 mass (117 ng/mL) was associated with a higher risk of developing clinical PAD (hazard ratio 1.28; 95% confidence interval 1.13, 1.45) and incident low ABI (odds ratio 1.16; 95% confidence interval 1.00, 1.33). Results per standard deviation increment in Lp-PLA2 activity (13 nmol/min per mL) were similar for clinical PAD (hazard ratio 1.24; 95% confidence interval 1.07, 1.44) and low ABI (odds ratio 1.28; 95% confidence interval 1.09, 1.50).

CONCLUSIONS: Higher Lp-PLA2 mass and activity were associated with development of both incident clinical PAD and low ABI. Future studies are needed to determine whether pharmacological inhibition of Lp-PLA2 reduces the incidence of PAD.

%B Arterioscler Thromb Vasc Biol %V 36 %P 750-6 %8 2016 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26848158?dopt=Abstract %R 10.1161/ATVBAHA.115.306647 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Longitudinal Relationships between Caloric Expenditure and Gray Matter in the Cardiovascular Health Study. %A Raji, Cyrus A %A Merrill, David A %A Eyre, Harris %A Mallam, Sravya %A Torosyan, Nare %A Erickson, Kirk I %A Lopez, Oscar L %A Becker, James T %A Carmichael, Owen T %A Gach, H Michael %A Thompson, Paul M %A Longstreth, W T %A Kuller, Lewis H %X

BACKGROUND: Physical activity (PA) can be neuroprotective and reduce the risk for Alzheimer's disease (AD). In assessing physical activity, caloric expenditure is a proxy marker reflecting the sum total of multiple physical activity types conducted by an individual.

OBJECTIVE: To assess caloric expenditure, as a proxy marker of PA, as a predictive measure of gray matter (GM) volumes in the normal and cognitively impaired elderly persons.

METHODS: All subjects in this study were recruited from the Institutional Review Board approved Cardiovascular Health Study (CHS), a multisite population-based longitudinal study in persons aged 65 and older. We analyzed a sub-sample of CHS participants 876 subjects (mean age 78.3, 57.5% F, 42.5% M) who had i) energy output assessed as kilocalories (kcal) per week using the standardized Minnesota Leisure-Time Activities questionnaire, ii) cognitive assessments for clinical classification of normal cognition, mild cognitive impairment (MCI), and AD, and iii) volumetric MR imaging of the brain. Voxel-based morphometry modeled the relationship between kcal/week and GM volumes while accounting for standard covariates including head size, age, sex, white matter hyperintensity lesions, MCI or AD status, and site. Multiple comparisons were controlled using a False Discovery Rate of 5 percent.

RESULTS: Higher energy output, from a variety of physical activity types, was associated with larger GM volumes in frontal, temporal, and parietal lobes, as well as hippocampus, thalamus, and basal ganglia. High levels of caloric expenditure moderated neurodegeneration-associated volume loss in the precuneus, posterior cingulate, and cerebellar vermis.

CONCLUSION: Increasing energy output from a variety of physical activities is related to larger gray matter volumes in the elderly, regardless of cognitive status.

%B J Alzheimers Dis %V 52 %P 719-29 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967227?dopt=Abstract %R 10.3233/JAD-160057 %0 Journal Article %J Nat Genet %D 2016 %T Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci. %A Liu, Chunyu %A Kraja, Aldi T %A Smith, Jennifer A %A Brody, Jennifer A %A Franceschini, Nora %A Bis, Joshua C %A Rice, Kenneth %A Morrison, Alanna C %A Lu, Yingchang %A Weiss, Stefan %A Guo, Xiuqing %A Palmas, Walter %A Martin, Lisa W %A Chen, Yii-Der Ida %A Surendran, Praveen %A Drenos, Fotios %A Cook, James P %A Auer, Paul L %A Chu, Audrey Y %A Giri, Ayush %A Zhao, Wei %A Jakobsdottir, Johanna %A Lin, Li-An %A Stafford, Jeanette M %A Amin, Najaf %A Mei, Hao %A Yao, Jie %A Voorman, Arend %A Larson, Martin G %A Grove, Megan L %A Smith, Albert V %A Hwang, Shih-Jen %A Chen, Han %A Huan, Tianxiao %A Kosova, Gulum %A Stitziel, Nathan O %A Kathiresan, Sekar %A Samani, Nilesh %A Schunkert, Heribert %A Deloukas, Panos %A Li, Man %A Fuchsberger, Christian %A Pattaro, Cristian %A Gorski, Mathias %A Kooperberg, Charles %A Papanicolaou, George J %A Rossouw, Jacques E %A Faul, Jessica D %A Kardia, Sharon L R %A Bouchard, Claude %A Raffel, Leslie J %A Uitterlinden, André G %A Franco, Oscar H %A Vasan, Ramachandran S %A O'Donnell, Christopher J %A Taylor, Kent D %A Liu, Kiang %A Bottinger, Erwin P %A Gottesman, Omri %A Daw, E Warwick %A Giulianini, Franco %A Ganesh, Santhi %A Salfati, Elias %A Harris, Tamara B %A Launer, Lenore J %A Dörr, Marcus %A Felix, Stephan B %A Rettig, Rainer %A Völzke, Henry %A Kim, Eric %A Lee, Wen-Jane %A Lee, I-Te %A Sheu, Wayne H-H %A Tsosie, Krystal S %A Edwards, Digna R Velez %A Liu, Yongmei %A Correa, Adolfo %A Weir, David R %A Völker, Uwe %A Ridker, Paul M %A Boerwinkle, Eric %A Gudnason, Vilmundur %A Reiner, Alexander P %A van Duijn, Cornelia M %A Borecki, Ingrid B %A Edwards, Todd L %A Chakravarti, Aravinda %A Rotter, Jerome I %A Psaty, Bruce M %A Loos, Ruth J F %A Fornage, Myriam %A Ehret, Georg B %A Newton-Cheh, Christopher %A Levy, Daniel %A Chasman, Daniel I %X

Meta-analyses of association results for blood pressure using exome-centric single-variant and gene-based tests identified 31 new loci in a discovery stage among 146,562 individuals, with follow-up and meta-analysis in 180,726 additional individuals (total n = 327,288). These blood pressure-associated loci are enriched for known variants for cardiometabolic traits. Associations were also observed for the aggregation of rare and low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein-protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure-associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.

%B Nat Genet %V 48 %P 1162-70 %8 2016 Oct %G eng %N 10 %R 10.1038/ng.3660 %0 Journal Article %J Hum Mol Genet %D 2016 %T A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration. %A de Vries, Paul S %A Chasman, Daniel I %A Sabater-Lleal, Maria %A Chen, Ming-Huei %A Huffman, Jennifer E %A Steri, Maristella %A Tang, Weihong %A Teumer, Alexander %A Marioni, Riccardo E %A Grossmann, Vera %A Hottenga, Jouke J %A Trompet, Stella %A Müller-Nurasyid, Martina %A Zhao, Jing Hua %A Brody, Jennifer A %A Kleber, Marcus E %A Guo, Xiuqing %A Wang, Jie Jin %A Auer, Paul L %A Attia, John R %A Yanek, Lisa R %A Ahluwalia, Tarunveer S %A Lahti, Jari %A Venturini, Cristina %A Tanaka, Toshiko %A Bielak, Lawrence F %A Joshi, Peter K %A Rocanin-Arjo, Ares %A Kolcic, Ivana %A Navarro, Pau %A Rose, Lynda M %A Oldmeadow, Christopher %A Riess, Helene %A Mazur, Johanna %A Basu, Saonli %A Goel, Anuj %A Yang, Qiong %A Ghanbari, Mohsen %A Willemsen, Gonneke %A Rumley, Ann %A Fiorillo, Edoardo %A de Craen, Anton J M %A Grotevendt, Anne %A Scott, Robert %A Taylor, Kent D %A Delgado, Graciela E %A Yao, Jie %A Kifley, Annette %A Kooperberg, Charles %A Qayyum, Rehan %A Lopez, Lorna M %A Berentzen, Tina L %A Räikkönen, Katri %A Mangino, Massimo %A Bandinelli, Stefania %A Peyser, Patricia A %A Wild, Sarah %A Trégouët, David-Alexandre %A Wright, Alan F %A Marten, Jonathan %A Zemunik, Tatijana %A Morrison, Alanna C %A Sennblad, Bengt %A Tofler, Geoffrey %A de Maat, Moniek P M %A de Geus, Eco J C %A Lowe, Gordon D %A Zoledziewska, Magdalena %A Sattar, Naveed %A Binder, Harald %A Völker, Uwe %A Waldenberger, Melanie %A Khaw, Kay-Tee %A McKnight, Barbara %A Huang, Jie %A Jenny, Nancy S %A Holliday, Elizabeth G %A Qi, Lihong %A Mcevoy, Mark G %A Becker, Diane M %A Starr, John M %A Sarin, Antti-Pekka %A Hysi, Pirro G %A Hernandez, Dena G %A Jhun, Min A %A Campbell, Harry %A Hamsten, Anders %A Rivadeneira, Fernando %A McArdle, Wendy L %A Slagboom, P Eline %A Zeller, Tanja %A Koenig, Wolfgang %A Psaty, Bruce M %A Haritunians, Talin %A Liu, Jingmin %A Palotie, Aarno %A Uitterlinden, André G %A Stott, David J %A Hofman, Albert %A Franco, Oscar H %A Polasek, Ozren %A Rudan, Igor %A Morange, Pierre-Emmanuel %A Wilson, James F %A Kardia, Sharon L R %A Ferrucci, Luigi %A Spector, Tim D %A Eriksson, Johan G %A Hansen, Torben %A Deary, Ian J %A Becker, Lewis C %A Scott, Rodney J %A Mitchell, Paul %A März, Winfried %A Wareham, Nick J %A Peters, Annette %A Greinacher, Andreas %A Wild, Philipp S %A Jukema, J Wouter %A Boomsma, Dorret I %A Hayward, Caroline %A Cucca, Francesco %A Tracy, Russell %A Watkins, Hugh %A Reiner, Alex P %A Folsom, Aaron R %A Ridker, Paul M %A O'Donnell, Christopher J %A Smith, Nicholas L %A Strachan, David P %A Dehghan, Abbas %X

Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ∼120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.

%B Hum Mol Genet %V 25 %P 358-70 %8 2016 Jan 15 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26561523?dopt=Abstract %R 10.1093/hmg/ddv454 %0 Journal Article %J J Med Genet %D 2016 %T Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels. %A van Leeuwen, Elisabeth M %A Sabo, Aniko %A Bis, Joshua C %A Huffman, Jennifer E %A Manichaikul, Ani %A Smith, Albert V %A Feitosa, Mary F %A Demissie, Serkalem %A Joshi, Peter K %A Duan, Qing %A Marten, Jonathan %A van Klinken, Jan B %A Surakka, Ida %A Nolte, Ilja M %A Zhang, Weihua %A Mbarek, Hamdi %A Li-Gao, Ruifang %A Trompet, Stella %A Verweij, Niek %A Evangelou, Evangelos %A Lyytikäinen, Leo-Pekka %A Tayo, Bamidele O %A Deelen, Joris %A van der Most, Peter J %A van der Laan, Sander W %A Arking, Dan E %A Morrison, Alanna %A Dehghan, Abbas %A Franco, Oscar H %A Hofman, Albert %A Rivadeneira, Fernando %A Sijbrands, Eric J %A Uitterlinden, André G %A Mychaleckyj, Josyf C %A Campbell, Archie %A Hocking, Lynne J %A Padmanabhan, Sandosh %A Brody, Jennifer A %A Rice, Kenneth M %A White, Charles C %A Harris, Tamara %A Isaacs, Aaron %A Campbell, Harry %A Lange, Leslie A %A Rudan, Igor %A Kolcic, Ivana %A Navarro, Pau %A Zemunik, Tatijana %A Salomaa, Veikko %A Kooner, Angad S %A Kooner, Jaspal S %A Lehne, Benjamin %A Scott, William R %A Tan, Sian-Tsung %A de Geus, Eco J %A Milaneschi, Yuri %A Penninx, Brenda W J H %A Willemsen, Gonneke %A de Mutsert, Renée %A Ford, Ian %A Gansevoort, Ron T %A Segura-Lepe, Marcelo P %A Raitakari, Olli T %A Viikari, Jorma S %A Nikus, Kjell %A Forrester, Terrence %A McKenzie, Colin A %A de Craen, Anton J M %A de Ruijter, Hester M %A Pasterkamp, Gerard %A Snieder, Harold %A Oldehinkel, Albertine J %A Slagboom, P Eline %A Cooper, Richard S %A Kähönen, Mika %A Lehtimäki, Terho %A Elliott, Paul %A van der Harst, Pim %A Jukema, J Wouter %A Mook-Kanamori, Dennis O %A Boomsma, Dorret I %A Chambers, John C %A Swertz, Morris %A Ripatti, Samuli %A Willems van Dijk, Ko %A Vitart, Veronique %A Polasek, Ozren %A Hayward, Caroline %A Wilson, James G %A Wilson, James F %A Gudnason, Vilmundur %A Rich, Stephen S %A Psaty, Bruce M %A Borecki, Ingrid B %A Boerwinkle, Eric %A Rotter, Jerome I %A Cupples, L Adrienne %A van Duijn, Cornelia M %X

BACKGROUND: So far, more than 170 loci have been associated with circulating lipid levels through genome-wide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels.

METHODS: We used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from ∼60 000 individuals in the discovery stage and ∼90 000 samples in the replication stage.

RESULTS: Our study resulted in the identification of five new associations with circulating lipid levels at four loci. All four loci are within genes that can be linked biologically to lipid metabolism. One of the variants, rs116843064, is a damaging missense variant within the ANGPTL4 gene.

CONCLUSIONS: This study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels.

%B J Med Genet %V 53 %P 441-9 %8 2016 Jul %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/27036123?dopt=Abstract %R 10.1136/jmedgenet-2015-103439 %0 Journal Article %J J Med Genet %D 2016 %T Meta-analysis of genome-wide association studies of HDL cholesterol response to statins. %A Postmus, Iris %A Warren, Helen R %A Trompet, Stella %A Arsenault, Benoit J %A Avery, Christy L %A Bis, Joshua C %A Chasman, Daniel I %A de Keyser, Catherine E %A Deshmukh, Harshal A %A Evans, Daniel S %A Feng, QiPing %A Li, Xiaohui %A Smit, Roelof A J %A Smith, Albert V %A Sun, Fangui %A Taylor, Kent D %A Arnold, Alice M %A Barnes, Michael R %A Barratt, Bryan J %A Betteridge, John %A Boekholdt, S Matthijs %A Boerwinkle, Eric %A Buckley, Brendan M %A Chen, Y-D Ida %A de Craen, Anton J M %A Cummings, Steven R %A Denny, Joshua C %A Dubé, Marie Pierre %A Durrington, Paul N %A Eiriksdottir, Gudny %A Ford, Ian %A Guo, Xiuqing %A Harris, Tamara B %A Heckbert, Susan R %A Hofman, Albert %A Hovingh, G Kees %A Kastelein, John J P %A Launer, Leonore J %A Liu, Ching-Ti %A Liu, Yongmei %A Lumley, Thomas %A McKeigue, Paul M %A Munroe, Patricia B %A Neil, Andrew %A Nickerson, Deborah A %A Nyberg, Fredrik %A O'Brien, Eoin %A O'Donnell, Christopher J %A Post, Wendy %A Poulter, Neil %A Vasan, Ramachandran S %A Rice, Kenneth %A Rich, Stephen S %A Rivadeneira, Fernando %A Sattar, Naveed %A Sever, Peter %A Shaw-Hawkins, Sue %A Shields, Denis C %A Slagboom, P Eline %A Smith, Nicholas L %A Smith, Joshua D %A Sotoodehnia, Nona %A Stanton, Alice %A Stott, David J %A Stricker, Bruno H %A Stürmer, Til %A Uitterlinden, André G %A Wei, Wei-Qi %A Westendorp, Rudi G J %A Whitsel, Eric A %A Wiggins, Kerri L %A Wilke, Russell A %A Ballantyne, Christie M %A Colhoun, Helen M %A Cupples, L Adrienne %A Franco, Oscar H %A Gudnason, Vilmundur %A Hitman, Graham %A Palmer, Colin N A %A Psaty, Bruce M %A Ridker, Paul M %A Stafford, Jeanette M %A Stein, Charles M %A Tardif, Jean-Claude %A Caulfield, Mark J %A Jukema, J Wouter %A Rotter, Jerome I %A Krauss, Ronald M %X

BACKGROUND: In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Inter-individual variation in HDL-C response to statins may be partially explained by genetic variation.

METHODS AND RESULTS: We performed a meta-analysis of genome-wide association studies (GWAS) to identify variants with an effect on statin-induced high density lipoprotein cholesterol (HDL-C) changes. The 123 most promising signals with p<1×10(-4) from the 16 769 statin-treated participants in the first analysis stage were followed up in an independent group of 10 951 statin-treated individuals, providing a total sample size of 27 720 individuals. The only associations of genome-wide significance (p<5×10(-8)) were between minor alleles at the CETP locus and greater HDL-C response to statin treatment.

CONCLUSIONS: Based on results from this study that included a relatively large sample size, we suggest that CETP may be the only detectable locus with common genetic variants that influence HDL-C response to statins substantially in individuals of European descent. Although CETP is known to be associated with HDL-C, we provide evidence that this pharmacogenetic effect is independent of its association with baseline HDL-C levels.

%B J Med Genet %V 53 %P 835-845 %8 2016 Dec %G eng %N 12 %R 10.1136/jmedgenet-2016-103966 %0 Journal Article %J Nat Genet %D 2016 %T Meta-analysis of rare and common exome chip variants identifies S1PR4 and other loci influencing blood cell traits. %X

Hematologic measures such as hematocrit and white blood cell (WBC) count are heritable and clinically relevant. We analyzed erythrocyte and WBC phenotypes in 52,531 individuals (37,775 of European ancestry, 11,589 African Americans, and 3,167 Hispanic Americans) from 16 population-based cohorts with Illumina HumanExome BeadChip genotypes. We then performed replication analyses of new discoveries in 18,018 European-American women and 5,261 Han Chinese. We identified and replicated four new erythrocyte trait-locus associations (CEP89, SHROOM3, FADS2, and APOE) and six new WBC loci for neutrophil count (S1PR4), monocyte count (BTBD8, NLRP12, and IL17RA), eosinophil count (IRF1), and total WBC count (MYB). The association of a rare missense variant in S1PR4 supports the role of sphingosine-1-phosphate signaling in leukocyte trafficking and circulating neutrophil counts. Loss-of-function experiments for S1pr4 in mouse and s1pr4 in zebrafish demonstrated phenotypes consistent with the association observed in humans and altered kinetics of neutrophil recruitment and resolution in response to tissue injury.

%B Nat Genet %V 48 %P 867-76 %8 2016 Aug %G ENG %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/27399967?dopt=Abstract %R 10.1038/ng.3607 %0 Journal Article %J Psychosom Med %D 2016 %T Mortality After Bereavement: The Role of Cardiovascular Disease and Depression. %A Stahl, Sarah T %A Arnold, Alice M %A Chen, Jia-Yuh %A Anderson, Stewart %A Schulz, Richard %X

OBJECTIVES: Late-life bereavement is associated with an increased risk of mortality. This study assesses the associations among bereavement, cardiovascular disease (CVD), and depressive symptoms on mortality in older men and women.

METHODS: We examined data from the Cardiovascular Health Study, a prospective population-based cohort study of older adults. We compared mortality in those who became bereaved from 1989 to 1999 (n = 593) to an age- and sex-matched sample of individuals who remained married (n = 593). Cox regression was used to examine the association between bereavement and 3-year all-cause mortality and whether or not the association differed by sex, presence of CVD, or postbereavement depressive symptoms.

RESULTS: One hundred ninety-nine (16.8%) individuals died. There was no association of bereavement with mortality (hazard ratio [HR] = 0.98 [0.74-1.30]). However, there were significant interaction effects of bereavement with participant sex (p < .001) and CVD (p = .010). Bereavement decreased the risk of mortality in women (HR = 0.67 [0.46-0.97]) and increased the risk of mortality in men (HR = 1.77 [1.14-2.75]). Within sex, the association of bereavement with mortality differed according to CVD status. The reduced risk of mortality associated with bereavement in women was only observed in women with CVD, and the increased risk in men was only observed in men without CVD. High levels of depressive symptoms attenuated the relation between bereavement and mortality in men without CVD.

CONCLUSIONS: The relation between bereavement and mortality was different in men and women and varied by CVD status. Bereavement decreased mortality in women with CVD and increased mortality in men without CVD.

%B Psychosom Med %V 78 %P 697-703 %8 2016 Jul-Aug %G ENG %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/26894326?dopt=Abstract %R 10.1097/PSY.0000000000000317 %0 Journal Article %J Circ Cardiovasc Genet %D 2016 %T Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis. %A Natarajan, Pradeep %A Bis, Joshua C %A Bielak, Lawrence F %A Cox, Amanda J %A Dörr, Marcus %A Feitosa, Mary F %A Franceschini, Nora %A Guo, Xiuqing %A Hwang, Shih-Jen %A Isaacs, Aaron %A Jhun, Min A %A Kavousi, Maryam %A Li-Gao, Ruifang %A Lyytikäinen, Leo-Pekka %A Marioni, Riccardo E %A Schminke, Ulf %A Stitziel, Nathan O %A Tada, Hayato %A van Setten, Jessica %A Smith, Albert V %A Vojinovic, Dina %A Yanek, Lisa R %A Yao, Jie %A Yerges-Armstrong, Laura M %A Amin, Najaf %A Baber, Usman %A Borecki, Ingrid B %A Carr, J Jeffrey %A Chen, Yii-Der Ida %A Cupples, L Adrienne %A de Jong, Pim A %A de Koning, Harry %A de Vos, Bob D %A Demirkan, Ayse %A Fuster, Valentin %A Franco, Oscar H %A Goodarzi, Mark O %A Harris, Tamara B %A Heckbert, Susan R %A Heiss, Gerardo %A Hoffmann, Udo %A Hofman, Albert %A Išgum, Ivana %A Jukema, J Wouter %A Kähönen, Mika %A Kardia, Sharon L R %A Kral, Brian G %A Launer, Lenore J %A Massaro, Joseph %A Mehran, Roxana %A Mitchell, Braxton D %A Mosley, Thomas H %A de Mutsert, Renée %A Newman, Anne B %A Nguyen, Khanh-Dung %A North, Kari E %A O'Connell, Jeffrey R %A Oudkerk, Matthijs %A Pankow, James S %A Peloso, Gina M %A Post, Wendy %A Province, Michael A %A Raffield, Laura M %A Raitakari, Olli T %A Reilly, Dermot F %A Rivadeneira, Fernando %A Rosendaal, Frits %A Sartori, Samantha %A Taylor, Kent D %A Teumer, Alexander %A Trompet, Stella %A Turner, Stephen T %A Uitterlinden, André G %A Vaidya, Dhananjay %A van der Lugt, Aad %A Völker, Uwe %A Wardlaw, Joanna M %A Wassel, Christina L %A Weiss, Stefan %A Wojczynski, Mary K %A Becker, Diane M %A Becker, Lewis C %A Boerwinkle, Eric %A Bowden, Donald W %A Deary, Ian J %A Dehghan, Abbas %A Felix, Stephan B %A Gudnason, Vilmundur %A Lehtimäki, Terho %A Mathias, Rasika %A Mook-Kanamori, Dennis O %A Psaty, Bruce M %A Rader, Daniel J %A Rotter, Jerome I %A Wilson, James G %A van Duijn, Cornelia M %A Völzke, Henry %A Kathiresan, Sekar %A Peyser, Patricia A %A O'Donnell, Christopher J %X

BACKGROUND: -The burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease (CHD). We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent CHD.

METHODS AND RESULTS: -We studied a total of 25,109 European ancestry and African-American participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52,869 with common carotid intima media thickness (CIMT) measured by ultrasonography within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Participants were genotyped for 247,870 DNA sequence variants (231,539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and CIMT. APOB p.Arg3527Gln was associated with four-fold excess CAC (P = 3×10(-10)). The APOE ε2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC (P = 1×10(-12)) and 1.4% reduced CIMT (P = 4×10(-14)) in carriers compared with non-carriers. In secondary analyses conditioning on LDL cholesterol concentration, the ε2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of ε2 was associated with reduced risk for CHD (OR 0.77; P = 1×10(-11)).

CONCLUSIONS: -Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE ε2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities as well as clinical CHD.

%B Circ Cardiovasc Genet %8 2016 Nov 21 %G eng %R 10.1161/CIRCGENETICS.116.001572 %0 Journal Article %J Lancet Diabetes Endocrinol %D 2016 %T Natriuretic peptides and integrated risk assessment for cardiovascular disease: an individual-participant-data meta-analysis. %A Willeit, Peter %A Kaptoge, Stephen %A Welsh, Paul %A Butterworth, Adam %A Chowdhury, Rajiv %A Spackman, Sarah %A Pennells, Lisa %A Gao, Pei %A Burgess, Stephen %A Freitag, Daniel %A Sweeting, Michael %A Wood, Angela %A Cook, Nancy %A Judd, Suzanne %A Trompet, Stella %A Nambi, Vijay %A Olsen, Michael %A Everett, Brendan %A Kee, Frank %A Arnlöv, Johan %A Salomaa, Veikko %A Levy, Daniel %A Kauhanen, Jussi %A Laukkanen, Jari %A Kavousi, Maryam %A Ninomiya, Toshiharu %A Casas, Juan-Pablo %A Daniels, Lori %A Lind, Lars %A Kistorp, Caroline %A Rosenberg, Jens %A Mueller, Thomas %A Rubattu, Speranza %A Panagiotakos, Demosthenes %A Franco, Oscar %A de Lemos, James %A Luchner, Andreas %A Kizer, Jorge %A Kiechl, Stefan %A Salonen, Jukka %A Goya Wannamethee, S %A de Boer, Rudolf %A Nordestgaard, Børge %A Andersson, Jonas %A Jørgensen, Torben %A Melander, Olle %A Ballantyne, Christie %A DeFilippi, Christopher %A Ridker, Paul %A Cushman, Mary %A Rosamond, Wayne %A Thompson, Simon %A Gudnason, Vilmundur %A Sattar, Naveed %A Danesh, John %A Di Angelantonio, Emanuele %K Aged %K Biomarkers %K Cardiovascular Diseases %K Female %K Humans %K Male %K Middle Aged %K Natriuretic Peptide, Brain %K Peptide Fragments %K Prospective Studies %K Risk Assessment %X

BACKGROUND: Guidelines for primary prevention of cardiovascular diseases focus on prediction of coronary heart disease and stroke. We assessed whether or not measurement of N-terminal-pro-B-type natriuretic peptide (NT-proBNP) concentration could enable a more integrated approach than at present by predicting heart failure and enhancing coronary heart disease and stroke risk assessment.

METHODS: In this individual-participant-data meta-analysis, we generated and harmonised individual-participant data from relevant prospective studies via both de-novo NT-proBNP concentration measurement of stored samples and collection of data from studies identified through a systematic search of the literature (PubMed, Scientific Citation Index Expanded, and Embase) for articles published up to Sept 4, 2014, using search terms related to natriuretic peptide family members and the primary outcomes, with no language restrictions. We calculated risk ratios and measures of risk discrimination and reclassification across predicted 10 year risk categories (ie, <5%, 5% to <7·5%, and ≥7·5%), adding assessment of NT-proBNP concentration to that of conventional risk factors (ie, age, sex, smoking status, systolic blood pressure, history of diabetes, and total and HDL cholesterol concentrations). Primary outcomes were the combination of coronary heart disease and stroke, and the combination of coronary heart disease, stroke, and heart failure.

FINDINGS: We recorded 5500 coronary heart disease, 4002 stroke, and 2212 heart failure outcomes among 95 617 participants without a history of cardiovascular disease in 40 prospective studies. Risk ratios (for a comparison of the top third vs bottom third of NT-proBNP concentrations, adjusted for conventional risk factors) were 1·76 (95% CI 1·56-1·98) for the combination of coronary heart disease and stroke and 2·00 (1·77-2·26) for the combination of coronary heart disease, stroke, and heart failure. Addition of information about NT-proBNP concentration to a model containing conventional risk factors was associated with a C-index increase of 0·012 (0·010-0·014) and a net reclassification improvement of 0·027 (0·019-0·036) for the combination of coronary heart disease and stroke and a C-index increase of 0·019 (0·016-0·022) and a net reclassification improvement of 0·028 (0·019-0·038) for the combination of coronary heart disease, stroke, and heart failure.

INTERPRETATION: In people without baseline cardiovascular disease, NT-proBNP concentration assessment strongly predicted first-onset heart failure and augmented coronary heart disease and stroke prediction, suggesting that NT-proBNP concentration assessment could be used to integrate heart failure into cardiovascular disease primary prevention.

FUNDING: British Heart Foundation, Austrian Science Fund, UK Medical Research Council, National Institute for Health Research, European Research Council, and European Commission Framework Programme 7.

%B Lancet Diabetes Endocrinol %V 4 %P 840-9 %8 2016 10 %G eng %N 10 %R 10.1016/S2213-8587(16)30196-6 %0 Journal Article %J Am J Epidemiol %D 2016 %T Neighborhood Socioeconomic Status and Cognitive Function in Late Life. %A Rosso, Andrea L %A Flatt, Jason D %A Carlson, Michelle C %A Lovasi, Gina S %A Rosano, Caterina %A Brown, Arleen F %A Matthews, Karen A %A Gianaros, Peter J %X

Neighborhood socioeconomic status (NSES) is associated with cognitive function, independently of individual demographic, health, and socioeconomic characteristics. However, research has been largely cross-sectional, and mechanisms of the association are unknown. In 1992-1993, Cardiovascular Health Study participants (n = 3,595; mean age = 74.8 years; 15.7% black) underwent cognitive testing and magnetic resonance imaging of white matter hyperintensities (WMH), and their addresses were geocoded. NSES was calculated using 1990 US Census data (block groups; 6 measures of wealth, education, and occupation). The Modified Mini-Mental State Examination (3MS) was used to assess general cognition, and the Digit Symbol Substitution Test (DSST) was used to assess speed of processing annually for 6 years. Associations of race-specific NSES tertiles with 3MS, DSST, and WMH were estimated using linear mixed-effects models accounting for geographic clustering, stratified by race, and adjusted for demographic, health, and individual socioeconomic status (education, income, lifetime occupational status) variables. In fully adjusted models, higher NSES was associated with higher 3MS scores in blacks (mean difference between highest and lowest NSES = 2.4 points; P = 0.004) and whites (mean difference = 0.7 points; P = 0.02) at baseline but not with changes in 3MS over time. NSES was marginally associated with DSST and was not associated with WMH. Adjustment for WMH did not attenuate NSES-3MS associations. Associations of NSES with cognition in late adulthood differ by race, are not explained by WMH, and are evident only at baseline.

%B Am J Epidemiol %V 183 %P 1088-97 %8 2016 Jun 15 %G eng %N 12 %R 10.1093/aje/kwv337 %0 Journal Article %J Mol Psychiatry %D 2016 %T A novel Alzheimer disease locus located near the gene encoding tau protein. %A Jun, G %A Ibrahim-Verbaas, C A %A Vronskaya, M %A Lambert, J-C %A Chung, J %A Naj, A C %A Kunkle, B W %A Wang, L-S %A Bis, J C %A Bellenguez, C %A Harold, D %A Lunetta, K L %A DeStefano, A L %A Grenier-Boley, B %A Sims, R %A Beecham, G W %A Smith, A V %A Chouraki, V %A Hamilton-Nelson, K L %A Ikram, M A %A Fiévet, N %A Denning, N %A Martin, E R %A Schmidt, H %A Kamatani, Y %A Dunstan, M L %A Valladares, O %A Laza, A R %A Zelenika, D %A Ramirez, A %A Foroud, T M %A Choi, S-H %A Boland, A %A Becker, T %A Kukull, W A %A van der Lee, S J %A Pasquier, F %A Cruchaga, C %A Beekly, D %A Fitzpatrick, A L %A Hanon, O %A Gill, M %A Barber, R %A Gudnason, V %A Campion, D %A Love, S %A Bennett, D A %A Amin, N %A Berr, C %A Tsolaki, Magda %A Buxbaum, J D %A Lopez, O L %A Deramecourt, V %A Fox, N C %A Cantwell, L B %A Tárraga, L %A Dufouil, C %A Hardy, J %A Crane, P K %A Eiriksdottir, G %A Hannequin, D %A Clarke, R %A Evans, D %A Mosley, T H %A Letenneur, L %A Brayne, C %A Maier, W %A De Jager, P %A Emilsson, V %A Dartigues, J-F %A Hampel, H %A Kamboh, M I %A de Bruijn, R F A G %A Tzourio, C %A Pastor, P %A Larson, E B %A Rotter, J I %A O'Donovan, M C %A Montine, T J %A Nalls, M A %A Mead, S %A Reiman, E M %A Jonsson, P V %A Holmes, C %A St George-Hyslop, P H %A Boada, M %A Passmore, P %A Wendland, J R %A Schmidt, R %A Morgan, K %A Winslow, A R %A Powell, J F %A Carasquillo, M %A Younkin, S G %A Jakobsdóttir, J %A Kauwe, J S K %A Wilhelmsen, K C %A Rujescu, D %A Nöthen, M M %A Hofman, A %A Jones, L %A Haines, J L %A Psaty, B M %A Van Broeckhoven, C %A Holmans, P %A Launer, L J %A Mayeux, R %A Lathrop, M %A Goate, A M %A Escott-Price, V %A Seshadri, S %A Pericak-Vance, M A %A Amouyel, P %A Williams, J %A van Duijn, C M %A Schellenberg, G D %A Farrer, L A %K Alzheimer Disease %K Apolipoprotein E4 %K Chromosomes, Human, Pair 17 %K Genome-Wide Association Study %K Humans %K Polymorphism, Single Nucleotide %K tau Proteins %X

APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P<1 × 10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ɛ4+: 1250 cases and 536 controls; APOE ɛ4-: 718 cases and 1699 controls). Among APOE ɛ4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10(-9)). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ɛ4+ subjects (CR1 and CLU) or APOE ɛ4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10(-7)) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P ⩽ 1.3 × 10(-8)), frontal cortex (P ⩽ 1.3 × 10(-9)) and temporal cortex (P⩽1.2 × 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10(-6)) and temporal cortex (P=2.6 × 10(-6)). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ɛ4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.

%B Mol Psychiatry %V 21 %P 108-17 %8 2016 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/25778476?dopt=Abstract %R 10.1038/mp.2015.23 %0 Journal Article %J Circ Cardiovasc Genet %D 2016 %T Novel Genetic Loci Associated With Retinal Microvascular Diameter. %A Jensen, Richard A %A Sim, Xueling %A Smith, Albert Vernon %A Li, Xiaohui %A Jakobsdottir, Johanna %A Cheng, Ching-Yu %A Brody, Jennifer A %A Cotch, Mary Frances %A McKnight, Barbara %A Klein, Ronald %A Wang, Jie Jin %A Kifley, Annette %A Harris, Tamara B %A Launer, Lenore J %A Taylor, Kent D %A Klein, Barbara E K %A Raffel, Leslie J %A Li, Xiang %A Ikram, M Arfan %A Klaver, Caroline C %A van der Lee, Sven J %A Mutlu, Unal %A Hofman, Albert %A Uitterlinden, André G %A Liu, Chunyu %A Kraja, Aldi T %A Mitchell, Paul %A Gudnason, Vilmundur %A Rotter, Jerome I %A Boerwinkle, Eric %A van Duijn, Cornelia M %A Psaty, Bruce M %A Wong, Tien Y %X

BACKGROUND: There is increasing evidence that retinal microvascular diameters are associated with cardiovascular and cerebrovascular conditions. The shared genetic effects of these associations are currently unknown. The aim of this study was to increase our understanding of the genetic factors that mediate retinal vessel size.

METHODS AND RESULTS: This study extends previous genome-wide association study results using 24 000+ multiethnic participants from 7 discovery cohorts and 5000+ subjects of European ancestry from 2 replication cohorts. Using the Illumina HumanExome BeadChip, we investigate the association of single-nucleotide polymorphisms and variants collectively across genes with summary measures of retinal vessel diameters, referred to as the central retinal venule equivalent and the central retinal arteriole equivalent. We report 4 new loci associated with central retinal venule equivalent, one of which is also associated with central retinal arteriole equivalent. The 4 single-nucleotide polymorphisms are rs7926971 in TEAD1 (P=3.1×10(-) (11); minor allele frequency=0.43), rs201259422 in TSPAN10 (P=4.4×10(-9); minor allele frequency=0.27), rs5442 in GNB3 (P=7.0×10(-10); minor allele frequency=0.05), and rs1800407 in OCA2 (P=3.4×10(-8); minor allele frequency=0.05). The latter single-nucleotide polymorphism, rs1800407, was also associated with central retinal arteriole equivalent (P=6.5×10(-12)). Results from the gene-based burden tests were null. In phenotype look-ups, single-nucleotide polymorphism rs201255422 was associated with both systolic (P=0.001) and diastolic blood pressures (P=8.3×10(-04)).

CONCLUSIONS: Our study expands the understanding of genetic factors influencing the size of the retinal microvasculature. These findings may also provide insight into the relationship between retinal and systemic microvascular disease.

%B Circ Cardiovasc Genet %V 9 %P 45-54 %8 2016 Feb %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26567291?dopt=Abstract %R 10.1161/CIRCGENETICS.115.001142 %0 Journal Article %J Nat Neurosci %D 2016 %T {Novel genetic loci underlying human intracranial volume identified through genome-wide association %A Adams, H. H. %A Hibar, D. P. %A Chouraki, V. %A Stein, J. L. %A Nyquist, P. A. %A Renter?a, M. E. %A Trompet, S. %A Arias-Vasquez, A. %A Seshadri, S. %A Desrivi?res, S. %A Beecham, A. H. %A Jahanshad, N. %A Wittfeld, K. %A van der Lee, S. J. %A Abramovic, L. %A Alhusaini, S. %A Amin, N. %A Andersson, M. %A Arfanakis, K. %A Aribisala, B. S. %A Armstrong, N. J. %A Athanasiu, L. %A Axelsson, T. %A Beiser, A. %A Bernard, M. %A Bis, J. C. %A Blanken, L. M. %A Blanton, S. H. %A Bohlken, M. M. %A Boks, M. P. %A Bralten, J. %A Brickman, A. M. %A Carmichael, O. %A Chakravarty, M. M. %A Chauhan, G. %A Chen, Q. %A Ching, C. R. %A Cuellar-Partida, G. %A Braber, A. D. %A Doan, N. T. %A Ehrlich, S. %A Filippi, I. %A Ge, T. %A Giddaluru, S. %A Goldman, A. L. %A Gottesman, R. F. %A Greven, C. U. %A Grimm, O. %A Griswold, M. E. %A Guadalupe, T. %A Hass, J. %A Haukvik, U. K. %A Hilal, S. %A Hofer, E. %A Hoehn, D. %A Holmes, A. J. %A Hoogman, M. %A Janowitz, D. %A Jia, T. %A Kasperaviciute, D. %A Kim, S. %A Klein, M. %A Kraemer, B. %A Lee, P. H. %A Liao, J. %A Liewald, D. C. %A Lopez, L. M. %A Luciano, M. %A Macare, C. %A Marquand, A. %A Matarin, M. %A Mather, K. A. %A Mattheisen, M. %A Mazoyer, B. %A McKay, D. R. %A McWhirter, R. %A Milaneschi, Y. %A Mirza-Schreiber, N. %A Muetzel, R. L. %A Maniega, S. M. %A Nho, K. %A Nugent, A. C. %A Loohuis, L. M. %A Oosterlaan, J. %A Papmeyer, M. %A Pappa, I. %A Pirpamer, L. %A Pudas, S. %A P?tz, B. %A Rajan, K. B. %A Ramasamy, A. %A Richards, J. S. %A Risacher, S. L. %A Roiz-Santia?ez, R. %A Rommelse, N. %A Rose, E. J. %A Royle, N. A. %A Rundek, T. %A S?mann, P. G. %A Satizabal, C. L. %A Schmaal, L. %A Schork, A. J. %A Shen, L. %A Shin, J. %A Shumskaya, E. %A Smith, A. V. %A Sprooten, E. %A Strike, L. T. %A Teumer, A. %A Thomson, R. %A Tordesillas-Gutierrez, D. %A Toro, R. %A Trabzuni, D. %A Vaidya, D. %A van der Grond, J. %A van der Meer, D. %A Van Donkelaar, M. M. %A Van Eijk, K. R. %A Van Erp, T. G. %A van Rooij, D. %A Walton, E. %A Westlye, L. T. %A Whelan, C. D. %A Windham, B. G. %A Winkler, A. M. %A Woldehawariat, G. %A Wolf, C. %A Wolfers, T. %A Xu, B. %A Yanek, L. R. %A Yang, J. %A Zijdenbos, A. %A Zwiers, M. P. %A Agartz, I. %A Aggarwal, N. T. %A Almasy, L. %A Ames, D. %A Amouyel, P. %A Andreassen, O. A. %A Arepalli, S. %A Assareh, A. A. %A Barral, S. %A Bastin, M. E. %A Becker, D. M. %A Becker, J. T. %A Bennett, D. A. %A Blangero, J. %A van Bokhoven, H. %A Boomsma, D. I. %A Brodaty, H. %A Brouwer, R. M. %A Brunner, H. G. %A Buckner, R. L. %A Buitelaar, J. K. %A Bulayeva, K. B. %A Cahn, W. %A Calhoun, V. D. %A Cannon, D. M. %A Cavalleri, G. L. %A Chen, C. %A Cheng, C. Y. %A Cichon, S. %A Cookson, M. R. %A Corvin, A. %A Crespo-Facorro, B. %A Curran, J. E. %A Czisch, M. %A Dale, A. M. %A Davies, G. E. %A De Geus, E. J. %A De Jager, P. L. %A de Zubicaray, G. I. %A Delanty, N. %A Depondt, C. %A DeStefano, A. L. %A Dillman, A. %A Djurovic, S. %A Donohoe, G. %A Drevets, W. C. %A Duggirala, R. %A Dyer, T. D. %A Erk, S. %A Espeseth, T. %A Evans, D. A. %A Fedko, I. O. %A Fern?ndez, G. %A Ferrucci, L. %A Fisher, S. E. %A Fleischman, D. A. %A Ford, I. %A Foroud, T. M. %A Fox, P. T. %A Francks, C. %A Fukunaga, M. %A Gibbs, J. R. %A Glahn, D. C. %A Gollub, R. L. %A G?ring, H. H. %A Grabe, H. J. %A Green, R. C. %A Gruber, O. %A Gudnason, V. %A Guelfi, S. %A Hansell, N. K. %A Hardy, J. %A Hartman, C. A. %A Hashimoto, R. %A Hegenscheid, K. %A Heinz, A. %A Le Hellard, S. %A Hernandez, D. G. %A Heslenfeld, D. J. %A Ho, B. C. %A Hoekstra, P. J. %A Hoffmann, W. %A Hofman, A. %A Holsboer, F. %A Homuth, G. %A Hosten, N. %A Hottenga, J. J. %A Hulshoff Pol, H. E. %A Ikeda, M. %A Ikram, M. K. %A Jack, C. R. %A Jenkinson, M. %A Johnson, R. %A J?nsson, E. G. %A Jukema, J. W. %A Kahn, R. S. %A Kanai, R. %A Kloszewska, I. %A Knopman, D. S. %A Kochunov, P. %A Kwok, J. B. %A Lawrie, S. M. %A Lema?tre, H. %A Liu, X. %A Longo, D. L. %A Longstreth, W. T. %A Lopez, O. L. %A Lovestone, S. %A Martinez, O. %A Martinot, J. L. %A Mattay, V. S. %A McDonald, C. %A McIntosh, A. M. %A McMahon, K. L. %A McMahon, F. J. %A Mecocci, P. %A Melle, I. %A Meyer-Lindenberg, A. %A Mohnke, S. %A Montgomery, G. W. %A Morris, D. W. %A Mosley, T. H. %A M?hleisen, T. W. %A M?ller-Myhsok, B. %A Nalls, M. A. %A Nauck, M. %A Nichols, T. E. %A Niessen, W. J. %A N?then, M. M. %A Nyberg, L. %A Ohi, K. %A Olvera, R. L. %A Ophoff, R. A. %A Pandolfo, M. %A Paus, T. %A Pausova, Z. %A Penninx, B. W. %A Pike, G. B. %A Potkin, S. G. %A Psaty, B. M. %A Reppermund, S. %A Rietschel, M. %A Roffman, J. L. %A Romanczuk-Seiferth, N. %A Rotter, J. I. %A Ryten, M. %A Sacco, R. L. %A Sachdev, P. S. %A Saykin, A. J. %A Schmidt, R. %A Schofield, P. R. %A Sigurdsson, S. %A Simmons, A. %A Singleton, A. %A Sisodiya, S. M. %A Smith, C. %A Smoller, J. W. %A Soininen, H. %A Srikanth, V. %A Steen, V. M. %A Stott, D. J. %A Sussmann, J. E. %A Thalamuthu, A. %A Tiemeier, H. %A Toga, A. W. %A Traynor, B. J. %A Troncoso, J. %A Turner, J. A. %A Tzourio, C. %A Uitterlinden, A. G. %A Hern?ndez, M. C. %A Van der Brug, M. %A van der Lugt, A. %A Van der Wee, N. J. %A van Duijn, C. M. %A Van Haren, N. E. %A Van T Ent, D. %A van Tol, M. J. %A Vardarajan, B. N. %A Veltman, D. J. %A Vernooij, M. W. %A V?lzke, H. %A Walter, H. %A Wardlaw, J. M. %A Wassink, T. H. %A Weale, M. E. %A Weinberger, D. R. %A Weiner, M. W. %A Wen, W. %A Westman, E. %A White, T. %A Wong, T. Y. %A Wright, C. B. %A Zielke, H. R. %A Zonderman, A. B. %A Deary, I. J. %A DeCarli, C. %A Schmidt, H. %A Martin, N. G. %A De Craen, A. J. %A Wright, M. J. %A Launer, L. J. %A Schumann, G. %A Fornage, M. %A Franke, B. %A Debette, S. %A Medland, S. E. %A Ikram, M. A. %A Thompson, P. M. %X Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits. %B Nat Neurosci %V 19 %P 1569–1582 %8 12 %G eng %0 Journal Article %J Am J Hypertens %D 2016 %T Orthostatic Hypotension and Risk of Venous Thromboembolism in 2 Cohort Studies. %A Bell, Elizabeth J %A Agarwal, Sunil K %A Cushman, Mary %A Heckbert, Susan R %A Lutsey, Pamela L %A Folsom, Aaron R %X

BACKGROUND: Although venous stasis is a risk factor for venous thromboembolism (VTE) and orthostatic hypotension (OH) can cause venous stasis, to our knowledge no study has examined the relationship between OH and VTE risk. We sought to quantify the association between OH and VTE (deep vein thrombosis or pulmonary embolism) using data from 2 large, prospective cohort studies: the Cardiovascular Health Study (CHS) and the Atherosclerosis Risk in Communities (ARIC) Study. We hypothesized that OH was positively associated with incident VTE.

METHODS: We measured OH-defined as a drop in systolic blood pressure (SBP) of at least 20 mm Hg or diastolic blood pressure (DBP) of at least 10 mm Hg within 3 minutes of standing-in participants aged 45-64 years in ARIC (n = 12,480) and ≥65 years in CHS (n = 5,027) at baseline visits (1987-1989 in ARIC; 1989-1990 and 1992-1993 in CHS), and followed participants for incident VTE (n = 568 in ARIC through 2011 and n = 148 in CHS through 2001). We calculated adjusted hazard ratios (HRs) and their 95% confidence intervals (CIs) for incident VTE in relation to OH status.

RESULTS: In CHS, there was a positive association between OH status and incident VTE (HR for VTE = 1.74 (95% CI: 1.20-2.51)). In contrast, there was no association between OH and VTE in the ARIC study (HR for VTE = 0.97 (95% CI: 0.70-1.33)).

CONCLUSIONS: Community-dwelling older adults with OH had a moderately increased risk of VTE. These results were not seen in a population-based middle-aged cohort.

%B Am J Hypertens %V 29 %P 634-40 %8 2016 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/26306405?dopt=Abstract %R 10.1093/ajh/hpv151 %0 Journal Article %J Am J Hum Genet %D 2016 %T Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals. %A Eicher, John D %A Chami, Nathalie %A Kacprowski, Tim %A Nomura, Akihiro %A Chen, Ming-Huei %A Yanek, Lisa R %A Tajuddin, Salman M %A Schick, Ursula M %A Slater, Andrew J %A Pankratz, Nathan %A Polfus, Linda %A Schurmann, Claudia %A Giri, Ayush %A Brody, Jennifer A %A Lange, Leslie A %A Manichaikul, Ani %A Hill, W David %A Pazoki, Raha %A Elliot, Paul %A Evangelou, Evangelos %A Tzoulaki, Ioanna %A Gao, He %A Vergnaud, Anne-Claire %A Mathias, Rasika A %A Becker, Diane M %A Becker, Lewis C %A Burt, Amber %A Crosslin, David R %A Lyytikäinen, Leo-Pekka %A Nikus, Kjell %A Hernesniemi, Jussi %A Kähönen, Mika %A Raitoharju, Emma %A Mononen, Nina %A Raitakari, Olli T %A Lehtimäki, Terho %A Cushman, Mary %A Zakai, Neil A %A Nickerson, Deborah A %A Raffield, Laura M %A Quarells, Rakale %A Willer, Cristen J %A Peloso, Gina M %A Abecasis, Goncalo R %A Liu, Dajiang J %A Deloukas, Panos %A Samani, Nilesh J %A Schunkert, Heribert %A Erdmann, Jeanette %A Fornage, Myriam %A Richard, Melissa %A Tardif, Jean-Claude %A Rioux, John D %A Dubé, Marie-Pierre %A de Denus, Simon %A Lu, Yingchang %A Bottinger, Erwin P %A Loos, Ruth J F %A Smith, Albert Vernon %A Harris, Tamara B %A Launer, Lenore J %A Gudnason, Vilmundur %A Velez Edwards, Digna R %A Torstenson, Eric S %A Liu, Yongmei %A Tracy, Russell P %A Rotter, Jerome I %A Rich, Stephen S %A Highland, Heather M %A Boerwinkle, Eric %A Li, Jin %A Lange, Ethan %A Wilson, James G %A Mihailov, Evelin %A Mägi, Reedik %A Hirschhorn, Joel %A Metspalu, Andres %A Esko, Tõnu %A Vacchi-Suzzi, Caterina %A Nalls, Mike A %A Zonderman, Alan B %A Evans, Michele K %A Engström, Gunnar %A Orho-Melander, Marju %A Melander, Olle %A O'Donoghue, Michelle L %A Waterworth, Dawn M %A Wallentin, Lars %A White, Harvey D %A Floyd, James S %A Bartz, Traci M %A Rice, Kenneth M %A Psaty, Bruce M %A Starr, J M %A Liewald, David C M %A Hayward, Caroline %A Deary, Ian J %A Greinacher, Andreas %A Völker, Uwe %A Thiele, Thomas %A Völzke, Henry %A van Rooij, Frank J A %A Uitterlinden, André G %A Franco, Oscar H %A Dehghan, Abbas %A Edwards, Todd L %A Ganesh, Santhi K %A Kathiresan, Sekar %A Faraday, Nauder %A Auer, Paul L %A Reiner, Alex P %A Lettre, Guillaume %A Johnson, Andrew D %X

Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets' important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.

%B Am J Hum Genet %V 99 %P 40-55 %8 2016 Jul 7 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27346686?dopt=Abstract %R 10.1016/j.ajhg.2016.05.005 %0 Journal Article %J Circ Heart Fail %D 2016 %T Predicting Heart Failure With Preserved and Reduced Ejection Fraction: The International Collaboration on Heart Failure Subtypes. %A Ho, Jennifer E %A Enserro, Danielle %A Brouwers, Frank P %A Kizer, Jorge R %A Shah, Sanjiv J %A Psaty, Bruce M %A Bartz, Traci M %A Santhanakrishnan, Rajalakshmi %A Lee, Douglas S %A Chan, Cheeling %A Liu, Kiang %A Blaha, Michael J %A Hillege, Hans L %A van der Harst, Pim %A van Gilst, Wiek H %A Kop, Willem J %A Gansevoort, Ron T %A Vasan, Ramachandran S %A Gardin, Julius M %A Levy, Daniel %A Gottdiener, John S %A de Boer, Rudolf A %A Larson, Martin G %X

BACKGROUND: Heart failure (HF) is a prevalent and deadly disease, and preventive strategies focused on at-risk individuals are needed. Current HF prediction models have not examined HF subtypes. We sought to develop and validate risk prediction models for HF with preserved and reduced ejection fraction (HFpEF, HFrEF).

METHODS AND RESULTS: Of 28,820 participants from 4 community-based cohorts, 982 developed incident HFpEF and 909 HFrEF during a median follow-up of 12 years. Three cohorts were combined, and a 2:1 random split was used for derivation and internal validation, with the fourth cohort as external validation. Models accounted for multiple competing risks (death, other HF subtype, and unclassified HF). The HFpEF-specific model included age, sex, systolic blood pressure, body mass index, antihypertensive treatment, and previous myocardial infarction; it had good discrimination in derivation (c-statistic 0.80; 95% confidence interval [CI], 0.78-0.82) and validation samples (internal: 0.79; 95% CI, 0.77-0.82 and external: 0.76; 95% CI: 0.71-0.80). The HFrEF-specific model additionally included smoking, left ventricular hypertrophy, left bundle branch block, and diabetes mellitus; it had good discrimination in derivation (c-statistic 0.82; 95% CI, 0.80-0.84) and validation samples (internal: 0.80; 95% CI, 0.78-0.83 and external: 0.76; 95% CI, 0.71-0.80). Age was more strongly associated with HFpEF, and male sex, left ventricular hypertrophy, bundle branch block, previous myocardial infarction, and smoking with HFrEF (P value for each comparison ≤0.02).

CONCLUSIONS: We describe and validate risk prediction models for HF subtypes and show good discrimination in a large sample. Some risk factors differed between HFpEF and HFrEF, supporting the notion of pathogenetic differences among HF subtypes.

%B Circ Heart Fail %V 9 %8 2016 Jun %G eng %N 6 %R 10.1161/CIRCHEARTFAILURE.115.003116 %0 Journal Article %J Nat Commun %D 2016 %T A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape. %A Ried, Janina S %A Jeff M, Janina %A Chu, Audrey Y %A Bragg-Gresham, Jennifer L %A van Dongen, Jenny %A Huffman, Jennifer E %A Ahluwalia, Tarunveer S %A Cadby, Gemma %A Eklund, Niina %A Eriksson, Joel %A Esko, Tõnu %A Feitosa, Mary F %A Goel, Anuj %A Gorski, Mathias %A Hayward, Caroline %A Heard-Costa, Nancy L %A Jackson, Anne U %A Jokinen, Eero %A Kanoni, Stavroula %A Kristiansson, Kati %A Kutalik, Zoltán %A Lahti, Jari %A Luan, Jian'an %A Mägi, Reedik %A Mahajan, Anubha %A Mangino, Massimo %A Medina-Gómez, Carolina %A Monda, Keri L %A Nolte, Ilja M %A Perusse, Louis %A Prokopenko, Inga %A Qi, Lu %A Rose, Lynda M %A Salvi, Erika %A Smith, Megan T %A Snieder, Harold %A Stančáková, Alena %A Ju Sung, Yun %A Tachmazidou, Ioanna %A Teumer, Alexander %A Thorleifsson, Gudmar %A van der Harst, Pim %A Walker, Ryan W %A Wang, Sophie R %A Wild, Sarah H %A Willems, Sara M %A Wong, Andrew %A Zhang, Weihua %A Albrecht, Eva %A Couto Alves, Alexessander %A Bakker, Stephan J L %A Barlassina, Cristina %A Bartz, Traci M %A Beilby, John %A Bellis, Claire %A Bergman, Richard N %A Bergmann, Sven %A Blangero, John %A Blüher, Matthias %A Boerwinkle, Eric %A Bonnycastle, Lori L %A Bornstein, Stefan R %A Bruinenberg, Marcel %A Campbell, Harry %A Chen, Yii-Der Ida %A Chiang, Charleston W K %A Chines, Peter S %A Collins, Francis S %A Cucca, Fracensco %A Cupples, L Adrienne %A D'Avila, Francesca %A de Geus, Eco J C %A Dedoussis, George %A Dimitriou, Maria %A Döring, Angela %A Eriksson, Johan G %A Farmaki, Aliki-Eleni %A Farrall, Martin %A Ferreira, Teresa %A Fischer, Krista %A Forouhi, Nita G %A Friedrich, Nele %A Gjesing, Anette Prior %A Glorioso, Nicola %A Graff, Mariaelisa %A Grallert, Harald %A Grarup, Niels %A Gräßler, Jürgen %A Grewal, Jagvir %A Hamsten, Anders %A Harder, Marie Neergaard %A Hartman, Catharina A %A Hassinen, Maija %A Hastie, Nicholas %A Hattersley, Andrew Tym %A Havulinna, Aki S %A Heliövaara, Markku %A Hillege, Hans %A Hofman, Albert %A Holmen, Oddgeir %A Homuth, Georg %A Hottenga, Jouke-Jan %A Hui, Jennie %A Husemoen, Lise Lotte %A Hysi, Pirro G %A Isaacs, Aaron %A Ittermann, Till %A Jalilzadeh, Shapour %A James, Alan L %A Jørgensen, Torben %A Jousilahti, Pekka %A Jula, Antti %A Marie Justesen, Johanne %A Justice, Anne E %A Kähönen, Mika %A Karaleftheri, Maria %A Tee Khaw, Kay %A Keinanen-Kiukaanniemi, Sirkka M %A Kinnunen, Leena %A Knekt, Paul B %A Koistinen, Heikki A %A Kolcic, Ivana %A Kooner, Ishminder K %A Koskinen, Seppo %A Kovacs, Peter %A Kyriakou, Theodosios %A Laitinen, Tomi %A Langenberg, Claudia %A Lewin, Alexandra M %A Lichtner, Peter %A Lindgren, Cecilia M %A Lindström, Jaana %A Linneberg, Allan %A Lorbeer, Roberto %A Lorentzon, Mattias %A Luben, Robert %A Lyssenko, Valeriya %A Männistö, Satu %A Manunta, Paolo %A Leach, Irene Mateo %A McArdle, Wendy L %A McKnight, Barbara %A Mohlke, Karen L %A Mihailov, Evelin %A Milani, Lili %A Mills, Rebecca %A Montasser, May E %A Morris, Andrew P %A Müller, Gabriele %A Musk, Arthur W %A Narisu, Narisu %A Ong, Ken K %A Oostra, Ben A %A Osmond, Clive %A Palotie, Aarno %A Pankow, James S %A Paternoster, Lavinia %A Penninx, Brenda W %A Pichler, Irene %A Pilia, Maria G %A Polasek, Ozren %A Pramstaller, Peter P %A Raitakari, Olli T %A Rankinen, Tuomo %A Rao, D C %A Rayner, Nigel W %A Ribel-Madsen, Rasmus %A Rice, Treva K %A Richards, Marcus %A Ridker, Paul M %A Rivadeneira, Fernando %A Ryan, Kathy A %A Sanna, Serena %A Sarzynski, Mark A %A Scholtens, Salome %A Scott, Robert A %A Sebert, Sylvain %A Southam, Lorraine %A Sparsø, Thomas Hempel %A Steinthorsdottir, Valgerdur %A Stirrups, Kathleen %A Stolk, Ronald P %A Strauch, Konstantin %A Stringham, Heather M %A Swertz, Morris A %A Swift, Amy J %A Tönjes, Anke %A Tsafantakis, Emmanouil %A van der Most, Peter J %A van Vliet-Ostaptchouk, Jana V %A Vandenput, Liesbeth %A Vartiainen, Erkki %A Venturini, Cristina %A Verweij, Niek %A Viikari, Jorma S %A Vitart, Veronique %A Vohl, Marie-Claude %A Vonk, Judith M %A Waeber, Gérard %A Widen, Elisabeth %A Willemsen, Gonneke %A Wilsgaard, Tom %A Winkler, Thomas W %A Wright, Alan F %A Yerges-Armstrong, Laura M %A Hua Zhao, Jing %A Zillikens, M Carola %A Boomsma, Dorret I %A Bouchard, Claude %A Chambers, John C %A Chasman, Daniel I %A Cusi, Daniele %A Gansevoort, Ron T %A Gieger, Christian %A Hansen, Torben %A Hicks, Andrew A %A Hu, Frank %A Hveem, Kristian %A Jarvelin, Marjo-Riitta %A Kajantie, Eero %A Kooner, Jaspal S %A Kuh, Diana %A Kuusisto, Johanna %A Laakso, Markku %A Lakka, Timo A %A Lehtimäki, Terho %A Metspalu, Andres %A Njølstad, Inger %A Ohlsson, Claes %A Oldehinkel, Albertine J %A Palmer, Lyle J %A Pedersen, Oluf %A Perola, Markus %A Peters, Annette %A Psaty, Bruce M %A Puolijoki, Hannu %A Rauramaa, Rainer %A Rudan, Igor %A Salomaa, Veikko %A Schwarz, Peter E H %A Shudiner, Alan R %A Smit, Jan H %A Sørensen, Thorkild I A %A Spector, Timothy D %A Stefansson, Kari %A Stumvoll, Michael %A Tremblay, Angelo %A Tuomilehto, Jaakko %A Uitterlinden, André G %A Uusitupa, Matti %A Völker, Uwe %A Vollenweider, Peter %A Wareham, Nicholas J %A Watkins, Hugh %A Wilson, James F %A Zeggini, Eleftheria %A Abecasis, Goncalo R %A Boehnke, Michael %A Borecki, Ingrid B %A Deloukas, Panos %A van Duijn, Cornelia M %A Fox, Caroline %A Groop, Leif C %A Heid, Iris M %A Hunter, David J %A Kaplan, Robert C %A McCarthy, Mark I %A North, Kari E %A O'Connell, Jeffrey R %A Schlessinger, David %A Thorsteinsdottir, Unnur %A Strachan, David P %A Frayling, Timothy %A Hirschhorn, Joel N %A Müller-Nurasyid, Martina %A Loos, Ruth J F %K Anthropometry %K Body Size %K Genome-Wide Association Study %K Genotype %K Humans %K Models, Genetic %K Principal Component Analysis %X

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.

%B Nat Commun %V 7 %P 13357 %8 2016 11 23 %G eng %R 10.1038/ncomms13357 %0 Journal Article %J Thromb Res %D 2016 %T Prospective study of γ' fibrinogen and incident venous thromboembolism: The Longitudinal Investigation of Thromboembolism Etiology (LITE). %A Folsom, Aaron R %A Tang, Weihong %A George, Kristen M %A Heckbert, Susan R %A MacLehose, Richard F %A Cushman, Mary %A Pankow, James S %X

INTRODUCTION: Epidemiological studies generally have not found plasma total fibrinogen to be a risk factor for venous thromboembolism (VTE), but several have reported associations between variants in the fibrinogen gamma gene (FGG) and VTE. A case-control study in whites suggested plasma γ' fibrinogen concentration may be associated inversely with VTE, but this was not replicated in African Americans.

OBJECTIVE: To examine the prospective association between γ' fibrinogen concentrations and occurrence of VTE.

METHODS: We used the Longitudinal Investigation of Thromboembolism Etiology (LITE), involving two pooled population-based cohorts in the United States including 16,234 participants. The cohorts comprised white and African American men and women, aged 50years and older at study onset in the early 1990s. We identified VTEs during follow-up and documented they met standardized diagnostic criteria.

RESULTS: During two decades of follow-up, neither γ' fibrinogen nor total fibrinogen nor their ratio was associated with VTE overall (n=521 VTEs), in subgroups defined by race, or in other subgroups. In both race groups, the minor allele of FGG rs2066865 was associated with lower γ' fibrinogen concentrations, but this allele was not associated with VTE.

CONCLUSIONS: A lower plasma concentration of γ' fibrinogen in healthy adults does not appear to increase VTE risk.

%B Thromb Res %V 139 %P 44-9 %8 2016 Mar %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/26916295?dopt=Abstract %R 10.1016/j.thromres.2016.01.008 %0 Journal Article %J Circ Cardiovasc Genet %D 2016 %T Rare Exome Sequence Variants in CLCN6 Reduce Blood Pressure Levels and Hypertension Risk. %A Yu, Bing %A Pulit, Sara L %A Hwang, Shih-Jen %A Brody, Jennifer A %A Amin, Najaf %A Auer, Paul L %A Bis, Joshua C %A Boerwinkle, Eric %A Burke, Gregory L %A Chakravarti, Aravinda %A Correa, Adolfo %A Dreisbach, Albert W %A Franco, Oscar H %A Ehret, Georg B %A Franceschini, Nora %A Hofman, Albert %A Lin, Dan-Yu %A Metcalf, Ginger A %A Musani, Solomon K %A Muzny, Donna %A Palmas, Walter %A Raffel, Leslie %A Reiner, Alex %A Rice, Ken %A Rotter, Jerome I %A Veeraraghavan, Narayanan %A Fox, Ervin %A Guo, Xiuqing %A North, Kari E %A Gibbs, Richard A %A van Duijn, Cornelia M %A Psaty, Bruce M %A Levy, Daniel %A Newton-Cheh, Christopher %A Morrison, Alanna C %X

BACKGROUND: Rare genetic variants influence blood pressure (BP).

METHODS AND RESULTS: Whole-exome sequencing was performed on DNA samples from 17 956 individuals of European ancestry and African ancestry (14 497, first-stage discovery and 3459, second-stage discovery) to examine the effect of rare variants on hypertension and 4 BP traits: systolic BP, diastolic BP, pulse pressure, and mean arterial pressure. Tests of ≈170 000 common variants (minor allele frequency, ≥1%; statistical significance, P≤2.9×10(-7)) and gene-based tests of rare variants (minor allele frequency, <1%; ≈17 000 genes; statistical significance, P≤1.5×10(-6)) were evaluated for each trait and ancestry, followed by multiethnic meta-analyses. In the first-stage discovery, rare coding variants (splicing, stop-gain, stop-loss, nonsynonymous variants, or indels) in CLCN6 were associated with lower diastolic BP (cumulative minor allele frequency, 1.3%; β=-3.20; P=4.1×10(-6)) and were independent of a nearby common variant (rs17367504) previously associated with BP. CLCN6 rare variants were also associated with lower systolic BP (β=-4.11; P=2.8×10(-4)), mean arterial pressure (β=-3.50; P=8.9×10(-6)), and reduced hypertension risk (odds ratio, 0.72; P=0.017). Meta-analysis of the 2-stage discovery samples showed that CLCN6 was associated with lower diastolic BP at exome-wide significance (cumulative minor allele frequency, 1.1%; β=-3.30; P=5.0×10(-7)).

CONCLUSIONS: These findings implicate the effect of rare coding variants in CLCN6 in BP variation and offer new insights into BP regulation.

%B Circ Cardiovasc Genet %V 9 %P 64-70 %8 2016 Feb %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26658788?dopt=Abstract %R 10.1161/CIRCGENETICS.115.001215 %0 Journal Article %J PLoS Genet %D 2016 %T Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease. %A Jakobsdottir, Johanna %A van der Lee, Sven J %A Bis, Joshua C %A Chouraki, Vincent %A Li-Kroeger, David %A Yamamoto, Shinya %A Grove, Megan L %A Naj, Adam %A Vronskaya, Maria %A Salazar, Jose L %A DeStefano, Anita L %A Brody, Jennifer A %A Smith, Albert V %A Amin, Najaf %A Sims, Rebecca %A Ibrahim-Verbaas, Carla A %A Choi, Seung-Hoan %A Satizabal, Claudia L %A Lopez, Oscar L %A Beiser, Alexa %A Ikram, M Arfan %A Garcia, Melissa E %A Hayward, Caroline %A Varga, Tibor V %A Ripatti, Samuli %A Franks, Paul W %A Hallmans, Göran %A Rolandsson, Olov %A Jansson, Jan-Håkon %A Porteous, David J %A Salomaa, Veikko %A Eiriksdottir, Gudny %A Rice, Kenneth M %A Bellen, Hugo J %A Levy, Daniel %A Uitterlinden, André G %A Emilsson, Valur %A Rotter, Jerome I %A Aspelund, Thor %A O'Donnell, Christopher J %A Fitzpatrick, Annette L %A Launer, Lenore J %A Hofman, Albert %A Wang, Li-San %A Williams, Julie %A Schellenberg, Gerard D %A Boerwinkle, Eric %A Psaty, Bruce M %A Seshadri, Sudha %A Shulman, Joshua M %A Gudnason, Vilmundur %A van Duijn, Cornelia M %X

We performed an exome-wide association analysis in 1393 late-onset Alzheimer's disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (~0.5% versus <0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES sub-study, P155L was associated with increased risk and earlier onset of LOAD [odds ratio (95% CI) = 7.5 (3.5-15.9), p = 6.6x10-9]. Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling. Human TM2D3 is capable of rescuing these phenotypes, but this activity is abolished by P155L, establishing it as a functionally damaging allele. Our results establish a rare TM2D3 variant in association with LOAD susceptibility, and together with prior work suggests possible links to the β-amyloid cascade.

%B PLoS Genet %V 12 %P e1006327 %8 2016 Oct %G eng %N 10 %R 10.1371/journal.pgen.1006327 %0 Journal Article %J Mol Psychiatry %D 2016 %T Rare, low frequency and common coding variants in CHRNA5 and their contribution to nicotine dependence in European and African Americans. %A Olfson, E %A Saccone, N L %A Johnson, E O %A Chen, L-S %A Culverhouse, R %A Doheny, K %A Foltz, S M %A Fox, L %A Gogarten, S M %A Hartz, S %A Hetrick, K %A Laurie, C C %A Marosy, B %A Amin, N %A Arnett, D %A Barr, R G %A Bartz, T M %A Bertelsen, S %A Borecki, I B %A Brown, M R %A Chasman, D I %A van Duijn, C M %A Feitosa, M F %A Fox, E R %A Franceschini, N %A Franco, O H %A Grove, M L %A Guo, X %A Hofman, A %A Kardia, S L R %A Morrison, A C %A Musani, S K %A Psaty, B M %A Rao, D C %A Reiner, A P %A Rice, K %A Ridker, P M %A Rose, L M %A Schick, U M %A Schwander, K %A Uitterlinden, A G %A Vojinovic, D %A Wang, J-C %A Ware, E B %A Wilson, G %A Yao, J %A Zhao, W %A Breslau, N %A Hatsukami, D %A Stitzel, J A %A Rice, J %A Goate, A %A Bierut, L J %X

The common nonsynonymous variant rs16969968 in the α5 nicotinic receptor subunit gene (CHRNA5) is the strongest genetic risk factor for nicotine dependence in European Americans and contributes to risk in African Americans. To comprehensively examine whether other CHRNA5 coding variation influences nicotine dependence risk, we performed targeted sequencing on 1582 nicotine-dependent cases (Fagerström Test for Nicotine Dependence score⩾4) and 1238 non-dependent controls, with independent replication of common and low frequency variants using 12 studies with exome chip data. Nicotine dependence was examined using logistic regression with individual common variants (minor allele frequency (MAF)⩾0.05), aggregate low frequency variants (0.05>MAF⩾0.005) and aggregate rare variants (MAF<0.005). Meta-analysis of primary results was performed with replication studies containing 12 174 heavy and 11 290 light smokers. Next-generation sequencing with 180 × coverage identified 24 nonsynonymous variants and 2 frameshift deletions in CHRNA5, including 9 novel variants in the 2820 subjects. Meta-analysis confirmed the risk effect of the only common variant (rs16969968, European ancestry: odds ratio (OR)=1.3, P=3.5 × 10(-11); African ancestry: OR=1.3, P=0.01) and demonstrated that three low frequency variants contributed an independent risk (aggregate term, European ancestry: OR=1.3, P=0.005; African ancestry: OR=1.4, P=0.0006). The remaining 22 rare coding variants were associated with increased risk of nicotine dependence in the European American primary sample (OR=12.9, P=0.01) and in the same risk direction in African Americans (OR=1.5, P=0.37). Our results indicate that common, low frequency and rare CHRNA5 coding variants are independently associated with nicotine dependence risk. These newly identified variants likely influence the risk for smoking-related diseases such as lung cancer.

%B Mol Psychiatry %V 21 %P 601-7 %8 2016 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/26239294?dopt=Abstract %R 10.1038/mp.2015.105 %0 Journal Article %J Blood Coagul Fibrinolysis %D 2016 %T Relation of coagulation factor XI with incident coronary heart disease and stroke: the Cardiovascular Health Study. %A Appiah, Duke %A Fashanu, Oluwaseun E %A Heckbert, Susa R %A Cushman, Mary %A Psaty, Bruce M %A Folsom, Aaron R %X

The role of coagulation factor XI (FXI) in the cause of arterial thrombotic events remains uncertain. We examined the association of FXI with incident coronary heart disease (CHD), ischemic stroke, and hemorrhagic stroke. Data were from 3394 adults (mean age: 74.5 years) enrolled in the Cardiovascular Health Study who had FXI antigen from plasma samples drawn in 1992-1993 and were followed for cardiovascular events until 30 June 2013. Approximately 63% of participants were women and 17% were black. FXI levels were higher in blacks and women, showed positive associations with high-density lipoprotein and total cholesterol, BMI and diabetes, and negative associations with age and alcohol intake. During median follow-up of 13 years, we identified 1232 incident CHD, 473 ischemic stroke, and 84 hemorrhagic stroke events. In multivariable Cox models adjusted for traditional cardiovascular disease risk factors, the hazard ratio per one SD (32.2 mg/dl) increment of FXI was 1.02 (95% confidence interval: 0.96-1.08) for CHD; 0.94 (0.85-1.04) for ischemic stroke, and 0.85 (0.65-1.10) for hemorrhagic stroke. In this prospective cohort of elderly adults, there was no statistically significant association of higher FXI levels with incident CHD and stroke.

%B Blood Coagul Fibrinolysis %8 2016 Dec 22 %G eng %R 10.1097/MBC.0000000000000616 %0 Journal Article %J Cerebrovasc Dis Extra %D 2016 %T Risk Factors for Incident Carotid Artery Revascularization among Older Adults: The Cardiovascular Health Study. %A Garg, Parveen K %A Koh, Willam J H %A Delaney, Joseph A %A Halm, Ethan A %A Hirsch, Calvin H %A Longstreth, William T %A Mukamal, Kenneth J %A Kucharska-Newton, Anna %A Polak, Joseph F %A Curtis, Lesley %X

BACKGROUND: Population-based risk factors for carotid artery revascularization are not known. We investigated the association between demographic and clinical characteristics and incident carotid artery revascularization in a cohort of older adults.

METHODS: Among Cardiovascular Health Study participants, a population-based cohort of 5,888 adults aged 65 years or older enrolled in two waves (1989-1990 and 1992-1993), 5,107 participants without a prior history of carotid endarterectomy (CEA) or cerebrovascular disease had a carotid ultrasound at baseline and were included in these analyses. Cox proportional hazards multivariable analysis was used to determine independent risk factors for incident carotid artery revascularization.

RESULTS: Over a mean follow-up of 13.5 years, 141 participants underwent carotid artery revascularization, 97% were CEA. Baseline degree of stenosis and incident ischemic cerebral events occurring during follow-up were the strongest predictors of incident revascularization. After adjustment for these, factors independently associated with an increased risk of incident revascularization were: hypertension (HR 1.53; 95% CI: 1.05-2.23), peripheral arterial disease (HR 2.57; 95% CI: 1.34-4.93), and low-density lipoprotein cholesterol (HR 1.23 per standard deviation [SD] increment [35.4 mg/dL]; 95% CI: 1.04-1.46). Factors independently associated with a lower risk of incident revascularization were: female gender (HR 0.51; 95% CI: 0.34-0.77) and older age (HR 0.69 per SD increment [5.5 years]; 95% CI: 0.56-0.86).

CONCLUSIONS: Even after accounting for carotid stenosis and incident cerebral ischemic events, carotid revascularization is related to age, gender, and cardiovascular risk factors. Further study of these demographic disparities and the role of risk factor control is warranted.

%B Cerebrovasc Dis Extra %V 6 %P 129-139 %8 2016 Nov 16 %G eng %N 3 %R 10.1159/000452426 %0 Journal Article %J Alzheimers Dement %D 2016 %T Risk of dementia and death in the long-term follow-up of the Pittsburgh Cardiovascular Health Study-Cognition Study. %A Kuller, Lewis H %A Lopez, Oscar L %A Becker, James T %A Chang, Yuefang %A Newman, Anne B %K African Continental Ancestry Group %K Aged %K Aged, 80 and over %K Apolipoprotein E4 %K Brain %K Cardiovascular Diseases %K Cognition %K Dementia %K European Continental Ancestry Group %K Female %K Follow-Up Studies %K Humans %K Magnetic Resonance Imaging %K Male %K Neuropsychological Tests %K Pennsylvania %K Risk Factors %K Walking %X

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

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

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

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

%B Alzheimers Dement %V 12 %P 170-83 %8 2016 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26519786?dopt=Abstract %R 10.1016/j.jalz.2015.08.165 %0 Journal Article %J Pharmacogenomics %D 2016 %T Rooted in risk: genetic predisposition for low-density lipoprotein cholesterol level associates with diminished low-density lipoprotein cholesterol response to statin treatment. %A Smit, Roelof Aj %A Postmus, Iris %A Trompet, Stella %A Barnes, Michael R %A Warren, Helen %A Arsenault, Benoit J %A Chasman, Daniel I %A Cupples, L Adrienne %A Hitman, Graham A %A Krauss, Ronald M %A Li, Xiaohui %A Psaty, Bruce M %A Stein, Charles M %A Rotter, Jerome I %A Jukema, J Wouter %K Cholesterol, LDL %K Genetic Predisposition to Disease %K Humans %K Hydroxymethylglutaryl-CoA Reductase Inhibitors %K Pharmacogenetics %K Polymorphism, Single Nucleotide %K Triglycerides %X

AIMS: To utilize previously reported lead SNPs for low-density lipoprotein cholesterol (LDL-c) levels to find additional loci of importance to statin response, and examine whether genetic predisposition to LDL-c levels associates with differential statin response.

METHODS: We investigated effects on statin response of 59 LDL-c SNPs, by combining summary level statistics from the Global Lipids Genetics and Genomic Investigation of Statin Therapy consortia.

RESULTS: Lead SNPs for APOE, SORT1 and NPC1L1 were associated with a decreased LDL-c response to statin treatment, as was overall genetic predisposition for increased LDL-c levels as quantified with 59 SNPs, with a 5.4% smaller statin response per standard deviation increase in genetically raised LDL-c levels.

CONCLUSION: Genetic predisposition for increased LDL-c level may decrease efficacy of statin therapy.

%B Pharmacogenomics %V 17 %P 1621-1628 %8 2016 10 %G eng %N 15 %R 10.2217/pgs-2016-0091 %0 Journal Article %J Osteoporos Int %D 2016 %T Soluble CD14 and fracture risk. %A Bethel, M %A Bůžková, P %A Fink, H A %A Robbins, J A %A Cauley, J A %A Lee, J %A Barzilay, J I %A Jalal, D I %A Carbone, L D %X

UNLABELLED: Soluble CD14 (sCD14) is an inflammatory marker associated with osteoclasts. Using Cox proportional hazards models, we found a positive association between plasma levels of sCD14 and risk of incident fracture among participants in the Cardiovascular Health Study. sCD14 may be useful in identifying those at risk for fracture.

INTRODUCTION: Soluble CD14, a proinflammatory cytokine, is primarily derived from macrophages/monocytes that can differentiate into osteoclasts. The purpose of this study was to examine the relationship between sCD14 levels and osteoporotic fractures.

METHODS: In the Cardiovascular Health Study, 5462 men and women had sCD14 levels measured at baseline. Incident hip fractures (median follow-up time 12.5 years) and incident composite fractures (defined as the first hip, pelvis, humerus, or distal radius fracture, median follow-up 8.6 years) were identified from hospital discharge summaries and/or Medicare claims data. Cox proportional hazards models were used to model the association between sCD14 levels and time to incident hip or composite fracture, overall and as a function of race and gender.

RESULTS: In unadjusted models, there was a positive association between sCD14 levels (per 1 standard deviation increase, i.e., 361.6 ng/mL) and incident hip (HR, 1.26; 95 % CI, 1.17, 1.36) and composite (HR, 1.20; 95 % CI, 1.12, 1.28) fractures. When models were fully adjusted for demographics, lifestyle factors, and medication use, these associations were no longer significant. However, in whites, the association of sCD14 levels with hip fractures remained significant in fully adjusted models (HR, 1.11; 95 % CI, 1.01-1.23). Associations of sCD14 levels with hip and composite fracture did not differ between men and women.

CONCLUSIONS: In this large cohort of community-dwelling older adults, higher sCD14 levels were associated with an increased risk of incident hip fractures in whites.

%B Osteoporos Int %V 27 %P 1755-63 %8 2016 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/26659065?dopt=Abstract %R 10.1007/s00198-015-3439-9 %0 Journal Article %J J Am Heart Assoc %D 2016 %T Soluble ST2 for Prediction of Heart Failure and Cardiovascular Death in an Elderly, Community-Dwelling Population. %A Parikh, Ravi H %A Seliger, Stephen L %A Christenson, Robert %A Gottdiener, John S %A Psaty, Bruce M %A deFilippi, Christopher R %X

BACKGROUND: Soluble ST2 (sST2), a marker of myocyte stretch and fibrosis, has prognostic value in many cardiovascular diseases. We hypothesized that sST2 levels are associated with incident heart failure (HF), including subtypes of preserved (HFpEF) and reduced (HFrEF) ejection fraction, and cardiovascular death.

METHODS AND RESULTS: Baseline serum sST2 was measured in 3915 older, community-dwelling subjects from the Cardiovascular Health Study without prevalent HF. sST2 levels were associated with older age, male sex, black race, traditional cardiovascular risk factors, other biomarkers of inflammation, cardiac stretch, myocardial injury, and fibrosis, and abnormal echocardiographic parameters. In longitudinal analysis, greater sST2 was associated with a higher risk of incident HF and cardiovascular death; however, in multivariate models adjusting for other cardiac risk factors and the cardiac-specific biomarker, N-terminal pro-type B natriuretic peptide, these associations were attenuated. In these models, an sST2 level above the US Food and Drug Administration-approved cut-off value (>35 ng/mL) was significantly associated with incident HF (hazard ratio [HR], 1.20; 95% CI, 1.02-1.43) and cardiovascular death (HR, 1.21; 95% CI, 1.02-1.44), and greater sST2 was continuously associated with cardiovascular death (per 1-ln increment: HR, 1.24; 95% CI, 1.02-1.50). sST2 was not associated with the HF subtypes of HFpEF and HFrEF in adjusted analysis. Addition of sST2 to existing risk models of HF and cardiovascular death modestly improved discrimination and reclassification into a higher risk.

CONCLUSIONS: The predictive value of sST2 for HF of all subtypes and cardiovascular death is modest in an elderly population despite strong cross-sectional associations with risk factors and underlying cardiac pathology.

%B J Am Heart Assoc %V 5 %8 2016 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/27481133?dopt=Abstract %R 10.1161/JAHA.115.003188 %0 Journal Article %J J Am Soc Nephrol %D 2016 %T SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function. %A Li, Man %A Li, Yong %A Weeks, Olivia %A Mijatovic, Vladan %A Teumer, Alexander %A Huffman, Jennifer E %A Tromp, Gerard %A Fuchsberger, Christian %A Gorski, Mathias %A Lyytikäinen, Leo-Pekka %A Nutile, Teresa %A Sedaghat, Sanaz %A Sorice, Rossella %A Tin, Adrienne %A Yang, Qiong %A Ahluwalia, Tarunveer S %A Arking, Dan E %A Bihlmeyer, Nathan A %A Böger, Carsten A %A Carroll, Robert J %A Chasman, Daniel I %A Cornelis, Marilyn C %A Dehghan, Abbas %A Faul, Jessica D %A Feitosa, Mary F %A Gambaro, Giovanni %A Gasparini, Paolo %A Giulianini, Franco %A Heid, Iris %A Huang, Jinyan %A Imboden, Medea %A Jackson, Anne U %A Jeff, Janina %A Jhun, Min A %A Katz, Ronit %A Kifley, Annette %A Kilpeläinen, Tuomas O %A Kumar, Ashish %A Laakso, Markku %A Li-Gao, Ruifang %A Lohman, Kurt %A Lu, Yingchang %A Mägi, Reedik %A Malerba, Giovanni %A Mihailov, Evelin %A Mohlke, Karen L %A Mook-Kanamori, Dennis O %A Robino, Antonietta %A Ruderfer, Douglas %A Salvi, Erika %A Schick, Ursula M %A Schulz, Christina-Alexandra %A Smith, Albert V %A Smith, Jennifer A %A Traglia, Michela %A Yerges-Armstrong, Laura M %A Zhao, Wei %A Goodarzi, Mark O %A Kraja, Aldi T %A Liu, Chunyu %A Wessel, Jennifer %A Boerwinkle, Eric %A Borecki, Ingrid B %A Bork-Jensen, Jette %A Bottinger, Erwin P %A Braga, Daniele %A Brandslund, Ivan %A Brody, Jennifer A %A Campbell, Archie %A Carey, David J %A Christensen, Cramer %A Coresh, Josef %A Crook, Errol %A Curhan, Gary C %A Cusi, Daniele %A de Boer, Ian H %A de Vries, Aiko P J %A Denny, Joshua C %A Devuyst, Olivier %A Dreisbach, Albert W %A Endlich, Karlhans %A Esko, Tõnu %A Franco, Oscar H %A Fulop, Tibor %A Gerhard, Glenn S %A Glümer, Charlotte %A Gottesman, Omri %A Grarup, Niels %A Gudnason, Vilmundur %A Harris, Tamara B %A Hayward, Caroline %A Hocking, Lynne %A Hofman, Albert %A Hu, Frank B %A Husemoen, Lise Lotte N %A Jackson, Rebecca D %A Jørgensen, Torben %A Jørgensen, Marit E %A Kähönen, Mika %A Kardia, Sharon L R %A König, Wolfgang %A Kooperberg, Charles %A Kriebel, Jennifer %A Launer, Lenore J %A Lauritzen, Torsten %A Lehtimäki, Terho %A Levy, Daniel %A Linksted, Pamela %A Linneberg, Allan %A Liu, Yongmei %A Loos, Ruth J F %A Lupo, Antonio %A Meisinger, Christine %A Melander, Olle %A Metspalu, Andres %A Mitchell, Paul %A Nauck, Matthias %A Nürnberg, Peter %A Orho-Melander, Marju %A Parsa, Afshin %A Pedersen, Oluf %A Peters, Annette %A Peters, Ulrike %A Polasek, Ozren %A Porteous, David %A Probst-Hensch, Nicole M %A Psaty, Bruce M %A Qi, Lu %A Raitakari, Olli T %A Reiner, Alex P %A Rettig, Rainer %A Ridker, Paul M %A Rivadeneira, Fernando %A Rossouw, Jacques E %A Schmidt, Frank %A Siscovick, David %A Soranzo, Nicole %A Strauch, Konstantin %A Toniolo, Daniela %A Turner, Stephen T %A Uitterlinden, André G %A Ulivi, Sheila %A Velayutham, Dinesh %A Völker, Uwe %A Völzke, Henry %A Waldenberger, Melanie %A Wang, Jie Jin %A Weir, David R %A Witte, Daniel %A Kuivaniemi, Helena %A Fox, Caroline S %A Franceschini, Nora %A Goessling, Wolfram %A Köttgen, Anna %A Chu, Audrey Y %X

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (nStage1: 111,666; nStage2: 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; PStage1<3.7×10(-7)), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 (P=5.4×10(-8) by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2-knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.

%B J Am Soc Nephrol %8 2016 Dec 05 %G eng %R 10.1681/ASN.2016020131 %0 Journal Article %J Circulation %D 2016 %T Study of Cardiovascular Health Outcomes in the Era of Claims Data: The Cardiovascular Health Study. %A Psaty, Bruce M %A Delaney, Joseph A %A Arnold, Alice M %A Curtis, Lesley H %A Fitzpatrick, Annette L %A Heckbert, Susan R %A McKnight, Barbara %A Ives, Diane %A Gottdiener, John S %A Kuller, Lewis H %A Longstreth, W T %K Blood Glucose %K Cardiovascular Diseases %K Female %K Follow-Up Studies %K Health Surveys %K Hospitalization %K Hospitals, Veterans %K Humans %K Insurance Claim Review %K International Classification of Diseases %K Lipids %K Male %K Managed Care Programs %K Medicare %K Risk Factors %K Sampling Studies %K Treatment Outcome %K United States %X

BACKGROUND: Increasingly, the diagnostic codes from administrative claims data are being used as clinical outcomes.

METHODS AND RESULTS: Data from the Cardiovascular Health Study (CHS) were used to compare event rates and risk factor associations between adjudicated hospitalized cardiovascular events and claims-based methods of defining events. The outcomes of myocardial infarction (MI), stroke, and heart failure were defined in 3 ways: the CHS adjudicated event (CHS[adj]), selected International Classification of Diseases, Ninth Edition diagnostic codes only in the primary position for Medicare claims data from the Center for Medicare & Medicaid Services (CMS[1st]), and the same selected diagnostic codes in any position (CMS[any]). Conventional claims-based methods of defining events had high positive predictive values but low sensitivities. For instance, the positive predictive value of International Classification of Diseases, Ninth Edition code 410.x1 for a new acute MI in the first position was 90.6%, but this code identified only 53.8% of incident MIs. The observed event rates for CMS[1st] were low. For MI, the incidence was 14.9 events per 1000 person-years for CHS[adj] MI, 8.6 for CMS[1st] MI, and 12.2 for CMS[any] MI. In general, cardiovascular disease risk factor associations were similar across the 3 methods of defining events. Indeed, traditional cardiovascular disease risk factors were also associated with all first hospitalizations not resulting from an MI.

CONCLUSIONS: The use of diagnostic codes from claims data as clinical events, especially when restricted to primary diagnoses, leads to an underestimation of event rates. Additionally, claims-based events data represent a composite end point that includes the outcome of interest and selected (misclassified) nonevent hospitalizations.

%B Circulation %V 133 %P 156-64 %8 2016 Jan 12 %G ENG %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26538580?dopt=Abstract %R 10.1161/CIRCULATIONAHA.115.018610 %0 Journal Article %J Osteoporos Int %D 2016 %T Systemic markers of microvascular disease and bone mineral density in older adults : The cardiovascular health study. %A Barzilay, J I %A Bůžková, P %A Fink, H A %A Cauley, J A %A Robbins, J A %A Garimella, P S %A Jalal, D I %A Mukamal, K J %X

Here we report that abnormal brain white matter and, to a lesser extent, albuminuria are associated with reduced bone mineral density in the hip, spine, and total body in men and women. These findings may explain the increased hip fracture risk reported in some studies in association with microvascular disorders.

INTRODUCTION: Markers of microvascular disease have been individually associated with increased risk of osteoporotic fractures in some studies. Here, we examine whether these markers are associated with reduced bone mineral density (BMD) individually and together.

METHODS: BMD testing using dual x-ray absorptiometry of the hip, lumbar spine, and total body was performed in 1473 participants from the Cardiovascular Health Study (mean age ~ 78 years): 1215 were assessed for urinary albumin-creatinine ratio, 944 for abnormal white matter disease (AWMD) by brain MRI, and 541 for retinal vascular disease with fundus photographs. Linear regression models were used to evaluate the cross-sectional association of each marker with BMD accounting for potentially confounding factors.

RESULTS: AWMD was associated with lower hip, spine, and total body BMD in women (β -3.08 to -4.53; p < 0.01 for all) and lower hip and total body BMD in men (β -2.90 to -4.24; p = 0.01-0.03). Albuminuria was associated with lower hip (β -3.37; p = .05) and total body (β -3.21; p = .02) BMD in men, but not in women. The associations of AWMD and albuminuria with BMD persisted with mutual adjustment and appeared to be additive to each other. Retinal vascular disease was not associated with BMD in men or women.

CONCLUSION: AWMD and, to a lesser extent, albuminuria were independently associated with lower BMD, suggesting that microvascular disease may play a role in the pathogenesis of reduced BMD. These findings need to be confirmed by longitudinal studies.

%B Osteoporos Int %V 27 %P 3217-3225 %8 2016 Nov %G ENG %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/27250972?dopt=Abstract %R 10.1007/s00198-016-3649-9 %0 Journal Article %J Hum Mol Genet %D 2016 %T Targeted Sequencing of Genome Wide Significant Loci Associated with Bone Mineral Density (BMD) Reveals Significant Novel and Rare Variants: The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study. %A Hsu, Yi-Hsiang %A Li, Guo %A Liu, Ching-Ti %A Brody, Jennifer A %A Karasik, David %A Chou, Wen-Chi %A Demissie, Serkalem %A Nandakumar, Kannabiran %A Zhou, Yanhua %A Cheng, Chia-Ho %A Gill, Richard %A Gibbs, Richard A %A Muzny, Donna %A Santibanez, Jireh %A Estrada, Karol %A Rivadeneira, Fernando %A Harris, Tamara %A Gudnason, Vilmundur %A Uitterlinden, Andre %A Psaty, Bruce M %A Robbins, John A %A Adrienne Cupples, L %A Kiel, Douglas P %X

BACKGROUND: Bone mineral density (BMD) is a heritable phenotype that predicts fracture risk. We performed fine-mapping by targeted sequencing at WLS, MEF2C, ARHGAP1/F2 and JAG1 loci prioritized by eQTL and bioinformatic approaches among 56 BMD loci from our previous GWAS meta-analysis.

METHODS AND RESULTS: Targeted sequencing was conducted in 1,291 Caucasians from the Framingham Heart Study (n=925) and Cardiovascular Health Study (n=366), including 206 women and men with extreme low femoral neck (FN) BMD. A total of 4,964 sequence variants (SNVs) were observed and 80% were rare with MAF <1%. The associations between previously identified SNPs in these loci and BMD, while nominally significant in sequenced participants, were no longer significant after multiple testing corrections. Conditional analyses did not find protein-coding variants that may be responsible for GWAS signals. On the other hand, in the sequenced subjects, we identified novel associations in WLS, ARHGAP1, and 5' of MEF2C (p-values < 8x10(-5); false discovery rate (FDR) q-values < 0.01) that were much more strongly associated with BMD compared to the GWAS SNPs. These associated SNVs are less-common; independent from previous GWAS signals in the same loci; and located in gene regulatory elements.

CONCLUSIONS: Our findings suggest that protein-coding variants in selected GWAS loci did not contribute to GWAS signals. By performing targeted sequencing in GWAS loci, we identified less-common and rare non-coding SNVs associated with BMD independently from GWAS common SNPs, suggesting both common and less-common variants may associate with disease risks and phenotypes in the same loci.

%B Hum Mol Genet %8 2016 Sep 11 %G eng %R 10.1093/hmg/ddw289 %0 Journal Article %J J Clin Endocrinol Metab %D 2016 %T Thyroid Function Within the Reference Range and the Risk of Stroke: An Individual Participant Data Analysis. %A Chaker, Layal %A Baumgartner, Christine %A den Elzen, Wendy P J %A Collet, Tinh-Hai %A Ikram, M Arfan %A Blum, Manuel R %A Dehghan, Abbas %A Drechsler, Christiane %A Luben, Robert N %A Portegies, Marileen L P %A Iervasi, Giorgio %A Medici, Marco %A Stott, David J %A Dullaart, Robin P %A Ford, Ian %A Bremner, Alexandra %A Newman, Anne B %A Wanner, Christoph %A Sgarbi, José A %A Dörr, Marcus %A Longstreth, W T %A Psaty, Bruce M %A Ferrucci, Luigi %A Maciel, Rui M B %A Westendorp, Rudi G %A Jukema, J Wouter %A Ceresini, Graziano %A Imaizumi, Misa %A Hofman, Albert %A Bakker, Stephan J L %A Franklyn, Jayne A %A Khaw, Kay-Tee %A Bauer, Douglas C %A Walsh, John P %A Razvi, Salman %A Gussekloo, Jacobijn %A Völzke, Henry %A Franco, Oscar H %A Cappola, Anne R %A Rodondi, Nicolas %A Peeters, Robin P %X

CONTEXT: The currently applied reference ranges for thyroid function are under debate. Despite evidence that thyroid function within the reference range is related with several cardiovascular disorders, its association with the risk of stroke has not been evaluated previously.

DESIGN AND SETTING: We identified studies through a systematic literature search and the Thyroid Studies Collaboration, a collaboration of prospective cohort studies. Studies measuring baseline TSH, free T4, and stroke outcomes were included, and we collected individual participant data from each study, including thyroid function measurements and incident all stroke (combined fatal and nonfatal) and fatal stroke. The applied reference range for TSH levels was between 0.45 and 4.49 mIU/L.

RESULTS: We collected individual participant data on 43 598 adults with TSH within the reference range from 17 cohorts, with a median follow-up of 11.6 years (interquartile range 5.1-13.9), including 449 908 person-years. Age- and sex-adjusted pooled hazard ratio for TSH was 0.78 (95% confidence interval [CI] 0.65-0.95 across the reference range of TSH) for all stroke and 0.83 (95% CI 0.62-1.09) for fatal stroke. For the free T4 analyses, the hazard ratio was 1.08 (95% CI 0.99-1.15 per SD increase) for all stroke and 1.10 (95% CI 1.04-1.19) for fatal stroke. This was independent of cardiovascular risk factors including systolic blood pressure, total cholesterol, smoking, and prevalent diabetes.

CONCLUSION: Higher levels of TSH within the reference range may decrease the risk of stroke, highlighting the need for further research focusing on the clinical consequences associated with differences within the reference range of thyroid function.

%B J Clin Endocrinol Metab %V 101 %P 4270-4282 %8 2016 Nov %G eng %N 11 %R 10.1210/jc.2016-2255 %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 Am J Kidney Dis %D 2016 %T Urinary Uromodulin and Risk of Urinary Tract Infections: The Cardiovascular Health Study. %A Garimella, Pranav S %A Bartz, Traci M %A Ix, Joachim H %A Chonchol, Michel %A Shlipak, Michael G %A Devarajan, Prasad %A Bennett, Michael R %A Sarnak, Mark J %X

BACKGROUND: Laboratory studies suggest that urinary uromodulin, the most common protein in the urine of healthy adults, may protect against urinary tract infection (UTI). Epidemiologic studies evaluating this relationship in humans are lacking.

STUDY DESIGN: Prospective longitudinal cohort study.

SETTING & PARTICIPANTS: 953 participants enrolled in the Cardiovascular Health Study.

PREDICTOR: Uromodulin assayed using enzyme-linked immunosorbent assay in spot urine samples.

OUTCOMES: Composite of outpatient UTI events or UTI-related hospitalizations and each of them individually identified using International Classification of Diseases, Ninth Revision (ICD-9) codes using negative binomial regression with robust standard errors adjusted for age, race, sex, body mass index, diabetes, estimated glomerular filtration rate, and urinary albumin and urinary creatinine excretion.

RESULTS: Median uromodulin level was 25.9 (IQR, 17.3-38.9) μg/mL, mean age of participants was 78 years, 61% were women, and 15% were black. There were 331 outpatient UTI events and 87 UTI-related hospitalizations among 186 participants during a median 9.9 years of follow-up. Persons in the highest quartile (>38.93μg/mL) of uromodulin concentration had a significantly lower risk for the composite outcome (incidence rate ratio [IRR], 0.47; 95% CI, 0.29-0.79) compared with those in the lowest quartile (≤17.26μg/mL). This association remained significant for outpatient UTI events (highest vs lowest quartile even after excluding those with prior UTI: IRR, 0.42; 95% CI, 0.23-0.77). The direction of association with UTI hospitalization was similar, but not statistically significant (IRR, 0.78; 95% CI, 0.39-1.58).

LIMITATIONS: Use of ICD-9 codes to identify outcomes and lack of generalizability to younger populations.

CONCLUSIONS: High urinary uromodulin levels are associated with lower risk for UTI in older community-dwelling adults independent of traditional UTI risk factors. This finding supports prior laboratory data indicating a protective role of uromodulin against UTI. Further research is needed to understand if this may lead to new treatments to prevent or treat UTI.

%B Am J Kidney Dis %8 2016 Oct 28 %G eng %R 10.1053/j.ajkd.2016.08.022 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Vitamin D and Memory Decline: Two Population-Based Prospective Studies. %A Kuźma, Elżbieta %A Soni, Maya %A Littlejohns, Thomas J %A Ranson, Janice M %A van Schoor, Natasja M %A Deeg, Dorly J H %A Comijs, Hannie %A Chaves, Paulo H M %A Kestenbaum, Bryan R %A Kuller, Lewis H %A Lopez, Oscar L %A Becker, James T %A Langa, Kenneth M %A Henley, William E %A Lang, Iain A %A Ukoumunne, Obioha C %A Llewellyn, David J %X

BACKGROUND: Vitamin D deficiency has been linked with dementia risk, cognitive decline, and executive dysfunction. However, the association with memory remains largely unknown.

OBJECTIVE: To investigate whether low serum 25-hydroxyvitamin D (25(OH)D) concentrations are associated with memory decline.

METHODS: We used data on 1,291 participants from the US Cardiovascular Health Study (CHS) and 915 participants from the Dutch Longitudinal Aging Study Amsterdam (LASA) who were dementia-free at baseline, had valid vitamin D measurements, and follow-up memory assessments. The Benton Visual Retention Test (in the CHS) and Rey's Auditory Verbal Learning Test (in the LASA) were used to assess visual and verbal memory, respectively.

RESULTS: In the CHS, those moderately and severely deficient in serum 25(OH)D changed -0.03 SD (95% CI: -0.06 to 0.01) and -0.10 SD (95% CI: -0.19 to -0.02) per year respectively in visual memory compared to those sufficient (p = 0.02). In the LASA, moderate and severe deficiency in serum 25(OH)D was associated with a mean change of 0.01 SD (95% CI: -0.01 to 0.02) and -0.01 SD (95% CI: -0.04 to 0.02) per year respectively in verbal memory compared to sufficiency (p = 0.34).

CONCLUSIONS: Our findings suggest an association between severe vitamin D deficiency and visual memory decline but no association with verbal memory decline. They warrant further investigation in prospective studies assessing different memory subtypes.

%B J Alzheimers Dis %V 50 %P 1099-108 %8 2016 %G ENG %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836174?dopt=Abstract %R 10.3233/JAD-150811 %0 Journal Article %J PLoS One %D 2016 %T Vitamin D and Risk of Neuroimaging Abnormalities. %A Littlejohns, Thomas J %A Kos, Katarina %A Henley, William E %A Lang, Iain A %A Annweiler, Cedric %A Beauchet, Olivier %A Chaves, Paulo H M %A Kestenbaum, Bryan R %A Kuller, Lewis H %A Langa, Kenneth M %A Lopez, Oscar L %A Llewellyn, David J %X

Vitamin D deficiency has been linked with an increased risk of incident all-cause dementia and Alzheimer's disease. The aim of the current study was to explore the potential mechanisms underlying these associations by determining whether low vitamin D concentrations are associated with the development of incident cerebrovascular and neurodegenerative neuroimaging abnormalities. The population consisted of 1,658 participants aged ≥65 years from the US-based Cardiovascular Health Study who were free from prevalent cardiovascular disease, stroke and dementia at baseline in 1992-93. Serum 25-hydroxyvitamin D (25(OH)D) concentrations were determined by liquid chromatography-tandem mass spectrometry from blood samples collected at baseline. The first MRI scan was conducted between 1991-1994 and the second MRI scan was conducted between 1997-1999. Change in white matter grade, ventricular grade and presence of infarcts between MRI scan one and two were used to define neuroimaging abnormalities. During a mean follow-up of 5.0 years, serum 25(OH)D status was not significantly associated with the development of any neuroimaging abnormalities. Using logistic regression models, the multivariate adjusted odds ratios (95% confidence interval) for worsening white matter grade in participants who were severely 25(OH)D deficient (<25 nmol/L) and deficient (≥25-50 nmol/L) were 0.76 (0.35-1.66) and 1.09 (0.76-1.55) compared to participants with sufficient concentrations (≥50 nmol/L). The multivariate adjusted odds ratios for ventricular grade in participants who were severely 25(OH)D deficient and deficient were 0.49 (0.20-1.19) and 1.12 (0.79-1.59) compared to those sufficient. The multivariate adjusted odds ratios for incident infarcts in participants who were severely 25(OH)D deficient and deficient were 1.95 (0.84-4.54) and 0.73 (0.47-1.95) compared to those sufficient. Overall, serum vitamin D concentrations could not be shown to be associated with the development of cerebrovascular or neurodegenerative neuroimaging abnormalities in Cardiovascular Health Study participants.

%B PLoS One %V 11 %P e0154896 %8 2016 %G eng %N 5 %R 10.1371/journal.pone.0154896 %0 Journal Article %J PLoS Genet %D 2016 %T Whole Exome Sequencing in Atrial Fibrillation. %A Lubitz, Steven A %A Brody, Jennifer A %A Bihlmeyer, Nathan A %A Roselli, Carolina %A Weng, Lu-Chen %A Christophersen, Ingrid E %A Alonso, Alvaro %A Boerwinkle, Eric %A Gibbs, Richard A %A Bis, Joshua C %A Cupples, L Adrienne %A Mohler, Peter J %A Nickerson, Deborah A %A Muzny, Donna %A Perez, Marco V %A Psaty, Bruce M %A Soliman, Elsayed Z %A Sotoodehnia, Nona %A Lunetta, Kathryn L %A Benjamin, Emelia J %A Heckbert, Susan R %A Arking, Dan E %A Ellinor, Patrick T %A Lin, Honghuang %X

Atrial fibrillation (AF) is a morbid and heritable arrhythmia. Over 35 genes have been reported to underlie AF, most of which were described in small candidate gene association studies. Replication remains lacking for most, and therefore the contribution of coding variation to AF susceptibility remains poorly understood. We examined whole exome sequencing data in a large community-based sample of 1,734 individuals with and 9,423 without AF from the Framingham Heart Study, Cardiovascular Health Study, Atherosclerosis Risk in Communities Study, and NHLBI-GO Exome Sequencing Project and meta-analyzed the results. We also examined whether genetic variation was enriched in suspected AF genes (N = 37) in AF cases versus controls. The mean age ranged from 59 to 73 years; 8,656 (78%) were of European ancestry. None of the 99,404 common variants evaluated was significantly associated after adjusting for multiple testing. Among the most significantly associated variants was a common (allele frequency = 86%) missense variant in SYNPO2L (rs3812629, p.Pro707Leu, [odds ratio 1.27, 95% confidence interval 1.13-1.43, P = 6.6x10-5]) which lies at a known AF susceptibility locus and is in linkage disequilibrium with a top marker from prior analyses at the locus. We did not observe significant associations between rare variants and AF in gene-based tests. Individuals with AF did not display any statistically significant enrichment for common or rare coding variation in previously implicated AF genes. In conclusion, we did not observe associations between coding genetic variants and AF, suggesting that large-effect coding variation is not the predominant mechanism underlying AF. A coding variant in SYNPO2L requires further evaluation to determine whether it is causally related to AF. Efforts to identify biologically meaningful coding variation underlying AF may require large sample sizes or populations enriched for large genetic effects.

%B PLoS Genet %V 12 %P e1006284 %8 2016 Sep %G eng %N 9 %R 10.1371/journal.pgen.1006284 %0 Journal Article %J Am J Hum Genet %D 2016 %T Whole-Exome Sequencing Identifies Loci Associated with Blood Cell Traits and Reveals a Role for Alternative GFI1B Splice Variants in Human Hematopoiesis. %A Polfus, Linda M %A Khajuria, Rajiv K %A Schick, Ursula M %A Pankratz, Nathan %A Pazoki, Raha %A Brody, Jennifer A %A Chen, Ming-Huei %A Auer, Paul L %A Floyd, James S %A Huang, Jie %A Lange, Leslie %A van Rooij, Frank J A %A Gibbs, Richard A %A Metcalf, Ginger %A Muzny, Donna %A Veeraraghavan, Narayanan %A Walter, Klaudia %A Chen, Lu %A Yanek, Lisa %A Becker, Lewis C %A Peloso, Gina M %A Wakabayashi, Aoi %A Kals, Mart %A Metspalu, Andres %A Esko, Tõnu %A Fox, Keolu %A Wallace, Robert %A Franceschini, Nora %A Matijevic, Nena %A Rice, Kenneth M %A Bartz, Traci M %A Lyytikäinen, Leo-Pekka %A Kähönen, Mika %A Lehtimäki, Terho %A Raitakari, Olli T %A Li-Gao, Ruifang %A Mook-Kanamori, Dennis O %A Lettre, Guillaume %A van Duijn, Cornelia M %A Franco, Oscar H %A Rich, Stephen S %A Rivadeneira, Fernando %A Hofman, Albert %A Uitterlinden, André G %A Wilson, James G %A Psaty, Bruce M %A Soranzo, Nicole %A Dehghan, Abbas %A Boerwinkle, Eric %A Zhang, Xiaoling %A Johnson, Andrew D %A O'Donnell, Christopher J %A Johnsen, Jill M %A Reiner, Alexander P %A Ganesh, Santhi K %A Sankaran, Vijay G %B Am J Hum Genet %V 99 %P 785 %8 2016 Sep 01 %G eng %N 3 %R 10.1016/j.ajhg.2016.08.002 %0 Journal Article %J Lancet Diabetes Endocrinol %D 2017 %T 740 adults from 20 prospective cohort studies %A Wu, J. H. Y. %A Marklund, M. %A Imamura, F. %A Tintle, N. %A Ardisson Korat, A. V. %A de Goede, J. %A Zhou, X. %A Yang, W. S. %A de Oliveira Otto, M. C. %A ger, J. %A Qureshi, W. %A Virtanen, J. K. %A Bassett, J. K. %A Frazier-Wood, A. C. %A Lankinen, M. %A Murphy, R. A. %A Rajaobelina, K. %A Del Gobbo, L. C. %A Forouhi, N. G. %A Luben, R. %A Khaw, K. T. %A Wareham, N. %A Kalsbeek, A. %A Veenstra, J. %A Luo, J. %A Hu, F. B. %A Lin, H. J. %A Siscovick, D. S. %A Boeing, H. %A Chen, T. A. %A Steffen, B. %A Steffen, L. M. %A Hodge, A. %A Eriksdottir, G. %A Smith, A. V. %A Gudnason, V. %A Harris, T. B. %A Brouwer, I. A. %A Berr, C. %A Helmer, C. %A Samieri, C. %A Laakso, M. %A Tsai, M. Y. %A Giles, G. G. %A Nurmi, T. %A Wagenknecht, L. %A Schulze, M. B. %A Lemaitre, R. N. %A Chien, K. L. %A Soedamah-Muthu, S. S. %A Geleijnse, J. M. %A Sun, Q. %A Harris, W. S. %A Lind, L. %A v, J. %A Riserus, U. %A Micha, R. %A Mozaffarian, D. %X The metabolic effects of omega-6 polyunsaturated fatty acids (PUFAs) remain contentious, and little evidence is available regarding their potential role in primary prevention of type 2 diabetes. We aimed to assess the associations of linoleic acid and arachidonic acid biomarkers with incident type 2 diabetes.\ We did a pooled analysis of new, harmonised, individual-level analyses for the biomarkers linoleic acid and its metabolite arachidonic acid and incident type 2 diabetes. We analysed data from 20 prospective cohort studies from ten countries (Iceland, the Netherlands, the USA, Taiwan, the UK, Germany, Finland, Australia, Sweden, and France), with biomarkers sampled between 1970 and 2010. Participants included in the analyses were aged 18 years or older and had data available for linoleic acid and arachidonic acid biomarkers at baseline. We excluded participants with type 2 diabetes at baseline. The main outcome was the association between omega-6 PUFA biomarkers and incident type 2 diabetes. We assessed the relative risk of type 2 diabetes prospectively for each cohort and lipid compartment separately using a prespecified analytic plan for exposures, covariates, effect modifiers, and analysis, and the findings were then pooled using inverse-variance weighted meta-analysis.\ 13).\ Findings suggest that linoleic acid has long-term benefits for the prevention of type 2 diabetes and that arachidonic acid is not harmful.\ Funders are shown in the appendix. %B Lancet Diabetes Endocrinol %V 5 %P 965–974 %8 Dec %G eng %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 Neurol Genet %D 2017 %T The Alzheimer's Disease Sequencing Project: Study design and sample selection. %A Beecham, Gary W %A Bis, J C %A Martin, E R %A Choi, S-H %A DeStefano, A L %A van Duijn, C M %A Fornage, M %A Gabriel, S B %A Koboldt, D C %A Larson, D E %A Naj, A C %A Psaty, B M %A Salerno, W %A Bush, W S %A Foroud, T M %A Wijsman, E %A Farrer, L A %A Goate, A %A Haines, J L %A Pericak-Vance, Margaret A %A Boerwinkle, E %A Mayeux, R %A Seshadri, S %A Schellenberg, G %B Neurol Genet %V 3 %P e194 %8 2017 Oct %G eng %N 5 %R 10.1212/NXG.0000000000000194 %0 Journal Article %J Nat Genet %D 2017 %T Analysis commons, a team approach to discovery in a big-data environment for genetic epidemiology. %A Brody, Jennifer A %A Morrison, Alanna C %A Bis, Joshua C %A O'Connell, Jeffrey R %A Brown, Michael R %A Huffman, Jennifer E %A Ames, Darren C %A Carroll, Andrew %A Conomos, Matthew P %A Gabriel, Stacey %A Gibbs, Richard A %A Gogarten, Stephanie M %A Gupta, Namrata %A Jaquish, Cashell E %A Johnson, Andrew D %A Lewis, Joshua P %A Liu, Xiaoming %A Manning, Alisa K %A Papanicolaou, George J %A Pitsillides, Achilleas N %A Rice, Kenneth M %A Salerno, William %A Sitlani, Colleen M %A Smith, Nicholas L %A Heckbert, Susan R %A Laurie, Cathy C %A Mitchell, Braxton D %A Vasan, Ramachandran S %A Rich, Stephen S %A Rotter, Jerome I %A Wilson, James G %A Boerwinkle, Eric %A Psaty, Bruce M %A Cupples, L Adrienne %B Nat Genet %V 49 %P 1560-1563 %8 2017 Oct 27 %G eng %N 11 %R 10.1038/ng.3968 %0 Journal Article %J Hum Genet %D 2017 %T Assessing the causal relationship between obesity and venous thromboembolism through a Mendelian Randomization study. %A Lindström, Sara %A Germain, Marine %A Crous-Bou, Marta %A Smith, Erin N %A Morange, Pierre-Emmanuel %A van Hylckama Vlieg, Astrid %A de Haan, Hugoline G %A Chasman, Daniel %A Ridker, Paul %A Brody, Jennifer %A de Andrade, Mariza %A Heit, John A %A Tang, Weihong %A DeVivo, Immaculata %A Grodstein, Francine %A Smith, Nicholas L %A Tregouet, David %A Kabrhel, Christopher %K Adult %K Body Mass Index %K Case-Control Studies %K European Continental Ancestry Group %K Female %K Genome-Wide Association Study %K Humans %K Incidence %K Logistic Models %K Male %K Mendelian Randomization Analysis %K Obesity %K Polymorphism, Single Nucleotide %K Proportional Hazards Models %K Venous Thromboembolism %X

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

%B Hum Genet %V 136 %P 897-902 %8 2017 07 %G eng %N 7 %R 10.1007/s00439-017-1811-x %0 Journal Article %J J Clin Endocrinol Metab %D 2017 %T The Association Between IGF-I and IGFBP-3 and Incident Diabetes in an Older Population of Men and Women in the Cardiovascular Health Study. %A Aneke-Nash, Chino S %A Xue, XiaoNan %A Qi, Qibin %A Biggs, Mary L %A Cappola, Anne %A Kuller, Lewis %A Pollak, Michael %A Psaty, Bruce M %A Siscovick, David %A Mukamal, Kenneth %A Strickler, Howard D %A Kaplan, Robert C %K Aged %K Aged, 80 and over %K Biomarkers %K Blood Glucose %K Cardiovascular Diseases %K Cohort Studies %K Diabetes Mellitus %K Female %K Humans %K Incidence %K Insulin-Like Growth Factor Binding Protein 3 %K Insulin-Like Growth Factor I %K Longitudinal Studies %K Male %K New England %K Prospective Studies %K Risk %X

Context: Insulin-like growth factor-I (IGF-I) has structural and functional similarities to insulin and may play a role in glucose homeostasis, along with insulin-like growth factor binding protein-3 (IGFBP-3), which binds the majority of circulating IGF-I.

Objective: To assess whether IGF-I and IGFBP-3 are associated with a higher risk of incident diabetes in older adults.

Design: Participants in the Cardiovascular Health Study (n = 3133), a cohort of adults aged ≥65 years, were observed for 16 years (n = 3133) for the development of incident diabetes. Statistical models were fit separately for men and women because of interactions with sex (P interaction: IGF-I, 0.02; IGFBP-3, 0.009) and were adjusted for relevant covariates.

Setting: General community.

Participants: Older adults who were nondiabetic at baseline and who did not develop diabetes within the first year of follow-up.

Interventions: Not applicable.

Main Outcome Measure: Incident diabetes as measured by fasting plasma glucose (FPG) ≥126 mg/dL, non-FPG ≥200 mg/dL, use of pharmacological treatment of diabetes, or existence of two or more inpatient or three or more outpatient or (at least one inpatient and at least one outpatient) Centers for Medicare & Medicaid Services claims with the diagnostic International Classification of Diseases, Ninth Revision, Clinical Modification code of 250.xx.

Results: In women, higher IGFBP-3 (hazard ratio tertile 3 vs tertile 1 = 2.30; 95% confidence interval, 1.55 to 3.40; P trend < 0.0001) was significantly associated with incident diabetes. Total IGF-I was not significantly associated with incident diabetes. In men, neither IGF-I nor IGFBP-3 was significantly associated with incident diabetes.

Conclusions: We confirmed a previously reported association between circulating IGFBP-3 and diabetes risk in the older adult population, establishing that this association is present among women but could not be shown to be associated in men.

%B J Clin Endocrinol Metab %V 102 %P 4541-4547 %8 2017 Dec 01 %G eng %N 12 %R 10.1210/jc.2017-01273 %0 Journal Article %J JAMA Oncol %D 2017 %T Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study. %A Haycock, Philip C %A Burgess, Stephen %A Nounu, Aayah %A Zheng, Jie %A Okoli, George N %A Bowden, Jack %A Wade, Kaitlin Hazel %A Timpson, Nicholas J %A Evans, David M %A Willeit, Peter %A Aviv, Abraham %A Gaunt, Tom R %A Hemani, Gibran %A Mangino, Massimo %A Ellis, Hayley Patricia %A Kurian, Kathreena M %A Pooley, Karen A %A Eeles, Rosalind A %A Lee, Jeffrey E %A Fang, Shenying %A Chen, Wei V %A Law, Matthew H %A Bowdler, Lisa M %A Iles, Mark M %A Yang, Qiong %A Worrall, Bradford B %A Markus, Hugh Stephen %A Hung, Rayjean J %A Amos, Chris I %A Spurdle, Amanda B %A Thompson, Deborah J %A O'Mara, Tracy A %A Wolpin, Brian %A Amundadottir, Laufey %A Stolzenberg-Solomon, Rachael %A Trichopoulou, Antonia %A Onland-Moret, N Charlotte %A Lund, Eiliv %A Duell, Eric J %A Canzian, Federico %A Severi, Gianluca %A Overvad, Kim %A Gunter, Marc J %A Tumino, Rosario %A Svenson, Ulrika %A van Rij, Andre %A Baas, Annette F %A Bown, Matthew J %A Samani, Nilesh J %A van t'Hof, Femke N G %A Tromp, Gerard %A Jones, Gregory T %A Kuivaniemi, Helena %A Elmore, James R %A Johansson, Mattias %A Mckay, James %A Scelo, Ghislaine %A Carreras-Torres, Robert %A Gaborieau, Valerie %A Brennan, Paul %A Bracci, Paige M %A Neale, Rachel E %A Olson, Sara H %A Gallinger, Steven %A Li, Donghui %A Petersen, Gloria M %A Risch, Harvey A %A Klein, Alison P %A Han, Jiali %A Abnet, Christian C %A Freedman, Neal D %A Taylor, Philip R %A Maris, John M %A Aben, Katja K %A Kiemeney, Lambertus A %A Vermeulen, Sita H %A Wiencke, John K %A Walsh, Kyle M %A Wrensch, Margaret %A Rice, Terri %A Turnbull, Clare %A Litchfield, Kevin %A Paternoster, Lavinia %A Standl, Marie %A Abecasis, Goncalo R %A SanGiovanni, John Paul %A Li, Yong %A Mijatovic, Vladan %A Sapkota, Yadav %A Low, Siew-Kee %A Zondervan, Krina T %A Montgomery, Grant W %A Nyholt, Dale R %A van Heel, David A %A Hunt, Karen %A Arking, Dan E %A Ashar, Foram N %A Sotoodehnia, Nona %A Woo, Daniel %A Rosand, Jonathan %A Comeau, Mary E %A Brown, W Mark %A Silverman, Edwin K %A Hokanson, John E %A Cho, Michael H %A Hui, Jennie %A Ferreira, Manuel A %A Thompson, Philip J %A Morrison, Alanna C %A Felix, Janine F %A Smith, Nicholas L %A Christiano, Angela M %A Petukhova, Lynn %A Betz, Regina C %A Fan, Xing %A Zhang, Xuejun %A Zhu, Caihong %A Langefeld, Carl D %A Thompson, Susan D %A Wang, Feijie %A Lin, Xu %A Schwartz, David A %A Fingerlin, Tasha %A Rotter, Jerome I %A Cotch, Mary Frances %A Jensen, Richard A %A Munz, Matthias %A Dommisch, Henrik %A Schaefer, Arne S %A Han, Fang %A Ollila, Hanna M %A Hillary, Ryan P %A Albagha, Omar %A Ralston, Stuart H %A Zeng, Chenjie %A Zheng, Wei %A Shu, Xiao-Ou %A Reis, Andre %A Uebe, Steffen %A Hüffmeier, Ulrike %A Kawamura, Yoshiya %A Otowa, Takeshi %A Sasaki, Tsukasa %A Hibberd, Martin Lloyd %A Davila, Sonia %A Xie, Gang %A Siminovitch, Katherine %A Bei, Jin-Xin %A Zeng, Yi-Xin %A Försti, Asta %A Chen, Bowang %A Landi, Stefano %A Franke, Andre %A Fischer, Annegret %A Ellinghaus, David %A Flores, Carlos %A Noth, Imre %A Ma, Shwu-Fan %A Foo, Jia Nee %A Liu, Jianjun %A Kim, Jong-Won %A Cox, David G %A Delattre, Olivier %A Mirabeau, Olivier %A Skibola, Christine F %A Tang, Clara S %A Garcia-Barcelo, Merce %A Chang, Kai-Ping %A Su, Wen-Hui %A Chang, Yu-Sun %A Martin, Nicholas G %A Gordon, Scott %A Wade, Tracey D %A Lee, Chaeyoung %A Kubo, Michiaki %A Cha, Pei-Chieng %A Nakamura, Yusuke %A Levy, Daniel %A Kimura, Masayuki %A Hwang, Shih-Jen %A Hunt, Steven %A Spector, Tim %A Soranzo, Nicole %A Manichaikul, Ani W %A Barr, R Graham %A Kahali, Bratati %A Speliotes, Elizabeth %A Yerges-Armstrong, Laura M %A Cheng, Ching-Yu %A Jonas, Jost B %A Wong, Tien Yin %A Fogh, Isabella %A Lin, Kuang %A Powell, John F %A Rice, Kenneth %A Relton, Caroline L %A Martin, Richard M %A Davey Smith, George %K Adult %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Germ-Line Mutation %K Humans %K Male %K Mendelian Randomization Analysis %K Middle Aged %K Neoplasms %K Polymorphism, Single Nucleotide %K Risk Assessment %K Telomere %K Telomere Homeostasis %X

Importance: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation.

Objective: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases.

Data Sources: Genomewide association studies (GWAS) published up to January 15, 2015.

Study Selection: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available.

Data Extraction and Synthesis: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population.

Main Outcomes and Measures: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation.

Results: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]).

Conclusions and Relevance: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.

%B JAMA Oncol %V 3 %P 636-651 %8 2017 May 01 %G eng %N 5 %R 10.1001/jamaoncol.2016.5945 %0 Journal Article %J JAMA Ophthalmol %D 2017 %T Association of Diabetic Macular Edema and Proliferative Diabetic Retinopathy With Cardiovascular Disease: A Systematic Review and Meta-analysis. %A Xie, Jing %A Ikram, M Kamran %A Cotch, Mary Frances %A Klein, Barbara %A Varma, Rohit %A Shaw, Jonathan E %A Klein, Ronald %A Mitchell, Paul %A Lamoureux, Ecosse L %A Wong, Tien Yin %K Cardiovascular Diseases %K Diabetic Retinopathy %K Global Health %K Humans %K Incidence %K Macular Edema %K Risk Factors %X

Importance: Previous studies on the relationship between diabetic retinopathy (DR) and cardiovascular disease (CVD) focused on the early stages of DR. Understanding whether patients with type 2 diabetes and severe stages of DR (diabetic macular edema [DME] and proliferative diabetic retinopathy [PDR]) have a higher risk of CVD will allow physicians to more effectively counsel patients.

Objective: To examine the association of severe stages of DR (DME and PDR) with incident CVD in patients with type 2 diabetes.

Data Sources: English-language publications were reviewed for articles evaluating the relationship of DR and CVD in MEDLINE, EMBASE, Current Contents, and the Cochrane Library from inception (January 1, 1950) to December 31, 2014, using the search terms diabetic retinopathy OR macular edema AND stroke OR cerebrovascular disease OR coronary artery disease OR heart failure OR myocardial infarction OR angina pectoris OR acute coronary syndrome OR coronary artery disease OR cardiomyopathy.

Study Selection: Among 656 studies screened for eligibility, 7604 individuals were included from 8 prospective population-based studies with data on photographic-based DR grading, follow-up visits, and well-defined incident CVD end point.

Data Extraction and Synthesis: Two independent reviewers conducted a systematic search of the 4 databases, and a single pooled database was developed. Incidence rate ratios (IRRs) were estimated for patients with DME, PDR, and vision-threatening DR, compared with persons without these conditions, by using individual participant data followed by a standard inverse-variance meta-analysis (2-step analysis). The review and analyses were performed from January 1, 2009, to January 1, 2017.

Main Outcome and Measures: Incident CVD, including coronary heart disease, stroke, or death from cardiovascular causes.

Results: Among 7604 patients with type 2 diabetes, the prevalence of DME was 4.6% and PDR, 7.4%. After a mean follow-up of 5.9 years (range, 3.2-10.1 years), 1203 incident CVD events, including 916 coronary heart disease cases, were reported. Persons with DME or PDR were more likely to have incident CVD (IRR, 1.39; 95% CI, 1.16-1.67) and fatal CVD (IRR, 2.33; 95% CI, 1.49-3.67) compared with those without DME or PDR.

Conclusions and Relevance: Patients with type 2 diabetes and DME or PDR have an increased risk of incident CVD, which suggests that these persons should be followed up more closely to prevent CVD.

%B JAMA Ophthalmol %V 135 %P 586-593 %8 2017 Jun 01 %G eng %N 6 %R 10.1001/jamaophthalmol.2017.0988 %0 Journal Article %J Osteoporos Int %D 2017 %T Association of DPP-4 activity with BMD, body composition, and incident hip fracture: the Cardiovascular Health Study. %A Carbone, L D %A Bůžková, P %A Fink, H A %A Robbins, J A %A Bethel, M %A Isales, C M %A Hill, W D %X

There was no association of plasma DPP-4 activity levels with bone mineral density (BMD), body composition, or incident hip fractures in a cohort of elderly community-dwelling adults.

INTRODUCTION: Dipeptidyl peptidase IV (DPP-4) inactivates several key hormones including those that stimulate postprandial insulin secretion, and DPP-4 inhibitors (gliptins) are approved to treat diabetes. While DPP-4 is known to modulate osteogenesis, the relationship between DPP-4 activity and skeletal health is uncertain. The purpose of the present study was to examine possible associations between DPP-4 activity in elderly subjects enrolled in the Cardiovascular Health Study (CHS) and BMD, body composition measurements, and incident hip fractures.

METHODS: All 1536 male and female CHS participants who had evaluable DXA scans and plasma for DPP-4 activity were included in the analyses. The association between (1) BMD of the total hip, femoral neck, lumbar spine, and total body; (2) body composition measurements (% lean, % fat, and total body mass); and (3) incident hip fractures and plasma levels of DPP-4 activity were determined.

RESULTS: Mean plasma levels of DPP-4 activity were significantly higher in blacks (227 ± 78) compared with whites (216 ± 89) (p = 0.04). However, there was no significant association of DPP-4 activity with age or gender (p ≥ 0.14 for both). In multivariable adjusted models, there was no association of plasma DPP-4 activity with BMD overall (p ≥ 0.55 for all) or in gender stratified analyses (p ≥ 0.23). There was also no association of DPP-4 levels and incident hip fractures overall (p ≥ 0.24) or in gender stratified analyses (p ≥ 0.39).

CONCLUSION: Plasma DPP-4 activity, within the endogenous physiological range, was significantly associated with race, but not with BMD, body composition, or incident hip fractures in elderly community-dwelling subjects.

%B Osteoporos Int %V 28 %P 1631-1640 %8 2017 May %G eng %N 5 %R 10.1007/s00198-017-3916-4 %0 Journal Article %J JAMA Cardiol %D 2017 %T Association of Mitochondrial DNA Copy Number With Cardiovascular Disease. %A Ashar, Foram N %A Zhang, Yiyi %A Longchamps, Ryan J %A Lane, John %A Moes, Anna %A Grove, Megan L %A Mychaleckyj, Josyf C %A Taylor, Kent D %A Coresh, Josef %A Rotter, Jerome I %A Boerwinkle, Eric %A Pankratz, Nathan %A Guallar, Eliseo %A Arking, Dan E %X

Importance: Mitochondrial dysfunction is a core component of the aging process and may play a key role in atherosclerotic cardiovascular disease. Mitochondrial DNA copy number (mtDNA-CN), which represents the number of mitochondria per cell and number of mitochondrial genomes per mitochondrion, is an indirect biomarker of mitochondrial function.

Objective: To determine whether mtDNA-CN, measured in an easily accessible tissue (buffy coat/circulating leukocytes), can improve risk classification for cardiovascular disease (CVD) and help guide initiation of statin therapy for primary prevention of CVD.

Design, Setting, and Participants: Prospective, population-based cohort analysis including 21 870 participants (20 163 free from CVD at baseline) from 3 studies: Cardiovascular Health Study (CHS), Atherosclerosis Risk in Communities Study (ARIC), and Multiethnic Study of Atherosclerosis (MESA). The mean follow-up was 13.5 years. The study included 11 153 participants from ARIC, 4830 from CHS, and 5887 from MESA. Analysis of the data was conducted from March 10, 2014, to January 29, 2017.

Exposures: Mitochondrial DNA-CN measured from buffy coat/circulating leukocytes.

Main Outcomes and Measures: Incident CVD, which combines coronary heart disease, defined as the first incident myocardial infarction or death owing to coronary heart disease, and stroke, defined as the first nonfatal stroke or death owing to stroke.

Results: Of the 21 870 participants, the mean age was 62.4 years (ARIC, 57.9 years; MESA, 62.4 years; and CHS, 72.5 years), and 54.7% of participants were women. The hazard ratios for incident coronary heart disease, stroke, and CVD associated with a 1-SD decrease in mtDNA-CN were 1.29 (95% CI, 1.24-1.33), 1.11 (95% CI, 1.06-1.16), and 1.23 (95% CI, 1.19-1.26). The associations persisted after adjustment for traditional CVD risk factors. Addition of mtDNA-CN to the 2013 American College of Cardiology/American Heart Association Pooled Cohorts Equations for estimating 10-year hard atherosclerosis CVD risk was associated with improved risk classification (continuous net reclassification index, 0.194; 95% CI, 0.130-0.258; P < .001). Mitochondrial DNA-CN further improved sensitivity and specificity for the 2013 American College of Cardiology/American Heart Association recommendations on initiating statin therapy for primary prevention of ASCVD (net 221 individuals appropriately downclassified and net 15 individuals appropriately upclassified).

Conclusions and Relevance: Mitochondrial DNA-CN was independently associated with incident CVD in 3 large prospective studies and may have potential clinical utility in improving CVD risk classification.

%B JAMA Cardiol %V 2 %P 1247-1255 %8 2017 Nov 01 %G eng %N 11 %R 10.1001/jamacardio.2017.3683 %0 Journal Article %J Calcif Tissue Int %D 2017 %T Association of Plasma SDF-1 with Bone Mineral Density, Body Composition, and Hip Fractures in Older Adults: The Cardiovascular Health Study. %A Carbone, Laura D %A Bůzková, Petra %A Fink, Howard A %A Robbins, John A %A Bethel, Monique %A Hamrick, Mark W %A Hill, William D %X

Aging is associated with an increase in circulating inflammatory factors. One, the cytokine stromal cell-derived factor 1 (SDF-1 or CXCL12), is critical to stem cell mobilization, migration, and homing as well as to bone marrow stem cell (BMSC), osteoblast, and osteoclast function. SDF-1 has pleiotropic roles in bone formation and BMSC differentiation into osteoblasts/osteocytes, and in osteoprogenitor cell survival. The objective of this study was to examine the association of plasma SDF-1 in participants in the cardiovascular health study (CHS) with bone mineral density (BMD), body composition, and incident hip fractures. In 1536 CHS participants, SDF-1 plasma levels were significantly associated with increasing age (p < 0.01) and male gender (p = 0.04), but not with race (p = 0.63). In multivariable-adjusted models, higher SDF-1 levels were associated with lower total hip BMD (p = 0.02). However, there was no significant association of SDF-1 with hip fractures (p = 0.53). In summary, circulating plasma levels of SDF-1 are associated with increasing age and independently associated with lower total hip BMD in both men and women. These findings suggest that SDF-1 levels are linked to bone homeostasis.

%B Calcif Tissue Int %V 100 %P 599-608 %8 2017 Jun %G eng %N 6 %R 10.1007/s00223-017-0245-8 %0 Journal Article %J Heart Rhythm %D 2017 %T Atrial ectopy as a mediator of the association between race and atrial fibrillation. %A Christensen, Matthew A %A Nguyen, Kaylin T %A Stein, Phyllis K %A Fohtung, Raymond B %A Soliman, Elsayed Z %A Dewland, Thomas A %A Vittinghoff, Eric %A Psaty, Bruce M %A Heckbert, Susan R %A Marcus, Gregory M %X

BACKGROUND: Blacks have a lower risk of atrial fibrillation (AF) despite having more AF risk factors, but the mechanism remains unknown. Premature atrial contraction (PAC) burden is a recently identified risk factor for AF.

OBJECTIVE: The purpose of this study was to determine whether the burden of PACs explains racial differences in AF risk.

METHODS: PAC burden (number per hour) was assessed by 24-hour ambulatory electrocardiographic (ECG) monitoring in a randomly selected subset of patients in the Cardiovascular Health Study. Participants were followed prospectively for the development of AF, diagnosed by study ECG and hospital admission records.

RESULTS: Among 938 participants (median age 73 years; 34% black; 58% female), 206 (22%) developed AF over a median follow-up of 11.0 years (interquartile range 6.1-13.4). After adjusting for age, sex, body mass index, coronary disease, congestive heart failure, diabetes, hypertension, alcohol consumption, smoking status, and study site, black race was associated with a 42% lower risk of AF (hazard ratio 0.58, 95% confidence interval [CI] 0.40-0.85; P = .005). The baseline PAC burden was 2.10 times (95% CI 1.57-2.83; P <.001) higher in whites than blacks. There was no detectable difference in premature ventricular contraction (PVC) burden by race. PAC burden mediated 19.5% (95% CI 6.3-52.5) of the adjusted association between race and AF.

CONCLUSION: On average, whites exhibited more PACs than blacks, and this difference statistically explains a modest proportion of the differential risk of AF by race. The differential PAC burden, without differences in PVCs, by race suggests that identifiable common exposures or genetic influences might be important to atrial pathophysiology.

%B Heart Rhythm %V 14 %P 1856-1861 %8 2017 Dec %G eng %N 12 %R 10.1016/j.hrthm.2017.09.034 %0 Journal Article %J BMC Med Inform Decis Mak %D 2017 %T Automatic identification of variables in epidemiological datasets using logic regression. %A Lorenz, Matthias W %A Abdi, Negin Ashtiani %A Scheckenbach, Frank %A Pflug, Anja %A Bülbül, Alpaslan %A Catapano, Alberico L %A Agewall, Stefan %A Ezhov, Marat %A Bots, Michiel L %A Kiechl, Stefan %A Orth, Andreas %X

BACKGROUND: For an individual participant data (IPD) meta-analysis, multiple datasets must be transformed in a consistent format, e.g. using uniform variable names. When large numbers of datasets have to be processed, this can be a time-consuming and error-prone task. Automated or semi-automated identification of variables can help to reduce the workload and improve the data quality. For semi-automation high sensitivity in the recognition of matching variables is particularly important, because it allows creating software which for a target variable presents a choice of source variables, from which a user can choose the matching one, with only low risk of having missed a correct source variable.

METHODS: For each variable in a set of target variables, a number of simple rules were manually created. With logic regression, an optimal Boolean combination of these rules was searched for every target variable, using a random subset of a large database of epidemiological and clinical cohort data (construction subset). In a second subset of this database (validation subset), this optimal combination rules were validated.

RESULTS: In the construction sample, 41 target variables were allocated on average with a positive predictive value (PPV) of 34%, and a negative predictive value (NPV) of 95%. In the validation sample, PPV was 33%, whereas NPV remained at 94%. In the construction sample, PPV was 50% or less in 63% of all variables, in the validation sample in 71% of all variables.

CONCLUSIONS: We demonstrated that the application of logic regression in a complex data management task in large epidemiological IPD meta-analyses is feasible. However, the performance of the algorithm is poor, which may require backup strategies.

%B BMC Med Inform Decis Mak %V 17 %P 40 %8 2017 Apr 13 %G eng %N 1 %R 10.1186/s12911-017-0429-1 %0 Journal Article %J Psychosom Med %D 2017 %T Bivariate Genome-Wide Association Study of Depressive Symptoms with Type 2 Diabetes and Quantitative Glycemic Traits. %A Haljas, Kadri %A Amare, Azmeraw T %A Alizadeh, Behrooz Z %A Hsu, Yi-Hsiang %A Mosley, Thomas %A Newman, Anne %A Murabito, Joanne %A Tiemeier, Henning %A Tanaka, Toshiko %A van Duijn, Cornelia %A Ding, Jingzhong %A Llewellyn, David J %A Bennett, David A %A Terracciano, Antonio %A Launer, Lenore %A Ladwig, Karl-Heinz %A Cornelis, Marylin C %A Teumer, Alexander %A Grabe, Hans %A Kardia, Sharon L R %A Ware, Erin B %A Smith, Jennifer A %A Snieder, Harold %A Eriksson, Johan G %A Groop, Leif %A Räikkönen, Katri %A Lahti, Jari %X

OBJECTIVE: Shared genetic background may explain phenotypic associations between depression and Type-2-Diabetes (T2D). We aimed to study, on a genome-wide level, if genetic correlation and pleiotropic loci exist between depressive symptoms and T2D or glycemic traits.

METHODS: We estimated SNP-based heritability and analyzed genetic correlation between depressive symptoms and T2D and glycemic traits with the LD Score Regression (LDSC) by combining summary statistics of previously conducted meta-analyses for depressive symptoms by CHARGE consortium (N = 51,258), T2D by Diagram consortium (N = 34,840 patients and 114,981 controls), fasting glucose, fasting insulin, HOMA-β, and HOMA-IR by MAGIC consortium (N = 58,074). Finally, we investigated pleiotropic loci using a bivariate GWAS approach with summary statistics from GWAS meta-analyses and reported loci with genome-wide significant bivariate association p-value (p < 5x10). Biological annotation and function of significant pleiotropic SNPs were assessed in several databases.

RESULTS: The SNP-based heritability ranged from 0.04 to 0.10 in each individual trait. In the LDSC analyses, depressive symptoms showed no significant genetic correlation with T2D or glycemic traits (p > 0.37). Yet, we identified pleiotropic genetic variations for depressive symptoms and T2D (in the IGF2BP2, CDKAL1, CDKN2B-AS, and PLEKHA1 genes), and fasting glucose (in the MADD, CDKN2B-AS, PEX16, and MTNR1B genes).

CONCLUSIONS: We found no significant overall genetic correlations between depressive symptoms, T2D or glycemic traits suggesting major differences in underlying biology of these traits. Yet, several potential pleiotropic loci were identified between depressive symptoms, T2D and fasting glucose suggesting that previously established phenotypic associations may be partly explained by genetic variation in these specific loci.

%B Psychosom Med %8 2017 Dec 27 %G eng %R 10.1097/PSY.0000000000000555 %0 Journal Article %J J Am Heart Assoc %D 2017 %T Bone Mineral Density and Risk of Heart Failure in Older Adults: The Cardiovascular Health Study. %A Fohtung, Raymond B %A Brown, David L %A Koh, William J H %A Bartz, Traci M %A Carbone, Laura D %A Civitelli, Roberto %A Stein, Phyllis K %A Chaves, Paulo H M %A Kestenbaum, Bryan R %A Kizer, Jorge R %X

BACKGROUND: Despite increasing evidence of a common link between bone and heart health, the relationship between bone mineral density (BMD) and heart failure (HF) risk remains insufficiently studied.

METHODS AND RESULTS: We investigated whether BMD measured by dual-energy x-ray absorptiometry was associated with incident HF in an older cohort. Cox models were stratified by sex and interactions of BMD with race assessed. BMD was examined at the total hip and femoral neck separately, both continuously and by World Health Organization categories. Of 1250 participants, 442 (55% women) developed HF during the median follow-up of 10.5 years. In both black and nonblack women, neither total hip nor femoral neck BMD was significantly associated with HF; there was no significant interaction by race. In black and nonblack men, total hip, but not femoral neck, BMD was significantly associated with HF, with evidence of an interaction by race. In nonblack men, lower total hip BMD was associated with higher HF risk (hazard ratio, 1.13 [95% CI, 1.01-1.26] per 0.1 g/cm(2) decrement), whereas in black men, lower total hip BMD was associated with lower HF risk (hazard ratio, 0.74 [95% CI, 0.59-0.94]). There were no black men with total hip osteoporosis. Among nonblack men, total hip osteoporosis was associated with higher HF risk (hazard ratio, 2.83 [95% CI, 1.39-5.74]) compared with normal BMD.

CONCLUSIONS: Among older adults, lower total hip BMD was associated with higher HF risk in nonblack men but lower risk in black men, with no evidence of an association in women. Further research is needed to replicate these findings and to study potential underlying pathways.

%B J Am Heart Assoc %V 6 %8 2017 Mar 13 %G eng %N 3 %R 10.1161/JAHA.116.004344 %0 Journal Article %J Exp Gerontol %D 2017 %T Causal effects of cardiovascular risk factors on onset of major age-related diseases: A time-to-event Mendelian randomization study. %A He, Liang %A Culminskaya, Irina %A Loika, Yury %A Arbeev, Konstantin G %A Bagley, Olivia %A Duan, Matt %A Yashin, Anatoliy I %A Kulminski, Alexander M %X

BACKGROUNDS: Elucidating the causal effects of common intermediate risk factors on the onset of age-related diseases is indispensable for developing prevention and intervention procedures.

METHODS: We conducted two-stage time-to-event Mendelian randomization meta-analyses combining five large-scale longitudinal cohorts to investigate dynamic causal effects of cardiovascular disease risk factors including body mass index (BMI), systolic blood pressure (SBP), and lipids on the age-at-onset of age-related diseases. We constructed weighted polygenic scores based on genetic markers from previously reported genome-wide association studies as instrumental variables to estimate the causal effects. To avoid false positive due to potential pleiotropic effects of the genetic markers, we performed a leave-one-out sensitivity analysis and an MR-Egger sensitivity analysis that we expanded in the survival context.

RESULTS: Our results show that elevated BMI increases the absolute risk of type 2 diabetes (T2D) (p=7.68e-04), heart failure (p=9.03e-03), and cardiovascular diseases (CVD) (p=1.69e-03) and the causal effects start at different ages. A significant association between BMI and the risk of stroke is observed; however, the sensitivity analyses suggest that the association is attributed to the potential pleiotropic effects of rs2867125 and rs1558902. Raised SBP levels are significantly associated with the development of atrial fibrillation (p=6.42e-03). Low-density lipoprotein cholesterol (LDL-C) levels are inversely associated with the age-at-onset of T2D (p=1.05e-02). In addition, LDL-C and triglycerides are inversely associated with the risks of cancer and T2D, respectively. Nevertheless, the sensitivity analyses suggest that these associations are probably due to pleiotropic effects of several single-nucleotide polymorphisms including rs4970834 and rs1260326.

CONCLUSIONS: Our results highlight the involvement of BMI in the development of multiple age-related diseases. Some observed causal associations can attribute to pleiotropic effects of some genetic variations. These findings have important implications in unraveling causal effects of common risk factors on age-related diseases and guiding effective intervention strategies to reduce the incidence of these diseases.

%B Exp Gerontol %8 2017 Sep 28 %G eng %R 10.1016/j.exger.2017.09.019 %0 Journal Article %J PLoS One %D 2017 %T Comparison of HapMap and 1000 Genomes Reference Panels in a Large-Scale Genome-Wide Association Study. %A de Vries, Paul S %A Sabater-Lleal, Maria %A Chasman, Daniel I %A Trompet, Stella %A Ahluwalia, Tarunveer S %A Teumer, Alexander %A Kleber, Marcus E %A Chen, Ming-Huei %A Wang, Jie Jin %A Attia, John R %A Marioni, Riccardo E %A Steri, Maristella %A Weng, Lu-Chen %A Pool, Rene %A Grossmann, Vera %A Brody, Jennifer A %A Venturini, Cristina %A Tanaka, Toshiko %A Rose, Lynda M %A Oldmeadow, Christopher %A Mazur, Johanna %A Basu, Saonli %A Frånberg, Mattias %A Yang, Qiong %A Ligthart, Symen %A Hottenga, Jouke J %A Rumley, Ann %A Mulas, Antonella %A de Craen, Anton J M %A Grotevendt, Anne %A Taylor, Kent D %A Delgado, Graciela E %A Kifley, Annette %A Lopez, Lorna M %A Berentzen, Tina L %A Mangino, Massimo %A Bandinelli, Stefania %A Morrison, Alanna C %A Hamsten, Anders %A Tofler, Geoffrey %A de Maat, Moniek P M %A Draisma, Harmen H M %A Lowe, Gordon D %A Zoledziewska, Magdalena %A Sattar, Naveed %A Lackner, Karl J %A Völker, Uwe %A McKnight, Barbara %A Huang, Jie %A Holliday, Elizabeth G %A McEvoy, Mark A %A Starr, John M %A Hysi, Pirro G %A Hernandez, Dena G %A Guan, Weihua %A Rivadeneira, Fernando %A McArdle, Wendy L %A Slagboom, P Eline %A Zeller, Tanja %A Psaty, Bruce M %A Uitterlinden, André G %A de Geus, Eco J C %A Stott, David J %A Binder, Harald %A Hofman, Albert %A Franco, Oscar H %A Rotter, Jerome I %A Ferrucci, Luigi %A Spector, Tim D %A Deary, Ian J %A März, Winfried %A Greinacher, Andreas %A Wild, Philipp S %A Cucca, Francesco %A Boomsma, Dorret I %A Watkins, Hugh %A Tang, Weihong %A Ridker, Paul M %A Jukema, Jan W %A Scott, Rodney J %A Mitchell, Paul %A Hansen, Torben %A O'Donnell, Christopher J %A Smith, Nicholas L %A Strachan, David P %A Dehghan, Abbas %X

An increasing number of genome-wide association (GWA) studies are now using the higher resolution 1000 Genomes Project reference panel (1000G) for imputation, with the expectation that 1000G imputation will lead to the discovery of additional associated loci when compared to HapMap imputation. In order to assess the improvement of 1000G over HapMap imputation in identifying associated loci, we compared the results of GWA studies of circulating fibrinogen based on the two reference panels. Using both HapMap and 1000G imputation we performed a meta-analysis of 22 studies comprising the same 91,953 individuals. We identified six additional signals using 1000G imputation, while 29 loci were associated using both HapMap and 1000G imputation. One locus identified using HapMap imputation was not significant using 1000G imputation. The genome-wide significance threshold of 5×10-8 is based on the number of independent statistical tests using HapMap imputation, and 1000G imputation may lead to further independent tests that should be corrected for. When using a stricter Bonferroni correction for the 1000G GWA study (P-value < 2.5×10-8), the number of loci significant only using HapMap imputation increased to 4 while the number of loci significant only using 1000G decreased to 5. In conclusion, 1000G imputation enabled the identification of 20% more loci than HapMap imputation, although the advantage of 1000G imputation became less clear when a stricter Bonferroni correction was used. More generally, our results provide insights that are applicable to the implementation of other dense reference panels that are under development.

%B PLoS One %V 12 %P e0167742 %8 2017 %G eng %N 1 %R 10.1371/journal.pone.0167742 %0 Journal Article %J Aging (Albany NY) %D 2017 %T The complex genetics of gait speed: genome-wide meta-analysis approach. %A Ben-Avraham, Dan %A Karasik, David %A Verghese, Joe %A Lunetta, Kathryn L %A Smith, Jennifer A %A Eicher, John D %A Vered, Rotem %A Deelen, Joris %A Arnold, Alice M %A Buchman, Aron S %A Tanaka, Toshiko %A Faul, Jessica D %A Nethander, Maria %A Fornage, Myriam %A Adams, Hieab H %A Matteini, Amy M %A Callisaya, Michele L %A Smith, Albert V %A Yu, Lei %A De Jager, Philip L %A Evans, Denis A %A Gudnason, Vilmundur %A Hofman, Albert %A Pattie, Alison %A Corley, Janie %A Launer, Lenore J %A Knopman, Davis S %A Parimi, Neeta %A Turner, Stephen T %A Bandinelli, Stefania %A Beekman, Marian %A Gutman, Danielle %A Sharvit, Lital %A Mooijaart, Simon P %A Liewald, David C %A Houwing-Duistermaat, Jeanine J %A Ohlsson, Claes %A Moed, Matthijs %A Verlinden, Vincent J %A Mellström, Dan %A van der Geest, Jos N %A Karlsson, Magnus %A Hernandez, Dena %A McWhirter, Rebekah %A Liu, Yongmei %A Thomson, Russell %A Tranah, Gregory J %A Uitterlinden, André G %A Weir, David R %A Zhao, Wei %A Starr, John M %A Johnson, Andrew D %A Ikram, M Arfan %A Bennett, David A %A Cummings, Steven R %A Deary, Ian J %A Harris, Tamara B %A Kardia, Sharon L R %A Mosley, Thomas H %A Srikanth, Velandai K %A Windham, Beverly G %A Newman, Ann B %A Walston, Jeremy D %A Davies, Gail %A Evans, Daniel S %A Slagboom, Eline P %A Ferrucci, Luigi %A Kiel, Douglas P %A Murabito, Joanne M %A Atzmon, Gil %X

Emerging evidence suggests that the basis for variation in late-life mobility is attributable, in part, to genetic factors, which may become increasingly important with age. Our objective was to systematically assess the contribution of genetic variation to gait speed in older individuals. We conducted a meta-analysis of gait speed GWASs in 31,478 older adults from 17 cohorts of the CHARGE consortium, and validated our results in 2,588 older adults from 4 independent studies. We followed our initial discoveries with network and eQTL analysis of candidate signals in tissues. The meta-analysis resulted in a list of 536 suggestive genome wide significant SNPs in or near 69 genes. Further interrogation with Pathway Analysis placed gait speed as a polygenic complex trait in five major networks. Subsequent eQTL analysis revealed several SNPs significantly associated with the expression of PRSS16, WDSUB1 and PTPRT, which in addition to the meta-analysis and pathway suggested that genetic effects on gait speed may occur through synaptic function and neuronal development pathways. No genome-wide significant signals for gait speed were identified from this moderately large sample of older adults, suggesting that more refined physical function phenotypes will be needed to identify the genetic basis of gait speed in aging.

%B Aging (Albany NY) %V 9 %P 209-246 %8 2017 Jan 10 %G eng %N 1 %R 10.18632/aging.101151 %0 Journal Article %J BMJ %D 2017 %T Dairy consumption, systolic blood pressure, and risk of hypertension: Mendelian randomization study. %A Ding, Ming %A Huang, Tao %A Bergholdt, Helle Km %A Nordestgaard, Børge G %A Ellervik, Christina %A Qi, Lu %K Blood Pressure %K Dairy Products %K Feeding Behavior %K Genetic Predisposition to Disease %K Humans %K Hypertension %K Lactase %K Mendelian Randomization Analysis %K Observational Studies as Topic %K Polymorphism, Single Nucleotide %K Randomized Controlled Trials as Topic %X

Objective To examine whether previous observed inverse associations of dairy intake with systolic blood pressure and risk of hypertension were causal.Design Mendelian randomization study using the single nucleotide polymorphism rs4988235 related to lactase persistence as an instrumental variable.Setting CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium.Participants Data from 22 studies with 171 213 participants, and an additional 10 published prospective studies with 26 119 participants included in the observational analysis.Main outcome measures The instrumental variable estimation was conducted using the ratio of coefficients approach. Using meta-analysis, an additional eight published randomized clinical trials on the association of dairy consumption with systolic blood pressure were summarized.Results Compared with the CC genotype (CC is associated with complete lactase deficiency), the CT/TT genotype (TT is associated with lactose persistence, and CT is associated with certain lactase deficiency) of LCT-13910 (lactase persistence gene) rs4988235 was associated with higher dairy consumption (0.23 (about 55 g/day), 95% confidence interval 0.17 to 0.29) serving/day; P<0.001) and was not associated with systolic blood pressure (0.31, 95% confidence interval -0.05 to 0.68 mm Hg; P=0.09) or risk of hypertension (odds ratio 1.01, 95% confidence interval 0.97 to 1.05; P=0.27). Using LCT-13910 rs4988235 as the instrumental variable, genetically determined dairy consumption was not associated with systolic blood pressure (β=1.35, 95% confidence interval -0.28 to 2.97 mm Hg for each serving/day) or risk of hypertension (odds ratio 1.04, 0.88 to 1.24). Moreover, meta-analysis of the published clinical trials showed that higher dairy intake has no significant effect on change in systolic blood pressure for interventions over one month to 12 months (intervention compared with control groups: β=-0.21, 95% confidence interval -0.98 to 0.57 mm Hg). In observational analysis, each serving/day increase in dairy consumption was associated with -0.11 (95% confidence interval -0.20 to -0.02 mm Hg; P=0.02) lower systolic blood pressure but not risk of hypertension (odds ratio 0.98, 0.97 to 1.00; P=0.11).Conclusion The weak inverse association between dairy intake and systolic blood pressure in observational studies was not supported by a comprehensive instrumental variable analysis and systematic review of existing clinical trials.

%B BMJ %V 356 %P j1000 %8 2017 03 16 %G eng %R 10.1136/bmj.j1000 %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 Med Care %D 2017 %T Development of a Claims-based Frailty Indicator Anchored to a Well-established Frailty Phenotype. %A Segal, Jodi B %A Chang, Hsien-Yen %A Du, Yu %A D Walston, Jeremy %A C Carlson, Michelle %A Varadhan, Ravi %X

BACKGROUND: Fried and colleagues described a frailty phenotype measured in the Cardiovascular Health Study (CHS). This phenotype is manifest when ≥3 of the following are present: low grip strength, low energy, slowed waking speed, low physical activity, or unintentional weight loss. We sought to approximate frailty phenotype using only administrative claims data to enable frailty to be assessed without physical performance measures.

STUDY DESIGN: We used the CHS cohort data linked to participants Medicare claims. The reference standard was the frailty phenotype measured at visits 5 and 9. With penalized logistic regression, we developed a parsimonious index for predicting the frailty phenotype using a linear combination of diagnoses, operationalized with claims data. We assessed the predictive validity of frailty index by examining how well it predicted common aging-related outcomes including hospitalization, disability, and death.

RESULTS: There were 4454 CHS participants from 4 clinical sites. In total, 84% were white, 58% were women and their mean age was 72 years at enrollment. Approximately 11% of the cohort was frail. The model had an area under the receiver operating curve of 0.75 to concurrently predict a frailty phenotype. This Claims-based Frailty Indicator significantly predicted death (odds ratio, 1.84), time to death (hazards ratio, 1.71), number of hospital admissions (incidence rate ratio, 1.74), and nursing home admission (odds ratio, 1.47) in models adjusted for age and sex.

CONCLUSIONS: Claims data alone can be used to classify individuals as frail and nonfrail. The Claims-based Frailty Indicator might be used in research with large datasets for confounding adjustment or risk prediction. The indicator might also be used for emergency preparedness for identification of regions enriched with frail individuals.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/.

%B Med Care %8 2017 Apr 21 %G eng %R 10.1097/MLR.0000000000000729 %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 BioData Min %D 2017 %T Discovery and replication of SNP-SNP interactions for quantitative lipid traits in over 60,000 individuals. %A Holzinger, Emily R %A Verma, Shefali S %A Moore, Carrie B %A Hall, Molly %A De, Rishika %A Gilbert-Diamond, Diane %A Lanktree, Matthew B %A Pankratz, Nathan %A Amuzu, Antoinette %A Burt, Amber %A Dale, Caroline %A Dudek, Scott %A Furlong, Clement E %A Gaunt, Tom R %A Kim, Daniel Seung %A Riess, Helene %A Sivapalaratnam, Suthesh %A Tragante, Vinicius %A van Iperen, Erik P A %A Brautbar, Ariel %A Carrell, David S %A Crosslin, David R %A Jarvik, Gail P %A Kuivaniemi, Helena %A Kullo, Iftikhar J %A Larson, Eric B %A Rasmussen-Torvik, Laura J %A Tromp, Gerard %A Baumert, Jens %A Cruickshanks, Karen J %A Farrall, Martin %A Hingorani, Aroon D %A Hovingh, G K %A Kleber, Marcus E %A Klein, Barbara E %A Klein, Ronald %A Koenig, Wolfgang %A Lange, Leslie A %A Mӓrz, Winfried %A North, Kari E %A Charlotte Onland-Moret, N %A Reiner, Alex P %A Talmud, Philippa J %A van der Schouw, Yvonne T %A Wilson, James G %A Kivimaki, Mika %A Kumari, Meena %A Moore, Jason H %A Drenos, Fotios %A Asselbergs, Folkert W %A Keating, Brendan J %A Ritchie, Marylyn D %X

BACKGROUND: The genetic etiology of human lipid quantitative traits is not fully elucidated, and interactions between variants may play a role. We performed a gene-centric interaction study for four different lipid traits: low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG).

RESULTS: Our analysis consisted of a discovery phase using a merged dataset of five different cohorts (n = 12,853 to n = 16,849 depending on lipid phenotype) and a replication phase with ten independent cohorts totaling up to 36,938 additional samples. Filters are often applied before interaction testing to correct for the burden of testing all pairwise interactions. We used two different filters: 1. A filter that tested only single nucleotide polymorphisms (SNPs) with a main effect of p < 0.001 in a previous association study. 2. A filter that only tested interactions identified by Biofilter 2.0. Pairwise models that reached an interaction significance level of p < 0.001 in the discovery dataset were tested for replication. We identified thirteen SNP-SNP models that were significant in more than one replication cohort after accounting for multiple testing.

CONCLUSIONS: These results may reveal novel insights into the genetic etiology of lipid levels. Furthermore, we developed a pipeline to perform a computationally efficient interaction analysis with multi-cohort replication.

%B BioData Min %V 10 %P 25 %8 2017 %G eng %R 10.1186/s13040-017-0145-5 %0 Journal Article %J Hum Mol Genet %D 2017 %T Discovery of novel heart rate-associated loci using the Exome Chip. %A van den Berg, Marten E %A Warren, Helen R %A Cabrera, Claudia P %A Verweij, Niek %A Mifsud, Borbala %A Haessler, Jeffrey %A Bihlmeyer, Nathan A %A Fu, Yi-Ping %A Weiss, Stefan %A Lin, Henry J %A Grarup, Niels %A Li-Gao, Ruifang %A Pistis, Giorgio %A Shah, Nabi %A Brody, Jennifer A %A Müller-Nurasyid, Martina %A Lin, Honghuang %A Mei, Hao %A Smith, Albert V %A Lyytikäinen, Leo-Pekka %A Hall, Leanne M %A van Setten, Jessica %A Trompet, Stella %A Prins, Bram P %A Isaacs, Aaron %A Radmanesh, Farid %A Marten, Jonathan %A Entwistle, Aiman %A Kors, Jan A %A Silva, Claudia T %A Alonso, Alvaro %A Bis, Joshua C %A de Boer, Rudolf %A de Haan, Hugoline G %A de Mutsert, Renée %A Dedoussis, George %A Dominiczak, Anna F %A Doney, Alex S F %A Ellinor, Patrick T %A Eppinga, Ruben N %A Felix, Stephan B %A Guo, Xiuqing %A Hagemeijer, Yanick %A Hansen, Torben %A Harris, Tamara B %A Heckbert, Susan R %A Huang, Paul L %A Hwang, Shih-Jen %A Kähönen, Mika %A Kanters, Jørgen K %A Kolcic, Ivana %A Launer, Lenore J %A Li, Man %A Yao, Jie %A Linneberg, Allan %A Liu, Simin %A Macfarlane, Peter W %A Mangino, Massimo %A Morris, Andrew D %A Mulas, Antonella %A Murray, Alison D %A Nelson, Christopher P %A Orrù, Marco %A Padmanabhan, Sandosh %A Peters, Annette %A Porteous, David J %A Poulter, Neil %A Psaty, Bruce M %A Qi, Lihong %A Raitakari, Olli T %A Rivadeneira, Fernando %A Roselli, Carolina %A Rudan, Igor %A Sattar, Naveed %A Sever, Peter %A Sinner, Moritz F %A Soliman, Elsayed Z %A Spector, Timothy D %A Stanton, Alice V %A Stirrups, Kathleen E %A Taylor, Kent D %A Tobin, Martin D %A Uitterlinden, Andre %A Vaartjes, Ilonca %A Hoes, Arno W %A van der Meer, Peter %A Völker, Uwe %A Waldenberger, Melanie %A Xie, Zhijun %A Zoledziewska, Magdalena %A Tinker, Andrew %A Polasek, Ozren %A Rosand, Jonathan %A Jamshidi, Yalda %A van Duijn, Cornelia M %A Zeggini, Eleftheria %A Wouter Jukema, J %A Asselbergs, Folkert W %A Samani, Nilesh J %A Lehtimäki, Terho %A Gudnason, Vilmundur %A Wilson, James %A Lubitz, Steven A %A Kääb, Stefan %A Sotoodehnia, Nona %A Caulfield, Mark J %A Palmer, Colin N A %A Sanna, Serena %A Mook-Kanamori, Dennis O %A Deloukas, Panos %A Pedersen, Oluf %A Rotter, Jerome I %A Dörr, Marcus %A O'Donnell, Chris J %A Hayward, Caroline %A Arking, Dan E %A Kooperberg, Charles %A van der Harst, Pim %A Eijgelsheim, Mark %A Stricker, Bruno H %A Munroe, Patricia B %X

Background Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. GWAS analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9% of the variation.Aim To discover new genetic loci associated with heart rate from Exome Chip meta-analyses.Methods Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104,452 European-ancestry individuals from 30 cohorts, genotyped using the Exome Chip. Twenty-four variants were selected for follow-up in an independent dataset (UK Biobank, N = 134,251). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods.Results We discovered five novel heart rate loci, and one new independent low-frequency non-synonymous variant in an established heart rate locus (KIAA1755). Lead variants in four of the novel loci are non-synonymous variants in the genes C10orf71, DALDR3, TESK2, SEC31B. The variant at SEC31B is significantly associated with SEC31B expression in heart and tibial nerve tissue. Further candidate genes were detected from long range regulatory chromatin interactions in heart tissue (SCD, SLF2, MAPK8). We observed significant enrichment in DNase I hypersensitive sites in fetal heart and lung. Moreover, enrichment was seen for the first time in human neuronal progenitor cells (derived from embryonic stem cells) and fetal muscle samples by including our novel variants.Conclusion Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies.

%B Hum Mol Genet %8 2017 Apr 03 %G eng %R 10.1093/hmg/ddx113 %0 Journal Article %J Am J Hum Genet %D 2017 %T DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation. %A Richard, Melissa A %A Huan, Tianxiao %A Ligthart, Symen %A Gondalia, Rahul %A Jhun, Min A %A Brody, Jennifer A %A Irvin, Marguerite R %A Marioni, Riccardo %A Shen, Jincheng %A Tsai, Pei-Chien %A Montasser, May E %A Jia, Yucheng %A Syme, Catriona %A Salfati, Elias L %A Boerwinkle, Eric %A Guan, Weihua %A Mosley, Thomas H %A Bressler, Jan %A Morrison, Alanna C %A Liu, Chunyu %A Mendelson, Michael M %A Uitterlinden, André G %A van Meurs, Joyce B %A Franco, Oscar H %A Zhang, Guosheng %A Li, Yun %A Stewart, James D %A Bis, Joshua C %A Psaty, Bruce M %A Chen, Yii-Der Ida %A Kardia, Sharon L R %A Zhao, Wei %A Turner, Stephen T %A Absher, Devin %A Aslibekyan, Stella %A Starr, John M %A McRae, Allan F %A Hou, Lifang %A Just, Allan C %A Schwartz, Joel D %A Vokonas, Pantel S %A Menni, Cristina %A Spector, Tim D %A Shuldiner, Alan %A Damcott, Coleen M %A Rotter, Jerome I %A Palmas, Walter %A Liu, Yongmei %A Paus, Tomáš %A Horvath, Steve %A O'Connell, Jeffrey R %A Guo, Xiuqing %A Pausova, Zdenka %A Assimes, Themistocles L %A Sotoodehnia, Nona %A Smith, Jennifer A %A Arnett, Donna K %A Deary, Ian J %A Baccarelli, Andrea A %A Bell, Jordana T %A Whitsel, Eric %A Dehghan, Abbas %A Levy, Daniel %A Fornage, Myriam %K Aged %K Blood Pressure %K CpG Islands %K Cross-Sectional Studies %K DNA Methylation %K Epigenesis, Genetic %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Mendelian Randomization Analysis %K Middle Aged %K Nerve Tissue Proteins %K Quantitative Trait Loci %K Tetraspanins %X

Genome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p < 1.0 × 10-7; replication: N = 7,182, p < 1.6 × 10-3). The replicated methylation sites are heritable (h2 > 30%) and independent of known BP genetic variants, explaining an additional 1.4% and 2.0% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.

%B Am J Hum Genet %V 101 %P 888-902 %8 2017 Dec 07 %G eng %N 6 %R 10.1016/j.ajhg.2017.09.028 %0 Journal Article %J J Am Heart Assoc %D 2017 %T Ectopy on a Single 12-Lead ECG, Incident Cardiac Myopathy, and Death in the Community. %A Nguyen, Kaylin T %A Vittinghoff, Eric %A Dewland, Thomas A %A Dukes, Jonathan W %A Soliman, Elsayed Z %A Stein, Phyllis K %A Gottdiener, John S %A Alonso, Alvaro %A Chen, Lin Y %A Psaty, Bruce M %A Heckbert, Susan R %A Marcus, Gregory M %X

BACKGROUND: Atrial fibrillation and heart failure are 2 of the most common diseases, yet ready means to identify individuals at risk are lacking. The 12-lead ECG is one of the most accessible tests in medicine. Our objective was to determine whether a premature atrial contraction observed on a standard 12-lead ECG would predict atrial fibrillation and mortality and whether a premature ventricular contraction would predict heart failure and mortality.

METHODS AND RESULTS: We utilized the CHS (Cardiovascular Health) Study, which followed 5577 participants for a median of 12 years, as the primary cohort. The ARIC (Atherosclerosis Risk in Communities Study), the replication cohort, captured data from 15 792 participants over a median of 22 years. In the CHS, multivariable analyses revealed that a baseline 12-lead ECG premature atrial contraction predicted a 60% increased risk of atrial fibrillation (hazard ratio, 1.6; 95% CI, 1.3-2.0; P<0.001) and a premature ventricular contraction predicted a 30% increased risk of heart failure (hazard ratio, 1.3; 95% CI, 1.0-1.6; P=0.021). In the negative control analyses, neither predicted incident myocardial infarction. A premature atrial contraction was associated with a 30% increased risk of death (hazard ratio, 1.3; 95% CI, 1.1-1.5; P=0.008) and a premature ventricular contraction was associated with a 20% increased risk of death (hazard ratio, 1.2; 95% CI, 1.0-1.3; P=0.044). Similarly statistically significant results for each analysis were also observed in ARIC.

CONCLUSIONS: Based on a single standard ECG, a premature atrial contraction predicted incident atrial fibrillation and death and a premature ventricular contraction predicted incident heart failure and death, suggesting that this commonly used test may predict future disease.

%B J Am Heart Assoc %V 6 %8 2017 Aug 03 %G eng %N 8 %R 10.1161/JAHA.117.006028 %0 Journal Article %J Nat Genet %D 2017 %T Exome-wide association study of plasma lipids in >300,000 individuals. %A Liu, Dajiang J %A Peloso, Gina M %A Yu, Haojie %A Butterworth, Adam S %A Wang, Xiao %A Mahajan, Anubha %A Saleheen, Danish %A Emdin, Connor %A Alam, Dewan %A Alves, Alexessander Couto %A Amouyel, Philippe %A Di Angelantonio, Emanuele %A Arveiler, Dominique %A Assimes, Themistocles L %A Auer, Paul L %A Baber, Usman %A Ballantyne, Christie M %A Bang, Lia E %A Benn, Marianne %A Bis, Joshua C %A Boehnke, Michael %A Boerwinkle, Eric %A Bork-Jensen, Jette %A Bottinger, Erwin P %A Brandslund, Ivan %A Brown, Morris %A Busonero, Fabio %A Caulfield, Mark J %A Chambers, John C %A Chasman, Daniel I %A Chen, Y Eugene %A Chen, Yii-Der Ida %A Chowdhury, Rajiv %A Christensen, Cramer %A Chu, Audrey Y %A Connell, John M %A Cucca, Francesco %A Cupples, L Adrienne %A Damrauer, Scott M %A Davies, Gail %A Deary, Ian J %A Dedoussis, George %A Denny, Joshua C %A Dominiczak, Anna %A Dubé, Marie-Pierre %A Ebeling, Tapani %A Eiriksdottir, Gudny %A Esko, Tõnu %A Farmaki, Aliki-Eleni %A Feitosa, Mary F %A Ferrario, Marco %A Ferrieres, Jean %A Ford, Ian %A Fornage, Myriam %A Franks, Paul W %A Frayling, Timothy M %A Frikke-Schmidt, Ruth %A Fritsche, Lars G %A Frossard, Philippe %A Fuster, Valentin %A Ganesh, Santhi K %A Gao, Wei %A Garcia, Melissa E %A Gieger, Christian %A Giulianini, Franco %A Goodarzi, Mark O %A Grallert, Harald %A Grarup, Niels %A Groop, Leif %A Grove, Megan L %A Gudnason, Vilmundur %A Hansen, Torben %A Harris, Tamara B %A Hayward, Caroline %A Hirschhorn, Joel N %A Holmen, Oddgeir L %A Huffman, Jennifer %A Huo, Yong %A Hveem, Kristian %A Jabeen, Sehrish %A Jackson, Anne U %A Jakobsdottir, Johanna %A Jarvelin, Marjo-Riitta %A Jensen, Gorm B %A Jørgensen, Marit E %A Jukema, J Wouter %A Justesen, Johanne M %A Kamstrup, Pia R %A Kanoni, Stavroula %A Karpe, Fredrik %A Kee, Frank %A Khera, Amit V %A Klarin, Derek %A Koistinen, Heikki A %A Kooner, Jaspal S %A Kooperberg, Charles %A Kuulasmaa, Kari %A Kuusisto, Johanna %A Laakso, Markku %A Lakka, Timo %A Langenberg, Claudia %A Langsted, Anne %A Launer, Lenore J %A Lauritzen, Torsten %A Liewald, David C M %A Lin, Li An %A Linneberg, Allan %A Loos, Ruth J F %A Lu, Yingchang %A Lu, Xiangfeng %A Mägi, Reedik %A Mälarstig, Anders %A Manichaikul, Ani %A Manning, Alisa K %A Mäntyselkä, Pekka %A Marouli, Eirini %A Masca, Nicholas G D %A Maschio, Andrea %A Meigs, James B %A Melander, Olle %A Metspalu, Andres %A Morris, Andrew P %A Morrison, Alanna C %A Mulas, Antonella %A Müller-Nurasyid, Martina %A Munroe, Patricia B %A Neville, Matt J %A Nielsen, Jonas B %A Nielsen, Sune F %A Nordestgaard, Børge G %A Ordovas, Jose M %A Mehran, Roxana %A O'Donnell, Christoper J %A Orho-Melander, Marju %A Molony, Cliona M %A Muntendam, Pieter %A Padmanabhan, Sandosh %A Palmer, Colin N A %A Pasko, Dorota %A Patel, Aniruddh P %A Pedersen, Oluf %A Perola, Markus %A Peters, Annette %A Pisinger, Charlotta %A Pistis, Giorgio %A Polasek, Ozren %A Poulter, Neil %A Psaty, Bruce M %A Rader, Daniel J %A Rasheed, Asif %A Rauramaa, Rainer %A Reilly, Dermot F %A Reiner, Alex P %A Renstrom, Frida %A Rich, Stephen S %A Ridker, Paul M %A Rioux, John D %A Robertson, Neil R %A Roden, Dan M %A Rotter, Jerome I %A Rudan, Igor %A Salomaa, Veikko %A Samani, Nilesh J %A Sanna, Serena %A Sattar, Naveed %A Schmidt, Ellen M %A Scott, Robert A %A Sever, Peter %A Sevilla, Raquel S %A Shaffer, Christian M %A Sim, Xueling %A Sivapalaratnam, Suthesh %A Small, Kerrin S %A Smith, Albert V %A Smith, Blair H %A Somayajula, Sangeetha %A Southam, Lorraine %A Spector, Timothy D %A Speliotes, Elizabeth K %A Starr, John M %A Stirrups, Kathleen E %A Stitziel, Nathan %A Strauch, Konstantin %A Stringham, Heather M %A Surendran, Praveen %A Tada, Hayato %A Tall, Alan R %A Tang, Hua %A Tardif, Jean-Claude %A Taylor, Kent D %A Trompet, Stella %A Tsao, Philip S %A Tuomilehto, Jaakko %A Tybjaerg-Hansen, Anne %A van Zuydam, Natalie R %A Varbo, Anette %A Varga, Tibor V %A Virtamo, Jarmo %A Waldenberger, Melanie %A Wang, Nan %A Wareham, Nick J %A Warren, Helen R %A Weeke, Peter E %A Weinstock, Joshua %A Wessel, Jennifer %A Wilson, James G %A Wilson, Peter W F %A Xu, Ming %A Yaghootkar, Hanieh %A Young, Robin %A Zeggini, Eleftheria %A Zhang, He %A Zheng, Neil S %A Zhang, Weihua %A Zhang, Yan %A Zhou, Wei %A Zhou, Yanhua %A Zoledziewska, Magdalena %A Howson, Joanna M M %A Danesh, John %A McCarthy, Mark I %A Cowan, Chad A %A Abecasis, Goncalo %A Deloukas, Panos %A Musunuru, Kiran %A Willer, Cristen J %A Kathiresan, Sekar %K Coronary Artery Disease %K Diabetes Mellitus, Type 2 %K Exome %K Genetic Association Studies %K Genetic Predisposition to Disease %K Genetic Variation %K Genotype %K Humans %K Lipids %K Macular Degeneration %K Phenotype %K Risk Factors %X

We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.

%B Nat Genet %V 49 %P 1758-1766 %8 2017 Dec %G eng %N 12 %R 10.1038/ng.3977 %0 Journal Article %J Stroke %D 2017 %T Factors Associated With Ischemic Stroke Survival and Recovery in Older Adults. %A Winovich, Divya Thekkethala %A Longstreth, William T %A Arnold, Alice M %A Varadhan, Ravi %A Zeki Al Hazzouri, Adina %A Cushman, Mary %A Newman, Anne B %A Odden, Michelle C %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Brain Ischemia %K Cohort Studies %K Female %K Follow-Up Studies %K Frail Elderly %K Humans %K Male %K Recovery of Function %K Risk Factors %K Stroke %K Survival Rate %X

BACKGROUND AND PURPOSE: Little is known about factors that predispose older adults to poor recovery after a stroke. In this study, we sought to evaluate prestroke measures of frailty and related factors as markers of vulnerability to poor outcomes after ischemic stroke.

METHODS: In participants aged 65 to 99 years with incident ischemic strokes from the Cardiovascular Health Study, we evaluated the association of several risk factors (frailty, frailty components, C-reactive protein, interleukin-6, and cystatin C) assessed before stroke with stroke outcomes of survival, cognitive decline (≥5 points on Modified Mini-Mental State Examination), and activities of daily living decline (increase in limitations).

RESULTS: Among 717 participants with incident ischemic stroke with survival data, slow walking speed, low grip strength, and cystatin C were independently associated with shorter survival. Among participants <80 years of age, frailty and interleukin-6 were also associated with shorter survival. Among 509 participants with recovery data, slow walking speed, and low grip strength were associated with both cognitive and activities of daily living decline poststroke. C-reactive protein and interleukin-6 were associated with poststroke cognitive decline among men only. Frailty status was associated with activities of daily living decline among women only.

CONCLUSIONS: Markers of physical function-walking speed and grip strength-were consistently associated with survival and recovery after ischemic stroke. Inflammation, kidney function, and frailty also seemed to be determinants of survival and recovery after an ischemic stroke. These markers of vulnerability may identify targets for differing pre and poststroke medical management and rehabilitation among older adults at risk of poor stroke outcomes.

%B Stroke %V 48 %P 1818-1826 %8 2017 Jul %G eng %N 7 %R 10.1161/STROKEAHA.117.016726 %0 Journal Article %J J Am Soc Nephrol %D 2017 %T Fibroblast Growth Factor 23 and the Risk of Infection-Related Hospitalization in Older Adults. %A Nowak, Kristen L %A Bartz, Traci M %A Dalrymple, Lorien %A de Boer, Ian H %A Kestenbaum, Bryan %A Shlipak, Michael G %A Garimella, Pranav S %A Ix, Joachim H %A Chonchol, Michel %X

Within monocytes, 1,25-dihydroxyvitamin D [1,25(OH)2D] is important for production of cathelicidins, which in turn, are critical for antibacterial action. Fibroblast growth factor 23 (FGF23) decreases 1,25(OH)2D production and thus, could increase infection risk. We examined this possibility in 3141 community-dwelling adults ages ≥65 years old at baseline in the Cardiovascular Health Study using Cox proportional hazards models to examine the association between FGF23 concentrations and first infection-related hospitalizations and determine whether associations differed by the presence of CKD (eGFR<60 ml/min per 1.73 m(2) [n=832] or urine albumin-to-creatinine ratio >30 mg/g [n=577]). Mean±SD age of participants was 78±5 years old, 60% of participants were women, and the median plasma FGF23 concentration was 70 (interquartile range, 53-99) relative units per milliliter. In fully adjusted models, higher FGF23 concentrations associated with higher risk of first infection-related hospitalization (hazard ratio [HR], 1.11; 95% confidence interval [95% CI], 1.03 to 1.20 per doubling of FGF23) during a median follow-up of 8.6 years. In participants with or without CKD (defined by eGFR), FGF23 concentration associated with first infection-related hospitalization with HRs of 1.24 (95% CI, 1.08 to 1.42) and 1.06 (95% CI, 0.97 to 1.17) per doubling of FGF23, respectively (P=0.13 for interaction). Associations did not differ between groups when stratified by urine albumin-to-creatinine ratio. In sensitivity analyses, the addition of serum calcium, phosphorus, 25-hydroxyvitamin D, intact parathyroid hormone, and 24,25-dihydroxyvitamin D did not meaningfully change the estimates. In conclusion, in community-dwelling older adults, higher plasma FGF23 concentrations independently associated with the risk of first infection-related hospitalization.

%B J Am Soc Nephrol %V 28 %P 1239-1246 %8 2017 Apr %G eng %N 4 %R 10.1681/ASN.2016040401 %0 Journal Article %J Circ Cardiovasc Genet %D 2017 %T Fifteen Genetic Loci Associated With the Electrocardiographic P Wave. %A Christophersen, Ingrid E %A Magnani, Jared W %A Yin, Xiaoyan %A Barnard, John %A Weng, Lu-Chen %A Arking, Dan E %A Niemeijer, Maartje N %A Lubitz, Steven A %A Avery, Christy L %A Duan, Qing %A Felix, Stephan B %A Bis, Joshua C %A Kerr, Kathleen F %A Isaacs, Aaron %A Müller-Nurasyid, Martina %A Müller, Christian %A North, Kari E %A Reiner, Alex P %A Tinker, Lesley F %A Kors, Jan A %A Teumer, Alexander %A Petersmann, Astrid %A Sinner, Moritz F %A Bůzková, Petra %A Smith, Jonathan D %A Van Wagoner, David R %A Völker, Uwe %A Waldenberger, Melanie %A Peters, Annette %A Meitinger, Thomas %A Limacher, Marian C %A Wilhelmsen, Kirk C %A Psaty, Bruce M %A Hofman, Albert %A Uitterlinden, Andre %A Krijthe, Bouwe P %A Zhang, Zhu-Ming %A Schnabel, Renate B %A Kääb, Stefan %A van Duijn, Cornelia %A Rotter, Jerome I %A Sotoodehnia, Nona %A Dörr, Marcus %A Li, Yun %A Chung, Mina K %A Soliman, Elsayed Z %A Alonso, Alvaro %A Whitsel, Eric A %A Stricker, Bruno H %A Benjamin, Emelia J %A Heckbert, Susan R %A Ellinor, Patrick T %K Arrhythmias, Cardiac %K Caveolin 1 %K Caveolin 2 %K Electrocardiography %K Genetic Loci %K Genome-Wide Association Study %K Genotype %K Heart Atria %K Humans %K NAV1.5 Voltage-Gated Sodium Channel %K NAV1.8 Voltage-Gated Sodium Channel %K T-Box Domain Proteins %X

BACKGROUND: The P wave on an ECG is a measure of atrial electric function, and its characteristics may serve as predictors for atrial arrhythmias. Increased mean P-wave duration and P-wave terminal force traditionally have been used as markers for left atrial enlargement, and both have been associated with increased risk of atrial fibrillation. Here, we explore the genetic basis of P-wave morphology through meta-analysis of genome-wide association study results for P-wave duration and P-wave terminal force from 12 cohort studies.

METHODS AND RESULTS: We included 44 456 individuals, of which 6778 (16%) were of African ancestry. Genotyping, imputation, and genome-wide association study were performed at each study site. Summary-level results were meta-analyzed centrally using inverse-variance weighting. In meta-analyses of P-wave duration, we identified 6 significant (P<5×10-8) novel loci and replicated a prior association with SCN10A. We identified 3 loci at SCN5A, TBX5, and CAV1/CAV2 that were jointly associated with the PR interval, PR segment, and P-wave duration. We identified 6 novel loci in meta-analysis of P-wave terminal force. Four of the identified genetic loci were significantly associated with gene expression in 329 left atrial samples. Finally, we observed that some of the loci associated with the P wave were linked to overall atrial conduction, whereas others identified distinct phases of atrial conduction.

CONCLUSIONS: We have identified 6 novel genetic loci associated with P-wave duration and 6 novel loci associated with P-wave terminal force. Future studies of these loci may aid in identifying new targets for drugs that may modify atrial conduction or treat atrial arrhythmias.

%B Circ Cardiovasc Genet %V 10 %8 2017 Aug %G eng %N 4 %R 10.1161/CIRCGENETICS.116.001667 %0 Journal Article %J Heart Rhythm %D 2017 %T Fine mapping of QT interval regions in global populations refines previously identified QT interval loci and identifies signals unique to African and Hispanic descent populations. %A Avery, Christy L %A Wassel, Christina L %A Richard, Melissa A %A Highland, Heather M %A Bien, Stephanie %A Zubair, Niha %A Soliman, Elsayed Z %A Fornage, Myriam %A Bielinski, Suzette J %A Tao, Ran %A Seyerle, Amanda A %A Shah, Sanjiv J %A Lloyd-Jones, Donald M %A Buyske, Steven %A Rotter, Jerome I %A Post, Wendy S %A Rich, Stephen S %A Hindorff, Lucia A %A Jeff, Janina M %A Shohet, Ralph V %A Sotoodehnia, Nona %A Lin, Dan Yu %A Whitsel, Eric A %A Peters, Ulrike %A Haiman, Christopher A %A Crawford, Dana C %A Kooperberg, Charles %A North, Kari E %X

BACKGROUND: The electrocardiographically measured QT interval (QT) is heritable and its prolongation is an established risk factor for several cardiovascular diseases. Yet, most QT genetic studies have been performed in European ancestral populations, possibly reducing their global relevance.

OBJECTIVE: To leverage diversity and improve biological insight, we fine mapped 16 of the 35 previously identified QT loci (46%) in populations of African American (n = 12,410) and Hispanic/Latino (n = 14,837) ancestry.

METHODS: Racial/ethnic-specific multiple linear regression analyses adjusted for heart rate and clinical covariates were examined separately and in combination after inverse-variance weighted trans-ethnic meta-analysis.

RESULTS: The 16 fine-mapped QT loci included on the Illumina Metabochip represented 21 independent signals, of which 16 (76%) were significantly (P-value≤9.1×10(-5)) associated with QT. Through sequential conditional analysis we also identified three trans-ethnic novel SNPs at ATP1B1, SCN5A-SCN10A, and KCNQ1 and three Hispanic/Latino-specific novel SNPs at NOS1AP and SCN5A-SCN10A (two novel SNPs) with evidence of associations with QT independent of previous identified GWAS lead SNPs. Linkage disequilibrium patterns helped to narrow the region likely to contain the functional variants at several loci, including NOS1AP, USP50-TRPM7, and PRKCA, although intervals surrounding SLC35F1-PLN and CNOT1 remained broad in size (>100 kb). Finally, bioinformatics-based functional characterization suggested a regulatory function in cardiac tissues for the majority of independent signals that generalized and the novel SNPs.

CONCLUSION: Our findings suggest that a majority of identified SNPs implicate gene regulatory dysfunction in QT prolongation, that the same loci influence variation in QT across global populations, and that additional, novel, population-specific QT signals exist.

%B Heart Rhythm %V 14 %P 572-580 %8 2017 Apr %G eng %N 4 %R 10.1016/j.hrthm.2016.12.021 %0 Journal Article %J Res Pract Thromb Haemost %D 2017 %T Galectin-3 and Venous Thromboembolism Incidence: the Atherosclerosis Risk in Communities (ARIC) Study. %A Fashanu, Oluwaseun E %A Heckbert, Susan R %A Aguilar, David %A Jensen, Paul N %A Ballantyne, Christie M %A Basu, Saonli %A Hoogeveen, Ron C %A DeFilippi, Christopher %A Cushman, Mary %A Folsom, Aaron R %X

Background: The inflammatory biomarker galectin-3 contributes to pathologic conditions such as heart failure and stimulates murine thrombogenesis. Its association with venous thromboembolism (VTE) has been sparsely studied.

Objectives: To assess the prospective association of plasma galectin-3 and the LGALS3 rs4644 SNP with VTE incidence.

Methods: We measured plasma galectin-3 in 9,916 participants in the Atherosclerosis Risk in Communities (ARIC) study cohort in 1996 - 1998 and identified VTEs through 2013. Using Cox regression, we estimated the hazard ratio associating galectin-3 with incident VTE over a median of 13.9 years. Replication was sought in the Cardiovascular Health Study (CHS).

Results: ARIC included 21.8% blacks and 56.2% females with mean baseline age of 62.7 years. The incidence rate of VTE (n=389 events) increased across quintiles of galectin-3, with hazard ratios (95% CI) of 1 (reference), 1.13 (0.80 - 1.61), 1.00 (0.70 - 1.43), 1.36 (0.96 - 1.91), and 1.55 (1.09 - 2.19) (p-trend = 0.005), adjusted for age, sex, race, body mass index, diabetes status, and renal function. Results did not replicate in the CHS (124 VTE), but meta-analysis of both studies yielded a pooled hazard ratio (95% CI) for 1 SD increment in log galectin-3 of 1.10 (1.00 - 1.22). In ARIC, the C allele of rs4644 in the LGALS3 gene was associated with higher galectin-3 level, and in whites, with an increased rate of VTE.

Conclusion: Galectin-3 levels were associated positively with VTE incidence.

%B Res Pract Thromb Haemost %V 1 %P 223-230 %8 2017 Oct %G eng %N 2 %R 10.1002/rth2.12038 %0 Journal Article %J Int J Obes (Lond) %D 2017 %T Generalization and fine mapping of European ancestry-based central adiposity variants in African ancestry populations. %A Yoneyama, S %A Yao, J %A Guo, X %A Fernandez-Rhodes, L %A Lim, U %A Boston, J %A Bůžková, P %A Carlson, C S %A Cheng, I %A Cochran, B %A Cooper, R %A Ehret, G %A Fornage, M %A Gong, J %A Gross, M %A Gu, C C %A Haessler, J %A Haiman, C A %A Henderson, B %A Hindorff, L A %A Houston, D %A Irvin, M R %A Jackson, R %A Kuller, L %A Leppert, M %A Lewis, C E %A Li, R %A Le Marchand, L %A Matise, T C %A Nguyen, K-Dh %A Chakravarti, A %A Pankow, J S %A Pankratz, N %A Pooler, L %A Ritchie, M D %A Bien, S A %A Wassel, C L %A Chen, Y-DI %A Taylor, K D %A Allison, M %A Rotter, J I %A Schreiner, P J %A Schumacher, F %A Wilkens, L %A Boerwinkle, E %A Kooperberg, C %A Peters, U %A Buyske, S %A Graff, M %A North, K E %X

BACKGROUND/OBJECTIVES: Central adiposity measures such as waist circumference (WC) and waist-to-hip ratio (WHR) are associated with cardiometabolic disorders independently of body mass index (BMI) and are gaining clinically utility. Several studies report genetic variants associated with central adiposity, but most utilize only European ancestry populations. Understanding whether the genetic associations discovered among mainly European descendants are shared with African ancestry populations will help elucidate the biological underpinnings of abdominal fat deposition.

SUBJECTS/METHODS: To identify the underlying functional genetic determinants of body fat distribution, we conducted an array-wide association meta-analysis among persons of African ancestry across seven studies/consortia participating in the Population Architecture using Genomics and Epidemiology (PAGE) consortium. We used the Metabochip array, designed for fine-mapping cardiovascular-associated loci, to explore novel array-wide associations with WC and WHR among 15 945 African descendants using all and sex-stratified groups. We further interrogated 17 known WHR regions for African ancestry-specific variants.

RESULTS: Of the 17 WHR loci, eight single-nucleotide polymorphisms (SNPs) located in four loci were replicated in the sex-combined or sex-stratified meta-analyses. Two of these eight independently associated with WHR after conditioning on the known variant in European descendants (rs12096179 in TBX15-WARS2 and rs2059092 in ADAMTS9). In the fine-mapping assessment, the putative functional region was reduced across all four loci but to varying degrees (average 40% drop in number of putative SNPs and 20% drop in genomic region). Similar to previous studies, the significant SNPs in the female-stratified analysis were stronger than the significant SNPs from the sex-combined analysis. No novel associations were detected in the array-wide analyses.

CONCLUSIONS: Of 17 previously identified loci, four loci replicated in the African ancestry populations of this study. Utilizing different linkage disequilibrium patterns observed between European and African ancestries, we narrowed the suggestive region containing causative variants for all four loci.

%B Int J Obes (Lond) %V 41 %P 324-331 %8 2017 Feb %G eng %N 2 %R 10.1038/ijo.2016.207 %0 Journal Article %J Sci Rep %D 2017 %T Genetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation: The AFGen Consortium. %A Weng, Lu-Chen %A Lunetta, Kathryn L %A Müller-Nurasyid, Martina %A Smith, Albert Vernon %A Thériault, Sébastien %A Weeke, Peter E %A Barnard, John %A Bis, Joshua C %A Lyytikäinen, Leo-Pekka %A Kleber, Marcus E %A Martinsson, Andreas %A Lin, Henry J %A Rienstra, Michiel %A Trompet, Stella %A Krijthe, Bouwe P %A Dörr, Marcus %A Klarin, Derek %A Chasman, Daniel I %A Sinner, Moritz F %A Waldenberger, Melanie %A Launer, Lenore J %A Harris, Tamara B %A Soliman, Elsayed Z %A Alonso, Alvaro %A Paré, Guillaume %A Teixeira, Pedro L %A Denny, Joshua C %A Shoemaker, M Benjamin %A Van Wagoner, David R %A Smith, Jonathan D %A Psaty, Bruce M %A Sotoodehnia, Nona %A Taylor, Kent D %A Kähönen, Mika %A Nikus, Kjell %A Delgado, Graciela E %A Melander, Olle %A Engström, Gunnar %A Yao, Jie %A Guo, Xiuqing %A Christophersen, Ingrid E %A Ellinor, Patrick T %A Geelhoed, Bastiaan %A Verweij, Niek %A Macfarlane, Peter %A Ford, Ian %A Heeringa, Jan %A Franco, Oscar H %A Uitterlinden, André G %A Völker, Uwe %A Teumer, Alexander %A Rose, Lynda M %A Kääb, Stefan %A Gudnason, Vilmundur %A Arking, Dan E %A Conen, David %A Roden, Dan M %A Chung, Mina K %A Heckbert, Susan R %A Benjamin, Emelia J %A Lehtimäki, Terho %A März, Winfried %A Smith, J Gustav %A Rotter, Jerome I %A van der Harst, Pim %A Jukema, J Wouter %A Stricker, Bruno H %A Felix, Stephan B %A Albert, Christine M %A Lubitz, Steven A %X

It is unclear whether genetic markers interact with risk factors to influence atrial fibrillation (AF) risk. We performed genome-wide interaction analyses between genetic variants and age, sex, hypertension, and body mass index in the AFGen Consortium. Study-specific results were combined using meta-analysis (88,383 individuals of European descent, including 7,292 with AF). Variants with nominal interaction associations in the discovery analysis were tested for association in four independent studies (131,441 individuals, including 5,722 with AF). In the discovery analysis, the AF risk associated with the minor rs6817105 allele (at the PITX2 locus) was greater among subjects ≤ 65 years of age than among those > 65 years (interaction p-value = 4.0 × 10-5). The interaction p-value exceeded genome-wide significance in combined discovery and replication analyses (interaction p-value = 1.7 × 10-8). We observed one genome-wide significant interaction with body mass index and several suggestive interactions with age, sex, and body mass index in the discovery analysis. However, none was replicated in the independent sample. Our findings suggest that the pathogenesis of AF may differ according to age in individuals of European descent, but we did not observe evidence of statistically significant genetic interactions with sex, body mass index, or hypertension on AF risk.

%B Sci Rep %V 7 %P 11303 %8 2017 Sep 12 %G eng %N 1 %R 10.1038/s41598-017-09396-7 %0 Journal Article %J Nat Genet %D 2017 %T Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis. %A Hobbs, Brian D %A de Jong, Kim %A Lamontagne, Maxime %A Bossé, Yohan %A Shrine, Nick %A Artigas, Maria Soler %A Wain, Louise V %A Hall, Ian P %A Jackson, Victoria E %A Wyss, Annah B %A London, Stephanie J %A North, Kari E %A Franceschini, Nora %A Strachan, David P %A Beaty, Terri H %A Hokanson, John E %A Crapo, James D %A Castaldi, Peter J %A Chase, Robert P %A Bartz, Traci M %A Heckbert, Susan R %A Psaty, Bruce M %A Gharib, Sina A %A Zanen, Pieter %A Lammers, Jan W %A Oudkerk, Matthijs %A Groen, H J %A Locantore, Nicholas %A Tal-Singer, Ruth %A Rennard, Stephen I %A Vestbo, Jørgen %A Timens, Wim %A Paré, Peter D %A Latourelle, Jeanne C %A Dupuis, Josée %A O'Connor, George T %A Wilk, Jemma B %A Kim, Woo Jin %A Lee, Mi Kyeong %A Oh, Yeon-Mok %A Vonk, Judith M %A de Koning, Harry J %A Leng, Shuguang %A Belinsky, Steven A %A Tesfaigzi, Yohannes %A Manichaikul, Ani %A Wang, Xin-Qun %A Rich, Stephen S %A Barr, R Graham %A Sparrow, David %A Litonjua, Augusto A %A Bakke, Per %A Gulsvik, Amund %A Lahousse, Lies %A Brusselle, Guy G %A Stricker, Bruno H %A Uitterlinden, André G %A Ampleford, Elizabeth J %A Bleecker, Eugene R %A Woodruff, Prescott G %A Meyers, Deborah A %A Qiao, Dandi %A Lomas, David A %A Yim, Jae-Joon %A Kim, Deog Kyeom %A Hawrylkiewicz, Iwona %A Sliwinski, Pawel %A Hardin, Megan %A Fingerlin, Tasha E %A Schwartz, David A %A Postma, Dirkje S %A MacNee, William %A Tobin, Martin D %A Silverman, Edwin K %A Boezen, H Marike %A Cho, Michael H %X

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P < 5 × 10(-6)) in 9,498 cases and 9,748 controls. In the combined meta-analysis, we identified 22 loci associated at genome-wide significance, including 13 new associations with COPD. Nine of these 13 loci have been associated with lung function in general population samples, while 4 (EEFSEC, DSP, MTCL1, and SFTPD) are new. We noted two loci shared with pulmonary fibrosis (FAM13A and DSP) but that had opposite risk alleles for COPD. None of our loci overlapped with genome-wide associations for asthma, although one locus has been implicated in joint susceptibility to asthma and obesity. We also identified genetic correlation between COPD and asthma. Our findings highlight new loci associated with COPD, demonstrate the importance of specific loci associated with lung function to COPD, and identify potential regions of genetic overlap between COPD and other respiratory diseases.

%B Nat Genet %V 49 %P 426-432 %8 2017 Mar %G eng %N 3 %R 10.1038/ng.3752 %0 Journal Article %J Nat Commun %D 2017 %T Genetic loci associated with heart rate variability and their effects on cardiac disease risk. %A Nolte, Ilja M %A Munoz, M Loretto %A Tragante, Vinicius %A Amare, Azmeraw T %A Jansen, Rick %A Vaez, Ahmad %A von der Heyde, Benedikt %A Avery, Christy L %A Bis, Joshua C %A Dierckx, Bram %A van Dongen, Jenny %A Gogarten, Stephanie M %A Goyette, Philippe %A Hernesniemi, Jussi %A Huikari, Ville %A Hwang, Shih-Jen %A Jaju, Deepali %A Kerr, Kathleen F %A Kluttig, Alexander %A Krijthe, Bouwe P %A Kumar, Jitender %A van der Laan, Sander W %A Lyytikäinen, Leo-Pekka %A Maihofer, Adam X %A Minassian, Arpi %A van der Most, Peter J %A Müller-Nurasyid, Martina %A Nivard, Michel %A Salvi, Erika %A Stewart, James D %A Thayer, Julian F %A Verweij, Niek %A Wong, Andrew %A Zabaneh, Delilah %A Zafarmand, Mohammad H %A Abdellaoui, Abdel %A Albarwani, Sulayma %A Albert, Christine %A Alonso, Alvaro %A Ashar, Foram %A Auvinen, Juha %A Axelsson, Tomas %A Baker, Dewleen G %A de Bakker, Paul I W %A Barcella, Matteo %A Bayoumi, Riad %A Bieringa, Rob J %A Boomsma, Dorret %A Boucher, Gabrielle %A Britton, Annie R %A Christophersen, Ingrid %A Dietrich, Andrea %A Ehret, George B %A Ellinor, Patrick T %A Eskola, Markku %A Felix, Janine F %A Floras, John S %A Franco, Oscar H %A Friberg, Peter %A Gademan, Maaike G J %A Geyer, Mark A %A Giedraitis, Vilmantas %A Hartman, Catharina A %A Hemerich, Daiane %A Hofman, Albert %A Hottenga, Jouke-Jan %A Huikuri, Heikki %A Hutri-Kähönen, Nina %A Jouven, Xavier %A Junttila, Juhani %A Juonala, Markus %A Kiviniemi, Antti M %A Kors, Jan A %A Kumari, Meena %A Kuznetsova, Tatiana %A Laurie, Cathy C %A Lefrandt, Joop D %A Li, Yong %A Li, Yun %A Liao, Duanping %A Limacher, Marian C %A Lin, Henry J %A Lindgren, Cecilia M %A Lubitz, Steven A %A Mahajan, Anubha %A McKnight, Barbara %A Zu Schwabedissen, Henriette Meyer %A Milaneschi, Yuri %A Mononen, Nina %A Morris, Andrew P %A Nalls, Mike A %A Navis, Gerjan %A Neijts, Melanie %A Nikus, Kjell %A North, Kari E %A O'Connor, Daniel T %A Ormel, Johan %A Perz, Siegfried %A Peters, Annette %A Psaty, Bruce M %A Raitakari, Olli T %A Risbrough, Victoria B %A Sinner, Moritz F %A Siscovick, David %A Smit, Johannes H %A Smith, Nicholas L %A Soliman, Elsayed Z %A Sotoodehnia, Nona %A Staessen, Jan A %A Stein, Phyllis K %A Stilp, Adrienne M %A Stolarz-Skrzypek, Katarzyna %A Strauch, Konstantin %A Sundström, Johan %A Swenne, Cees A %A Syvänen, Ann-Christine %A Tardif, Jean-Claude %A Taylor, Kent D %A Teumer, Alexander %A Thornton, Timothy A %A Tinker, Lesley E %A Uitterlinden, André G %A van Setten, Jessica %A Voss, Andreas %A Waldenberger, Melanie %A Wilhelmsen, Kirk C %A Willemsen, Gonneke %A Wong, Quenna %A Zhang, Zhu-Ming %A Zonderman, Alan B %A Cusi, Daniele %A Evans, Michele K %A Greiser, Halina K %A van der Harst, Pim %A Hassan, Mohammad %A Ingelsson, Erik %A Jarvelin, Marjo-Riitta %A Kääb, Stefan %A Kähönen, Mika %A Kivimaki, Mika %A Kooperberg, Charles %A Kuh, Diana %A Lehtimäki, Terho %A Lind, Lars %A Nievergelt, Caroline M %A O'Donnell, Chris J %A Oldehinkel, Albertine J %A Penninx, Brenda %A Reiner, Alexander P %A Riese, Harriëtte %A van Roon, Arie M %A Rioux, John D %A Rotter, Jerome I %A Sofer, Tamar %A Stricker, Bruno H %A Tiemeier, Henning %A Vrijkotte, Tanja G M %A Asselbergs, Folkert W %A Brundel, Bianca J J M %A Heckbert, Susan R %A Whitsel, Eric A %A den Hoed, Marcel %A Snieder, Harold %A de Geus, Eco J C %X

Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74 %B Nat Commun %V 8 %P 15805 %8 2017 Jun 14 %G eng %R 10.1038/ncomms15805 %0 Journal Article %J Circulation %D 2017 %T {Genetic Risk Prediction of Atrial Fibrillation %A Lubitz, S. A. %A Yin, X. %A Lin, H. J. %A Kolek, M. %A Smith, J. G. %A Trompet, S. %A Rienstra, M. %A Rost, N. S. %A Teixeira, P. L. %A Almgren, P. %A Anderson, C. D. %A Chen, L. Y. %A Engstr?m, G. %A Ford, I. %A Furie, K. L. %A Guo, X. %A Larson, M. G. %A Lunetta, K. L. %A Macfarlane, P. W. %A Psaty, B. M. %A Soliman, E. Z. %A Sotoodehnia, N. %A Stott, D. J. %A Taylor, K. D. %A Weng, L. C. %A Yao, J. %A Geelhoed, B. %A Verweij, N. %A Siland, J. E. %A Kathiresan, S. %A Roselli, C. %A Roden, D. M. %A van der Harst, P. %A Darbar, D. %A Jukema, J. W. %A Melander, O. %A Rosand, J. %A Rotter, J. I. %A Heckbert, S. R. %A Ellinor, P. T. %A Alonso, A. %A Benjamin, E. J. %X Atrial fibrillation (AF) has a substantial genetic basis. Identification of individuals at greatest AF risk could minimize the incidence of cardioembolic stroke.\ To determine whether genetic data can stratify risk for development of AF, we examined associations between AF genetic risk scores and incident AF in 5 prospective studies comprising 18 919 individuals of European ancestry. We examined associations between AF genetic risk scores and ischemic stroke in a separate study of 509 ischemic stroke cases (202 cardioembolic [40%]) and 3028 referents. Scores were based on 11 to 719 common variants (≥5%) associated with AF at P values ranging from <1×10-3 to <1×10-8 in a prior independent genetic association study.\ Incident AF occurred in 1032 individuals (5.5%). AF genetic risk scores were associated with new-onset AF after adjustment for clinical risk factors. The pooled hazard ratio for incident AF for the highest versus lowest quartile of genetic risk scores ranged from 1.28 (719 variants; 95% confidence interval, 1.13-1.46; P=1.5×10-4) to 1.67 (25 variants; 95% confidence interval, 1.47-1.90; P=9.3×10-15). Discrimination of combined clinical and genetic risk scores varied across studies and scores (maximum C statistic, 0.629-0.811; maximum ΔC statistic from clinical score alone, 0.009-0.017). AF genetic risk was associated with stroke in age- and sex-adjusted models. For example, individuals in the highest versus lowest quartile of a 127-variant score had a 2.49-fold increased odds of cardioembolic stroke (95% confidence interval, 1.39-4.58; P=2.7×10-3). The effect persisted after the exclusion of individuals (n=70) with known AF (odds ratio, 2.25; 95% confidence interval, 1.20-4.40; P=0.01).\ Comprehensive AF genetic risk scores were associated with incident AF beyond associations for clinical AF risk factors but offered small improvements in discrimination. AF genetic risk was also associated with cardioembolic stroke in age- and sex-adjusted analyses. Efforts are warranted to determine whether AF genetic risk may improve identification of subclinical AF or help distinguish between stroke mechanisms. %B Circulation %V 135 %P 1311–1320 %8 Apr %G eng %0 Journal Article %J Diabetes %D 2017 %T Genetically Determined Plasma Lipid Levels and Risk of Diabetic Retinopathy: A Mendelian Randomization Study. %A Sobrin, Lucia %A Chong, Yong He %A Fan, Qiao %A Gan, Alfred %A Stanwyck, Lynn K %A Kaidonis, Georgia %A Craig, Jamie E %A Kim, Jihye %A Liao, Wen-Ling %A Huang, Yu-Chuen %A Lee, Wen-Jane %A Hung, Yi-Jen %A Guo, Xiuqing %A Hai, Yang %A Ipp, Eli %A Pollack, Samuela %A Hancock, Heather %A Price, Alkes %A Penman, Alan %A Mitchell, Paul %A Liew, Gerald %A Smith, Albert V %A Gudnason, Vilmundur %A Tan, Gavin %A Klein, Barbara E K %A Kuo, Jane %A Li, Xiaohui %A Christiansen, Mark W %A Psaty, Bruce M %A Sandow, Kevin %A Jensen, Richard A %A Klein, Ronald %A Cotch, Mary Frances %A Wang, Jie Jin %A Jia, Yucheng %A Chen, Ching J %A Chen, Yii-Der Ida %A Rotter, Jerome I %A Tsai, Fuu-Jen %A Hanis, Craig L %A Burdon, Kathryn P %A Wong, Tien Yin %A Cheng, Ching-Yu %K Aged %K Diabetic Retinopathy %K Female %K Genome-Wide Association Study %K Humans %K Lipids %K Male %K Mendelian Randomization Analysis %K Middle Aged %K Polymorphism, Single Nucleotide %K Risk %X

Results from observational studies examining dyslipidemia as a risk factor for diabetic retinopathy (DR) have been inconsistent. We evaluated the causal relationship between plasma lipids and DR using a Mendelian randomization approach. We pooled genome-wide association studies summary statistics from 18 studies for two DR phenotypes: any DR (N = 2,969 case and 4,096 control subjects) and severe DR (N = 1,277 case and 3,980 control subjects). Previously identified lipid-associated single nucleotide polymorphisms served as instrumental variables. Meta-analysis to combine the Mendelian randomization estimates from different cohorts was conducted. There was no statistically significant change in odds ratios of having any DR or severe DR for any of the lipid fractions in the primary analysis that used single nucleotide polymorphisms that did not have a pleiotropic effect on another lipid fraction. Similarly, there was no significant association in the Caucasian and Chinese subgroup analyses. This study did not show evidence of a causal role of the four lipid fractions on DR. However, the study had limited power to detect odds ratios less than 1.23 per SD in genetically induced increase in plasma lipid levels, thus we cannot exclude that causal relationships with more modest effect sizes exist.

%B Diabetes %V 66 %P 3130-3141 %8 2017 12 %G eng %N 12 %R 10.2337/db17-0398 %0 Journal Article %J Nat Genet %D 2017 %T {Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk %A Warren, H. R. %A Evangelou, E. %A Cabrera, C. P. %A Gao, H. %A Ren, M. %A Mifsud, B. %A Ntalla, I. %A Surendran, P. %A Liu, C. %A Cook, J. P. %A Kraja, A. T. %A Drenos, F. %A Loh, M. %A Verweij, N. %A Marten, J. %A Karaman, I. %A Lepe, M. P. %A O'Reilly, P. F. %A Knight, J. %A Snieder, H. %A Kato, N. %A He, J. %A Tai, E. S. %A Said, M. A. %A Porteous, D. %A Alver, M. %A Poulter, N. %A Farrall, M. %A Gansevoort, R. T. %A Padmanabhan, S. %A M?gi, R. %A Stanton, A. %A Connell, J. %A Bakker, S. J. %A Metspalu, A. %A Shields, D. C. %A Thom, S. %A Brown, M. %A Sever, P. %A Esko, T. %A Hayward, C. %A van der Harst, P. %A Saleheen, D. %A Chowdhury, R. %A Chambers, J. C. %A Chasman, D. I. %A Chakravarti, A. %A Newton-Cheh, C. %A Lindgren, C. M. %A Levy, D. %A Kooner, J. S. %A Keavney, B. %A Tomaszewski, M. %A Samani, N. J. %A Howson, J. M. %A Tobin, M. D. %A Munroe, P. B. %A Ehret, G. B. %A Wain, L. V. %A V?lker, U. %A Vollenweider, P. %A Wild, S. %A Willemsen, G. %A Wright, A. F. %A Yao, J. %A Th?riault, S. %A Conen, D. %A John, A. %A Sever, P. %A Debette, S. %A Mook-Kanamori, D. O. %A Zeggini, E. %A Spector, T. D. %A van der Harst, P. %A Palmer, C. N. %A Vergnaud, A. C. %A Loos, R. J. %A Polasek, O. %A Starr, J. M. %A Girotto, G. %A Hayward, C. %A Kooner, J. S. %A Lindgren, C. M. %A Vitart, V. %A Samani, N. J. %A Tuomilehto, J. %A Gyllensten, U. %A Knekt, P. %A Deary, I. J. %A Ciullo, M. %A Elosua, R. %A Keavney, B. D. %A Hicks, A. A. %A Scott, R. A. %A Gasparini, P. %A Laan, M. %A Liu, Y. %A Watkins, H. %A Hartman, C. A. %A Salomaa, V. %A Toniolo, D. %A Perola, M. %A Wilson, J. F. %A Schmidt, H. %A Zhao, J. H. %A Lehtim?ki, T. %A van Duijn, C. M. %A Gudnason, V. %A Psaty, B. M. %A Peters, A. %A Rettig, R. %A James, A. %A Jukema, J. W. %A Strachan, D. P. %A Palmas, W. %A Metspalu, A. %A Ingelsson, E. %A Boomsma, D. I. %A Franco, O. H. %A Bochud, M. %A Newton-Cheh, C. %A Munroe, P. B. %A Elliott, P. %A Chasman, D. I. %A Chakravarti, A. %A Knight, J. %A Morris, A. P. %A Levy, D. %A Tobin, M. D. %A Snieder, H. %A Caulfield, M. J. %A Ehret, G. B. %A Barnes, M. R. %A Tzoulaki, I. %A Caulfield, M. J. %A Elliott, P. %X Elevated blood pressure is the leading heritable risk factor for cardiovascular disease worldwide. We report genetic association of blood pressure (systolic, diastolic, pulse pressure) among UK Biobank participants of European ancestry with independent replication in other cohorts, and robust validation of 107 independent loci. We also identify new independent variants at 11 previously reported blood pressure loci. In combination with results from a range of in silico functional analyses and wet bench experiments, our findings highlight new biological pathways for blood pressure regulation enriched for genes expressed in vascular tissues and identify potential therapeutic targets for hypertension. Results from genetic risk score models raise the possibility of a precision medicine approach through early lifestyle intervention to offset the impact of blood pressure-raising genetic variants on future cardiovascular disease risk. %B Nat Genet %V 49 %P 403–415 %8 Mar %G eng %0 Journal Article %J PLoS One %D 2017 %T Genome-wide association meta-analysis of fish and EPA+DHA consumption in 17 US and European cohorts. %A Mozaffarian, Dariush %A Dashti, Hassan S %A Wojczynski, Mary K %A Chu, Audrey Y %A Nettleton, Jennifer A %A Männistö, Satu %A Kristiansson, Kati %A Reedik, Mägi %A Lahti, Jari %A Houston, Denise K %A Cornelis, Marilyn C %A van Rooij, Frank J A %A Dimitriou, Maria %A Kanoni, Stavroula %A Mikkilä, Vera %A Steffen, Lyn M %A de Oliveira Otto, Marcia C %A Qi, Lu %A Psaty, Bruce %A Djoussé, Luc %A Rotter, Jerome I %A Harald, Kennet %A Perola, Markus %A Rissanen, Harri %A Jula, Antti %A Krista, Fischer %A Mihailov, Evelin %A Feitosa, Mary F %A Ngwa, Julius S %A Xue, Luting %A Jacques, Paul F %A Perälä, Mia-Maria %A Palotie, Aarno %A Liu, Yongmei %A Nalls, Nike A %A Ferrucci, Luigi %A Hernandez, Dena %A Manichaikul, Ani %A Tsai, Michael Y %A Kiefte-de Jong, Jessica C %A Hofman, Albert %A Uitterlinden, André G %A Rallidis, Loukianos %A Ridker, Paul M %A Rose, Lynda M %A Buring, Julie E %A Lehtimäki, Terho %A Kähönen, Mika %A Viikari, Jorma %A Lemaitre, Rozenn %A Salomaa, Veikko %A Knekt, Paul %A Metspalu, Andres %A Borecki, Ingrid B %A Cupples, L Adrienne %A Eriksson, Johan G %A Kritchevsky, Stephen B %A Bandinelli, Stefania %A Siscovick, David %A Franco, Oscar H %A Deloukas, Panos %A Dedoussis, George %A Chasman, Daniel I %A Raitakari, Olli %A Tanaka, Toshiko %K Adult %K Aged %K Cohort Studies %K Docosahexaenoic Acids %K Eicosapentaenoic Acid %K Europe %K European Continental Ancestry Group %K Female %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Seafood %K United States %X

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

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

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

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

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

%B PLoS One %V 12 %P e0186456 %8 2017 %G eng %N 12 %R 10.1371/journal.pone.0186456 %0 Journal Article %J Circ Cardiovasc Genet %D 2017 %T Genome-Wide Association Study Meta-Analysis of Long-Term Average Blood Pressure in East Asians. %A Li, Changwei %A Kim, Yun Kyoung %A Dorajoo, Rajkumar %A Li, Huaixing %A Lee, I-Te %A Cheng, Ching-Yu %A He, Meian %A Sheu, Wayne H-H %A Guo, Xiuqing %A Ganesh, Santhi K %A He, Jiang %A Lee, Juyoung %A Liu, Jianjun %A Hu, Yao %A Rao, Dabeeru C %A Tsai, Fuu-Jen %A Koh, Jia Yu %A Hu, Hua %A Liang, Kae-Woei %A Palmas, Walter %A Hixson, James E %A Han, Sohee %A Teo, Yik-Ying %A Wang, Yiqin %A Chen, Jing %A Lu, Chieh Hsiang %A Zheng, Yingfeng %A Gui, Lixuan %A Lee, Wen-Jane %A Yao, Jie %A Gu, Dongfeng %A Han, Bok-Ghee %A Sim, Xueling %A Sun, Liang %A Zhao, Jinying %A Chen, Chien-Hsiun %A Kumari, Neelam %A He, Yunfeng %A Taylor, Kent D %A Raffel, Leslie J %A Moon, Sanghoon %A Rotter, Jerome I %A Ida Chen, Yii-Der %A Wu, Tangchun %A Wong, Tien Yin %A Wu, Jer-Yuarn %A Lin, Xu %A Tai, E-Shyong %A Kim, Bong-Jo %A Kelly, Tanika N %K Asian Continental Ancestry Group %K Blood Pressure %K Far East %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Male %K Phenotype %K Polymorphism, Single Nucleotide %X

BACKGROUND: Genome-wide single marker and gene-based meta-analyses of long-term average (LTA) blood pressure (BP) phenotypes may reveal novel findings for BP.

METHODS AND RESULTS: We conducted genome-wide analysis among 18 422 East Asian participants (stage 1) followed by replication study of ≤46 629 participants of European ancestry (stage 2). Significant single-nucleotide polymorphisms and genes were determined by a P<5.0×10-8 and 2.5×10-6, respectively, in joint analyses of stage-1 and stage-2 data. We identified 1 novel ARL3 variant, rs4919669 at 10q24.32, influencing LTA systolic BP (stage-1 P=5.03×10-8, stage-2 P=8.64×10-3, joint P=2.63×10-8) and mean arterial pressure (stage-1 P=3.59×10-9, stage-2 P=2.35×10-2, joint P=2.64×10-8). Three previously reported BP loci (WBP1L, NT5C2, and ATP2B1) were also identified for all BP phenotypes. Gene-based analysis provided the first robust evidence for association of KCNJ11 with LTA systolic BP (stage-1 P=8.55×10-6, stage-2 P=1.62×10-5, joint P=3.28×10-9) and mean arterial pressure (stage-1 P=9.19×10-7, stage-2 P=9.69×10-5, joint P=2.15×10-9) phenotypes. Fourteen genes (TMEM180, ACTR1A, SUFU, ARL3, SFXN2, WBP1L, CYP17A1, C10orf32, C10orf32-ASMT, AS3MT, CNNM2, and NT5C2 at 10q24.32; ATP2B1 at 12q21.33; and NCR3LG1 at 11p15.1) implicated by previous genome-wide association study meta-analyses were also identified. Among the loci identified by the previous genome-wide association study meta-analysis of LTA BP, we transethnically replicated associations of the KCNK3 marker rs1275988 at 2p23.3 with LTA systolic BP and mean arterial pressure phenotypes (P=1.27×10-4 and 3.30×10-4, respectively).

CONCLUSIONS: We identified 1 novel variant and 1 novel gene and present the first direct evidence of relevance of the KCNK3 locus for LTA BP among East Asians.

%B Circ Cardiovasc Genet %V 10 %P e001527 %8 2017 Apr %G eng %N 2 %R 10.1161/CIRCGENETICS.116.001527 %0 Journal Article %J J Med Genet %D 2017 %T A genome-wide interaction analysis of tricyclic/tetracyclic antidepressants and RR and QT intervals: a pharmacogenomics study from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. %A Noordam, Raymond %A Sitlani, Colleen M %A Avery, Christy L %A Stewart, James D %A Gogarten, Stephanie M %A Wiggins, Kerri L %A Trompet, Stella %A Warren, Helen R %A Sun, Fangui %A Evans, Daniel S %A Li, Xiaohui %A Li, Jin %A Smith, Albert V %A Bis, Joshua C %A Brody, Jennifer A %A Busch, Evan L %A Caulfield, Mark J %A Chen, Yii-der I %A Cummings, Steven R %A Cupples, L Adrienne %A Duan, Qing %A Franco, Oscar H %A Méndez-Giráldez, Rául %A Harris, Tamara B %A Heckbert, Susan R %A van Heemst, Diana %A Hofman, Albert %A Floyd, James S %A Kors, Jan A %A Launer, Lenore J %A Li, Yun %A Li-Gao, Ruifang %A Lange, Leslie A %A Lin, Henry J %A de Mutsert, Renée %A Napier, Melanie D %A Newton-Cheh, Christopher %A Poulter, Neil %A Reiner, Alexander P %A Rice, Kenneth M %A Roach, Jeffrey %A Rodriguez, Carlos J %A Rosendaal, Frits R %A Sattar, Naveed %A Sever, Peter %A Seyerle, Amanda A %A Slagboom, P Eline %A Soliman, Elsayed Z %A Sotoodehnia, Nona %A Stott, David J %A Stürmer, Til %A Taylor, Kent D %A Thornton, Timothy A %A Uitterlinden, André G %A Wilhelmsen, Kirk C %A Wilson, James G %A Gudnason, Vilmundur %A Jukema, J Wouter %A Laurie, Cathy C %A Liu, Yongmei %A Mook-Kanamori, Dennis O %A Munroe, Patricia B %A Rotter, Jerome I %A Vasan, Ramachandran S %A Psaty, Bruce M %A Stricker, Bruno H %A Whitsel, Eric A %X

BACKGROUND: Increased heart rate and a prolonged QT interval are important risk factors for cardiovascular morbidity and mortality, and can be influenced by the use of various medications, including tricyclic/tetracyclic antidepressants (TCAs). We aim to identify genetic loci that modify the association between TCA use and RR and QT intervals.

METHODS AND RESULTS: We conducted race/ethnic-specific genome-wide interaction analyses (with HapMap phase II imputed reference panel imputation) of TCAs and resting RR and QT intervals in cohorts of European (n=45 706; n=1417 TCA users), African (n=10 235; n=296 TCA users) and Hispanic/Latino (n=13 808; n=147 TCA users) ancestry, adjusted for clinical covariates. Among the populations of European ancestry, two genome-wide significant loci were identified for RR interval: rs6737205 in BRE (β=56.3, pinteraction=3.9e(-9)) and rs9830388 in UBE2E2 (β=25.2, pinteraction=1.7e(-8)). In Hispanic/Latino cohorts, rs2291477 in TGFBR3 significantly modified the association between TCAs and QT intervals (β=9.3, pinteraction=2.55e(-8)). In the meta-analyses of the other ethnicities, these loci either were excluded from the meta-analyses (as part of quality control), or their effects did not reach the level of nominal statistical significance (pinteraction>0.05). No new variants were identified in these ethnicities. No additional loci were identified after inverse-variance-weighted meta-analysis of the three ancestries.

CONCLUSIONS: Among Europeans, TCA interactions with variants in BRE and UBE2E2 were identified in relation to RR intervals. Among Hispanic/Latinos, variants in TGFBR3 modified the relation between TCAs and QT intervals. Future studies are required to confirm our results.

%B J Med Genet %V 54 %P 313-323 %8 2017 May %G eng %N 5 %R 10.1136/jmedgenet-2016-104112 %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 Nat Commun %D 2017 %T Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity. %A Joshi, Peter K %A Pirastu, Nicola %A Kentistou, Katherine A %A Fischer, Krista %A Hofer, Edith %A Schraut, Katharina E %A Clark, David W %A Nutile, Teresa %A Barnes, Catriona L K %A Timmers, Paul R H J %A Shen, Xia %A Gandin, Ilaria %A McDaid, Aaron F %A Hansen, Thomas Folkmann %A Gordon, Scott D %A Giulianini, Franco %A Boutin, Thibaud S %A Abdellaoui, Abdel %A Zhao, Wei %A Medina-Gómez, Carolina %A Bartz, Traci M %A Trompet, Stella %A Lange, Leslie A %A Raffield, Laura %A van der Spek, Ashley %A Galesloot, Tessel E %A Proitsi, Petroula %A Yanek, Lisa R %A Bielak, Lawrence F %A Payton, Antony %A Murgia, Federico %A Concas, Maria Pina %A Biino, Ginevra %A Tajuddin, Salman M %A Seppälä, Ilkka %A Amin, Najaf %A Boerwinkle, Eric %A Børglum, Anders D %A Campbell, Archie %A Demerath, Ellen W %A Demuth, Ilja %A Faul, Jessica D %A Ford, Ian %A Gialluisi, Alessandro %A Gögele, Martin %A Graff, Mariaelisa %A Hingorani, Aroon %A Hottenga, Jouke-Jan %A Hougaard, David M %A Hurme, Mikko A %A Ikram, M Arfan %A Jylhä, Marja %A Kuh, Diana %A Ligthart, Lannie %A Lill, Christina M %A Lindenberger, Ulman %A Lumley, Thomas %A Mägi, Reedik %A Marques-Vidal, Pedro %A Medland, Sarah E %A Milani, Lili %A Nagy, Reka %A Ollier, William E R %A Peyser, Patricia A %A Pramstaller, Peter P %A Ridker, Paul M %A Rivadeneira, Fernando %A Ruggiero, Daniela %A Saba, Yasaman %A Schmidt, Reinhold %A Schmidt, Helena %A Slagboom, P Eline %A Smith, Blair H %A Smith, Jennifer A %A Sotoodehnia, Nona %A Steinhagen-Thiessen, Elisabeth %A van Rooij, Frank J A %A Verbeek, André L %A Vermeulen, Sita H %A Vollenweider, Peter %A Wang, Yunpeng %A Werge, Thomas %A Whitfield, John B %A Zonderman, Alan B %A Lehtimäki, Terho %A Evans, Michele K %A Pirastu, Mario %A Fuchsberger, Christian %A Bertram, Lars %A Pendleton, Neil %A Kardia, Sharon L R %A Ciullo, Marina %A Becker, Diane M %A Wong, Andrew %A Psaty, Bruce M %A van Duijn, Cornelia M %A Wilson, James G %A Jukema, J Wouter %A Kiemeney, Lambertus %A Uitterlinden, André G %A Franceschini, Nora %A North, Kari E %A Weir, David R %A Metspalu, Andres %A Boomsma, Dorret I %A Hayward, Caroline %A Chasman, Daniel %A Martin, Nicholas G %A Sattar, Naveed %A Campbell, Harry %A Esko, Tõnu %A Kutalik, Zoltán %A Wilson, James F %X

Genomic analysis of longevity offers the potential to illuminate the biology of human aging. Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA). We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity. Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated. We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD. Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan.Variability in human longevity is genetically influenced. Using genetic data of parental lifespan, the authors identify associations at HLA-DQA/DRB1 and LPA and find that genetic variants that increase educational attainment have a positive effect on lifespan whereas increasing BMI negatively affects lifespan.

%B Nat Commun %V 8 %P 910 %8 2017 Oct 13 %G eng %N 1 %R 10.1038/s41467-017-00934-5 %0 Journal Article %J Nat Commun %D 2017 %T {Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits %A Justice, A. E. %A Winkler, T. W. %A Feitosa, M. F. %A Graff, M. %A Fisher, V. A. %A Young, K. %A Barata, L. %A Deng, X. %A Czajkowski, J. %A Hadley, D. %A Ngwa, J. S. %A Ahluwalia, T. S. %A Chu, A. Y. %A Heard-Costa, N. L. %A Lim, E. %A Perez, J. %A Eicher, J. D. %A Kutalik, Z. %A Xue, L. %A Mahajan, A. %A Renstr?m, F. %A Wu, J. %A Qi, Q. %A Ahmad, S. %A Alfred, T. %A Amin, N. %A Bielak, L. F. %A Bonnefond, A. %A Bragg, J. %A Cadby, G. %A Chittani, M. %A Coggeshall, S. %A Corre, T. %A Direk, N. %A Eriksson, J. %A Fischer, K. %A Gorski, M. %A Neergaard Harder, M. %A Horikoshi, M. %A Huang, T. %A Huffman, J. E. %A Jackson, A. U. %A Justesen, J. M. %A Kanoni, S. %A Kinnunen, L. %A Kleber, M. E. %A Komulainen, P. %A Kumari, M. %A Lim, U. %A Luan, J. %A Lyytik?inen, L. P. %A Mangino, M. %A Manichaikul, A. %A Marten, J. %A Middelberg, R. P. S. %A M?ller-Nurasyid, M. %A Navarro, P. %A P?russe, L. %A Pervjakova, N. %A Sarti, C. %A Smith, A. V. %A Smith, J. A. %A Stan??kov?, A. %A Strawbridge, R. J. %A Stringham, H. M. %A Sung, Y. J. %A Tanaka, T. %A Teumer, A. %A Trompet, S. %A van der Laan, S. W. %A van der Most, P. J. %A Van Vliet-Ostaptchouk, J. V. %A Vedantam, S. L. %A Verweij, N. %A Vink, J. M. %A Vitart, V. %A Wu, Y. %A Yengo, L. %A Zhang, W. %A Hua Zhao, J. %A Zimmermann, M. E. %A Zubair, N. %A Abecasis, G. R. %A Adair, L. S. %A Afaq, S. %A Afzal, U. %A Bakker, S. J. L. %A Bartz, T. M. %A Beilby, J. %A Bergman, R. N. %A Bergmann, S. %A Biffar, R. %A Blangero, J. %A Boerwinkle, E. %A Bonnycastle, L. L. %A Bottinger, E. %A Braga, D. %A Buckley, B. M. %A Buyske, S. %A Campbell, H. %A Chambers, J. C. %A Collins, F. S. %A Curran, J. E. %A de Borst, G. J. %A de Craen, A. J. M. %A de Geus, E. J. C. %A Dedoussis, G. %A Delgado, G. E. %A den Ruijter, H. M. %A Eiriksdottir, G. %A Eriksson, A. L. %A Esko, T. %A Faul, J. D. %A Ford, I. %A Forrester, T. %A Gertow, K. %A Gigante, B. %A Glorioso, N. %A Gong, J. %A Grallert, H. %A Grammer, T. B. %A Grarup, N. %A Haitjema, S. %A Hallmans, G. %A Hamsten, A. %A Hansen, T. %A Harris, T. B. %A Hartman, C. A. %A Hassinen, M. %A Hastie, N. D. %A Heath, A. C. %A Hernandez, D. %A Hindorff, L. %A Hocking, L. J. %A Hollensted, M. %A Holmen, O. L. %A Homuth, G. %A Jan Hottenga, J. %A Huang, J. %A Hung, J. %A Hutri-K?h?nen, N. %A Ingelsson, E. %A James, A. L. %A Jansson, J. O. %A Jarvelin, M. R. %A Jhun, M. A. %A J?rgensen, M. E. %A Juonala, M. %A K?h?nen, M. %A Karlsson, M. %A Koistinen, H. A. %A Kolcic, I. %A Kolovou, G. %A Kooperberg, C. %A Kr?mer, B. K. %A Kuusisto, J. %A Kval?y, K. %A Lakka, T. A. %A Langenberg, C. %A Launer, L. J. %A Leander, K. %A Lee, N. R. %A Lind, L. %A Lindgren, C. M. %A Linneberg, A. %A Lobbens, S. %A Loh, M. %A Lorentzon, M. %A Luben, R. %A Lubke, G. %A Ludolph-Donislawski, A. %A Lupoli, S. %A Madden, P. A. F. %A M?nnikk?, R. %A Marques-Vidal, P. %A Martin, N. G. %A McKenzie, C. A. %A McKnight, B. %A Mellstr?m, D. %A Menni, C. %A Montgomery, G. W. %A Musk, A. B. %A Narisu, N. %A Nauck, M. %A Nolte, I. M. %A Oldehinkel, A. J. %A Olden, M. %A Ong, K. K. %A Padmanabhan, S. %A Peyser, P. A. %A Pisinger, C. %A Porteous, D. J. %A Raitakari, O. T. %A Rankinen, T. %A Rao, D. C. %A Rasmussen-Torvik, L. J. %A Rawal, R. %A Rice, T. %A Ridker, P. M. %A Rose, L. M. %A Bien, S. A. %A Rudan, I. %A Sanna, S. %A Sarzynski, M. A. %A Sattar, N. %A Savonen, K. %A Schlessinger, D. %A Scholtens, S. %A Schurmann, C. %A Scott, R. A. %A Sennblad, B. %A Siemelink, M. A. %A Silbernagel, G. %A Slagboom, P. E. %A Snieder, H. %A Staessen, J. A. %A Stott, D. J. %A Swertz, M. A. %A Swift, A. J. %A Taylor, K. D. %A Tayo, B. O. %A Thorand, B. %A Thuillier, D. %A Tuomilehto, J. %A Uitterlinden, A. G. %A Vandenput, L. %A Vohl, M. C. %A V?lzke, H. %A Vonk, J. M. %A Waeber, G. %A Waldenberger, M. %A Westendorp, R. G. J. %A Wild, S. %A Willemsen, G. %A Wolffenbuttel, B. H. R. %A Wong, A. %A Wright, A. F. %A Zhao, W. %A Zillikens, M. C. %A Baldassarre, D. %A Balkau, B. %A Bandinelli, S. %A B?ger, C. A. %A Boomsma, D. I. %A Bouchard, C. %A Bruinenberg, M. %A Chasman, D. I. %A Chen, Y. D. %A Chines, P. S. %A Cooper, R. S. %A Cucca, F. %A Cusi, D. %A Faire, U. %A Ferrucci, L. %A Franks, P. W. %A Froguel, P. %A Gordon-Larsen, P. %A Grabe, H. J. %A Gudnason, V. %A Haiman, C. A. %A Hayward, C. %A Hveem, K. %A Johnson, A. D. %A Wouter Jukema, J. %A Kardia, S. L. R. %A Kivimaki, M. %A Kooner, J. S. %A Kuh, D. %A Laakso, M. %A Lehtim?ki, T. %A Marchand, L. L. %A M?rz, W. %A McCarthy, M. I. %A Metspalu, A. %A Morris, A. P. %A Ohlsson, C. %A Palmer, L. J. %A Pasterkamp, G. %A Pedersen, O. %A Peters, A. %A Peters, U. %A Polasek, O. %A Psaty, B. M. %A Qi, L. %A Rauramaa, R. %A Smith, B. H. %A S?rensen, T. I. A. %A Strauch, K. %A Tiemeier, H. %A Tremoli, E. %A van der Harst, P. %A Vestergaard, H. %A Vollenweider, P. %A Wareham, N. J. %A Weir, D. R. %A Whitfield, J. B. %A Wilson, J. F. %A Tyrrell, J. %A Frayling, T. M. %A Barroso, I. %A Boehnke, M. %A Deloukas, P. %A Fox, C. S. %A Hirschhorn, J. N. %A Hunter, D. J. %A Spector, T. D. %A Strachan, D. P. %A van Duijn, C. M. %A Heid, I. M. %A Mohlke, K. L. %A Marchini, J. %A Loos, R. J. F. %A Kilpel?inen, T. O. %A Liu, C. T. %A Borecki, I. B. %A North, K. E. %A Cupples, L. A. %X Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution. %B Nat Commun %V 8 %P 14977 %8 04 %G eng %0 Journal Article %J Am J Hum Genet %D 2017 %T Genome-wide Trans-ethnic Meta-analysis Identifies Seven Genetic Loci Influencing Erythrocyte Traits and a Role for RBPMS in Erythropoiesis. %A van Rooij, Frank J A %A Qayyum, Rehan %A Smith, Albert V %A Zhou, Yi %A Trompet, Stella %A Tanaka, Toshiko %A Keller, Margaux F %A Chang, Li-Ching %A Schmidt, Helena %A Yang, Min-Lee %A Chen, Ming-Huei %A Hayes, James %A Johnson, Andrew D %A Yanek, Lisa R %A Mueller, Christian %A Lange, Leslie %A Floyd, James S %A Ghanbari, Mohsen %A Zonderman, Alan B %A Jukema, J Wouter %A Hofman, Albert %A van Duijn, Cornelia M %A Desch, Karl C %A Saba, Yasaman %A Ozel, Ayse B %A Snively, Beverly M %A Wu, Jer-Yuarn %A Schmidt, Reinhold %A Fornage, Myriam %A Klein, Robert J %A Fox, Caroline S %A Matsuda, Koichi %A Kamatani, Naoyuki %A Wild, Philipp S %A Stott, David J %A Ford, Ian %A Slagboom, P Eline %A Yang, Jaden %A Chu, Audrey Y %A Lambert, Amy J %A Uitterlinden, André G %A Franco, Oscar H %A Hofer, Edith %A Ginsburg, David %A Hu, Bella %A Keating, Brendan %A Schick, Ursula M %A Brody, Jennifer A %A Li, Jun Z %A Chen, Zhao %A Zeller, Tanja %A Guralnik, Jack M %A Chasman, Daniel I %A Peters, Luanne L %A Kubo, Michiaki %A Becker, Diane M %A Li, Jin %A Eiriksdottir, Gudny %A Rotter, Jerome I %A Levy, Daniel %A Grossmann, Vera %A Patel, Kushang V %A Chen, Chien-Hsiun %A Ridker, Paul M %A Tang, Hua %A Launer, Lenore J %A Rice, Kenneth M %A Li-Gao, Ruifang %A Ferrucci, Luigi %A Evans, Michelle K %A Choudhuri, Avik %A Trompouki, Eirini %A Abraham, Brian J %A Yang, Song %A Takahashi, Atsushi %A Kamatani, Yoichiro %A Kooperberg, Charles %A Harris, Tamara B %A Jee, Sun Ha %A Coresh, Josef %A Tsai, Fuu-Jen %A Longo, Dan L %A Chen, Yuan-Tsong %A Felix, Janine F %A Yang, Qiong %A Psaty, Bruce M %A Boerwinkle, Eric %A Becker, Lewis C %A Mook-Kanamori, Dennis O %A Wilson, James G %A Gudnason, Vilmundur %A O'Donnell, Christopher J %A Dehghan, Abbas %A Cupples, L Adrienne %A Nalls, Michael A %A Morris, Andrew P %A Okada, Yukinori %A Reiner, Alexander P %A Zon, Leonard I %A Ganesh, Santhi K %X

Genome-wide association studies (GWASs) have identified loci for erythrocyte traits in primarily European ancestry populations. We conducted GWAS meta-analyses of six erythrocyte traits in 71,638 individuals from European, East Asian, and African ancestries using a Bayesian approach to account for heterogeneity in allelic effects and variation in the structure of linkage disequilibrium between ethnicities. We identified seven loci for erythrocyte traits including a locus (RBPMS/GTF2E2) associated with mean corpuscular hemoglobin and mean corpuscular volume. Statistical fine-mapping at this locus pointed to RBPMS at this locus and excluded nearby GTF2E2. Using zebrafish morpholino to evaluate loss of function, we observed a strong in vivo erythropoietic effect for RBPMS but not for GTF2E2, supporting the statistical fine-mapping at this locus and demonstrating that RBPMS is a regulator of erythropoiesis. Our findings show the utility of trans-ethnic GWASs for discovery and characterization of genetic loci influencing hematologic traits.

%B Am J Hum Genet %V 100 %P 51-63 %8 2017 Jan 05 %G eng %N 1 %R 10.1016/j.ajhg.2016.11.016 %0 Journal Article %J Sci Adv %D 2017 %T The GH receptor exon 3 deletion is a marker of male-specific exceptional longevity associated with increased GH sensitivity and taller stature. %A Ben-Avraham, Danny %A Govindaraju, Diddahally R %A Budagov, Temuri %A Fradin, Delphine %A Durda, Peter %A Liu, Bing %A Ott, Sandy %A Gutman, Danielle %A Sharvit, Lital %A Kaplan, Robert %A Bougnères, Pierre %A Reiner, Alex %A Shuldiner, Alan R %A Cohen, Pinchas %A Barzilai, Nir %A Atzmon, Gil %X

Although both growth hormone (GH) and insulin-like growth factor 1 (IGF-1) signaling were shown to regulate life span in lower organisms, the role of GH signaling in human longevity remains unclear. Because a GH receptor exon 3 deletion (d3-GHR) appears to modulate GH sensitivity in humans, we hypothesized that this polymorphism could play a role in human longevity. We report a linear increased prevalence of d3-GHR homozygosity with age in four independent cohorts of long-lived individuals: 841 participants [567 of the Longevity Genes Project (LGP) (8% increase; P = 0.01), 152 of the Old Order Amish (16% increase; P = 0.02), 61 of the Cardiovascular Health Study (14.2% increase; P = 0.14), and 61 of the French Long-Lived Study (23.5% increase; P = 0.02)]. In addition, mega analysis of males in all cohorts resulted in a significant positive trend with age (26% increase; P = 0.007), suggesting sexual dimorphism for GH action in longevity. Further, on average, LGP d3/d3 homozygotes were 1 inch taller than the wild-type (WT) allele carriers (P = 0.05) and also showed lower serum IGF-1 levels (P = 0.003). Multivariate regression analysis indicated that the presence of d3/d3 genotype adds approximately 10 years to life span. The LGP d3/d3-GHR transformed lymphocytes exhibited superior growth and extracellular signal-regulated kinase activation, to GH treatment relative to WT GHR lymphocytes (P < 0.01), indicating a GH dose response. The d3-GHR variant is a common genetic polymorphism that modulates GH responsiveness throughout the life span and positively affects male longevity.

%B Sci Adv %V 3 %P e1602025 %8 2017 Jun %G eng %N 6 %R 10.1126/sciadv.1602025 %0 Journal Article %J Exp Gerontol %D 2017 %T Hidden heterogeneity in Alzheimer's disease: Insights from genetic association studies and other analyses. %A Yashin, Anatoliy I %A Fang, Fang %A Kovtun, Mikhail %A Wu, Deqing %A Duan, Matt %A Arbeev, Konstantin %A Akushevich, Igor %A Kulminski, Alexander %A Culminskaya, Irina %A Zhbannikov, Ilya %A Yashkin, Arseniy %A Stallard, Eric %A Ukraintseva, Svetlana %X

Despite evident success in clarifying many important features of Alzheimer's disease (AD) the efficient methods of its prevention and treatment are not yet available. The reasons are likely to be the fact that AD is a multifactorial and heterogeneous health disorder with multiple alternative pathways of disease development and progression. The availability of genetic data on individuals participated in longitudinal studies of aging health and longevity, as well as on participants of cross-sectional case-control studies allow for investigating genetic and non-genetic connections with AD and to link the results of these analyses with research findings obtained in clinical, experimental, and molecular biological studies of this health disorder. The objective of this paper is to perform GWAS of AD in several study populations and investigate possible roles of detected genetic factors in developing AD hallmarks and in other health disorders. The data collected in the Framingham Heart Study (FHS), Cardiovascular Health Study (CHS), Health and Retirement Study (HRS) and Late Onset Alzheimer's Disease Family Study (LOADFS) were used in these analyses. The logistic regression and Cox's regression were used as statistical models in GWAS. The results of analyses confirmed strong associations of genetic variants from well-known genes APOE, TOMM40, PVRL2 (NECTIN2), and APOC1 with AD. Possible roles of these genes in pathological mechanisms resulting in development of hallmarks of AD are described. Many genes whose connection with AD was detected in other studies showed nominally significant associations with this health disorder in our study. The evidence on genetic connections between AD and vulnerability to infection, as well as between AD and other health disorders, such as cancer and type 2 diabetes, were investigated. The progress in uncovering hidden heterogeneity in AD would be substantially facilitated if common mechanisms involved in development of AD, its hallmarks, and AD related chronic conditions were investigated in their mutual connection.

%B Exp Gerontol %8 2017 Oct 26 %G eng %R 10.1016/j.exger.2017.10.020 %0 Journal Article %J BMC Nephrol %D 2017 %T Higher plasma transforming growth factor (TGF)-β is associated with kidney disease in older community dwelling adults. %A Mehta, Tapan %A Bůzková, Petra %A Kizer, Jorge R %A Djoussé, Luc %A Chonchol, Michel %A Mukamal, Kenneth J %A Shlipak, Michael %A Ix, Joachim H %A Jalal, Diana %X

BACKGROUND: TGF-β is induced in the vasculature with aging suggesting that high plasma TGF-β levels may be a risk factor for chronic kidney disease (CKD) in older adults.

METHODS: We conducted a cross-sectional analysis of the association between plasma TGF-β levels and CKD including data for 1722 older adults who had participated in the 1996/97 visit of the Cardiovascular Health Study (CHS). Prevalent CKD was defined as eGFR < 60 mL/min/1.73 m(2) or urinary albumin/creatinine ratio (ACR) ≥30 mg/g. We also evaluated whether baseline TGF-β levels predicted change in eGFR, cardiovascular (CV) events, or mortality in longitudinal analysis.

RESULTS: Plasma TGF-β levels were significantly and independently associated with lower eGFR in cross-sectional analysis. Doubling of TGF-β was significantly associated with lower eGFR (β estimate after adjusting for CV risk factors = -1.18, 95% CI -2.03, -0.32). We observed no association with albuminuria. There was no association between baseline TGF-β and change in eGFR, but each doubling of TGF-β at baseline was associated with increased risk of a composite outcome of CV events and mortality, adjusted HR 1.10 (95% C.I. 1.02- 1.20, p = 0.006).

CONCLUSION: In this large cohort of community-dwelling older individuals, high plasma TGF-β levels are modestly, but independently associated with lower eGFR but not with albuminuria in cross-sectional analysis. In addition, TGF-β levels are associated with increased risk of CV events and mortality. Further research is needed to determine the direction of association between plasma TGF-β and the risk of CKD and CKD-associated morbidities in older adults.

%B BMC Nephrol %V 18 %P 98 %8 2017 Mar 21 %G eng %N 1 %R 10.1186/s12882-017-0509-6 %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 Osteoporos Int %D 2017 %T Incident atrial fibrillation and the risk of fracture in the cardiovascular health study. %A Wallace, E R %A Siscovick, D S %A Sitlani, C M %A Dublin, S %A Mitchell, P %A Robbins, J A %A Fink, H A %A Cauley, J A %A Bůžková, P %A Carbone, L %A Chen, Z %A Heckbert, S R %X

In this prospective cohort of 4462 older adults, incident atrial fibrillation (AF) was not statistically significantly associated with subsequent risk of incident fracture.

INTRODUCTION: AF is associated with stroke, heart failure, dementia, and death, but its association with fracture is unknown. Therefore, we examined the association of incident AF with the risk of subsequent fracture in the Cardiovascular Health Study (CHS) cohort.

METHODS: Of the CHS participants aged ≥65 years, 4462 were followed between 1991 and 2009, mean follow-up 8.8 years. Incident AF was identified by annual study electrocardiogram (ECG), hospital discharge diagnosis codes, or Medicare claims. Fractures of the hip, distal forearm, humerus, or pelvis were identified using hospital discharge diagnosis codes or Medicare claims. We used Cox proportional hazard models to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) for the association between incident AF (time-varying) and the risk of subsequent fracture. We also evaluated whether AF was associated with risk of sustaining a fall.

RESULTS: Crude incident fracture rate was 22.9 per 1000 person-years in participants with AF and 17.7 per 1000 person-years in participants without AF. Individuals with incident AF were not at significantly higher risk of hip fracture (adjusted HR = 1.09, 95 % CI 0.83-1.42) or fracture at any selected site (adjusted HR = 0.97, 95 % CI 0.77-1.22) or risk of sustaining a fall (adjusted HR = 1.00, 95 % CI = 0.87-1.16) compared with those without AF.

CONCLUSION: In this cohort of older, community-dwelling adults, incident AF was not shown to be associated with falls or hip or other fractures.

%B Osteoporos Int %V 28 %P 719-725 %8 2017 Feb %G eng %N 2 %R 10.1007/s00198-016-3778-1 %0 Journal Article %J Nat Commun %D 2017 %T Large meta-analysis of genome-wide association studies identifies five loci for lean body mass. %A Zillikens, M Carola %A Demissie, Serkalem %A Hsu, Yi-Hsiang %A Yerges-Armstrong, Laura M %A Chou, Wen-Chi %A Stolk, Lisette %A Livshits, Gregory %A Broer, Linda %A Johnson, Toby %A Koller, Daniel L %A Kutalik, Zoltán %A Luan, Jian'an %A Malkin, Ida %A Ried, Janina S %A Smith, Albert V %A Thorleifsson, Gudmar %A Vandenput, Liesbeth %A Hua Zhao, Jing %A Zhang, Weihua %A Aghdassi, Ali %A Åkesson, Kristina %A Amin, Najaf %A Baier, Leslie J %A Barroso, Inês %A Bennett, David A %A Bertram, Lars %A Biffar, Rainer %A Bochud, Murielle %A Boehnke, Michael %A Borecki, Ingrid B %A Buchman, Aron S %A Byberg, Liisa %A Campbell, Harry %A Campos Obanda, Natalia %A Cauley, Jane A %A Cawthon, Peggy M %A Cederberg, Henna %A Chen, Zhao %A Cho, Nam H %A Jin Choi, Hyung %A Claussnitzer, Melina %A Collins, Francis %A Cummings, Steven R %A De Jager, Philip L %A Demuth, Ilja %A Dhonukshe-Rutten, Rosalie A M %A Diatchenko, Luda %A Eiriksdottir, Gudny %A Enneman, Anke W %A Erdos, Mike %A Eriksson, Johan G %A Eriksson, Joel %A Estrada, Karol %A Evans, Daniel S %A Feitosa, Mary F %A Fu, Mao %A Garcia, Melissa %A Gieger, Christian %A Girke, Thomas %A Glazer, Nicole L %A Grallert, Harald %A Grewal, Jagvir %A Han, Bok-Ghee %A Hanson, Robert L %A Hayward, Caroline %A Hofman, Albert %A Hoffman, Eric P %A Homuth, Georg %A Hsueh, Wen-Chi %A Hubal, Monica J %A Hubbard, Alan %A Huffman, Kim M %A Husted, Lise B %A Illig, Thomas %A Ingelsson, Erik %A Ittermann, Till %A Jansson, John-Olov %A Jordan, Joanne M %A Jula, Antti %A Karlsson, Magnus %A Khaw, Kay-Tee %A Kilpeläinen, Tuomas O %A Klopp, Norman %A Kloth, Jacqueline S L %A Koistinen, Heikki A %A Kraus, William E %A Kritchevsky, Stephen %A Kuulasmaa, Teemu %A Kuusisto, Johanna %A Laakso, Markku %A Lahti, Jari %A Lang, Thomas %A Langdahl, Bente L %A Launer, Lenore J %A Lee, Jong-Young %A Lerch, Markus M %A Lewis, Joshua R %A Lind, Lars %A Lindgren, Cecilia %A Liu, Yongmei %A Liu, Tian %A Liu, Youfang %A Ljunggren, Osten %A Lorentzon, Mattias %A Luben, Robert N %A Maixner, William %A McGuigan, Fiona E %A Medina-Gómez, Carolina %A Meitinger, Thomas %A Melhus, Håkan %A Mellström, Dan %A Melov, Simon %A Michaëlsson, Karl %A Mitchell, Braxton D %A Morris, Andrew P %A Mosekilde, Leif %A Newman, Anne %A Nielson, Carrie M %A O'Connell, Jeffrey R %A Oostra, Ben A %A Orwoll, Eric S %A Palotie, Aarno %A Parker, Stephen C J %A Peacock, Munro %A Perola, Markus %A Peters, Annette %A Polasek, Ozren %A Prince, Richard L %A Räikkönen, Katri %A Ralston, Stuart H %A Ripatti, Samuli %A Robbins, John A %A Rotter, Jerome I %A Rudan, Igor %A Salomaa, Veikko %A Satterfield, Suzanne %A Schadt, Eric E %A Schipf, Sabine %A Scott, Laura %A Sehmi, Joban %A Shen, Jian %A Soo Shin, Chan %A Sigurdsson, Gunnar %A Smith, Shad %A Soranzo, Nicole %A Stančáková, Alena %A Steinhagen-Thiessen, Elisabeth %A Streeten, Elizabeth A %A Styrkarsdottir, Unnur %A Swart, Karin M A %A Tan, Sian-Tsung %A Tarnopolsky, Mark A %A Thompson, Patricia %A Thomson, Cynthia A %A Thorsteinsdottir, Unnur %A Tikkanen, Emmi %A Tranah, Gregory J %A Tuomilehto, Jaakko %A van Schoor, Natasja M %A Verma, Arjun %A Vollenweider, Peter %A Völzke, Henry %A Wactawski-Wende, Jean %A Walker, Mark %A Weedon, Michael N %A Welch, Ryan %A Wichmann, H-Erich %A Widen, Elisabeth %A Williams, Frances M K %A Wilson, James F %A Wright, Nicole C %A Xie, Weijia %A Yu, Lei %A Zhou, Yanhua %A Chambers, John C %A Döring, Angela %A van Duijn, Cornelia M %A Econs, Michael J %A Gudnason, Vilmundur %A Kooner, Jaspal S %A Psaty, Bruce M %A Spector, Timothy D %A Stefansson, Kari %A Rivadeneira, Fernando %A Uitterlinden, André G %A Wareham, Nicholas J %A Ossowski, Vicky %A Waterworth, Dawn %A Loos, Ruth J F %A Karasik, David %A Harris, Tamara B %A Ohlsson, Claes %A Kiel, Douglas P %X

Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 × 10-8) or suggestively genome wide (p < 2.3 × 10-6). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass.Lean body mass is a highly heritable trait and is associated with various health conditions. Here, Kiel and colleagues perform a meta-analysis of genome-wide association studies for whole body lean body mass and find five novel genetic loci to be significantly associated.

%B Nat Commun %V 8 %P 80 %8 2017 Jul 19 %G eng %N 1 %R 10.1038/s41467-017-00031-7 %0 Journal Article %J Nat Genet %D 2017 %T Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation. %A Christophersen, Ingrid E %A Rienstra, Michiel %A Roselli, Carolina %A Yin, Xiaoyan %A Geelhoed, Bastiaan %A Barnard, John %A Lin, Honghuang %A Arking, Dan E %A Smith, Albert V %A Albert, Christine M %A Chaffin, Mark %A Tucker, Nathan R %A Li, Molong %A Klarin, Derek %A Bihlmeyer, Nathan A %A Low, Siew-Kee %A Weeke, Peter E %A Müller-Nurasyid, Martina %A Smith, J Gustav %A Brody, Jennifer A %A Niemeijer, Maartje N %A Dörr, Marcus %A Trompet, Stella %A Huffman, Jennifer %A Gustafsson, Stefan %A Schurmann, Claudia %A Kleber, Marcus E %A Lyytikäinen, Leo-Pekka %A Seppälä, Ilkka %A Malik, Rainer %A Horimoto, Andrea R V R %A Perez, Marco %A Sinisalo, Juha %A Aeschbacher, Stefanie %A Thériault, Sébastien %A Yao, Jie %A Radmanesh, Farid %A Weiss, Stefan %A Teumer, Alexander %A Choi, Seung Hoan %A Weng, Lu-Chen %A Clauss, Sebastian %A Deo, Rajat %A Rader, Daniel J %A Shah, Svati H %A Sun, Albert %A Hopewell, Jemma C %A Debette, Stephanie %A Chauhan, Ganesh %A Yang, Qiong %A Worrall, Bradford B %A Paré, Guillaume %A Kamatani, Yoichiro %A Hagemeijer, Yanick P %A Verweij, Niek %A Siland, Joylene E %A Kubo, Michiaki %A Smith, Jonathan D %A Van Wagoner, David R %A Bis, Joshua C %A Perz, Siegfried %A Psaty, Bruce M %A Ridker, Paul M %A Magnani, Jared W %A Harris, Tamara B %A Launer, Lenore J %A Shoemaker, M Benjamin %A Padmanabhan, Sandosh %A Haessler, Jeffrey %A Bartz, Traci M %A Waldenberger, Melanie %A Lichtner, Peter %A Arendt, Marina %A Krieger, Jose E %A Kähönen, Mika %A Risch, Lorenz %A Mansur, Alfredo J %A Peters, Annette %A Smith, Blair H %A Lind, Lars %A Scott, Stuart A %A Lu, Yingchang %A Bottinger, Erwin B %A Hernesniemi, Jussi %A Lindgren, Cecilia M %A Wong, Jorge A %A Huang, Jie %A Eskola, Markku %A Morris, Andrew P %A Ford, Ian %A Reiner, Alex P %A Delgado, Graciela %A Chen, Lin Y %A Chen, Yii-Der Ida %A Sandhu, Roopinder K %A Li, Man %A Boerwinkle, Eric %A Eisele, Lewin %A Lannfelt, Lars %A Rost, Natalia %A Anderson, Christopher D %A Taylor, Kent D %A Campbell, Archie %A Magnusson, Patrik K %A Porteous, David %A Hocking, Lynne J %A Vlachopoulou, Efthymia %A Pedersen, Nancy L %A Nikus, Kjell %A Orho-Melander, Marju %A Hamsten, Anders %A Heeringa, Jan %A Denny, Joshua C %A Kriebel, Jennifer %A Darbar, Dawood %A Newton-Cheh, Christopher %A Shaffer, Christian %A Macfarlane, Peter W %A Heilmann-Heimbach, Stefanie %A Almgren, Peter %A Huang, Paul L %A Sotoodehnia, Nona %A Soliman, Elsayed Z %A Uitterlinden, André G %A Hofman, Albert %A Franco, Oscar H %A Völker, Uwe %A Jöckel, Karl-Heinz %A Sinner, Moritz F %A Lin, Henry J %A Guo, Xiuqing %A Dichgans, Martin %A Ingelsson, Erik %A Kooperberg, Charles %A Melander, Olle %A Loos, Ruth J F %A Laurikka, Jari %A Conen, David %A Rosand, Jonathan %A van der Harst, Pim %A Lokki, Marja-Liisa %A Kathiresan, Sekar %A Pereira, Alexandre %A Jukema, J Wouter %A Hayward, Caroline %A Rotter, Jerome I %A März, Winfried %A Lehtimäki, Terho %A Stricker, Bruno H %A Chung, Mina K %A Felix, Stephan B %A Gudnason, Vilmundur %A Alonso, Alvaro %A Roden, Dan M %A Kääb, Stefan %A Chasman, Daniel I %A Heckbert, Susan R %A Benjamin, Emelia J %A Tanaka, Toshihiro %A Lunetta, Kathryn L %A Lubitz, Steven A %A Ellinor, Patrick T %X

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery.

%B Nat Genet %V 49 %P 946-952 %8 2017 Jun %G eng %N 6 %R 10.1038/ng.3843 %0 Journal Article %J Cell Rep %D 2017 %T Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets. %A Lam, Max %A Trampush, Joey W %A Yu, Jin %A Knowles, Emma %A Davies, Gail %A Liewald, David C %A Starr, John M %A Djurovic, Srdjan %A Melle, Ingrid %A Sundet, Kjetil %A Christoforou, Andrea %A Reinvang, Ivar %A DeRosse, Pamela %A Lundervold, Astri J %A Steen, Vidar M %A Espeseth, Thomas %A Räikkönen, Katri %A Widen, Elisabeth %A Palotie, Aarno %A Eriksson, Johan G %A Giegling, Ina %A Konte, Bettina %A Roussos, Panos %A Giakoumaki, Stella %A Burdick, Katherine E %A Payton, Antony %A Ollier, William %A Chiba-Falek, Ornit %A Attix, Deborah K %A Need, Anna C %A Cirulli, Elizabeth T %A Voineskos, Aristotle N %A Stefanis, Nikos C %A Avramopoulos, Dimitrios %A Hatzimanolis, Alex %A Arking, Dan E %A Smyrnis, Nikolaos %A Bilder, Robert M %A Freimer, Nelson A %A Cannon, Tyrone D %A London, Edythe %A Poldrack, Russell A %A Sabb, Fred W %A Congdon, Eliza %A Conley, Emily Drabant %A Scult, Matthew A %A Dickinson, Dwight %A Straub, Richard E %A Donohoe, Gary %A Morris, Derek %A Corvin, Aiden %A Gill, Michael %A Hariri, Ahmad R %A Weinberger, Daniel R %A Pendleton, Neil %A Bitsios, Panos %A Rujescu, Dan %A Lahti, Jari %A Le Hellard, Stephanie %A Keller, Matthew C %A Andreassen, Ole A %A Deary, Ian J %A Glahn, David C %A Malhotra, Anil K %A Lencz, Todd %X

Here, we present a large (n = 107,207) genome-wide association study (GWAS) of general cognitive ability ("g"), further enhanced by combining results with a large-scale GWAS of educational attainment. We identified 70 independent genomic loci associated with general cognitive ability. Results showed significant enrichment for genes causing Mendelian disorders with an intellectual disability phenotype. Competitive pathway analysis implicated the biological processes of neurogenesis and synaptic regulation, as well as the gene targets of two pharmacologic agents: cinnarizine, a T-type calcium channel blocker, and LY97241, a potassium channel inhibitor. Transcriptome-wide and epigenome-wide analysis revealed that the implicated loci were enriched for genes expressed across all brain regions (most strongly in the cerebellum). Enrichment was exclusive to genes expressed in neurons but not oligodendrocytes or astrocytes. Finally, we report genetic correlations between cognitive ability and disparate phenotypes including psychiatric disorders, several autoimmune disorders, longevity, and maternal age at first birth.

%B Cell Rep %V 21 %P 2597-2613 %8 2017 Nov 28 %G eng %N 9 %R 10.1016/j.celrep.2017.11.028 %0 Journal Article %J J Clin Invest %D 2017 %T Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function. %A Wild, Philipp S %A Felix, Janine F %A Schillert, Arne %A Teumer, Alexander %A Chen, Ming-Huei %A Leening, Maarten J G %A Völker, Uwe %A Großmann, Vera %A Brody, Jennifer A %A Irvin, Marguerite R %A Shah, Sanjiv J %A Pramana, Setia %A Lieb, Wolfgang %A Schmidt, Reinhold %A Stanton, Alice V %A Malzahn, Dörthe %A Smith, Albert Vernon %A Sundström, Johan %A Minelli, Cosetta %A Ruggiero, Daniela %A Lyytikäinen, Leo-Pekka %A Tiller, Daniel %A Smith, J Gustav %A Monnereau, Claire %A Di Tullio, Marco R %A Musani, Solomon K %A Morrison, Alanna C %A Pers, Tune H %A Morley, Michael %A Kleber, Marcus E %A Aragam, Jayashri %A Benjamin, Emelia J %A Bis, Joshua C %A Bisping, Egbert %A Broeckel, Ulrich %A Cheng, Susan %A Deckers, Jaap W %A del Greco M, Fabiola %A Edelmann, Frank %A Fornage, Myriam %A Franke, Lude %A Friedrich, Nele %A Harris, Tamara B %A Hofer, Edith %A Hofman, Albert %A Huang, Jie %A Hughes, Alun D %A Kähönen, Mika %A Investigators, Knhi %A Kruppa, Jochen %A Lackner, Karl J %A Lannfelt, Lars %A Laskowski, Rafael %A Launer, Lenore J %A Leosdottir, Margrét %A Lin, Honghuang %A Lindgren, Cecilia M %A Loley, Christina %A MacRae, Calum A %A Mascalzoni, Deborah %A Mayet, Jamil %A Medenwald, Daniel %A Morris, Andrew P %A Müller, Christian %A Müller-Nurasyid, Martina %A Nappo, Stefania %A Nilsson, Peter M %A Nuding, Sebastian %A Nutile, Teresa %A Peters, Annette %A Pfeufer, Arne %A Pietzner, Diana %A Pramstaller, Peter P %A Raitakari, Olli T %A Rice, Kenneth M %A Rivadeneira, Fernando %A Rotter, Jerome I %A Ruohonen, Saku T %A Sacco, Ralph L %A Samdarshi, Tandaw E %A Schmidt, Helena %A Sharp, Andrew S P %A Shields, Denis C %A Sorice, Rossella %A Sotoodehnia, Nona %A Stricker, Bruno H %A Surendran, Praveen %A Thom, Simon %A Töglhofer, Anna M %A Uitterlinden, André G %A Wachter, Rolf %A Völzke, Henry %A Ziegler, Andreas %A Münzel, Thomas %A März, Winfried %A Cappola, Thomas P %A Hirschhorn, Joel N %A Mitchell, Gary F %A Smith, Nicholas L %A Fox, Ervin R %A Dueker, Nicole D %A Jaddoe, Vincent W V %A Melander, Olle %A Russ, Martin %A Lehtimäki, Terho %A Ciullo, Marina %A Hicks, Andrew A %A Lind, Lars %A Gudnason, Vilmundur %A Pieske, Burkert %A Barron, Anthony J %A Zweiker, Robert %A Schunkert, Heribert %A Ingelsson, Erik %A Liu, Kiang %A Arnett, Donna K %A Psaty, Bruce M %A Blankenberg, Stefan %A Larson, Martin G %A Felix, Stephan B %A Franco, Oscar H %A Zeller, Tanja %A Vasan, Ramachandran S %A Dörr, Marcus %X

BACKGROUND: Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function.

METHODS: A GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function.

RESULTS: The discovery analysis included 21 cohorts for structural and systolic function traits (n = 32,212) and 17 cohorts for diastolic function traits (n = 21,852). Replication was performed in 5 cohorts (n = 14,321) and 6 cohorts (n = 16,308), respectively. Besides 5 previously reported loci, the combined meta-analysis identified 10 additional genome-wide significant SNPs: rs12541595 near MTSS1 and rs10774625 in ATXN2 for LV end-diastolic internal dimension; rs806322 near KCNRG, rs4765663 in CACNA1C, rs6702619 near PALMD, rs7127129 in TMEM16A, rs11207426 near FGGY, rs17608766 in GOSR2, and rs17696696 in CFDP1 for aortic root diameter; and rs12440869 in IQCH for Doppler transmitral A-wave peak velocity. Findings were in part validated in other cohorts and in GWAS of related disease traits. The genetic loci showed associations with putative signaling pathways, and with gene expression in whole blood, monocytes, and myocardial tissue.

CONCLUSION: The additional genetic loci identified in this large meta-analysis of cardiac structure and function provide insights into the underlying genetic architecture of cardiac structure and warrant follow-up in future functional studies.

FUNDING: For detailed information per study, see Acknowledgments.

%B J Clin Invest %V 127 %P 1798-1812 %8 2017 May 01 %G eng %N 5 %R 10.1172/JCI84840 %0 Journal Article %J Nat Commun %D 2017 %T Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness. %A Willems, Sara M %A Wright, Daniel J %A Day, Felix R %A Trajanoska, Katerina %A Joshi, Peter K %A Morris, John A %A Matteini, Amy M %A Garton, Fleur C %A Grarup, Niels %A Oskolkov, Nikolay %A Thalamuthu, Anbupalam %A Mangino, Massimo %A Liu, Jun %A Demirkan, Ayse %A Lek, Monkol %A Xu, Liwen %A Wang, Guan %A Oldmeadow, Christopher %A Gaulton, Kyle J %A Lotta, Luca A %A Miyamoto-Mikami, Eri %A Rivas, Manuel A %A White, Tom %A Loh, Po-Ru %A Aadahl, Mette %A Amin, Najaf %A Attia, John R %A Austin, Krista %A Benyamin, Beben %A Brage, Søren %A Cheng, Yu-Ching %A Cięszczyk, Paweł %A Derave, Wim %A Eriksson, Karl-Fredrik %A Eynon, Nir %A Linneberg, Allan %A Lucia, Alejandro %A Massidda, Myosotis %A Mitchell, Braxton D %A Miyachi, Motohiko %A Murakami, Haruka %A Padmanabhan, Sandosh %A Pandey, Ashutosh %A Papadimitriou, Ioannis %A Rajpal, Deepak K %A Sale, Craig %A Schnurr, Theresia M %A Sessa, Francesco %A Shrine, Nick %A Tobin, Martin D %A Varley, Ian %A Wain, Louise V %A Wray, Naomi R %A Lindgren, Cecilia M %A MacArthur, Daniel G %A Waterworth, Dawn M %A McCarthy, Mark I %A Pedersen, Oluf %A Khaw, Kay-Tee %A Kiel, Douglas P %A Pitsiladis, Yannis %A Fuku, Noriyuki %A Franks, Paul W %A North, Kathryn N %A van Duijn, Cornelia M %A Mather, Karen A %A Hansen, Torben %A Hansson, Ola %A Spector, Tim %A Murabito, Joanne M %A Richards, J Brent %A Rivadeneira, Fernando %A Langenberg, Claudia %A Perry, John R B %A Wareham, Nick J %A Scott, Robert A %X

Hand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined sample of 195,180 individuals and identify 16 loci associated with grip strength (P<5 × 10) in combined analyses. A number of these loci contain genes implicated in structure and function of skeletal muscle fibres (ACTG1), neuronal maintenance and signal transduction (PEX14, TGFA, SYT1), or monogenic syndromes with involvement of psychomotor impairment (PEX14, LRPPRC and KANSL1). Mendelian randomization analyses are consistent with a causal effect of higher genetically predicted grip strength on lower fracture risk. In conclusion, our findings provide new biological insight into the mechanistic underpinnings of grip strength and the causal role of muscular strength in age-related morbidities and mortality.

%B Nat Commun %V 8 %P 16015 %8 2017 Jul 12 %G eng %R 10.1038/ncomms16015 %0 Journal Article %J Am J Geriatr Psychiatry %D 2017 %T Late-Life Depressive Symptoms as Partial Mediators in the Associations between Subclinical Cardiovascular Disease with Onset of Mild Cognitive Impairment and Dementia. %A Armstrong, Nicole M %A Carlson, Michelle C %A Schrack, Jennifer %A Xue, Qian-Li %A Carnethon, Mercedes R %A Rosano, Caterina %A Chaves, Paulo H M %A Gross, Alden L %X

OBJECTIVE: To study whether depression contributes to the association between subclinical cardiovascular disease (CVD) and dementia, and identify the contribution's magnitude.

METHODS: Among participants from the Cardiovascular Health Study Cognition Study who did not have baseline CVD-related events (N = 2,450), causal mediation methodology was implemented to examine whether late-life depressive symptoms, defined as 10-item Center for Epidemiologic Studies-Depression (mCES-D) Scale scores ≥8 from 2 to 3 years after baseline, partially mediated the association of baseline subclinical CVD (CAC, carotid intimal medial thickness, stenosis, and ankle brachial index) with mild cognitive impairment (MCI)/dementia onset occurring between 5 and 10 years from baseline. The total effect was decomposed into direct and indirect effects (via late-life depressive symptoms), obtained from an accelerated failure time model with weights derived from multivariable logistic regression of late-life depressive symptoms on subclinical CVD. Analyses were adjusted by baseline covariates: age, race, sex, poverty status, marital status, body mass index, smoking status, ApoE4 status, and mCES-D.

RESULTS: Participants contributed 20,994 person-years of follow-up with a median follow-up time of 9.4 years. Subclinical CVD was associated with 12% faster time to MCI/dementia (time ratio [TR]: 0.88; 95% CI: 0.83, 0.93). The total effect of subclinical CVD on MCI/dementia onset was decomposed into a direct effect (TR: 0.95, 95% CI: 0.92, 0.98) and indirect effect (TR: 0.92, 95% CI: 0.88, 0.97); 64.5% of the total effect was mediated by late-life depressive symptoms.

CONCLUSIONS: These data suggest late-life depressive symptoms partially mediate the association of subclinical CVD with MCI/dementia onset.

%B Am J Geriatr Psychiatry %8 2017 Nov 20 %G eng %R 10.1016/j.jagp.2017.11.004 %0 Journal Article %J Exp Gerontol %D 2017 %T Leisure-time physical activity and leukocyte telomere length among older women. %A Shadyab, Aladdin H %A Lamonte, Michael J %A Kooperberg, Charles %A Reiner, Alexander P %A Carty, Cara L %A Manini, Todd M %A Hou, Lifang %A Di, Chongzhi %A Macera, Caroline A %A Gallo, Linda C %A Shaffer, Richard A %A Jain, Sonia %A LaCroix, Andrea Z %X

BACKGROUND: Shortened leukocyte telomere length (LTL), a purported marker of cellular aging, is associated with morbidity and mortality. However, the association of physical activity, a modifiable lifestyle behavior, with LTL has not been adequately studied among older adults.

METHODS: In this cross-sectional study, we examined associations of various intensity levels of leisure-time physical activity with LTL among 1476 older white and African American women from the Women's Health Initiative Objective Physical Activity and Cardiovascular Health study. Self-reported physical activity was assessed by questionnaire, and LTL was measured by Southern blot. The association between physical activity and LTL was evaluated using multiple linear regression models adjusted for demographic characteristics, lifestyle behaviors, and health-related variables.

RESULTS: Women were on average aged 79.2 (standard deviation 6.7) years old. In the final model adjusted for age, race/ethnicity, education, marital status, smoking, alcohol, body mass index, a history of chronic diseases, and hormone therapy use, LTL was on average 110 (95% confidence interval, 20-190) base pairs longer among women in the highest (≥17.00MET-hours/week) compared with the lowest (<1.25MET-hours/week) level of total leisure-time physical activity (P for trend=0.02). Higher levels of moderate-to-vigorous physical activity (P for trend=0.04) and faster walking speed (P for trend=0.03) were also associated with longer LTL in the fully-adjusted models.

CONCLUSION: Older women participating in greater amounts of total leisure-time physical activity and moderate-to-vigorous physical activity had longer LTL.

%B Exp Gerontol %V 95 %P 141-147 %8 2017 Sep %G eng %R 10.1016/j.exger.2017.05.019 %0 Journal Article %J Am J Hum Genet %D 2017 %T Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis. %A Manousaki, Despoina %A Dudding, Tom %A Haworth, Simon %A Hsu, Yi-Hsiang %A Liu, Ching-Ti %A Medina-Gómez, Carolina %A Voortman, Trudy %A van der Velde, Nathalie %A Melhus, Håkan %A Robinson-Cohen, Cassianne %A Cousminer, Diana L %A Nethander, Maria %A Vandenput, Liesbeth %A Noordam, Raymond %A Forgetta, Vincenzo %A Greenwood, Celia M T %A Biggs, Mary L %A Psaty, Bruce M %A Rotter, Jerome I %A Zemel, Babette S %A Mitchell, Jonathan A %A Taylor, Bruce %A Lorentzon, Mattias %A Karlsson, Magnus %A Jaddoe, Vincent V W %A Tiemeier, Henning %A Campos-Obando, Natalia %A Franco, Oscar H %A Utterlinden, Andre G %A Broer, Linda %A van Schoor, Natasja M %A Ham, Annelies C %A Ikram, M Arfan %A Karasik, David %A de Mutsert, Renée %A Rosendaal, Frits R %A den Heijer, Martin %A Wang, Thomas J %A Lind, Lars %A Orwoll, Eric S %A Mook-Kanamori, Dennis O %A Michaëlsson, Karl %A Kestenbaum, Bryan %A Ohlsson, Claes %A Mellström, Dan %A de Groot, Lisette C P G M %A Grant, Struan F A %A Kiel, Douglas P %A Zillikens, M Carola %A Rivadeneira, Fernando %A Sawcer, Stephen %A Timpson, Nicholas J %A Richards, J Brent %K Cholestanetriol 26-Monooxygenase %K Cytochrome P450 Family 2 %K Gene Frequency %K Genetic Predisposition to Disease %K Genome, Human %K Genome-Wide Association Study %K Humans %K Multiple Sclerosis %K Polymorphism, Single Nucleotide %K Risk Factors %K Vitamin D %K Vitamin D Deficiency %X

Vitamin D insufficiency is common, correctable, and influenced by genetic factors, and it has been associated with risk of several diseases. We sought to identify low-frequency genetic variants that strongly increase the risk of vitamin D insufficiency and tested their effect on risk of multiple sclerosis, a disease influenced by low vitamin D concentrations. We used whole-genome sequencing data from 2,619 individuals through the UK10K program and deep-imputation data from 39,655 individuals genotyped genome-wide. Meta-analysis of the summary statistics from 19 cohorts identified in CYP2R1 the low-frequency (minor allele frequency = 2.5%) synonymous coding variant g.14900931G>A (p.Asp120Asp) (rs117913124[A]), which conferred a large effect on 25-hydroxyvitamin D (25OHD) levels (-0.43 SD of standardized natural log-transformed 25OHD per A allele; p value = 1.5 × 10(-88)). The effect on 25OHD was four times larger and independent of the effect of a previously described common variant near CYP2R1. By analyzing 8,711 individuals, we showed that heterozygote carriers of this low-frequency variant have an increased risk of vitamin D insufficiency (odds ratio [OR] = 2.2, 95% confidence interval [CI] = 1.78-2.78, p = 1.26 × 10(-12)). Individuals carrying one copy of this variant also had increased odds of multiple sclerosis (OR = 1.4, 95% CI = 1.19-1.64, p = 2.63 × 10(-5)) in a sample of 5,927 case and 5,599 control subjects. In conclusion, we describe a low-frequency CYP2R1 coding variant that exerts the largest effect upon 25OHD levels identified to date in the general European population and implicates vitamin D in the etiology of multiple sclerosis.

%B Am J Hum Genet %V 101 %P 227-238 %8 2017 Aug 03 %G eng %N 2 %R 10.1016/j.ajhg.2017.06.014 %0 Journal Article %J Lancet Diabetes Endocrinol %D 2017 %T Measures of chronic kidney disease and risk of incident peripheral artery disease: a collaborative meta-analysis of individual participant data. %A Matsushita, Kunihiro %A Ballew, Shoshana H %A Coresh, Josef %A Arima, Hisatomi %A Arnlöv, Johan %A Cirillo, Massimo %A Ebert, Natalie %A Hiramoto, Jade S %A Kimm, Heejin %A Shlipak, Michael G %A Visseren, Frank L J %A Gansevoort, Ron T %A Kovesdy, Csaba P %A Shalev, Varda %A Woodward, Mark %A Kronenberg, Florian %X

BACKGROUND: Some evidence suggests that chronic kidney disease is a risk factor for lower-extremity peripheral artery disease. We aimed to quantify the independent and joint associations of two measures of chronic kidney disease (estimated glomerular filtration rate [eGFR] and albuminuria) with the incidence of peripheral artery disease.

METHODS: In this collaborative meta-analysis of international cohorts included in the Chronic Kidney Disease Prognosis Consortium (baseline measurements obtained between 1972 and 2014) with baseline measurements of eGFR and albuminuria, at least 1000 participants (this criterion not applied to cohorts exclusively enrolling patients with chronic kidney disease), and at least 50 peripheral artery disease events, we analysed adult participants without peripheral artery disease at baseline at the individual patient level with Cox proportional hazards models to quantify associations of creatinine-based eGFR, urine albumin-to-creatinine ratio (ACR), and dipstick proteinuria with the incidence of peripheral artery disease (including hospitalisation with a diagnosis of peripheral artery disease, intermittent claudication, leg revascularisation, and leg amputation). We assessed discrimination improvement through c-statistics.

FINDINGS: We analysed 817 084 individuals without a history of peripheral artery disease at baseline from 21 cohorts. 18 261 cases of peripheral artery disease were recorded during follow-up across cohorts (median follow-up was 7·4 years [IQR 5·7-8·9], range 2·0-15·8 years across cohorts). Both chronic kidney disease measures were independently associated with the incidence of peripheral artery disease. Compared with an eGFR of 95 mL/min per 1·73 m2, adjusted hazard ratios (HRs) for incident study-specific peripheral artery disease was 1·22 (95% CI 1·14-1·30) at an eGFR of 45 mL/min per 1·73 m2 and 2·06 (1·70-2·48) at an eGFR of 15 mL/min per 1·73 m2. Compared with an ACR of 5 mg/g, the adjusted HR for incident study-specific peripheral artery disease was 1·50 (1·41-1·59) at an ACR of 30 mg/g and 2·28 (2·12-2·44) at an ACR of 300 mg/g. The adjusted HR at an ACR of 300 mg/g versus 5 mg/g was 3·68 (95% CI 3·00-4·52) for leg amputation. eGFR and albuminuria contributed multiplicatively (eg, adjusted HR 5·76 [4·90-6·77] for incident peripheral artery disease and 10·61 [5·70-19·77] for amputation in eGFR <30 mL/min per 1·73 m2 plus ACR ≥300 mg/g or dipstick proteinuria 2+ or higher vs eGFR ≥90 mL/min per 1·73 m2 plus ACR <10 mg/g or dipstick proteinuria negative). Both eGFR and ACR significantly improved peripheral artery disease risk discrimination beyond traditional predictors, with a substantial improvement prediction of amputation with ACR (difference in c-statistic 0·058, 95% CI 0·045-0·070). Patterns were consistent across clinical subgroups.

INTERPRETATION: Even mild-to-moderate chronic kidney disease conferred increased risk of incident peripheral artery disease, with a strong association between albuminuria and amputation. Clinical attention should be paid to the development of peripheral artery disease symptoms and signs in people with any stage of chronic kidney disease.

FUNDING: American Heart Association, US National Kidney Foundation, and US National Institute of Diabetes and Digestive and Kidney Diseases.

%B Lancet Diabetes Endocrinol %V 5 %P 718-728 %8 2017 Sep %G eng %N 9 %R 10.1016/S2213-8587(17)30183-3 %0 Journal Article %J Circ Cardiovasc Genet %D 2017 %T Multiancestry Study of Gene-Lifestyle Interactions for Cardiovascular Traits in 610 475 Individuals From 124 Cohorts: Design and Rationale. %A Rao, D C %A Sung, Yun J %A Winkler, Thomas W %A Schwander, Karen %A Borecki, Ingrid %A Cupples, L Adrienne %A Gauderman, W James %A Rice, Kenneth %A Munroe, Patricia B %A Psaty, Bruce M %X

BACKGROUND: Several consortia have pursued genome-wide association studies for identifying novel genetic loci for blood pressure, lipids, hypertension, etc. They demonstrated the power of collaborative research through meta-analysis of study-specific results.

METHODS AND RESULTS: The Gene-Lifestyle Interactions Working Group was formed to facilitate the first large, concerted, multiancestry study to systematically evaluate gene-lifestyle interactions. In stage 1, genome-wide interaction analysis is performed in 53 cohorts with a total of 149 684 individuals from multiple ancestries. In stage 2 involving an additional 71 cohorts with 460 791 individuals from multiple ancestries, focused analysis is performed for a subset of the most promising variants from stage 1. In all, the study involves up to 610 475 individuals. Current focus is on cardiovascular traits including blood pressure and lipids, and lifestyle factors including smoking, alcohol, education (as a surrogate for socioeconomic status), physical activity, psychosocial variables, and sleep. The total sample sizes vary among projects because of missing data. Large-scale gene-lifestyle or more generally gene-environment interaction (G×E) meta-analysis studies can be cumbersome and challenging. This article describes the design and some of the approaches pursued in the interaction projects.

CONCLUSIONS: The Gene-Lifestyle Interactions Working Group provides an excellent framework for understanding the lifestyle context of genetic effects and to identify novel trait loci through analysis of interactions. An important and novel feature of our study is that the gene-lifestyle interaction (G×E) results may improve our knowledge about the underlying mechanisms for novel and already known trait loci.

%B Circ Cardiovasc Genet %V 10 %8 2017 Jun %G eng %N 3 %R 10.1161/CIRCGENETICS.116.001649 %0 Journal Article %J Circ Cardiovasc Genet %D 2017 %T New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475 000 Individuals. %A Kraja, Aldi T %A Cook, James P %A Warren, Helen R %A Surendran, Praveen %A Liu, Chunyu %A Evangelou, Evangelos %A Manning, Alisa K %A Grarup, Niels %A Drenos, Fotios %A Sim, Xueling %A Smith, Albert Vernon %A Amin, Najaf %A Blakemore, Alexandra I F %A Bork-Jensen, Jette %A Brandslund, Ivan %A Farmaki, Aliki-Eleni %A Fava, Cristiano %A Ferreira, Teresa %A Herzig, Karl-Heinz %A Giri, Ayush %A Giulianini, Franco %A Grove, Megan L %A Guo, Xiuqing %A Harris, Sarah E %A Have, Christian T %A Havulinna, Aki S %A Zhang, He %A Jørgensen, Marit E %A Käräjämäki, AnneMari %A Kooperberg, Charles %A Linneberg, Allan %A Little, Louis %A Liu, Yongmei %A Bonnycastle, Lori L %A Lu, Yingchang %A Mägi, Reedik %A Mahajan, Anubha %A Malerba, Giovanni %A Marioni, Riccardo E %A Mei, Hao %A Menni, Cristina %A Morrison, Alanna C %A Padmanabhan, Sandosh %A Palmas, Walter %A Poveda, Alaitz %A Rauramaa, Rainer %A Rayner, Nigel William %A Riaz, Muhammad %A Rice, Ken %A Richard, Melissa A %A Smith, Jennifer A %A Southam, Lorraine %A Stančáková, Alena %A Stirrups, Kathleen E %A Tragante, Vinicius %A Tuomi, Tiinamaija %A Tzoulaki, Ioanna %A Varga, Tibor V %A Weiss, Stefan %A Yiorkas, Andrianos M %A Young, Robin %A Zhang, Weihua %A Barnes, Michael R %A Cabrera, Claudia P %A Gao, He %A Boehnke, Michael %A Boerwinkle, Eric %A Chambers, John C %A Connell, John M %A Christensen, Cramer K %A de Boer, Rudolf A %A Deary, Ian J %A Dedoussis, George %A Deloukas, Panos %A Dominiczak, Anna F %A Dörr, Marcus %A Joehanes, Roby %A Edwards, Todd L %A Esko, Tõnu %A Fornage, Myriam %A Franceschini, Nora %A Franks, Paul W %A Gambaro, Giovanni %A Groop, Leif %A Hallmans, Göran %A Hansen, Torben %A Hayward, Caroline %A Heikki, Oksa %A Ingelsson, Erik %A Tuomilehto, Jaakko %A Jarvelin, Marjo-Riitta %A Kardia, Sharon L R %A Karpe, Fredrik %A Kooner, Jaspal S %A Lakka, Timo A %A Langenberg, Claudia %A Lind, Lars %A Loos, Ruth J F %A Laakso, Markku %A McCarthy, Mark I %A Melander, Olle %A Mohlke, Karen L %A Morris, Andrew P %A Palmer, Colin N A %A Pedersen, Oluf %A Polasek, Ozren %A Poulter, Neil R %A Province, Michael A %A Psaty, Bruce M %A Ridker, Paul M %A Rotter, Jerome I %A Rudan, Igor %A Salomaa, Veikko %A Samani, Nilesh J %A Sever, Peter J %A Skaaby, Tea %A Stafford, Jeanette M %A Starr, John M %A van der Harst, Pim %A van der Meer, Peter %A van Duijn, Cornelia M %A Vergnaud, Anne-Claire %A Gudnason, Vilmundur %A Wareham, Nicholas J %A Wilson, James G %A Willer, Cristen J %A Witte, Daniel R %A Zeggini, Eleftheria %A Saleheen, Danish %A Butterworth, Adam S %A Danesh, John %A Asselbergs, Folkert W %A Wain, Louise V %A Ehret, Georg B %A Chasman, Daniel I %A Caulfield, Mark J %A Elliott, Paul %A Lindgren, Cecilia M %A Levy, Daniel %A Newton-Cheh, Christopher %A Munroe, Patricia B %A Howson, Joanna M M %X

BACKGROUND: Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association.

METHODS AND RESULTS: Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant (P<5×10-8) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1), and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at DBH) was genome-wide significant.

CONCLUSIONS: We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.

%B Circ Cardiovasc Genet %V 10 %8 2017 Oct %G eng %N 5 %R 10.1161/CIRCGENETICS.117.001778 %0 Journal Article %J Hypertension %D 2017 %T Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney. %A Wain, Louise V %A Vaez, Ahmad %A Jansen, Rick %A Joehanes, Roby %A van der Most, Peter J %A Erzurumluoglu, A Mesut %A O'Reilly, Paul F %A Cabrera, Claudia P %A Warren, Helen R %A Rose, Lynda M %A Verwoert, Germaine C %A Hottenga, Jouke-Jan %A Strawbridge, Rona J %A Esko, Tõnu %A Arking, Dan E %A Hwang, Shih-Jen %A Guo, Xiuqing %A Kutalik, Zoltán %A Trompet, Stella %A Shrine, Nick %A Teumer, Alexander %A Ried, Janina S %A Bis, Joshua C %A Smith, Albert V %A Amin, Najaf %A Nolte, Ilja M %A Lyytikäinen, Leo-Pekka %A Mahajan, Anubha %A Wareham, Nicholas J %A Hofer, Edith %A Joshi, Peter K %A Kristiansson, Kati %A Traglia, Michela %A Havulinna, Aki S %A Goel, Anuj %A Nalls, Mike A %A Sõber, Siim %A Vuckovic, Dragana %A Luan, Jian'an %A del Greco M, Fabiola %A Ayers, Kristin L %A Marrugat, Jaume %A Ruggiero, Daniela %A Lopez, Lorna M %A Niiranen, Teemu %A Enroth, Stefan %A Jackson, Anne U %A Nelson, Christopher P %A Huffman, Jennifer E %A Zhang, Weihua %A Marten, Jonathan %A Gandin, Ilaria %A Harris, Sarah E %A Zemunik, Tatijana %A Lu, Yingchang %A Evangelou, Evangelos %A Shah, Nabi %A de Borst, Martin H %A Mangino, Massimo %A Prins, Bram P %A Campbell, Archie %A Li-Gao, Ruifang %A Chauhan, Ganesh %A Oldmeadow, Christopher %A Abecasis, Goncalo %A Abedi, Maryam %A Barbieri, Caterina M %A Barnes, Michael R %A Batini, Chiara %A Beilby, John %A Blake, Tineka %A Boehnke, Michael %A Bottinger, Erwin P %A Braund, Peter S %A Brown, Morris %A Brumat, Marco %A Campbell, Harry %A Chambers, John C %A Cocca, Massimiliano %A Collins, Francis %A Connell, John %A Cordell, Heather J %A Damman, Jeffrey J %A Davies, Gail %A de Geus, Eco J %A de Mutsert, Renée %A Deelen, Joris %A Demirkale, Yusuf %A Doney, Alex S F %A Dörr, Marcus %A Farrall, Martin %A Ferreira, Teresa %A Frånberg, Mattias %A Gao, He %A Giedraitis, Vilmantas %A Gieger, Christian %A Giulianini, Franco %A Gow, Alan J %A Hamsten, Anders %A Harris, Tamara B %A Hofman, Albert %A Holliday, Elizabeth G %A Hui, Jennie %A Jarvelin, Marjo-Riitta %A Johansson, Asa %A Johnson, Andrew D %A Jousilahti, Pekka %A Jula, Antti %A Kähönen, Mika %A Kathiresan, Sekar %A Khaw, Kay-Tee %A Kolcic, Ivana %A Koskinen, Seppo %A Langenberg, Claudia %A Larson, Marty %A Launer, Lenore J %A Lehne, Benjamin %A Liewald, David C M %A Lin, Li %A Lind, Lars %A Mach, François %A Mamasoula, Chrysovalanto %A Menni, Cristina %A Mifsud, Borbala %A Milaneschi, Yuri %A Morgan, Anna %A Morris, Andrew D %A Morrison, Alanna C %A Munson, Peter J %A Nandakumar, Priyanka %A Nguyen, Quang Tri %A Nutile, Teresa %A Oldehinkel, Albertine J %A Oostra, Ben A %A Org, Elin %A Padmanabhan, Sandosh %A Palotie, Aarno %A Paré, Guillaume %A Pattie, Alison %A Penninx, Brenda W J H %A Poulter, Neil %A Pramstaller, Peter P %A Raitakari, Olli T %A Ren, Meixia %A Rice, Kenneth %A Ridker, Paul M %A Riese, Harriëtte %A Ripatti, Samuli %A Robino, Antonietta %A Rotter, Jerome I %A Rudan, Igor %A Saba, Yasaman %A Saint Pierre, Aude %A Sala, Cinzia F %A Sarin, Antti-Pekka %A Schmidt, Reinhold %A Scott, Rodney %A Seelen, Marc A %A Shields, Denis C %A Siscovick, David %A Sorice, Rossella %A Stanton, Alice %A Stott, David J %A Sundström, Johan %A Swertz, Morris %A Taylor, Kent D %A Thom, Simon %A Tzoulaki, Ioanna %A Tzourio, Christophe %A Uitterlinden, André G %A Völker, Uwe %A Vollenweider, Peter %A Wild, Sarah %A Willemsen, Gonneke %A Wright, Alan F %A Yao, Jie %A Thériault, Sébastien %A Conen, David %A Attia, John %A Sever, Peter %A Debette, Stephanie %A Mook-Kanamori, Dennis O %A Zeggini, Eleftheria %A Spector, Tim D %A van der Harst, Pim %A Palmer, Colin N A %A Vergnaud, Anne-Claire %A Loos, Ruth J F %A Polasek, Ozren %A Starr, John M %A Girotto, Giorgia %A Hayward, Caroline %A Kooner, Jaspal S %A Lindgren, Cecila M %A Vitart, Veronique %A Samani, Nilesh J %A Tuomilehto, Jaakko %A Gyllensten, Ulf %A Knekt, Paul %A Deary, Ian J %A Ciullo, Marina %A Elosua, Roberto %A Keavney, Bernard D %A Hicks, Andrew A %A Scott, Robert A %A Gasparini, Paolo %A Laan, Maris %A Liu, Yongmei %A Watkins, Hugh %A Hartman, Catharina A %A Salomaa, Veikko %A Toniolo, Daniela %A Perola, Markus %A Wilson, James F %A Schmidt, Helena %A Zhao, Jing Hua %A Lehtimäki, Terho %A van Duijn, Cornelia M %A Gudnason, Vilmundur %A Psaty, Bruce M %A Peters, Annette %A Rettig, Rainer %A James, Alan %A Jukema, J Wouter %A Strachan, David P %A Palmas, Walter %A Metspalu, Andres %A Ingelsson, Erik %A Boomsma, Dorret I %A Franco, Oscar H %A Bochud, Murielle %A Newton-Cheh, Christopher %A Munroe, Patricia B %A Elliott, Paul %A Chasman, Daniel I %A Chakravarti, Aravinda %A Knight, Joanne %A Morris, Andrew P %A Levy, Daniel %A Tobin, Martin D %A Snieder, Harold %A Caulfield, Mark J %A Ehret, Georg B %X

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.

%B Hypertension %8 2017 Jul 24 %G eng %R 10.1161/HYPERTENSIONAHA.117.09438 %0 Journal Article %J Nat Commun %D 2017 %T {Novel genetic loci associated with hippocampal volume %A Hibar, D. P. %A Adams, H. H. H. %A Jahanshad, N. %A Chauhan, G. %A Stein, J. L. %A Hofer, E. %A Renteria, M. E. %A Bis, J. C. %A Arias-Vasquez, A. %A Ikram, M. K. %A Desrivi?res, S. %A Vernooij, M. W. %A Abramovic, L. %A Alhusaini, S. %A Amin, N. %A Andersson, M. %A Arfanakis, K. %A Aribisala, B. S. %A Armstrong, N. J. %A Athanasiu, L. %A Axelsson, T. %A Beecham, A. H. %A Beiser, A. %A Bernard, M. %A Blanton, S. H. %A Bohlken, M. M. %A Boks, M. P. %A Bralten, J. %A Brickman, A. M. %A Carmichael, O. %A Chakravarty, M. M. %A Chen, Q. %A Ching, C. R. K. %A Chouraki, V. %A Cuellar-Partida, G. %A Crivello, F. %A den Braber, A. %A Doan, N. T. %A Ehrlich, S. %A Giddaluru, S. %A Goldman, A. L. %A Gottesman, R. F. %A Grimm, O. %A Griswold, M. E. %A Guadalupe, T. %A Gutman, B. A. %A Hass, J. %A Haukvik, U. K. %A Hoehn, D. %A Holmes, A. J. %A Hoogman, M. %A Janowitz, D. %A Jia, T. %A J?rgensen, K. N. %A Karbalai, N. %A Kasperaviciute, D. %A Kim, S. %A Klein, M. %A Kraemer, B. %A Lee, P. H. %A Liewald, D. C. M. %A Lopez, L. M. %A Luciano, M. %A Macare, C. %A Marquand, A. F. %A Matarin, M. %A Mather, K. A. %A Mattheisen, M. %A McKay, D. R. %A Milaneschi, Y. %A Mu?oz Maniega, S. %A Nho, K. %A Nugent, A. C. %A Nyquist, P. %A Loohuis, L. M. O. %A Oosterlaan, J. %A Papmeyer, M. %A Pirpamer, L. %A P?tz, B. %A Ramasamy, A. %A Richards, J. S. %A Risacher, S. L. %A Roiz-Santia?ez, R. %A Rommelse, N. %A Ropele, S. %A Rose, E. J. %A Royle, N. A. %A Rundek, T. %A S?mann, P. G. %A Saremi, A. %A Satizabal, C. L. %A Schmaal, L. %A Schork, A. J. %A Shen, L. %A Shin, J. %A Shumskaya, E. %A Smith, A. V. %A Sprooten, E. %A Strike, L. T. %A Teumer, A. %A Tordesillas-Gutierrez, D. %A Toro, R. %A Trabzuni, D. %A Trompet, S. %A Vaidya, D. %A van der Grond, J. %A van der Lee, S. J. %A van der Meer, D. %A van Donkelaar, M. M. J. %A Van Eijk, K. R. %A van Erp, T. G. M. %A van Rooij, D. %A Walton, E. %A Westlye, L. T. %A Whelan, C. D. %A Windham, B. G. %A Winkler, A. M. %A Wittfeld, K. %A Woldehawariat, G. %A Wolf, C. %A Wolfers, T. %A Yanek, L. R. %A Yang, J. %A Zijdenbos, A. %A Zwiers, M. P. %A Agartz, I. %A Almasy, L. %A Ames, D. %A Amouyel, P. %A Andreassen, O. A. %A Arepalli, S. %A Assareh, A. A. %A Barral, S. %A Bastin, M. E. %A Becker, D. M. %A Becker, J. T. %A Bennett, D. A. %A Blangero, J. %A van Bokhoven, H. %A Boomsma, D. I. %A Brodaty, H. %A Brouwer, R. M. %A Brunner, H. G. %A Buckner, R. L. %A Buitelaar, J. K. %A Bulayeva, K. B. %A Cahn, W. %A Calhoun, V. D. %A Cannon, D. M. %A Cavalleri, G. L. %A Cheng, C. Y. %A Cichon, S. %A Cookson, M. R. %A Corvin, A. %A Crespo-Facorro, B. %A Curran, J. E. %A Czisch, M. %A Dale, A. M. %A Davies, G. E. %A de Craen, A. J. M. %A de Geus, E. J. C. %A De Jager, P. L. %A de Zubicaray, G. I. %A Deary, I. J. %A Debette, S. %A DeCarli, C. %A Delanty, N. %A Depondt, C. %A DeStefano, A. %A Dillman, A. %A Djurovic, S. %A Donohoe, G. %A Drevets, W. C. %A Duggirala, R. %A Dyer, T. D. %A Enzinger, C. %A Erk, S. %A Espeseth, T. %A Fedko, I. O. %A Fern?ndez, G. %A Ferrucci, L. %A Fisher, S. E. %A Fleischman, D. A. %A Ford, I. %A Fornage, M. %A Foroud, T. M. %A Fox, P. T. %A Francks, C. %A Fukunaga, M. %A Gibbs, J. R. %A Glahn, D. C. %A Gollub, R. L. %A G?ring, H. H. H. %A Green, R. C. %A Gruber, O. %A Gudnason, V. %A Guelfi, S. %A H?berg, A. K. %A Hansell, N. K. %A Hardy, J. %A Hartman, C. A. %A Hashimoto, R. %A Hegenscheid, K. %A Heinz, A. %A Le Hellard, S. %A Hernandez, D. G. %A Heslenfeld, D. J. %A Ho, B. C. %A Hoekstra, P. J. %A Hoffmann, W. %A Hofman, A. %A Holsboer, F. %A Homuth, G. %A Hosten, N. %A Hottenga, J. J. %A Huentelman, M. %A Hulshoff Pol, H. E. %A Ikeda, M. %A Jack, C. R. %A Jenkinson, M. %A Johnson, R. %A J?nsson, E. G. %A Jukema, J. W. %A Kahn, R. S. %A Kanai, R. %A Kloszewska, I. %A Knopman, D. S. %A Kochunov, P. %A Kwok, J. B. %A Lawrie, S. M. %A Lema?tre, H. %A Liu, X. %A Longo, D. L. %A Lopez, O. L. %A Lovestone, S. %A Martinez, O. %A Martinot, J. L. %A Mattay, V. S. %A McDonald, C. %A McIntosh, A. M. %A McMahon, F. J. %A McMahon, K. L. %A Mecocci, P. %A Melle, I. %A Meyer-Lindenberg, A. %A Mohnke, S. %A Montgomery, G. W. %A Morris, D. W. %A Mosley, T. H. %A M?hleisen, T. W. %A M?ller-Myhsok, B. %A Nalls, M. A. %A Nauck, M. %A Nichols, T. E. %A Niessen, W. J. %A N?then, M. M. %A Nyberg, L. %A Ohi, K. %A Olvera, R. L. %A Ophoff, R. A. %A Pandolfo, M. %A Paus, T. %A Pausova, Z. %A Penninx, B. W. J. H. %A Pike, G. B. %A Potkin, S. G. %A Psaty, B. M. %A Reppermund, S. %A Rietschel, M. %A Roffman, J. L. %A Romanczuk-Seiferth, N. %A Rotter, J. I. %A Ryten, M. %A Sacco, R. L. %A Sachdev, P. S. %A Saykin, A. J. %A Schmidt, R. %A Schmidt, H. %A Schofield, P. R. %A Sigursson, S. %A Simmons, A. %A Singleton, A. %A Sisodiya, S. M. %A Smith, C. %A Smoller, J. W. %A Soininen, H. %A Steen, V. M. %A Stott, D. J. %A Sussmann, J. E. %A Thalamuthu, A. %A Toga, A. W. %A Traynor, B. J. %A Troncoso, J. %A Tsolaki, M. %A Tzourio, C. %A Uitterlinden, A. G. %A Hern?ndez, M. C. V. %A Van der Brug, M. %A van der Lugt, A. %A Van der Wee, N. J. A. %A van Haren, N. E. M. %A van 't Ent, D. %A van Tol, M. J. %A Vardarajan, B. N. %A Vellas, B. %A Veltman, D. J. %A V?lzke, H. %A Walter, H. %A Wardlaw, J. M. %A Wassink, T. H. %A Weale, M. E. %A Weinberger, D. R. %A Weiner, M. W. %A Wen, W. %A Westman, E. %A White, T. %A Wong, T. Y. %A Wright, C. B. %A Zielke, R. H. %A Zonderman, A. B. %A Martin, N. G. %A van Duijn, C. M. %A Wright, M. J. %A Longstreth, W. T. %A Schumann, G. %A Grabe, H. J. %A Franke, B. %A Launer, L. J. %A Medland, S. E. %A Seshadri, S. %A Thompson, P. M. %A Ikram, M. A. %X The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg=-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness. %B Nat Commun %V 8 %P 13624 %8 01 %G eng %0 Journal Article %J Circ Cardiovasc Genet %D 2017 %T PCSK9 Loss-of-Function Variants, Low-Density Lipoprotein Cholesterol, and Risk of Coronary Heart Disease and Stroke: Data From 9 Studies of Blacks and Whites. %A Kent, Shia T %A Rosenson, Robert S %A Avery, Christy L %A Chen, Yii-der I %A Correa, Adolfo %A Cummings, Steven R %A Cupples, L Adrienne %A Cushman, Mary %A Evans, Daniel S %A Gudnason, Vilmundur %A Harris, Tamara B %A Howard, George %A Irvin, Marguerite R %A Judd, Suzanne E %A Jukema, J Wouter %A Lange, Leslie %A Levitan, Emily B %A Li, Xiaohui %A Liu, Yongmei %A Post, Wendy S %A Postmus, Iris %A Psaty, Bruce M %A Rotter, Jerome I %A Safford, Monika M %A Sitlani, Colleen M %A Smith, Albert V %A Stewart, James D %A Trompet, Stella %A Sun, Fangui %A Vasan, Ramachandran S %A Woolley, J Michael %A Whitsel, Eric A %A Wiggins, Kerri L %A Wilson, James G %A Muntner, Paul %X

BACKGROUND: PCSK9 loss-of-function (LOF) variants allow for the examination of the effects of lifetime reduced low-density lipoprotein cholesterol (LDL-C) on cardiovascular events. We examined the association of PCSK9 LOF variants with LDL-C and incident coronary heart disease and stroke through a meta-analysis of data from 8 observational cohorts and 1 randomized trial of statin therapy.

METHODS AND RESULTS: These 9 studies together included 17 459 blacks with 403 (2.3%) having at least 1 Y142X or C679X variant and 31 306 whites with 955 (3.1%) having at least 1 R46L variant. Unadjusted odds ratios for associations between PCSK9 LOF variants and incident coronary heart disease (851 events in blacks and 2662 events in whites) and stroke (523 events in blacks and 1660 events in whites) were calculated using pooled Mantel-Haenszel estimates with continuity correction factors. Pooling results across studies using fixed-effects inverse-variance-weighted models, PCSK9 LOF variants were associated with 35 mg/dL (95% confidence interval [CI], 32-39) lower LDL-C in blacks and 13 mg/dL (95% CI, 11-16) lower LDL-C in whites. PCSK9 LOF variants were associated with a pooled odds ratio for coronary heart disease of 0.51 (95% CI, 0.28-0.92) in blacks and 0.82 (95% CI, 0.63-1.06) in whites. PCSK9 LOF variants were not associated with incident stroke (odds ratio, 0.84; 95% CI, 0.48-1.47 in blacks and odds ratio, 1.06; 95% CI, 0.80-1.41 in whites).

CONCLUSIONS: PCSK9 LOF variants were associated with lower LDL-C and coronary heart disease incidence. PCSK9 LOF variants were not associated with stroke risk.

%B Circ Cardiovasc Genet %V 10 %P e001632 %8 2017 Aug %G eng %N 4 %R 10.1161/CIRCGENETICS.116.001632 %0 Journal Article %J Pharmacogenomics J %D 2017 %T Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology. %A Seyerle, A A %A Sitlani, C M %A Noordam, R %A Gogarten, S M %A Li, J %A Li, X %A Evans, D S %A Sun, F %A Laaksonen, M A %A Isaacs, A %A Kristiansson, K %A Highland, H M %A Stewart, J D %A Harris, T B %A Trompet, S %A Bis, J C %A Peloso, G M %A Brody, J A %A Broer, L %A Busch, E L %A Duan, Q %A Stilp, A M %A O'Donnell, C J %A Macfarlane, P W %A Floyd, J S %A Kors, J A %A Lin, H J %A Li-Gao, R %A Sofer, T %A Méndez-Giráldez, R %A Cummings, S R %A Heckbert, S R %A Hofman, A %A Ford, I %A Li, Y %A Launer, L J %A Porthan, K %A Newton-Cheh, C %A Napier, M D %A Kerr, K F %A Reiner, A P %A Rice, K M %A Roach, J %A Buckley, B M %A Soliman, E Z %A de Mutsert, R %A Sotoodehnia, N %A Uitterlinden, A G %A North, K E %A Lee, C R %A Gudnason, V %A Stürmer, T %A Rosendaal, F R %A Taylor, K D %A Wiggins, K L %A Wilson, J G %A Chen, Y-DI %A Kaplan, R C %A Wilhelmsen, K %A Cupples, L A %A Salomaa, V %A van Duijn, C %A Jukema, J W %A Liu, Y %A Mook-Kanamori, D O %A Lange, L A %A Vasan, R S %A Smith, A V %A Stricker, B H %A Laurie, C C %A Rotter, J I %A Whitsel, E A %A Psaty, B M %A Avery, C L %X

Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, trans-ethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N=78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P<5 × 10(-8)), we found suggestive evidence (P<5 × 10(-6)) for SNPs modifying the thiazide-QT association at 22 loci, including ion transport loci (for example, NELL1, KCNQ3). The biologic plausibility of our suggestive results and simulations demonstrating modest power to detect interaction effects at genome-wide significant levels indicate that larger studies and innovative statistical methods are warranted in future efforts evaluating thiazide-SNP interactions.The Pharmacogenomics Journal advance online publication, 18 July 2017; doi:10.1038/tpj.2017.10.

%B Pharmacogenomics J %8 2017 Jul 18 %G eng %R 10.1038/tpj.2017.10 %0 Journal Article %J Eur J Heart Fail %D 2017 %T Predictors and outcomes of heart failure with mid-range ejection fraction. %A Bhambhani, Vijeta %A Kizer, Jorge R %A Lima, João A C %A van der Harst, Pim %A Bahrami, Hossein %A Nayor, Matthew %A de Filippi, Christopher R %A Enserro, Danielle %A Blaha, Michael J %A Cushman, Mary %A Wang, Thomas J %A Gansevoort, Ron T %A Fox, Caroline S %A Gaggin, Hanna K %A Kop, Willem J %A Liu, Kiang %A Vasan, Ramachandran S %A Psaty, Bruce M %A Lee, Douglas S %A Brouwers, Frank P %A Hillege, Hans L %A Bartz, Traci M %A Benjamin, Emelia J %A Chan, Cheeling %A Allison, Matthew %A Gardin, Julius M %A Januzzi, James L %A Levy, Daniel %A Herrington, David M %A van Gilst, Wiek H %A Bertoni, Alain G %A Larson, Martin G %A de Boer, Rudolf A %A Gottdiener, John S %A Shah, Sanjiv J %A Ho, Jennifer E %X

AIMS: While heart failure with preserved (HFpEF) and reduced ejection fraction (HFrEF) are well described, determinants and outcomes of heart failure with mid-range ejection fraction (HFmrEF) remain unclear. We sought to examine clinical and biochemical predictors of incident HFmrEF in the community.

METHODS AND RESULTS: We pooled data from four community-based longitudinal cohorts, with ascertainment of new heart failure (HF) classified into HFmrEF [ejection fraction (EF) 41-49%], HFpEF (EF ≥50%), and HFrEF (EF ≤40%). Predictors of incident HF subtypes were assessed using multivariable Cox models. Among 28 820 participants free of HF followed for a median of 12 years, there were 200 new HFmrEF cases, compared with 811 HFpEF and 1048 HFrEF. Clinical predictors of HFmrEF included age, male sex, systolic blood pressure, diabetes mellitus, and prior myocardial infarction (multivariable adjusted P ≤ 0.003 for all). Biomarkers that predicted HFmrEF included natriuretic peptides, cystatin-C, and high-sensitivity troponin (P ≤ 0.0004 for all). Natriuretic peptides were stronger predictors of HFrEF [hazard ratio (HR) 2.00 per 1 standard deviation increase, 95% confidence interval (CI) 1.81-2.20] than of HFmrEF (HR 1.51, 95% CI 1.20-1.90, P = 0.01 for difference), and did not differ in their association with incident HFmrEF and HFpEF (HR 1.56, 95% CI 1.41-1.73, P = 0.68 for difference). All-cause mortality following the onset of HFmrEF was worse than that of HFpEF (50 vs. 39 events per 1000 person-years, P = 0.02), but comparable to that of HFrEF (46 events per 1000 person-years, P = 0.78).

CONCLUSIONS: We found overlap in predictors of incident HFmrEF with other HF subtypes. In contrast, mortality risk after HFmrEF was worse than HFpEF, and similar to HFrEF.

%B Eur J Heart Fail %8 2017 Dec 11 %G eng %R 10.1002/ejhf.1091 %0 Journal Article %J Neurology %D 2017 %T Predictors of incident epilepsy in older adults: The Cardiovascular Health Study. %A Choi, Hyunmi %A Pack, Alison %A Elkind, Mitchell S V %A Longstreth, W T %A Ton, Thanh G N %A Onchiri, Frankline %X

OBJECTIVE: To determine the prevalence, incidence, and predictors of epilepsy among older adults in the Cardiovascular Health Study (CHS).

METHODS: We analyzed data prospectively collected in CHS and merged with data from outpatient Medicare administrative claims. We identified cases with epilepsy using self-report, antiepileptic medication, hospitalization discharge ICD-9 codes, and outpatient Medicare ICD-9 codes. We used Cox proportional hazards regression to identify factors independently associated with incident epilepsy.

RESULTS: At baseline, 42% of the 5,888 participants were men and 84% were white. At enrollment, 3.7% (215 of 5,888) met the criteria for prevalent epilepsy. During 14 years of follow-up totaling 48,651 person-years, 120 participants met the criteria for incident epilepsy, yielding an incidence rate of 2.47 per 1,000 person-years. The period prevalence of epilepsy by the end of follow-up was 5.7% (335 of 5,888). Epilepsy incidence rates were significantly higher among blacks than nonblacks: 4.44 vs 2.17 per 1,000 person-years (p < 0.001). In multivariable analyses, risk of incident epilepsy was significantly higher among blacks compared to nonblacks (hazard ratio [HR] 4.04, 95% confidence interval [CI] 1.99-8.17), those 75 to 79 compared to those 65 to 69 years of age (HR 2.07, 95% CI 1.21-3.55), and those with history of stroke (HR 3.49, 95% CI 1.37-8.88).

CONCLUSIONS: Epilepsy in older adults in the United States was common. Blacks, the very old, and those with history of stroke have a higher risk of incident epilepsy. The association with race remains unexplained.

%B Neurology %V 88 %P 870-877 %8 2017 Feb 28 %G eng %N 9 %R 10.1212/WNL.0000000000003662 %0 Journal Article %J Nat Genet %D 2017 %T Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. %A Sims, Rebecca %A van der Lee, Sven J %A Naj, Adam C %A Bellenguez, Céline %A Badarinarayan, Nandini %A Jakobsdottir, Johanna %A Kunkle, Brian W %A Boland, Anne %A Raybould, Rachel %A Bis, Joshua C %A Martin, Eden R %A Grenier-Boley, Benjamin %A Heilmann-Heimbach, Stefanie %A Chouraki, Vincent %A Kuzma, Amanda B %A Sleegers, Kristel %A Vronskaya, Maria %A Ruiz, Agustin %A Graham, Robert R %A Olaso, Robert %A Hoffmann, Per %A Grove, Megan L %A Vardarajan, Badri N %A Hiltunen, Mikko %A Nöthen, Markus M %A White, Charles C %A Hamilton-Nelson, Kara L %A Epelbaum, Jacques %A Maier, Wolfgang %A Choi, Seung-Hoan %A Beecham, Gary W %A Dulary, Cécile %A Herms, Stefan %A Smith, Albert V %A Funk, Cory C %A Derbois, Céline %A Forstner, Andreas J %A Ahmad, Shahzad %A Li, Hongdong %A Bacq, Delphine %A Harold, Denise %A Satizabal, Claudia L %A Valladares, Otto %A Squassina, Alessio %A Thomas, Rhodri %A Brody, Jennifer A %A Qu, Liming %A Sánchez-Juan, Pascual %A Morgan, Taniesha %A Wolters, Frank J %A Zhao, Yi %A Garcia, Florentino Sanchez %A Denning, Nicola %A Fornage, Myriam %A Malamon, John %A Naranjo, Maria Candida Deniz %A Majounie, Elisa %A Mosley, Thomas H %A Dombroski, Beth %A Wallon, David %A Lupton, Michelle K %A Dupuis, Josée %A Whitehead, Patrice %A Fratiglioni, Laura %A Medway, Christopher %A Jian, Xueqiu %A Mukherjee, Shubhabrata %A Keller, Lina %A Brown, Kristelle %A Lin, Honghuang %A Cantwell, Laura B %A Panza, Francesco %A McGuinness, Bernadette %A Moreno-Grau, Sonia %A Burgess, Jeremy D %A Solfrizzi, Vincenzo %A Proitsi, Petra %A Adams, Hieab H %A Allen, Mariet %A Seripa, Davide %A Pastor, Pau %A Cupples, L Adrienne %A Price, Nathan D %A Hannequin, Didier %A Frank-García, Ana %A Levy, Daniel %A Chakrabarty, Paramita %A Caffarra, Paolo %A Giegling, Ina %A Beiser, Alexa S %A Giedraitis, Vilmantas %A Hampel, Harald %A Garcia, Melissa E %A Wang, Xue %A Lannfelt, Lars %A Mecocci, Patrizia %A Eiriksdottir, Gudny %A Crane, Paul K %A Pasquier, Florence %A Boccardi, Virginia %A Henández, Isabel %A Barber, Robert C %A Scherer, Martin %A Tarraga, Lluis %A Adams, Perrie M %A Leber, Markus %A Chen, Yuning %A Albert, Marilyn S %A Riedel-Heller, Steffi %A Emilsson, Valur %A Beekly, Duane %A Braae, Anne %A Schmidt, Reinhold %A Blacker, Deborah %A Masullo, Carlo %A Schmidt, Helena %A Doody, Rachelle S %A Spalletta, Gianfranco %A Jr, W T Longstreth %A Fairchild, Thomas J %A Bossù, Paola %A Lopez, Oscar L %A Frosch, Matthew P %A Sacchinelli, Eleonora %A Ghetti, Bernardino %A Yang, Qiong %A Huebinger, Ryan M %A Jessen, Frank %A Li, Shuo %A Kamboh, M Ilyas %A Morris, John %A Sotolongo-Grau, Oscar %A Katz, Mindy J %A Corcoran, Chris %A Dunstan, Melanie %A Braddel, Amy %A Thomas, Charlene %A Meggy, Alun %A Marshall, Rachel %A Gerrish, Amy %A Chapman, Jade %A Aguilar, Miquel %A Taylor, Sarah %A Hill, Matt %A Fairén, Mònica Díez %A Hodges, Angela %A Vellas, Bruno %A Soininen, Hilkka %A Kloszewska, Iwona %A Daniilidou, Makrina %A Uphill, James %A Patel, Yogen %A Hughes, Joseph T %A Lord, Jenny %A Turton, James %A Hartmann, Annette M %A Cecchetti, Roberta %A Fenoglio, Chiara %A Serpente, Maria %A Arcaro, Marina %A Caltagirone, Carlo %A Orfei, Maria Donata %A Ciaramella, Antonio %A Pichler, Sabrina %A Mayhaus, Manuel %A Gu, Wei %A Lleo, Alberto %A Fortea, Juan %A Blesa, Rafael %A Barber, Imelda S %A Brookes, Keeley %A Cupidi, Chiara %A Maletta, Raffaele Giovanni %A Carrell, David %A Sorbi, Sandro %A Moebus, Susanne %A Urbano, Maria %A Pilotto, Alberto %A Kornhuber, Johannes %A Bosco, Paolo %A Todd, Stephen %A Craig, David %A Johnston, Janet %A Gill, Michael %A Lawlor, Brian %A Lynch, Aoibhinn %A Fox, Nick C %A Hardy, John %A Albin, Roger L %A Apostolova, Liana G %A Arnold, Steven E %A Asthana, Sanjay %A Atwood, Craig S %A Baldwin, Clinton T %A Barnes, Lisa L %A Barral, Sandra %A Beach, Thomas G %A Becker, James T %A Bigio, Eileen H %A Bird, Thomas D %A Boeve, Bradley F %A Bowen, James D %A Boxer, Adam %A Burke, James R %A Burns, Jeffrey M %A Buxbaum, Joseph D %A Cairns, Nigel J %A Cao, Chuanhai %A Carlson, Chris S %A Carlsson, Cynthia M %A Carney, Regina M %A Carrasquillo, Minerva M %A Carroll, Steven L %A Diaz, Carolina Ceballos %A Chui, Helena C %A Clark, David G %A Cribbs, David H %A Crocco, Elizabeth A %A DeCarli, Charles %A Dick, Malcolm %A Duara, Ranjan %A Evans, Denis A %A Faber, Kelley M %A Fallon, Kenneth B %A Fardo, David W %A Farlow, Martin R %A Ferris, Steven %A Foroud, Tatiana M %A Galasko, Douglas R %A Gearing, Marla %A Geschwind, Daniel H %A Gilbert, John R %A Graff-Radford, Neill R %A Green, Robert C %A Growdon, John H %A Hamilton, Ronald L %A Harrell, Lindy E %A Honig, Lawrence S %A Huentelman, Matthew J %A Hulette, Christine M %A Hyman, Bradley T %A Jarvik, Gail P %A Abner, Erin %A Jin, Lee-Way %A Jun, Gyungah %A Karydas, Anna %A Kaye, Jeffrey A %A Kim, Ronald %A Kowall, Neil W %A Kramer, Joel H %A LaFerla, Frank M %A Lah, James J %A Leverenz, James B %A Levey, Allan I %A Li, Ge %A Lieberman, Andrew P %A Lunetta, Kathryn L %A Lyketsos, Constantine G %A Marson, Daniel C %A Martiniuk, Frank %A Mash, Deborah C %A Masliah, Eliezer %A McCormick, Wayne C %A McCurry, Susan M %A McDavid, Andrew N %A McKee, Ann C %A Mesulam, Marsel %A Miller, Bruce L %A Miller, Carol A %A Miller, Joshua W %A Morris, John C %A Murrell, Jill R %A Myers, Amanda J %A O'Bryant, Sid %A Olichney, John M %A Pankratz, Vernon S %A Parisi, Joseph E %A Paulson, Henry L %A Perry, William %A Peskind, Elaine %A Pierce, Aimee %A Poon, Wayne W %A Potter, Huntington %A Quinn, Joseph F %A Raj, Ashok %A Raskind, Murray %A Reisberg, Barry %A Reitz, Christiane %A Ringman, John M %A Roberson, Erik D %A Rogaeva, Ekaterina %A Rosen, Howard J %A Rosenberg, Roger N %A Sager, Mark A %A Saykin, Andrew J %A Schneider, Julie A %A Schneider, Lon S %A Seeley, William W %A Smith, Amanda G %A Sonnen, Joshua A %A Spina, Salvatore %A Stern, Robert A %A Swerdlow, Russell H %A Tanzi, Rudolph E %A Thornton-Wells, Tricia A %A Trojanowski, John Q %A Troncoso, Juan C %A Van Deerlin, Vivianna M %A Van Eldik, Linda J %A Vinters, Harry V %A Vonsattel, Jean Paul %A Weintraub, Sandra %A Welsh-Bohmer, Kathleen A %A Wilhelmsen, Kirk C %A Williamson, Jennifer %A Wingo, Thomas S %A Woltjer, Randall L %A Wright, Clinton B %A Yu, Chang-En %A Yu, Lei %A Garzia, Fabienne %A Golamaully, Feroze %A Septier, Gislain %A Engelborghs, Sebastien %A Vandenberghe, Rik %A De Deyn, Peter P %A Fernadez, Carmen Muñoz %A Benito, Yoland Aladro %A Thonberg, Håkan %A Forsell, Charlotte %A Lilius, Lena %A Kinhult-Ståhlbom, Anne %A Kilander, Lena %A Brundin, RoseMarie %A Concari, Letizia %A Helisalmi, Seppo %A Koivisto, Anne Maria %A Haapasalo, Annakaisa %A Dermecourt, Vincent %A Fiévet, Nathalie %A Hanon, Olivier %A Dufouil, Carole %A Brice, Alexis %A Ritchie, Karen %A Dubois, Bruno %A Himali, Jayanadra J %A Keene, C Dirk %A Tschanz, JoAnn %A Fitzpatrick, Annette L %A Kukull, Walter A %A Norton, Maria %A Aspelund, Thor %A Larson, Eric B %A Munger, Ron %A Rotter, Jerome I %A Lipton, Richard B %A Bullido, María J %A Hofman, Albert %A Montine, Thomas J %A Coto, Eliecer %A Boerwinkle, Eric %A Petersen, Ronald C %A Alvarez, Victoria %A Rivadeneira, Fernando %A Reiman, Eric M %A Gallo, Maura %A O'Donnell, Christopher J %A Reisch, Joan S %A Bruni, Amalia Cecilia %A Royall, Donald R %A Dichgans, Martin %A Sano, Mary %A Galimberti, Daniela %A St George-Hyslop, Peter %A Scarpini, Elio %A Tsuang, Debby W %A Mancuso, Michelangelo %A Bonuccelli, Ubaldo %A Winslow, Ashley R %A Daniele, Antonio %A Wu, Chuang-Kuo %A Peters, Oliver %A Nacmias, Benedetta %A Riemenschneider, Matthias %A Heun, Reinhard %A Brayne, Carol %A Rubinsztein, David C %A Bras, Jose %A Guerreiro, Rita %A Al-Chalabi, Ammar %A Shaw, Christopher E %A Collinge, John %A Mann, David %A Tsolaki, Magda %A Clarimon, Jordi %A Sussams, Rebecca %A Lovestone, Simon %A O'Donovan, Michael C %A Owen, Michael J %A Behrens, Timothy W %A Mead, Simon %A Goate, Alison M %A Uitterlinden, André G %A Holmes, Clive %A Cruchaga, Carlos %A Ingelsson, Martin %A Bennett, David A %A Powell, John %A Golde, Todd E %A Graff, Caroline %A De Jager, Philip L %A Morgan, Kevin %A Ertekin-Taner, Nilufer %A Combarros, Onofre %A Psaty, Bruce M %A Passmore, Peter %A Younkin, Steven G %A Berr, Claudine %A Gudnason, Vilmundur %A Rujescu, Dan %A Dickson, Dennis W %A Dartigues, Jean-François %A DeStefano, Anita L %A Ortega-Cubero, Sara %A Hakonarson, Hakon %A Campion, Dominique %A Boada, Merce %A Kauwe, John Keoni %A Farrer, Lindsay A %A Van Broeckhoven, Christine %A Ikram, M Arfan %A Jones, Lesley %A Haines, Jonathan L %A Tzourio, Christophe %A Launer, Lenore J %A Escott-Price, Valentina %A Mayeux, Richard %A Deleuze, Jean-Francois %A Amin, Najaf %A Holmans, Peter A %A Pericak-Vance, Margaret A %A Amouyel, Philippe %A van Duijn, Cornelia M %A Ramirez, Alfredo %A Wang, Li-San %A Lambert, Jean-Charles %A Seshadri, Sudha %A Williams, Julie %A Schellenberg, Gerard D %K Adaptor Proteins, Signal Transducing %K Alzheimer Disease %K Amino Acid Sequence %K Case-Control Studies %K Exome %K Gene Expression Profiling %K Gene Frequency %K Genetic Predisposition to Disease %K Genotype %K Humans %K Immunity, Innate %K Linkage Disequilibrium %K Membrane Glycoproteins %K Microglia %K Odds Ratio %K Phospholipase C gamma %K Polymorphism, Single Nucleotide %K Protein Interaction Maps %K Receptors, Immunologic %K Sequence Homology, Amino Acid %X

We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

%B Nat Genet %V 49 %P 1373-1384 %8 2017 Sep %G eng %N 9 %R 10.1038/ng.3916 %0 Journal Article %J PLoS Genet %D 2017 %T Rare coding variants pinpoint genes that control human hematological traits. %A Mousas, Abdou %A Ntritsos, Georgios %A Chen, Ming-Huei %A Song, Ci %A Huffman, Jennifer E %A Tzoulaki, Ioanna %A Elliott, Paul %A Psaty, Bruce M %A Auer, Paul L %A Johnson, Andrew D %A Evangelou, Evangelos %A Lettre, Guillaume %A Reiner, Alexander P %K Asthma %K Databases, Genetic %K Endometriosis %K Female %K Fibrin Fibrinogen Degradation Products %K Gene Frequency %K Genetic Loci %K Genome, Human %K Genome-Wide Association Study %K Humans %K Interleukin-33 %K Linear Models %K Logistic Models %K Male %K Mutation, Missense %K Phenotype %K Plasminogen %K Platelet Count %K Polymorphism, Single Nucleotide %K Principal Component Analysis %K Protein Splicing %K Rhinitis, Allergic %K Sequence Analysis, DNA %X

The identification of rare coding or splice site variants remains the most straightforward strategy to link genes with human phenotypes. Here, we analyzed the association between 137,086 rare (minor allele frequency (MAF) <1%) coding or splice site variants and 15 hematological traits in up to 308,572 participants. We found 56 such rare coding or splice site variants at P<5x10-8, including 31 that are associated with a blood-cell phenotype for the first time. All but one of these 31 new independent variants map to loci previously implicated in hematopoiesis by genome-wide association studies (GWAS). This includes a rare splice acceptor variant (rs146597587, MAF = 0.5%) in interleukin 33 (IL33) associated with reduced eosinophil count (P = 2.4x10-23), and lower risk of asthma (P = 2.6x10-7, odds ratio [95% confidence interval] = 0.56 [0.45-0.70]) and allergic rhinitis (P = 4.2x10-4, odds ratio = 0.55 [0.39-0.76]). The single new locus identified in our study is defined by a rare p.Arg172Gly missense variant (rs145535174, MAF = 0.05%) in plasminogen (PLG) associated with increased platelet count (P = 6.8x10-9), and decreased D-dimer concentration (P = 0.018) and platelet reactivity (P<0.03). Finally, our results indicate that searching for rare coding or splice site variants in very large sample sizes can help prioritize causal genes at many GWAS loci associated with complex human diseases and traits.

%B PLoS Genet %V 13 %P e1006925 %8 2017 Aug %G eng %N 8 %R 10.1371/journal.pgen.1006925 %0 Journal Article %J J Am Coll Cardiol %D 2017 %T Relationship Between Physical Activity, Body Mass Index, and Risk of Heart Failure. %A Pandey, Ambarish %A LaMonte, Michael %A Klein, Liviu %A Ayers, Colby %A Psaty, Bruce M %A Eaton, Charles B %A Allen, Norrina B %A de Lemos, James A %A Carnethon, Mercedes %A Greenland, Philip %A Berry, Jarett D %X

BACKGROUND: Lower leisure-time physical activity (LTPA) and higher body mass index (BMI) are independently associated with risk of heart failure (HF). However, it is unclear if this relationship is consistent for both heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF).

OBJECTIVES: This study sought to quantify dose-response associations between LTPA, BMI, and the risk of different HF subtypes.

METHODS: Individual-level data from 3 cohort studies (WHI [Women's Health Initiative], MESA [Multi-Ethnic Study of Atherosclerosis], and CHS [Cardiovascular Health Study]) were pooled and participants were stratified into guideline-recommended categories of LTPA and BMI. Associations between LTPA, BMI, and risk of overall HF, HFpEF (ejection fraction ≥45%), and HFrEF (ejection fraction <45%) were assessed by using multivariable adjusted Cox models and restricted cubic splines.

RESULTS: The study included 51,451 participants with 3,180 HF events (1,252 HFpEF, 914 HFrEF, and 1,014 unclassified HF). In the adjusted analysis, there was a dose-dependent association between higher LTPA levels, lower BMI, and overall HF risk. Among HF subtypes, LTPA in any dose range was not associated with HFrEF risk. In contrast, lower levels of LTPA (<500 MET-min/week) were not associated with HFpEF risk, and dose-dependent associations with lower HFpEF risk were observed at higher levels. Compared with no LTPA, higher than twice the guideline-recommended minimum LTPA levels (>1,000 MET-min/week) were associated with an 19% lower risk of HFpEF (hazard ratio: 0.81; 95% confidence interval: 0.68 to 0.97). The dose-response relationship for BMI with HFpEF risk was also more consistent than with HFrEF risk, such that increasing BMI above the normal range (≥25 kg/m(2)) was associated with a greater increase in risk of HFpEF than HFrEF.

CONCLUSIONS: Our study findings show strong, dose-dependent associations between LTPA levels, BMI, and risk of overall HF. Among HF subtypes, higher LTPA levels and lower BMI were more consistently associated with lower risk of HFpEF compared with HFrEF.

%B J Am Coll Cardiol %V 69 %P 1129-1142 %8 2017 Mar 07 %G eng %N 9 %R 10.1016/j.jacc.2016.11.081 %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 Am J Epidemiol %D 2017 %T REPEATED MEASUREMENTS OF BLOOD PRESSURE AND CHOLESTEROL IMPROVES CARDIOVASCULAR DISEASE RISK PREDICTION: AN INDIVIDUAL-PARTICIPANT-DATA META-ANALYSIS. %A Paige, Ellie %A Barrett, Jessica %A Pennells, Lisa %A Sweeting, Michael %A Willeit, Peter %A Di Angelantonio, Emanuele %A Gudnason, Vilmundur %A Nordestgaard, Børge G %A Psaty, Bruce M %A Goldbourt, Uri %A Best, Lyle G %A Assmann, Gerd %A Salonen, Jukka T %A Nietert, Paul J %A Verschuren, Wm Monique %A Brunner, Eric J %A Kronmal, Richard A %A Salomaa, Veikko %A Bakker, Stephan Jl %A Dagenais, Gilles R %A Sato, Shinichi %A Jansson, Jan-Håkan %A Willeit, Johann %A Onat, Altan %A de la Cámara, Agustin Gómez %A Roussel, Ronan %A Völzke, Henry %A Dankner, Rachel %A Tipping, Robert W %A Meade, Tom W %A Donfrancesco, Chiara %A Kuller, Lewis H %A Peters, Annette %A Gallacher, John %A Kromhout, Daan %A Iso, Hiroyasu %A Knuiman, Matthew %A Casiglia, Edoardo %A Kavousi, Maryam %A Palmieri, Luigi %A Sundström, Johan %A Davis, Barry R %A Njølstad, Inger %A Couper, David %A Danesh, John %A Thompson, Simon G %A Wood, Angela %X

The added value of incorporating information from repeated measurements of blood pressure and cholesterol for cardiovascular disease (CVD) risk prediction has not been rigorously assessed. We used data from the Emerging Risk Factors Collaboration on 191,445 adults (38 cohorts from across 17 countries with data from 1962-2014) with > 1 million measurements of systolic blood pressure, total cholesterol and high-density lipoprotein cholesterol; over a median 12 years of follow-up, 21,170 CVD events occurred. Risk prediction models using cumulative means of repeated measurements and summary measures from longitudinal modelling of the repeated measurements were compared to models using measurements from a single time point. Risk discrimination (C-index) and net reclassification were calculated, and changes in C-indices were meta-analysed across studies. Compared to the single time point model, the cumulative means and the longitudinal models increased the C-index by 0.0040 (95% CI: 0.0023, 0.0057) and 0.0023 (0.0005, 0.0042), respectively. Reclassification was also improved in both models; compared to the single time point model, overall net reclassification improvements were 0.0369 (0.0303, 0.0436) for the cumulative means model and 0.0177 (0.0110, 0.0243) for the longitudinal model. In conclusion, incorporating repeated measurements of blood pressure and cholesterol into CVD risk prediction models slightly improves risk prediction.

%B Am J Epidemiol %8 2017 May 26 %G eng %R 10.1093/aje/kwx149 %0 Journal Article %J J Aging Health %D 2017 %T Role of Late-Life Depression in the Association of Subclinical Cardiovascular Disease With All-Cause Mortality: Cardiovascular Health Study. %A Armstrong, Nicole M %A Carlson, Michelle C %A Xue, Qian-Li %A Schrack, Jennifer %A Carnethon, Mercedes R %A Chaves, Paulo H M %A Gross, Alden L %X

OBJECTIVES: To evaluate whether late-life depression mediates the association of subclinical cardiovascular disease (CVD) with all-cause mortality.

METHOD: Using data from 3,473 Cardiovascular Health Study participants, the Cox proportional hazards model was used to examine the direct and indirect (via late-life depression) effects of the association between baseline subclinical CVD and all-cause mortality with weights derived from multivariable logistic regression of late-life depression on subclinical CVD.

RESULTS: Subclinical CVD led to a higher risk of all-cause mortality (hazard ratio [HR] = 1.51, 95% confidence interval, [CI] = [1.42, 1.94]). Total effect of subclinical CVD on all-cause mortality was decomposed into direct (HR = 1.41, 95% CI = [1.37, 1.58]) and indirect (HR = 1.07, 95% CI = [1.01, 1.23]) effects; 16.3% of the total effect of subclinical CVD on all-cause mortality was mediated by late-life depression.

DISCUSSION: Late-life depression accounts for little, if any, of the association between subclinical CVD, a risk factor of all-cause mortality, and all-cause mortality.

%B J Aging Health %P 898264317744921 %8 2017 Nov 01 %G eng %R 10.1177/0898264317744921 %0 Journal Article %J Transl Psychiatry %D 2017 %T Short telomere length is associated with impaired cognitive performance in European ancestry cohorts. %A Hägg, S %A Zhan, Y %A Karlsson, R %A Gerritsen, L %A Ploner, A %A van der Lee, S J %A Broer, L %A Deelen, J %A Marioni, R E %A Wong, A %A Lundquist, A %A Zhu, G %A Hansell, N K %A Sillanpää, E %A Fedko, I O %A Amin, N A %A Beekman, M %A de Craen, A J M %A Degerman, S %A Harris, S E %A Kan, K-J %A Martin-Ruiz, C M %A Montgomery, G W %A Adolfsson, A N %A Reynolds, C A %A Samani, N J %A Suchiman, H E D %A Viljanen, A %A von Zglinicki, T %A Wright, M J %A Hottenga, J-J %A Boomsma, D I %A Rantanen, T %A Kaprio, J A %A Nyholt, D R %A Martin, N G %A Nyberg, L %A Adolfsson, R %A Kuh, D %A Starr, J M %A Deary, I J %A Slagboom, P E %A van Duijn, C M %A Codd, V %A Pedersen, N L %K Adult %K Aged %K Apolipoprotein E4 %K Cognitive Dysfunction %K Cohort Studies %K European Continental Ancestry Group %K Female %K Genetic Carrier Screening %K Genotype %K Humans %K Male %K Mendelian Randomization Analysis %K Middle Aged %K Neuropsychological Tests %K Psychometrics %K Statistics as Topic %K Telomere %X

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

%B Transl Psychiatry %V 7 %P e1100 %8 2017 04 18 %G eng %N 4 %R 10.1038/tp.2017.73 %0 Journal Article %J PLoS Genet %D 2017 %T Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations. %A Liang, Jingjing %A Le, Thu H %A Edwards, Digna R Velez %A Tayo, Bamidele O %A Gaulton, Kyle J %A Smith, Jennifer A %A Lu, Yingchang %A Jensen, Richard A %A Chen, Guanjie %A Yanek, Lisa R %A Schwander, Karen %A Tajuddin, Salman M %A Sofer, Tamar %A Kim, Wonji %A Kayima, James %A McKenzie, Colin A %A Fox, Ervin %A Nalls, Michael A %A Young, J Hunter %A Sun, Yan V %A Lane, Jacqueline M %A Cechova, Sylvia %A Zhou, Jie %A Tang, Hua %A Fornage, Myriam %A Musani, Solomon K %A Wang, Heming %A Lee, Juyoung %A Adeyemo, Adebowale %A Dreisbach, Albert W %A Forrester, Terrence %A Chu, Pei-Lun %A Cappola, Anne %A Evans, Michele K %A Morrison, Alanna C %A Martin, Lisa W %A Wiggins, Kerri L %A Hui, Qin %A Zhao, Wei %A Jackson, Rebecca D %A Ware, Erin B %A Faul, Jessica D %A Reiner, Alex P %A Bray, Michael %A Denny, Joshua C %A Mosley, Thomas H %A Palmas, Walter %A Guo, Xiuqing %A Papanicolaou, George J %A Penman, Alan D %A Polak, Joseph F %A Rice, Kenneth %A Taylor, Ken D %A Boerwinkle, Eric %A Bottinger, Erwin P %A Liu, Kiang %A Risch, Neil %A Hunt, Steven C %A Kooperberg, Charles %A Zonderman, Alan B %A Laurie, Cathy C %A Becker, Diane M %A Cai, Jianwen %A Loos, Ruth J F %A Psaty, Bruce M %A Weir, David R %A Kardia, Sharon L R %A Arnett, Donna K %A Won, Sungho %A Edwards, Todd L %A Redline, Susan %A Cooper, Richard S %A Rao, D C %A Rotter, Jerome I %A Rotimi, Charles %A Levy, Daniel %A Chakravarti, Aravinda %A Zhu, Xiaofeng %A Franceschini, Nora %K African Americans %K Animals %K Basic Helix-Loop-Helix Transcription Factors %K Blood Pressure %K Cadherins %K Case-Control Studies %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Hypertension %K Male %K Membrane Proteins %K Mice %K Multifactorial Inheritance %K Polymorphism, Single Nucleotide %X

Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25×10-8) for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4) and multiple-trait analyses identified one novel locus (FRMD3) for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension.

%B PLoS Genet %V 13 %P e1006728 %8 2017 May %G eng %N 5 %R 10.1371/journal.pgen.1006728 %0 Journal Article %J J Bone Miner Res %D 2017 %T Soluble Inflammatory Markers and Risk of Incident Fractures in Older Adults: The Cardiovascular Health Study. %A Stojanović, Danijela %A Bůzková, Petra %A Mukamal, Kenneth J %A Heckbert, Susan R %A Psaty, Bruce M %A Fink, Howard A %A Cauley, Jane A %A Wallace, Erin %A Curtis, Lesley H %A Hirsch, Calvin %A Budoff, Matthew %A Li, Dong %A Young, Rebekah %A Jalal, Diana %A Delaney, Joseph Ac %X

Several in vitro and animal studies have showed that inflammatory markers play a role in bone remodeling and pathogenesis of osteoporosis. Additionally, some human longitudinal studies showed suggestive associations between elevated inflammatory markers and increased risk of nontraumatic fractures. We examined several inflammatory markers and multiple fracture types in a single study of older individuals with extensive follow-up. We assessed the association of four inflammatory markers with the risk of incident hip fractures among 5265 participants of the Cardiovascular Health Study (CHS) and a composite endpoint of incident fractures of the hip, pelvis, humerus, or proximal forearm in 4477 participants. Among CHS participants followed between 1992 and 2009, we observed 480 incident hip fractures during a median follow-up of 11 years. In the composite fracture analysis cohort of 4477 participants, we observed 711 fractures during a median follow-up of 7 years. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for hip fracture associated with doubling of IL-6 were HR 1.15 (95% CI, 1.02 to 1.30) overall and HR 1.17 (95% CI, 1.01 to 1.35) in women. We also observed a positive association between each unit increase in white blood cell (WBC) count and risk of hip fracture: HR 1.04 (95% CI, 1.01 to 1.06) overall and HR 1.06 (95% CI, 0.95 to 1.20) in women. We observed no significant associations between any of the four inflammatory markers and a composite fracture endpoint. Our findings suggest that chronic inflammatory and immune processes may be related to higher rates of incident hip fractures. © 2017 American Society for Bone and Mineral Research.

%B J Bone Miner Res %8 2017 Oct 04 %G eng %R 10.1002/jbmr.3301 %0 Journal Article %J J Am Heart Assoc %D 2017 %T Subclinical Atherosclerosis, Cardiac and Kidney Function, Heart Failure, and Dementia in the Very Elderly. %A Kuller, Lewis H %A Lopez, Oscar L %A Gottdiener, John S %A Kitzman, Dalane W %A Becker, James T %A Chang, Yuefang %A Newman, Anne B %X

BACKGROUND: Heart failure (HF) and dementia are major causes of disability and death among older individuals. Risk factors and biomarkers of HF may be determinants of dementia in the elderly. We evaluated the relationship between biomarkers of cardiovascular disease and HF and risk of dementia and death. Three hypotheses were tested: (1) higher levels of high-sensitivity cardiac troponin T, N-terminal of prohormone brain natriuretic peptide, and cystatin C predict risk of death, cardiovascular disease, HF, and dementia; (2) higher levels of cardiovascular disease biomarkers are associated with increased risk of HF and then secondary increased risk of dementia; and (3) risk of dementia is lower among participants with a combination of lower coronary artery calcium, atherosclerosis, and lower high-sensitivity cardiac troponin T (myocardial injury).

METHODS AND RESULTS: The Cardiovascular Health Study Cognition Study was a continuation of the Cardiovascular Health Study limited to the Pittsburgh, PA, center from 1998-1999 to 2014. In 1992-1994, 924 participants underwent magnetic resonance imaging of the brain. There were 199 deaths and 116 developed dementia before 1998-1999. Of the 609 participants eligible for the Pittsburgh Cardiovascular Health Study Cognition Study, 87.5% (n=532) were included in the study. There were 120 incident HF cases and 72% had dementia. In 80 of 87, dementia preceded HF. A combination of low coronary artery calcium score and low high-sensitivity cardiac troponin T was significantly associated with reduced risk of dementia and HF.

CONCLUSIONS: Most participants with HF had dementia but with onset before HF. Lower high-sensitivity cardiac troponin T and coronary artery calcium was associated with low risk of dementia based on a small number of events.

CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00005133.

%B J Am Heart Assoc %V 6 %8 2017 Jul 22 %G eng %N 7 %R 10.1161/JAHA.116.005353 %0 Journal Article %J Alzheimers Dement %D 2017 %T Systems biology approach to late-onset Alzheimer's disease genome-wide association study identifies novel candidate genes validated using brain expression data and Caenorhabditis elegans experiments. %A Mukherjee, Shubhabrata %A Russell, Joshua C %A Carr, Daniel T %A Burgess, Jeremy D %A Allen, Mariet %A Serie, Daniel J %A Boehme, Kevin L %A Kauwe, John S K %A Naj, Adam C %A Fardo, David W %A Dickson, Dennis W %A Montine, Thomas J %A Ertekin-Taner, Nilufer %A Kaeberlein, Matt R %A Crane, Paul K %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Animals %K Animals, Genetically Modified %K Antigens, Neoplasm %K Caenorhabditis elegans %K Disease Models, Animal %K Early Growth Response Protein 1 %K Female %K Gene Expression Regulation %K Genome-Wide Association Study %K Heparin-binding EGF-like Growth Factor %K Humans %K Male %K Membrane Transport Proteins %K Mitochondrial ADP, ATP Translocases %K NADH Dehydrogenase %K Polymorphism, Single Nucleotide %K Protein Interaction Maps %K RNA Interference %K Systems Biology %K Temporal Lobe %X

INTRODUCTION: We sought to determine whether a systems biology approach may identify novel late-onset Alzheimer's disease (LOAD) loci.

METHODS: We performed gene-wide association analyses and integrated results with human protein-protein interaction data using network analyses. We performed functional validation on novel genes using a transgenic Caenorhabditis elegans Aβ proteotoxicity model and evaluated novel genes using brain expression data from people with LOAD and other neurodegenerative conditions.

RESULTS: We identified 13 novel candidate LOAD genes outside chromosome 19. Of those, RNA interference knockdowns of the C. elegans orthologs of UBC, NDUFS3, EGR1, and ATP5H were associated with Aβ toxicity, and NDUFS3, SLC25A11, ATP5H, and APP were differentially expressed in the temporal cortex.

DISCUSSION: Network analyses identified novel LOAD candidate genes. We demonstrated a functional role for four of these in a C. elegans model and found enrichment of differentially expressed genes in the temporal cortex.

%B Alzheimers Dement %V 13 %P 1133-1142 %8 2017 Oct %G eng %N 10 %R 10.1016/j.jalz.2017.01.016 %0 Journal Article %J J Thromb Haemost %D 2017 %T Taller height as a risk factor for venous thromboembolism: a Mendelian randomization meta-analysis. %A Roetker, N S %A Armasu, S M %A Pankow, J S %A Lutsey, P L %A Tang, W %A Rosenberg, M A %A Palmer, T M %A MacLehose, R F %A Heckbert, S R %A Cushman, M %A de Andrade, M %A Folsom, A R %X

BACKGROUND: Taller height is associated with greater risk of venous thromboembolism (VTE).

OBJECTIVES: We used instrumental variable (IV) techniques (Mendelian randomization) to further explore this relationship METHODS: Participants of European ancestry were included from two cohort studies [Atherosclerosis Risk in Communities (ARIC) study and Cardiovascular Health Study (CHS)] and one case-control study [Mayo Clinic VTE Study (Mayo)]. We created two weighted genetic risk scores (GRS) for height; the full GRS included 668 single nucleotide polymorphisms (SNPs) from a previously published meta-analysis and the restricted GRS included a subset of 362 SNPs not associated with weight independently of height. Standard logistic regression and IV models were used to estimate odds ratios (ORs) for VTE per 10 cm increment in height. ORs were pooled across the three studies using inverse variance weighted random effects meta-analysis RESULTS: Among 9143 ARIC and 3180 CHS participants free of VTE at baseline, there were 367 and 109 incident VTE events. There were 1143 VTE cases and 1292 controls included from Mayo. The pooled ORs from non-IV models and models using the full and restricted GRSs as IVs were 1.27 (95% CI: 1.11, 1.46), 1.34 (95% CI: 1.04, 1.73), and 1.45 (95% CI: 1.04, 2.01) per 10 cm greater height, respectively CONCLUSIONS: Taller height is associated with an increased risk of VTE in adults of European ancestry. Possible explanations for this association, including that taller people may have greater venous surface area, greater number of venous valves, or greater hydrostatic pressure, need to be explored further. This article is protected by copyright. All rights reserved.

%B J Thromb Haemost %8 2017 Apr 26 %G eng %R 10.1111/jth.13719 %0 Journal Article %J Aging (Albany NY) %D 2017 %T Telomeres and the natural lifespan limit in humans. %A Steenstrup, Troels %A Kark, Jeremy D %A Verhulst, Simon %A Thinggaard, Mikael %A Hjelmborg, Jacob V B %A Dalgård, Christine %A Kyvik, Kirsten Ohm %A Christiansen, Lene %A Mangino, Massimo %A Spector, Timothy D %A Petersen, Inge %A Kimura, Masayuki %A Benetos, Athanase %A Labat, Carlos %A Sinnreich, Ronit %A Hwang, Shih-Jen %A Levy, Daniel %A Hunt, Steven C %A Fitzpatrick, Annette L %A Chen, Wei %A Berenson, Gerald S %A Barbieri, Michelangela %A Paolisso, Giuseppe %A Gadalla, Shahinaz M %A Savage, Sharon A %A Christensen, Kaare %A Yashin, Anatoliy I %A Arbeev, Konstantin G %A Aviv, Abraham %X

An ongoing debate in demography has focused on whether the human lifespan has a maximal natural limit. Taking a mechanistic perspective, and knowing that short telomeres are associated with diminished longevity, we examined whether telomere length dynamics during adult life could set a maximal natural lifespan limit. We define leukocyte telomere length of 5 kb as the 'telomeric brink', which denotes a high risk of imminent death. We show that a subset of adults may reach the telomeric brink within the current life expectancy and more so for a 100-year life expectancy. Thus, secular trends in life expectancy should confront a biological limit due to crossing the telomeric brink.

%B Aging (Albany NY) %V 9 %P 1130-1142 %8 2017 Apr %G eng %N 4 %R 10.18632/aging.101216 %0 Journal Article %J Circulation %D 2017 %T Thyroid Function Within the Normal Range, Subclinical Hypothyroidism, and the Risk of Atrial Fibrillation. %A Baumgartner, Christine %A da Costa, Bruno R %A Collet, Tinh-Hai %A Feller, Martin %A Floriani, Carmen %A Bauer, Douglas C %A Cappola, Anne R %A Heckbert, Susan R %A Ceresini, Graziano %A Gussekloo, Jacobijn %A den Elzen, Wendy P J %A Peeters, Robin P %A Luben, Robert %A Völzke, Henry %A Dörr, Marcus %A Walsh, John P %A Bremner, Alexandra %A Iacoviello, Massimo %A Macfarlane, Peter %A Heeringa, Jan %A Stott, David J %A Westendorp, Rudi G J %A Khaw, Kay-Tee %A Magnani, Jared W %A Aujesky, Drahomir %A Rodondi, Nicolas %K Adult %K Aged %K Aged, 80 and over %K Asymptomatic Diseases %K Atrial Fibrillation %K Biomarkers %K Chi-Square Distribution %K Female %K Humans %K Hypothyroidism %K Incidence %K Male %K Middle Aged %K Predictive Value of Tests %K Prognosis %K Proportional Hazards Models %K Risk Assessment %K Risk Factors %K Thyroid Function Tests %K Thyroid Gland %K Thyrotropin %K Thyroxine %K Time Factors %K Young Adult %X

BACKGROUND: Atrial fibrillation (AF) is a highly prevalent disorder leading to heart failure, stroke, and death. Enhanced understanding of modifiable risk factors may yield opportunities for prevention. The risk of AF is increased in subclinical hyperthyroidism, but it is uncertain whether variations in thyroid function within the normal range or subclinical hypothyroidism are also associated with AF.

METHODS: We conducted a systematic review and obtained individual participant data from prospective cohort studies that measured thyroid function at baseline and assessed incident AF. Studies were identified from MEDLINE and EMBASE databases from inception to July 27, 2016. The euthyroid state was defined as thyroid-stimulating hormone (TSH) 0.45 to 4.49 mIU/L, and subclinical hypothyroidism as TSH 4.5 to 19.9 mIU/L with free thyroxine (fT4) levels within reference range. The association of TSH levels in the euthyroid and subclinical hypothyroid range with incident AF was examined by using Cox proportional hazards models. In euthyroid participants, we additionally examined the association between fT4 levels and incident AF.

RESULTS: Of 30 085 participants from 11 cohorts (278 955 person-years of follow-up), 1958 (6.5%) had subclinical hypothyroidism and 2574 individuals (8.6%) developed AF during follow-up. TSH at baseline was not significantly associated with incident AF in euthyroid participants or those with subclinical hypothyroidism. Higher fT4 levels at baseline in euthyroid individuals were associated with increased AF risk in age- and sex-adjusted analyses (hazard ratio, 1.45; 95% confidence interval, 1.26-1.66, for the highest quartile versus the lowest quartile of fT4; P for trend ≤0.001 across quartiles). Estimates did not substantially differ after further adjustment for preexisting cardiovascular disease.

CONCLUSIONS: In euthyroid individuals, higher circulating fT4 levels, but not TSH levels, are associated with increased risk of incident AF.

%B Circulation %V 136 %P 2100-2116 %8 2017 Nov 28 %G eng %N 22 %R 10.1161/CIRCULATIONAHA.117.028753 %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2017 %T Trajectories of IGF-I Predict Mortality in Older Adults: The Cardiovascular Health Study. %A Sanders, Jason L %A Guo, Wensheng %A O'Meara, Ellen S %A Kaplan, Robert C %A Pollak, Michael N %A Bartz, Traci M %A Newman, Anne B %A Fried, Linda P %A Cappola, Anne R %X

Background: Disruption of insulin-like growth factor-I (IGF-I) increases health and life span in animal models, though this is unconfirmed in humans. If IGF-I stability indicates homeostasis, the absolute level of IGF-I may be less clinically relevant than maintaining an IGF-I setpoint.

Methods: Participants were 945 U.S. community-dwelling individuals aged ≥65 years enrolled in the Cardiovascular Health Study with IGF-I levels at 3-6 timepoints. We examined the association of baseline IGF-I level, trajectory slope, and variability around the trajectory with mortality.

Results: There were 633 deaths over median 11.3 years of follow-up. Lower IGF-I levels, declining or increasing slope, and increasing variability were each individually associated with higher mortality (all p < .001). In an adjusted model including all three trajectory parameters, baseline IGF-I levels <70 ng/mL (hazard ratio [HR] 1.58, 95% CI 1.28-1.96 relative to IGF-I levels of 170 ng/mL), steep declines and steep increases in trajectory slope (HR 2.22, 1.30-3.80 for a 15% decline; HR 1.40, 1.07-1.84 for a 10% decline; HR 1.80, 1.12-2.89 for a 15% increase; HR 1.31, 1.00-1.72 for a 10% increase, each vs no change), and variability ≥10% (HR 1.59, 1.09-2.32 for ≥ 30%; HR 1.36, 1.06-1.75 for 20%; and HR 1.17, 1.03-1.32 for 10% variability, each vs 0%) in IGF-I levels were independently associated with mortality.

Conclusions: In contrast to data from animal models, low IGF-I levels are associated with higher mortality in older humans. Irrespective of the actual IGF-I level, older individuals with stability of IGF-I levels have lower mortality than those whose IGF-I levels fluctuate over time.

%B J Gerontol A Biol Sci Med Sci %8 2017 Jul 23 %G eng %R 10.1093/gerona/glx143 %0 Journal Article %J Hum Genet %D 2017 %T Trans-ethnic fine-mapping of genetic loci for body mass index in the diverse ancestral populations of the Population Architecture using Genomics and Epidemiology (PAGE) Study reveals evidence for multiple signals at established loci. %A Fernandez-Rhodes, Lindsay %A Gong, Jian %A Haessler, Jeffrey %A Franceschini, Nora %A Graff, Mariaelisa %A Nishimura, Katherine K %A Wang, Yujie %A Highland, Heather M %A Yoneyama, Sachiko %A Bush, William S %A Goodloe, Robert %A Ritchie, Marylyn D %A Crawford, Dana %A Gross, Myron %A Fornage, Myriam %A Bůzková, Petra %A Tao, Ran %A Isasi, Carmen %A Avilés-Santa, Larissa %A Daviglus, Martha %A Mackey, Rachel H %A Houston, Denise %A Gu, C Charles %A Ehret, Georg %A Nguyen, Khanh-Dung H %A Lewis, Cora E %A Leppert, Mark %A Irvin, Marguerite R %A Lim, Unhee %A Haiman, Christopher A %A Le Marchand, Loïc %A Schumacher, Fredrick %A Wilkens, Lynne %A Lu, Yingchang %A Bottinger, Erwin P %A Loos, Ruth J L %A Sheu, Wayne H-H %A Guo, Xiuqing %A Lee, Wen-Jane %A Hai, Yang %A Hung, Yi-Jen %A Absher, Devin %A Wu, I-Chien %A Taylor, Kent D %A Lee, I-Te %A Liu, Yeheng %A Wang, Tzung-Dau %A Quertermous, Thomas %A Juang, Jyh-Ming J %A Rotter, Jerome I %A Assimes, Themistocles %A Hsiung, Chao A %A Chen, Yii-Der Ida %A Prentice, Ross %A Kuller, Lewis H %A Manson, JoAnn E %A Kooperberg, Charles %A Smokowski, Paul %A Robinson, Whitney R %A Gordon-Larsen, Penny %A Li, Rongling %A Hindorff, Lucia %A Buyske, Steven %A Matise, Tara C %A Peters, Ulrike %A North, Kari E %K Body Mass Index %K Ethnic Groups %K Genetics, Population %K Humans %K Obesity %X

Most body mass index (BMI) genetic loci have been identified in studies of primarily European ancestries. The effect of these loci in other racial/ethnic groups is less clear. Thus, we aimed to characterize the generalizability of 170 established BMI variants, or their proxies, to diverse US populations and trans-ethnically fine-map 36 BMI loci using a sample of >102,000 adults of African, Hispanic/Latino, Asian, European and American Indian/Alaskan Native descent from the Population Architecture using Genomics and Epidemiology Study. We performed linear regression of the natural log of BMI (18.5-70 kg/m(2)) on the additive single nucleotide polymorphisms (SNPs) at BMI loci on the MetaboChip (Illumina, Inc.), adjusting for age, sex, population stratification, study site, or relatedness. We then performed fixed-effect meta-analyses and a Bayesian trans-ethnic meta-analysis to empirically cluster by allele frequency differences. Finally, we approximated conditional and joint associations to test for the presence of secondary signals. We noted directional consistency with the previously reported risk alleles beyond what would have been expected by chance (binomial p < 0.05). Nearly, a quarter of the previously described BMI index SNPs and 29 of 36 densely-genotyped BMI loci on the MetaboChip replicated/generalized in trans-ethnic analyses. We observed multiple signals at nine loci, including the description of seven loci with novel multiple signals. This study supports the generalization of most common genetic loci to diverse ancestral populations and emphasizes the importance of dense multiethnic genomic data in refining the functional variation at genetic loci of interest and describing several loci with multiple underlying genetic variants.

%B Hum Genet %V 136 %P 771-800 %8 2017 Jun %G eng %N 6 %R 10.1007/s00439-017-1787-6 %0 Journal Article %J Eur J Epidemiol %D 2017 %T Trends in the incidence of dementia: design and methods in the Alzheimer Cohorts Consortium. %A Chibnik, Lori B %A Wolters, Frank J %A Bäckman, Kristoffer %A Beiser, Alexa %A Berr, Claudine %A Bis, Joshua C %A Boerwinkle, Eric %A Bos, Daniel %A Brayne, Carol %A Dartigues, Jean-François %A Darweesh, Sirwan K L %A Debette, Stephanie %A Davis-Plourde, Kendra L %A Dufouil, Carole %A Fornage, Myriam %A Grasset, Leslie %A Gudnason, Vilmundur %A Hadjichrysanthou, Christoforos %A Helmer, Catherine %A Ikram, M Arfan %A Ikram, M Kamran %A Kern, Silke %A Kuller, Lewis H %A Launer, Lenore %A Lopez, Oscar L %A Matthews, Fiona %A Meirelles, Osorio %A Mosley, Thomas %A Ower, Alison %A Psaty, Bruce M %A Satizabal, Claudia L %A Seshadri, Sudha %A Skoog, Ingmar %A Stephan, Blossom C M %A Tzourio, Christophe %A Waziry, Reem %A Wong, Mei Mei %A Zettergren, Anna %A Hofman, Albert %X

Several studies have reported a decline in incidence of dementia which may have large implications for the projected burden of disease, and provide important guidance to preventive efforts. However, reports are conflicting or inconclusive with regard to the impact of gender and education with underlying causes of a presumed declining trend remaining largely unidentified. The Alzheimer Cohorts Consortium aggregates data from nine international population-based cohorts to determine changes in the incidence of dementia since 1990. We will employ Poisson regression models to calculate incidence rates in each cohort and Cox proportional hazard regression to compare 5-year cumulative hazards across study-specific epochs. Finally, we will meta-analyse changes per decade across cohorts, and repeat all analysis stratified by sex, education and APOE genotype. In all cohorts combined, there are data on almost 69,000 people at risk of dementia with the range of follow-up years between 2 and 27. The average age at baseline is similar across cohorts ranging between 72 and 77. Uniting a wide range of disease-specific and methodological expertise in research teams, the first analyses within the Alzheimer Cohorts Consortium are underway to tackle outstanding challenges in the assessment of time-trends in dementia occurrence.

%B Eur J Epidemiol %V 32 %P 931-938 %8 2017 Oct %G eng %N 10 %R 10.1007/s10654-017-0320-5 %0 Journal Article %J Bone %D 2018 %T The 24,25 to 25-hydroxyvitamin D ratio and fracture risk in older adults: The cardiovascular health study. %A Ginsberg, Charles %A Katz, Ronit %A de Boer, Ian H %A Kestenbaum, Bryan R %A Chonchol, Michel %A Shlipak, Michael G %A Sarnak, Mark J %A Hoofnagle, Andrew N %A Rifkin, Dena E %A Garimella, Pranav S %A Ix, Joachim H %X

25-hydroxyvitamin D [25(OH)D] may not optimally indicate vitamin D receptor activity. Higher concentrations of its catabolic product 24,25-dihydroxyvitmin D [24,25(OH)2D] and a higher ratio of 24,25(OH)2D to 25(OH)D (the vitamin D metabolite ratio [VMR]) may provide additional information on receptor activity. We compared the strength of associations of these markers with serum PTH concentrations, hip bone mineral density (BMD), and risk of incident hip fracture in community-living older participants in the Cardiovascular Health Study. Among 890 participants, the mean age was 78years, 60% were women, and the mean 25(OH)D was 28±11ng/ml. In cross-sectional analysis, the strength of association of each vitamin D measure with PTH was similar; a 1% higher 25(OH)D, 24,25(OH)2D, and VMR were associated with 0.32%, 0.25%, and 0.26% lower PTH, respectively (p<0.05 for all). Among 358 participants with available BMD data, we found no associations of 25(OH)D or VMR with BMD, whereas higher 24,25(OH)2D was modestly associated with greater hip BMD (1% higher 24,25(OH)2D associated with 0.04% [95% CI 0.01-0.08%] higher BMD). Risk of incident hip fracture risk was evaluated using a case-cohort design. There were 289 hip fractures during a mean follow up time of 8.4years. Both higher 24,25(OH)2D and VMR were associated with lower risk of hip fracture (HR per SD higher, 0.73 [0.61, 0.87] and 0.74 [0.61, 0.88], respectively) whereas 25(OH)D was not associated with hip fracture (HR 0.93 [0.79, 1.10]). We conclude that evaluating vitamin D status by incorporating assessment of 24,25(OH)D and the VMR provides information on bone health above and beyond 25(OH)D alone.

%B Bone %V 107 %P 124-130 %8 2018 Feb %G eng %R 10.1016/j.bone.2017.11.011 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Aortic Stiffness is Associated with Increased Risk of Incident Dementia in Older Adults. %A Cui, Chendi %A Sekikawa, Akira %A Kuller, Lewis H %A Lopez, Oscar L %A Newman, Anne B %A Kuipers, Allison L %A Mackey, Rachel H %X

Cardiovascular disease risk factors, including age, hypertension, and diabetes, contribute to aortic stiffness and subclinical cardiovascular and brain disease, increasing dementia risk. Aortic stiffness, measured by carotid-femoral pulse wave velocity (cfPWV), reduces the buffering of pulsatile blood flow, exposing cerebral small arteries to microvascular damage. High cfPWV is related to white matter hyperintensities and brain amyloid deposition, and to cognitive decline, but it is unclear whether cfPWV independently predicts incident dementia. Therefore, we tested the hypothesis that cfPWV predicts incident dementia in older adults, independent of potential confounders. The Cardiovascular Health Study Cognition Study followed 532 non-demented older adults with annual cognitive exams from 1998-99 through 2013. CfPWV was measured on 356 (mean age = 78, 59% women) between 1996-2000. Over 15 years, 212 (59.6%) developed dementia (median time from cfPWV measurement = 4 years). In age and sex-adjusted Cox models, cfPWV was significantly associated with increased risk of dementia, but systolic blood pressure, mean arterial pressure and pulse pressure were not. CfPWV (transformed as - 1/cfPWV) remained significantly associated with dementia risk when further adjusted for education, race, APOEɛ4, diabetes, body mass index, mean arterial pressure, and anti-hypertensive medication (hazard ratio = 1.60, 95% CI = 1.02, 2.51). Results were similar when further adjusted for baseline global cognition, subclinical brain measures, and coronary artery calcification. Finally, higher cfPWV was related to lower physical activity intensity and higher systolic blood pressure, heart rate, and waist circumference measured 5 years prior. An important unanswered question is whether interventions to slow arterial stiffening can reduce the risk of dementia.

%B J Alzheimers Dis %V 66 %P 297-306 %8 2018 %G eng %N 1 %R 10.3233/JAD-180449 %0 Journal Article %J J Intern Med %D 2018 %T Association between subclinical thyroid dysfunction and change in bone mineral density in prospective cohorts. %A Segna, D %A Bauer, D C %A Feller, M %A Schneider, C %A Fink, H A %A Aubert, C E %A Collet, T-H %A da Costa, B R %A Fischer, K %A Peeters, R P %A Cappola, A R %A Blum, M R %A van Dorland, H A %A Robbins, J %A Naylor, K %A Eastell, R %A Uitterlinden, A G %A Rivadeneira Ramirez, F %A Gogakos, A %A Gussekloo, J %A Williams, G R %A Schwartz, A %A Cauley, J A %A Aujesky, D A %A Bischoff-Ferrari, H A %A Rodondi, N %K Aged %K Asymptomatic Diseases %K Bone Density %K Female %K Fractures, Bone %K Humans %K Hyperthyroidism %K Hypothyroidism %K Male %K Risk Factors %X

BACKGROUND: Subclinical hyperthyroidism (SHyper) has been associated with increased risk of hip and other fractures, but the linking mechanisms remain unclear.

OBJECTIVE: To investigate the association between subclinical thyroid dysfunction and bone loss.

METHODS: Individual participant data analysis was performed after a systematic literature search in MEDLINE/EMBASE (1946-2016). Two reviewers independently screened and selected prospective cohorts providing baseline thyroid status and serial bone mineral density (BMD) measurements. We classified thyroid status as euthyroidism (thyroid-stimulating hormone [TSH] 0.45-4.49 mIU/L), SHyper (TSH < 0.45 mIU/L) and subclinical hypothyroidism (SHypo, TSH ≥ 4.50-19.99 mIU/L) both with normal free thyroxine levels. Our primary outcome was annualized percentage BMD change (%ΔBMD) from serial dual X-ray absorptiometry scans of the femoral neck, total hip and lumbar spine, obtained from multivariable regression in a random-effects two-step approach.

RESULTS: Amongst 5458 individuals (median age 72 years, 49.1% women) from six prospective cohorts, 451 (8.3%) had SHypo and 284 (5.2%) had SHyper. During 36 569 person-years of follow-up, those with SHyper had a greater annual bone loss at the femoral neck versus euthyroidism: %ΔBMD = -0.18 (95% CI: -0.34, -0.02; I2 = 0%), with a nonstatistically significant pattern at the total hip: %ΔBMD = -0.14 (95% CI: -0.38, 0.10; I2 = 53%), but not at the lumbar spine: %ΔBMD = 0.03 (95% CI: -0.30, 0.36; I2 = 25%); especially participants with TSH < 0.10 mIU/L showed an increased bone loss in the femoral neck (%Δ BMD = -0.59; [95% CI: -0.99, -0.19]) and total hip region (%ΔBMD = -0.46 [95% CI: -1.05, -0.13]). In contrast, SHypo was not associated with bone loss at any site.

CONCLUSION: Amongst adults, SHyper was associated with increased femoral neck bone loss, potentially contributing to the increased fracture risk.

%B J Intern Med %V 283 %P 56-72 %8 2018 Jan %G eng %N 1 %R 10.1111/joim.12688 %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2018 %T Association of biomarker and physiologic indices with mortality in older adults: Cardiovascular Health Study. %A Sanders, Jason L %A Arnold, Alice M %A Boudreau, Robert M %A Hirsch, Calvin H %A Kizer, Jorge R %A Kaplan, Robert C %A Cappola, Anne R %A Cushman, Mary %A Jacob, Mini E %A Kritchevsky, Stephen B %A Newman, Anne B %X

Background: A goal of gerontology is discovering aging phenotypes that reflect biological aging distinct from disease pathogenesis. Biomarkers strongly and independently associated with mortality and which statistically attenuate chronologic age could be used to define such a phenotype. We determined the association of a Biomarker Index (BI) with mortality and compared it to a validated Physiologic Index (PI) in older adults.

Methods: The indices were constructed in the Cardiovascular Health Study, mean (SD) age 74.5 (5.1) years. The BI incorporated circulating levels of new biomarkers, including insulin-like growth factor (IGF)-1, IGF binding protein 3, amino-terminal pro-B-type natriuretic peptide, dehydroepiandrosterone sulfate, and interleukin-6, and was built in test (N=2197) and validation (N=1124) samples. The PI included carotid intima-media thickness, pulmonary capacity, brain white matter grade, cystatin-C, and fasting glucose. Multivariable Cox proportional hazards models predicting death were calculated with 10 years of follow-up.

Results: In separate age-adjusted models, the hazard ratio (HR) for mortality per point of the BI was 1.30 (95% CI 1.25, 1.34) and the BI attenuated age by 25%. The HR for the PI was 1.28 (1.24, 1.33) (29% age attenuation). In the same model, the HR for the BI was 1.23 (1.18, 1.28) and for the PI was 1.22 (1.17, 1.26), and age was attenuated 42.5%. Associations persisted after further adjustment.

Conclusions: The BI and PI were significantly and independently associated with mortality. Both attenuated the age effect on mortality substantially. The indices may be feasible phenotypes for developing interventions hoping to alter the trajectory of aging.

%B J Gerontol A Biol Sci Med Sci %8 2018 Apr 12 %G eng %R 10.1093/gerona/gly075 %0 Journal Article %J Bone %D 2018 %T Association of bone mineral density with hemoglobin and change in hemoglobin among older men and women: The Cardiovascular Health Study. %A Valderrábano, Rodrigo J %A Bůzková, Petra %A Chang, Po-Yin %A Zakai, Neil A %A Fink, Howard A %A Robbins, John A %A Lee, Jennifer S %A Wu, Joy Y %X

PURPOSE: Osteoblasts and their precursors support hematopoiesis in the bone marrow. We hypothesized that declines in Hgb levels are associated with bone mineral density (BMD).

METHODS: The Cardiovascular Health Study is a prospective longitudinal study that enrolled 5888 community-dwelling adults aged >65 years and measured hemoglobin twice, in 1989-90 and 1992-93, as well as BMD by dual-energy X-ray absorptiometry (DXA) in 1994-95. In a subset of 1513 men and women with a Hgb in 1992-93 and BMD, we used linear regression to estimate associations of Hgb (per standard deviation (SD)) with total hip (TH), lumbar spine (LS) and total body (TB) BMD, and used Poisson regression to estimate associations of anemia (in 1992-93; Hgb <13 g/dL in men; <12 g/dL in women) with "low BMD" defined as T-score less than -1 at the TH. In 1277 participants with Hgb measured on average 2.9 years apart and BMD, we used linear regression to estimate the associations of annualized change in Hgb with TH, LS and TB BMD. All models included age, sex, study-site, race, smoking, alcohol use, weight, height, steroid use, physical activity score, self-reported health, previous cardiovascular disease and prior anti-fracture medication use.

RESULTS: No significant association was observed between Hgb, measured a mean 2.2 years prior to BMD, and BMD at the TH and LS in men (TH beta = -0.60 [x 10 g/cmper 1.1 g/dL Hgb], 95% CI: -1.88 to 0.68; LS beta = -1.69, 95% CI: -3.83 to 0.45) or women (TH beta = -0.49 [x 10 g/cmper 1.3 g/dL Hgb], 95% CI: -1.57 to 0.59; LS beta = -0.40, 95% CI: -2.57 to 1.76). Anemia was not observed to be significantly associated with low BMD in men (RR = 0.99, 95% CI: 0.72-1.40) nor women (RR = 0.98, 95% CI: 0.82-1.17). The mean change in Hgb was a loss of 0.06 g/dL/year (SD = 0.32). Change in Hgb was not observed to be significantly associated with BMD in men (TH beta = -0.55[x 10 g/cmper 1 g/dL annualized Hgb change], 95% CI: -4.28 to 3.19; LS beta = 0.63, 95% CI: -5.38 to 6.65) or women (TH beta = 0.92, 95% CI: -1.96 to 3.79; LS beta = -1.77, 95% CI: -7.52 to 3.98). No significant association was observed between anemia and low bone density by T-score in men and women.

CONCLUSIONS: These findings support neither the hypothesis that low Hgb prior to bone density or decreases in Hgb are associated with bone density in older community-dwelling adults nor the use of Hgb level as a case-finding tool to prompt BMD measurement.

%B Bone %V 120 %P 321-326 %8 2018 Nov 15 %G eng %R 10.1016/j.bone.2018.11.010 %0 Journal Article %J JAMA Cardiol %D 2018 %T Association of Cardiovascular Biomarkers With Incident Heart Failure With Preserved and Reduced Ejection Fraction. %A de Boer, Rudolf A %A Nayor, Matthew %A deFilippi, Christopher R %A Enserro, Danielle %A Bhambhani, Vijeta %A Kizer, Jorge R %A Blaha, Michael J %A Brouwers, Frank P %A Cushman, Mary %A Lima, João A C %A Bahrami, Hossein %A van der Harst, Pim %A Wang, Thomas J %A Gansevoort, Ron T %A Fox, Caroline S %A Gaggin, Hanna K %A Kop, Willem J %A Liu, Kiang %A Vasan, Ramachandran S %A Psaty, Bruce M %A Lee, Douglas S %A Hillege, Hans L %A Bartz, Traci M %A Benjamin, Emelia J %A Chan, Cheeling %A Allison, Matthew %A Gardin, Julius M %A Januzzi, James L %A Shah, Sanjiv J %A Levy, Daniel %A Herrington, David M %A Larson, Martin G %A van Gilst, Wiek H %A Gottdiener, John S %A Bertoni, Alain G %A Ho, Jennifer E %X

Importance: Nearly half of all patients with heart failure have preserved ejection fraction (HFpEF) as opposed to reduced ejection fraction (HFrEF), yet associations of biomarkers with future heart failure subtype are incompletely understood.

Objective: To evaluate the associations of 12 cardiovascular biomarkers with incident HFpEF vs HFrEF among adults from the general population.

Design, Setting, and Participants: This study included 4 longitudinal community-based cohorts: the Cardiovascular Health Study (1989-1990; 1992-1993 for supplemental African-American cohort), the Framingham Heart Study (1995-1998), the Multi-Ethnic Study of Atherosclerosis (2000-2002), and the Prevention of Renal and Vascular End-stage Disease study (1997-1998). Each cohort had prospective ascertainment of incident HFpEF and HFrEF. Data analysis was performed from June 25, 2015, to November 9, 2017.

Exposures: The following biomarkers were examined: N-terminal pro B-type natriuretic peptide or brain natriuretic peptide, high-sensitivity troponin T or I, C-reactive protein (CRP), urinary albumin to creatinine ratio (UACR), renin to aldosterone ratio, D-dimer, fibrinogen, soluble suppressor of tumorigenicity, galectin-3, cystatin C, plasminogen activator inhibitor 1, and interleukin 6.

Main Outcomes and Measures: Development of incident HFpEF and incident HFrEF.

Results: Among the 22 756 participants in these 4 cohorts (12 087 women and 10 669 men; mean [SD] age, 60 [13] years) in the study, during a median follow-up of 12 years, 633 participants developed incident HFpEF, and 841 developed HFrEF. In models adjusted for clinical risk factors of heart failure, 2 biomarkers were significantly associated with incident HFpEF: UACR (hazard ratio [HR], 1.33; 95% CI, 1.20-1.48; P < .001) and natriuretic peptides (HR, 1.27; 95% CI, 1.16-1.40; P < .001), with suggestive associations for high-sensitivity troponin (HR, 1.11; 95% CI, 1.03-1.19; P = .008), plasminogen activator inhibitor 1 (HR, 1.22; 95% CI, 1.03-1.45; P = .02), and fibrinogen (HR, 1.12; 95% CI, 1.03-1.22; P = .01). By contrast, 6 biomarkers were associated with incident HFrEF: natriuretic peptides (HR, 1.54; 95% CI, 1.41-1.68; P < .001), UACR (HR, 1.21; 95% CI, 1.11-1.32; P < .001), high-sensitivity troponin (HR, 1.37; 95% CI, 1.29-1.46; P < .001), cystatin C (HR, 1.19; 95% CI, 1.11-1.27; P < .001), D-dimer (HR, 1.22; 95% CI, 1.11-1.35; P < .001), and CRP (HR, 1.19; 95% CI, 1.11-1.28; P < .001). When directly compared, natriuretic peptides, high-sensitivity troponin, and CRP were more strongly associated with HFrEF compared with HFpEF.

Conclusions and Relevance: Biomarkers of renal dysfunction, endothelial dysfunction, and inflammation were associated with incident HFrEF. By contrast, only natriuretic peptides and UACR were associated with HFpEF. These findings highlight the need for future studies focused on identifying novel biomarkers of the risk of HFpEF.

%B JAMA Cardiol %8 2018 Jan 10 %G eng %R 10.1001/jamacardio.2017.4987 %0 Journal Article %J Am Heart J %D 2018 %T Association of lipoprotein-associated phospholipase A and risk of incident atrial fibrillation: Findings from 3 cohorts. %A Garg, Parveen K %A Bartz, Traci M %A Norby, Faye L %A Jorgensen, Neal W %A McClelland, Robyn L %A Ballantyne, Christie M %A Chen, Lin Y %A Gottdiener, John S %A Greenland, Philip %A Hoogeveen, Ron %A Jenny, Nancy S %A Kizer, Jorge R %A Rosenson, Robert S %A Soliman, Elsayed Z %A Cushman, Mary %A Alonso, Alvaro %A Heckbert, Susan R %X

BACKGROUND: Multiple prospective studies have established an association between inflammation and higher risk of atrial fibrillation (AF), but the association between lipoprotein-associated phospholipase A (Lp-PLA) mass and activity and incident AF has not been extensively evaluated.

METHODS: Using data from 10,794 Atherosclerosis Risk In Communities (ARIC) study participants aged 53-75 years, 5,181 Cardiovascular Health Study (CHS) participants aged 65 to 100 years, and 5,425 Multi-Ethnic Study of Atherosclerosis (MESA) participants aged 45-84 years, we investigated the association between baseline Lp-PLA levels and the risk of developing AF. Incident AF was identified in each cohort by follow-up visit electrocardiograms, hospital discharge coding of AF, or Medicare claims data.

RESULTS: Over a mean of 13.1, 11.5, and 10.0 years of follow-up, 1,439 (13%), 2,084 (40%), and 615 (11%) incident AF events occurred in ARIC, CHS, and MESA, respectively. In adjusted analyses, each SD increment in Lp-PLA activity was associated with incident AF in both ARIC (hazard ratio [HR] 1.13, 95% CI 1.06-1.20) and MESA (HR 1.24, 95% CI 1.05-1.46). Each SD increment in Lp-PLA mass was also associated with incident AF in MESA (HR 1.25, 95% CI 1.11-1.41). No significant associations were observed among CHS participants.

CONCLUSIONS: Although higher Lp-PLA mass and activity were associated with development of AF in ARIC and MESA, this relationship was not observed in CHS, a cohort of older individuals.

%B Am Heart J %V 197 %P 62-69 %8 2018 Mar %G eng %R 10.1016/j.ahj.2017.11.010 %0 Journal Article %J JACC Heart Fail %D 2018 %T The Association of Obesity and Cardiometabolic Traits With Incident HFpEF and HFrEF. %A Savji, Nazir %A Meijers, Wouter C %A Bartz, Traci M %A Bhambhani, Vijeta %A Cushman, Mary %A Nayor, Matthew %A Kizer, Jorge R %A Sarma, Amy %A Blaha, Michael J %A Gansevoort, Ron T %A Gardin, Julius M %A Hillege, Hans L %A Ji, Fei %A Kop, Willem J %A Lau, Emily S %A Lee, Douglas S %A Sadreyev, Ruslan %A van Gilst, Wiek H %A Wang, Thomas J %A Zanni, Markella V %A Vasan, Ramachandran S %A Allen, Norrina B %A Psaty, Bruce M %A van der Harst, Pim %A Levy, Daniel %A Larson, Martin %A Shah, Sanjiv J %A de Boer, Rudolf A %A Gottdiener, John S %A Ho, Jennifer E %X

OBJECTIVES: This study evaluated the associations of obesity and cardiometabolic traits with incident heart failure with preserved versus reduced ejection fraction (HFpEF vs. HFrEF). Given known sex differences in HF subtype, we examined men and women separately.

BACKGROUND: Recent studies suggest that obesity confers greater risk of HFpEF versus HFrEF. Contributions of associated metabolic traits to HFpEF are less clear.

METHODS: We studied 22,681 participants from 4 community-based cohorts followed for incident HFpEF versus HFrEF (ejection fraction ≥50% vs. <50%). We evaluated the association of body mass index (BMI) and cardiometabolic traits with incident HF subtype using Cox models.

RESULTS: The mean age was 60 ± 13 years, and 53% were women. Over a median follow-up of 12 years, 628 developed incident HFpEF and 835 HFrEF. Greater BMI portended higher risk of HFpEF compared with HFrEF (hazard ratio [HR]: 1.34 per 1-SD increase in BMI; 95% confidence interval [CI]: 1.24 to 1.45 vs. HR: 1.18; 95% CI: 1.10 to 1.27). Similarly, insulin resistance (homeostatic model assessment of insulin resistance) was associated with HFpEF (HR: 1.20 per 1-SD; 95% CI: 1.05 to 1.37), but not HFrEF (HR: 0.99; 95% CI: 0.88 to 1.11; p < 0.05 for difference HFpEF vs. HFrEF). We found that the differential association of BMI with HFpEF versus HFrEF was more pronounced among women (p for difference HFpEF vs. HFrEF = 0.01) when compared with men (p = 0.34).

CONCLUSIONS: Obesity and related cardiometabolic traits including insulin resistance are more strongly associated with risk of future HFpEF versus HFrEF. The differential risk of HFpEF with obesity seems particularly pronounced among women and may underlie sex differences in HF subtypes.

%B JACC Heart Fail %V 6 %P 701-709 %8 2018 Aug %G eng %N 8 %R 10.1016/j.jchf.2018.05.018 %0 Journal Article %J J Thromb Haemost %D 2018 %T Associations of activated coagulation factor VII and factor VIIa-antithrombin levels with genome-wide polymorphisms and cardiovascular disease risk. %A Olson, N C %A Raffield, L M %A Lange, L A %A Lange, E M %A Longstreth, W T %A Chauhan, G %A Debette, S %A Seshadri, S %A Reiner, A P %A Tracy, R P %X

ESSENTIALS: Essentials A fraction of coagulation factor VII circulates in blood as an activated protease (FVIIa). We evaluated FVIIa and FVIIa-antithrombin (FVIIa-AT) levels in the Cardiovascular Health Study. Polymorphisms in the F7 and PROCR loci were associated with FVIIa and FVIIa-AT levels. FVIIa may be an ischemic stroke risk factor in older adults and FVIIa-AT may assess mortality risk.

SUMMARY: Background A fraction of coagulation factor (F) VII circulates as an active protease (FVIIa). FVIIa also circulates as an inactivated complex with antithrombin (FVIIa-AT). Objective Evaluate associations of FVIIa and FVIIa-AT with genome-wide single nucleotide polymorphisms (SNPs) and incident coronary heart disease, ischemic stroke and mortality. Patients/Methods We measured FVIIa and FVIIa-AT in 3486 Cardiovascular Health Study (CHS) participants. We performed a genome-wide association scan for FVIIa and FVIIa-AT in European-Americans (n = 2410) and examined associations of FVII phenotypes with incident cardiovascular disease. Results In European-Americans, the most significant SNP for FVIIa and FVIIa-AT was rs1755685 in the F7 promoter region on chromosome 13 (FVIIa, β = -25.9 mU mL-1 per minor allele; FVIIa-AT, β = -26.6 pm per minor allele). Phenotypes were also associated with rs867186 located in PROCR on chromosome 20 (FVIIa, β = 7.8 mU mL-1 per minor allele; FVIIa-AT, β = 9.9 per minor allele). Adjusted for risk factors, a one standard deviation higher FVIIa was associated with increased risk of ischemic stroke (hazard ratio [HR], 1.12; 95% confidence interval [CI], 1.01, 1.23). Higher FVIIa-AT was associated with mortality from all causes (HR, 1.08; 95% CI, 1.03, 1.12). Among European-American CHS participants the rs1755685 minor allele was associated with lower ischemic stroke (HR, 0.69; 95% CI, 0.54, 0.88), but this association was not replicated in a larger multi-cohort analysis. Conclusions The results support the importance of the F7 and PROCR loci in variation in circulating FVIIa and FVIIa-AT. The findings suggest FVIIa is a risk factor for ischemic stroke in older adults, whereas higher FVIIa-AT may reflect mortality risk.

%B J Thromb Haemost %V 16 %P 19-30 %8 2018 Jan %G eng %N 1 %R 10.1111/jth.13899 %0 Journal Article %J Osteoporos Int %D 2018 %T The associations of subclinical atherosclerotic cardiovascular disease with hip fracture risk and bone mineral density in elderly adults. %A Barzilay, JI %A Bůzková, Petra %A Cauley, J A %A Robbins, J. A. %A Fink, Howard A %A Mukamal, K J %K Bone mineral density %K Hip fracture %K Risk %K Subclinical atherosclerosis %X In the absence of clinically recognized cardiovascular disease, increased carotid artery intimal medial thickness was associated with higher hip fracture risk in older adults, despite its association with higher bone mineral density (BMD). Low ankle brachial index and aortic wall thickness were not associated with fracture risk or BMD. INTRODUCTION: Clinically recognized cardiovascular disease (CVD) is associated with osteoporosis and hip fracture risk, but the relationship of subclinical atherosclerosis to bone health is not certain. METHODS: We followed 3385 participants from the Cardiovascular Health Study (mean age 74.7 ± 5.3 years) with a median time to fracture of 12.1 years who underwent baseline carotid artery and aortic wall ultrasound scanning and ankle brachial blood pressure index (ABI) determinations. A subset underwent bone mineral density (BMD) testing. RESULTS: There were 494 hip fractures during follow-up. Among persons without clinical CVD, an average standard-deviation increase in a composite score of maximal common and internal carotid artery intimal medial thickness (cIMT) was associated with increased risk of hip fracture [(HR 1.18 [1.04, 1.35]), even though cIMT was positively associated with BMD. Neither aortic wall thickness nor ABI were associated with hip fracture risk or BMD. Among participants with clinical CVD, cIMT and aortic wall thickness, but not ABI, were associated with increased hip fracture risk. CONCLUSION: Subclinical cIMT is associated with an increased risk of hip fractures despite being associated with increased BMD. This finding suggests that vascular health, even in its early stages, is linked to bone health, by pathways other than BMD. %B Osteoporos Int %V 29 %P 2230 %8 08/2018 %G eng %U https://www.ncbi.nlm.nih.gov/pubmed/30132027 %N 10 %& 2219 %R 10.1007/s00198-018-4611-9 %0 Journal Article %J Clin Cardiol %D 2018 %T Atrial fibrillation in an African-American cohort: The Jackson Heart Study. %A Austin, Thomas R %A Wiggins, Kerri L %A Blackshear, Chad %A Yang, Yi %A Benjamin, Emelia J %A Curtis, Lesley H %A Sotoodehnia, Nona %A Correa, Adolfo %A Heckbert, Susan R %X

BACKGROUND: Atrial fibrillation (AF) is an important public health problem across race/ethnic groups. Data from US cohort studies initiated in the 1980s suggest a higher prevalence of AF risk factors among African-Americans (AAs) than whites, but lower AF incidence. The Jackson Heart Study (JHS) is a community-based study of 5306 AAs recruited starting in 2000.

HYPOTHESIS: Demographic, anthropometric, cardiovascular, and/or electrocardiographic factors are associated with AF incidence in JHS.

METHODS: Using baseline participant characteristics and incident AF identified through hospital surveillance, study electrocardiogram, and Medicare claims, we estimated age- and sex-specific AF incidence rates, compared them with rates in AA participants in the Multi-Ethnic Study of Atherosclerosis (MESA) and Cardiovascular Health Study (CHS), and examined associations of cardiovascular risk factors with AF.

RESULTS: A total of 66 participants had prevalent AF at baseline. Over an average follow-up of 8.5 years, 242 cases of incident AF were identified. Age- and sex-specific AF incidence rates in JHS were similar to those among AAs in MESA and appeared slightly lower than those among AAs in CHS. In an age- and sex-adjusted model, associations with incident AF were observed for modifiable risk factors: high body weight (HR = 1.23 per 15 kg, 95%CI 1.13-1.35), systolic blood pressure (HR = 1.29 per 20 mmHg, 95%CI 1.13-1.47), and current smoking (HR = 1.80, 95%CI 1.27-2.55). Risk estimates associated with these risk factors were only slightly attenuated after multivariable adjustments.

CONCLUSIONS: These findings underscore the potential additional benefits of interventions for weight management, control of hypertension, and smoking cessation for the prevention of AF among AAs.

%B Clin Cardiol %8 2018 Jul 02 %G eng %R 10.1002/clc.23020 %0 Journal Article %J Circ Genom Precis Med %D 2018 %T Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval. %A Lin, Honghuang %A van Setten, Jessica %A Smith, Albert V %A Bihlmeyer, Nathan A %A Warren, Helen R %A Brody, Jennifer A %A Radmanesh, Farid %A Hall, Leanne %A Grarup, Niels %A Müller-Nurasyid, Martina %A Boutin, Thibaud %A Verweij, Niek %A Lin, Henry J %A Li-Gao, Ruifang %A van den Berg, Marten E %A Marten, Jonathan %A Weiss, Stefan %A Prins, Bram P %A Haessler, Jeffrey %A Lyytikäinen, Leo-Pekka %A Mei, Hao %A Harris, Tamara B %A Launer, Lenore J %A Li, Man %A Alonso, Alvaro %A Soliman, Elsayed Z %A Connell, John M %A Huang, Paul L %A Weng, Lu-Chen %A Jameson, Heather S %A Hucker, William %A Hanley, Alan %A Tucker, Nathan R %A Chen, Yii-Der Ida %A Bis, Joshua C %A Rice, Kenneth M %A Sitlani, Colleen M %A Kors, Jan A %A Xie, Zhijun %A Wen, Chengping %A Magnani, Jared W %A Nelson, Christopher P %A Kanters, Jørgen K %A Sinner, Moritz F %A Strauch, Konstantin %A Peters, Annette %A Waldenberger, Melanie %A Meitinger, Thomas %A Bork-Jensen, Jette %A Pedersen, Oluf %A Linneberg, Allan %A Rudan, Igor %A de Boer, Rudolf A %A van der Meer, Peter %A Yao, Jie %A Guo, Xiuqing %A Taylor, Kent D %A Sotoodehnia, Nona %A Rotter, Jerome I %A Mook-Kanamori, Dennis O %A Trompet, Stella %A Rivadeneira, Fernando %A Uitterlinden, Andre %A Eijgelsheim, Mark %A Padmanabhan, Sandosh %A Smith, Blair H %A Völzke, Henry %A Felix, Stephan B %A Homuth, Georg %A Völker, Uwe %A Mangino, Massimo %A Spector, Timothy D %A Bots, Michiel L %A Perez, Marco %A Kähönen, Mika %A Raitakari, Olli T %A Gudnason, Vilmundur %A Arking, Dan E %A Munroe, Patricia B %A Psaty, Bruce M %A van Duijn, Cornelia M %A Benjamin, Emelia J %A Rosand, Jonathan %A Samani, Nilesh J %A Hansen, Torben %A Kääb, Stefan %A Polasek, Ozren %A van der Harst, Pim %A Heckbert, Susan R %A Jukema, J Wouter %A Stricker, Bruno H %A Hayward, Caroline %A Dörr, Marcus %A Jamshidi, Yalda %A Asselbergs, Folkert W %A Kooperberg, Charles %A Lehtimäki, Terho %A Wilson, James G %A Ellinor, Patrick T %A Lubitz, Steven A %A Isaacs, Aaron %X

BACKGROUND: Electrical conduction from the cardiac sinoatrial node to the ventricles is critical for normal heart function. Genome-wide association studies have identified more than a dozen common genetic loci that are associated with PR interval. However, it is unclear whether rare and low-frequency variants also contribute to PR interval heritability.

METHODS: We performed large-scale meta-analyses of the PR interval that included 83 367 participants of European ancestry and 9436 of African ancestry. We examined both common and rare variants associated with the PR interval.

RESULTS: We identified 31 genetic loci that were significantly associated with PR interval after Bonferroni correction (<1.2×10), including 11 novel loci that have not been reported previously. Many of these loci are involved in heart morphogenesis. In gene-based analysis, we found that multiple rare variants at (=5.9×10) and (=1.1×10) were associated with PR interval. locus also was implicated in the common variant analysis, whereas was a novel locus.

CONCLUSIONS: We identified common variants at 11 novel loci and rare variants within 2 gene regions that were significantly associated with PR interval. Our findings provide novel insights to the current understanding of atrioventricular conduction, which is critical for cardiac activity and an important determinant of health.

%B Circ Genom Precis Med %V 11 %P e002037 %8 2018 May %G eng %N 5 %R 10.1161/CIRCGEN.117.002037 %0 Journal Article %J Circ Genom Precis Med %D 2018 %T Common Coding Variants in Are Associated With the Nav1.8 Late Current and Cardiac Conduction. %A Macri, Vincenzo %A Brody, Jennifer A %A Arking, Dan E %A Hucker, William J %A Yin, Xiaoyan %A Lin, Honghuang %A Mills, Robert W %A Sinner, Moritz F %A Lubitz, Steven A %A Liu, Ching-Ti %A Morrison, Alanna C %A Alonso, Alvaro %A Li, Ning %A Fedorov, Vadim V %A Janssen, Paul M %A Bis, Joshua C %A Heckbert, Susan R %A Dolmatova, Elena V %A Lumley, Thomas %A Sitlani, Colleen M %A Cupples, L Adrienne %A Pulit, Sara L %A Newton-Cheh, Christopher %A Barnard, John %A Smith, Jonathan D %A Van Wagoner, David R %A Chung, Mina K %A Vlahakes, Gus J %A O'Donnell, Christopher J %A Rotter, Jerome I %A Margulies, Kenneth B %A Morley, Michael P %A Cappola, Thomas P %A Benjamin, Emelia J %A Muzny, Donna %A Gibbs, Richard A %A Jackson, Rebecca D %A Magnani, Jared W %A Herndon, Caroline N %A Rich, Stephen S %A Psaty, Bruce M %A Milan, David J %A Boerwinkle, Eric %A Mohler, Peter J %A Sotoodehnia, Nona %A Ellinor, Patrick T %X

BACKGROUND: Genetic variants at the / locus are strongly associated with electrocardiographic PR and QRS intervals. While is the canonical cardiac sodium channel gene, the role of in cardiac conduction is less well characterized.

METHODS: We sequenced the locus in 3699 European-ancestry individuals to identify variants associated with cardiac conduction, and replicated our findings in 21,000 individuals of European ancestry. We examined association with expression in human atrial tissue. We explored the biophysical effect of variation on channel function using cellular electrophysiology.

RESULTS: We identified 2 intronic single nucleotide polymorphisms in high linkage disequilibrium (  =0.86) with each other to be the strongest signals for PR (rs10428132, β=-4.74, =1.52×10) and QRS intervals (rs6599251, QRS β=-0.73; =1.2×10), respectively. Although these variants were not associated with or expression in human atrial tissue (n=490), they were in high linkage disequilibrium (  ≥0.72) with a common missense variant, rs6795970 (V1073A). In total, we identified 7 missense variants, 4 of which (I962V, P1045T, V1073A, and L1092P) were associated with cardiac conduction. These 4 missense variants cluster in the cytoplasmic linker of the second and third domains of the SCN10A protein and together form 6 common haplotypes. Using cellular electrophysiology, we found that haplotypes associated with shorter PR intervals had a significantly larger percentage of late current compared with wild-type (I962V+V1073A+L1092P, 20.2±3.3%, =0.03, and I962V+V1073A, 22.4±0.8%, =0.0004 versus wild-type 11.7±1.6%), and the haplotype associated with the longest PR interval had a significantly smaller late current percentage (P1045T, 6.4±1.2%, =0.03).

CONCLUSIONS: Our findings suggest an association between genetic variation in , the late sodium current, and alterations in cardiac conduction.

%B Circ Genom Precis Med %V 11 %P e001663 %8 2018 May %G eng %N 5 %R 10.1161/CIRCGEN.116.001663 %0 Journal Article %J JAMA %D 2018 %T Comparison of 2 Treatment Models: Precision Medicine and Preventive Medicine. %A Psaty, Bruce M %A Dekkers, Olaf M %A Cooper, Richard S %K Humans %K Precision Medicine %K Preventive Medicine %B JAMA %V 320 %P 751-752 %8 2018 08 28 %G eng %N 8 %R 10.1001/jama.2018.8377 %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 Clin Chem %D 2018 %T {Dairy Consumption and Body Mass Index Among Adults: Mendelian Randomization Analysis of 184802 Individuals from 25 Studies %A Huang, T. %A Ding, M. %A Bergholdt, H. K. M. %A Wang, T. %A Heianza, Y. %A Sun, D. %A Frazier-Wood, A. C. %A Aslibekyan, S. %A North, K. E. %A Voortman, T. %A Graff, M. %A Smith, C. E. %A Lai, C. Q. %A Varbo, A. %A Lemaitre, R. N. %A de Jonge, M. E. A. L. %A Fumeron, F. %A Corella, D. %A Wang, C. A. %A Tj?nneland, A. %A Overvad, K. %A S?rensen, T. I. A. %A Feitosa, M. F. %A Wojczynski, M. K. %A K?h?nen, M. %A Renstr?m, F. %A Psaty, B. M. %A Siscovick, D. S. %A Barroso, I. %A Johansson, I. %A Hernandez, D. %A Ferrucci, L. %A Bandinelli, S. %A Linneberg, A. %A Zillikens, M. C. %A Sandholt, C. H. %A Pedersen, O. %A Hansen, T. %A Schulz, C. A. %A Sonestedt, E. %A Orho-Melander, M. %A Chen, T. A. %A Rotter, J. I. %A Allison, M. A. %A Rich, S. S. %A Sorl?, J. V. %A Coltell, O. %A Pennell, C. E. %A Eastwood, P. %A Hofman, A. %A Uitterlinden, A. G. %A van Rooij, F. J. A. %A Chu, A. Y. %A Rose, L. M. %A Ridker, P. M. %A Viikari, J. %A Raitakari, O. %A Lehtim?ki, T. %A Mikkil?, V. %A Willett, W. C. %A Wang, Y. %A Tucker, K. L. %A Ordovas, J. M. %A Kilpel?inen, T. O. %A Province, M. A. %A Franks, P. W. %A Arnett, D. K. %A Tanaka, T. %A Toft, U. %A Ericson, U. %A Franco, O. H. %A Mozaffarian, D. %A Hu, F. B. %A Chasman, D. I. %A Nordestgaard, B. G. %A Ellervik, C. %A Qi, L. %X Associations between dairy intake and body mass index (BMI) have been inconsistently observed in epidemiological studies, and the causal relationship remains ill defined.\ We performed Mendelian randomization (MR) analysis using an established dairy intake-associated genetic polymorphism located upstream of the lactase gene (LCT-13910 C/T, rs4988235) as an instrumental variable (IV). Linear regression models were fitted to analyze associations between (a) dairy intake and BMI, (b) rs4988235 and dairy intake, and (c) rs4988235 and BMI in each study. The causal effect of dairy intake on BMI was quantified by IV estimators among 184802 participants from 25 studies.\ Higher dairy intake was associated with higher BMI (β = 0.03 kg/m2 per serving/day; 95% CI, 0.00-0.06; P = 0.04), whereas the LCT genotype with 1 or 2 T allele was significantly associated with 0.20 (95% CI, 0.14-0.25) serving/day higher dairy intake (P = 3.15 × 10-12) and 0.12 (95% CI, 0.06-0.17) kg/m2 higher BMI (P = 2.11 × 10-5). MR analysis showed that the genetically determined higher dairy intake was significantly associated with higher BMI (β = 0.60 kg/m2 per serving/day; 95% CI, 0.27-0.92; P = 3.0 × 10-4).\ The present study provides strong evidence to support a causal effect of higher dairy intake on increased BMI among adults. %B Clin Chem %V 64 %P 183–191 %8 01 %G eng %0 Journal Article %J Hum Mol Genet %D 2018 %T Discovery, fine-mapping, and conditional analyses of genetic variants associated with C-reactive protein in multiethnic populations using the Metabochip in the Population Architecture using Genomics and Epidemiology (PAGE) study. %A Kocarnik, Jonathan M %A Richard, Melissa %A Graff, Misa %A Haessler, Jeffrey %A Bien, Stephanie %A Carlson, Chris %A Carty, Cara L %A Reiner, Alexander P %A Avery, Christy L %A Ballantyne, Christie M %A LaCroix, Andrea Z %A Assimes, Themistocles L %A Barbalic, Maja %A Pankratz, Nathan %A Tang, Weihong %A Tao, Ran %A Chen, Dongquan %A Talavera, Gregory A %A Daviglus, Martha L %A Chirinos-Medina, Diana A %A Pereira, Rocio %A Nishimura, Katie %A Bůzková, Petra %A Best, Lyle G %A Ambite, Jose Luis %A Cheng, Iona %A Crawford, Dana C %A Hindorff, Lucia A %A Fornage, Myriam %A Heiss, Gerardo %A North, Kari E %A Haiman, Christopher A %A Peters, Ulrike %A Le Marchand, Loïc %A Kooperberg, Charles %X

C-reactive protein (CRP) is a circulating biomarker indicative of systemic inflammation. We aimed to evaluate genetic associations with CRP levels among non-European-ancestry populations through discovery, fine-mapping and conditional analyses. A total of 30 503 non-European-ancestry participants from 6 studies participating in the Population Architecture using Genomics and Epidemiology study had serum high-sensitivity CRP measurements and ∼200 000 single nucleotide polymorphisms (SNPs) genotyped on the Metabochip. We evaluated the association between each SNP and log-transformed CRP levels using multivariate linear regression, with additive genetic models adjusted for age, sex, the first four principal components of genetic ancestry, and study-specific factors. Differential linkage disequilibrium patterns between race/ethnicity groups were used to fine-map regions associated with CRP levels. Conditional analyses evaluated for multiple independent signals within genetic regions. One hundred and sixty-three unique variants in 12 loci in overall or race/ethnicity-stratified Metabochip-wide scans reached a Bonferroni-corrected P-value <2.5E-7. Three loci have no (HACL1, OLFML2B) or only limited (PLA2G6) previous associations with CRP levels. Six loci had different top hits in race/ethnicity-specific versus overall analyses. Fine-mapping refined the signal in six loci, particularly in HNF1A. Conditional analyses provided evidence for secondary signals in LEPR, IL1RN and HNF1A, and for multiple independent signals in CRP and APOE. We identified novel variants and loci associated with CRP levels, generalized known CRP associations to a multiethnic study population, refined association signals at several loci and found evidence for multiple independent signals at several well-known loci. This study demonstrates the benefit of conducting inclusive genetic association studies in large multiethnic populations.

%B Hum Mol Genet %V 27 %P 2940-2953 %8 2018 Aug 15 %G eng %N 16 %R 10.1093/hmg/ddy211 %0 Journal Article %J Eur Heart J %D 2018 %T Equalization of four cardiovascular risk algorithms after systematic recalibration: individual-participant meta-analysis of 86 prospective studies. %A Pennells, Lisa %A Kaptoge, Stephen %A Wood, Angela %A Sweeting, Mike %A Zhao, Xiaohui %A White, Ian %A Burgess, Stephen %A Willeit, Peter %A Bolton, Thomas %A Moons, Karel G M %A van der Schouw, Yvonne T %A Selmer, Randi %A Khaw, Kay-Tee %A Gudnason, Vilmundur %A Assmann, Gerd %A Amouyel, Philippe %A Salomaa, Veikko %A Kivimaki, Mika %A Nordestgaard, Børge G %A Blaha, Michael J %A Kuller, Lewis H %A Brenner, Hermann %A Gillum, Richard F %A Meisinger, Christa %A Ford, Ian %A Knuiman, Matthew W %A Rosengren, Annika %A Lawlor, Debbie A %A Völzke, Henry %A Cooper, Cyrus %A Marín Ibañez, Alejandro %A Casiglia, Edoardo %A Kauhanen, Jussi %A Cooper, Jackie A %A Rodriguez, Beatriz %A Sundström, Johan %A Barrett-Connor, Elizabeth %A Dankner, Rachel %A Nietert, Paul J %A Davidson, Karina W %A Wallace, Robert B %A Blazer, Dan G %A Björkelund, Cecilia %A Donfrancesco, Chiara %A Krumholz, Harlan M %A Nissinen, Aulikki %A Davis, Barry R %A Coady, Sean %A Whincup, Peter H %A Jørgensen, Torben %A Ducimetiere, Pierre %A Trevisan, Maurizio %A Engström, Gunnar %A Crespo, Carlos J %A Meade, Tom W %A Visser, Marjolein %A Kromhout, Daan %A Kiechl, Stefan %A Daimon, Makoto %A Price, Jackie F %A Gómez de la Cámara, Agustin %A Wouter Jukema, J %A Lamarche, Benoît %A Onat, Altan %A Simons, Leon A %A Kavousi, Maryam %A Ben-Shlomo, Yoav %A Gallacher, John %A Dekker, Jacqueline M %A Arima, Hisatomi %A Shara, Nawar %A Tipping, Robert W %A Roussel, Ronan %A Brunner, Eric J %A Koenig, Wolfgang %A Sakurai, Masaru %A Pavlovic, Jelena %A Gansevoort, Ron T %A Nagel, Dorothea %A Goldbourt, Uri %A Barr, Elizabeth L M %A Palmieri, Luigi %A Njølstad, Inger %A Sato, Shinichi %A Monique Verschuren, W M %A Varghese, Cherian V %A Graham, Ian %A Onuma, Oyere %A Greenland, Philip %A Woodward, Mark %A Ezzati, Majid %A Psaty, Bruce M %A Sattar, Naveed %A Jackson, Rod %A Ridker, Paul M %A Cook, Nancy R %A D'Agostino, Ralph B %A Thompson, Simon G %A Danesh, John %A Di Angelantonio, Emanuele %X

Aims: There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after 'recalibration', a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied.

Methods and results: Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at 'high' 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over-predicted CVD risk on average by 10%, 52%, and 41%, respectively, whereas RRS under-predicted by 10%. Original versions of algorithms classified 29-39% of individuals aged ≥40 years as high risk. By contrast, recalibration reduced this proportion to 22-24% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44-51 such individuals using original algorithms, in contrast to 37-39 individuals with recalibrated algorithms.

Conclusion: Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need.

%B Eur Heart J %8 2018 Nov 22 %G eng %R 10.1093/eurheartj/ehy653 %0 Journal Article %J Stroke %D 2018 %T Exome Chip Analysis Identifies Low-Frequency and Rare Variants in for White Matter Hyperintensities on Brain Magnetic Resonance Imaging. %A Jian, Xueqiu %A Satizabal, Claudia L %A Smith, Albert V %A Wittfeld, Katharina %A Bis, Joshua C %A Smith, Jennifer A %A Hsu, Fang-Chi %A Nho, Kwangsik %A Hofer, Edith %A Hagenaars, Saskia P %A Nyquist, Paul A %A Mishra, Aniket %A Adams, Hieab H H %A Li, Shuo %A Teumer, Alexander %A Zhao, Wei %A Freedman, Barry I %A Saba, Yasaman %A Yanek, Lisa R %A Chauhan, Ganesh %A van Buchem, Mark A %A Cushman, Mary %A Royle, Natalie A %A Bryan, R Nick %A Niessen, Wiro J %A Windham, Beverly G %A DeStefano, Anita L %A Habes, Mohamad %A Heckbert, Susan R %A Palmer, Nicholette D %A Lewis, Cora E %A Eiriksdottir, Gudny %A Maillard, Pauline %A Mathias, Rasika A %A Homuth, Georg %A Valdés-Hernández, Maria Del C %A Divers, Jasmin %A Beiser, Alexa S %A Langner, Sönke %A Rice, Kenneth M %A Bastin, Mark E %A Yang, Qiong %A Maldjian, Joseph A %A Starr, John M %A Sidney, Stephen %A Risacher, Shannon L %A Uitterlinden, André G %A Gudnason, Vilmundur G %A Nauck, Matthias %A Rotter, Jerome I %A Schreiner, Pamela J %A Boerwinkle, Eric %A van Duijn, Cornelia M %A Mazoyer, Bernard %A von Sarnowski, Bettina %A Gottesman, Rebecca F %A Levy, Daniel %A Sigurdsson, Sigurdur %A Vernooij, Meike W %A Turner, Stephen T %A Schmidt, Reinhold %A Wardlaw, Joanna M %A Psaty, Bruce M %A Mosley, Thomas H %A DeCarli, Charles S %A Saykin, Andrew J %A Bowden, Donald W %A Becker, Diane M %A Deary, Ian J %A Schmidt, Helena %A Kardia, Sharon L R %A Ikram, M Arfan %A Debette, Stephanie %A Grabe, Hans J %A Longstreth, W T %A Seshadri, Sudha %A Launer, Lenore J %A Fornage, Myriam %X

BACKGROUND AND PURPOSE: White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, age-related neurological disorders, such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored.

METHODS: In the discovery sample we recruited 20 719 stroke/dementia-free adults from 13 population-based cohort studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, among which 17 790 were of European ancestry and 2929 of African ancestry. We genotyped these participants at ≈250 000 mostly exonic variants with Illumina HumanExome BeadChip arrays. We performed ethnicity-specific linear regression on rank-normalized WMH in each study separately, which were then combined in meta-analyses to test for association with single variants and genes aggregating the effects of putatively functional low-frequency/rare variants. We then sought replication of the top findings in 1192 adults (European ancestry) with whole exome/genome sequencing data from 2 independent studies.

RESULTS: At 17q25, we confirmed the association of multiple common variants in , , and (<6×10). We also identified a novel association with 2 low-frequency nonsynonymous variants in (lead, rs34136221; =4.5×10) partially independent of known common signal (=1.4×10). We further identified a locus at 2q33 containing common variants in , , and (lead, rs2351524; =1.9×10). Although our novel findings were not replicated because of limited power and possible differences in study design, meta-analysis of the discovery and replication samples yielded stronger association for the 2 low-frequency variants (=2.8×10).

CONCLUSIONS: Both common and low-frequency/rare functional variants influence WMH. Larger replication and experimental follow-up are essential to confirm our findings and uncover the biological causal mechanisms of age-related WMH.

%B Stroke %8 2018 Jul 12 %G eng %R 10.1161/STROKEAHA.118.020689 %0 Journal Article %J Genome Biol %D 2018 %T Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6. %A Prins, Bram P %A Mead, Timothy J %A Brody, Jennifer A %A Sveinbjornsson, Gardar %A Ntalla, Ioanna %A Bihlmeyer, Nathan A %A van den Berg, Marten %A Bork-Jensen, Jette %A Cappellani, Stefania %A Van Duijvenboden, Stefan %A Klena, Nikolai T %A Gabriel, George C %A Liu, Xiaoqin %A Gulec, Cagri %A Grarup, Niels %A Haessler, Jeffrey %A Hall, Leanne M %A Iorio, Annamaria %A Isaacs, Aaron %A Li-Gao, Ruifang %A Lin, Honghuang %A Liu, Ching-Ti %A Lyytikäinen, Leo-Pekka %A Marten, Jonathan %A Mei, Hao %A Müller-Nurasyid, Martina %A Orini, Michele %A Padmanabhan, Sandosh %A Radmanesh, Farid %A Ramirez, Julia %A Robino, Antonietta %A Schwartz, Molly %A van Setten, Jessica %A Smith, Albert V %A Verweij, Niek %A Warren, Helen R %A Weiss, Stefan %A Alonso, Alvaro %A Arnar, David O %A Bots, Michiel L %A de Boer, Rudolf A %A Dominiczak, Anna F %A Eijgelsheim, Mark %A Ellinor, Patrick T %A Guo, Xiuqing %A Felix, Stephan B %A Harris, Tamara B %A Hayward, Caroline %A Heckbert, Susan R %A Huang, Paul L %A Jukema, J W %A Kähönen, Mika %A Kors, Jan A %A Lambiase, Pier D %A Launer, Lenore J %A Li, Man %A Linneberg, Allan %A Nelson, Christopher P %A Pedersen, Oluf %A Perez, Marco %A Peters, Annette %A Polasek, Ozren %A Psaty, Bruce M %A Raitakari, Olli T %A Rice, Kenneth M %A Rotter, Jerome I %A Sinner, Moritz F %A Soliman, Elsayed Z %A Spector, Tim D %A Strauch, Konstantin %A Thorsteinsdottir, Unnur %A Tinker, Andrew %A Trompet, Stella %A Uitterlinden, Andre %A Vaartjes, Ilonca %A van der Meer, Peter %A Völker, Uwe %A Völzke, Henry %A Waldenberger, Melanie %A Wilson, James G %A Xie, Zhijun %A Asselbergs, Folkert W %A Dörr, Marcus %A van Duijn, Cornelia M %A Gasparini, Paolo %A Gudbjartsson, Daniel F %A Gudnason, Vilmundur %A Hansen, Torben %A Kääb, Stefan %A Kanters, Jørgen K %A Kooperberg, Charles %A Lehtimäki, Terho %A Lin, Henry J %A Lubitz, Steven A %A Mook-Kanamori, Dennis O %A Conti, Francesco J %A Newton-Cheh, Christopher H %A Rosand, Jonathan %A Rudan, Igor %A Samani, Nilesh J %A Sinagra, Gianfranco %A Smith, Blair H %A Holm, Hilma %A Stricker, Bruno H %A Ulivi, Sheila %A Sotoodehnia, Nona %A Apte, Suneel S %A van der Harst, Pim %A Stefansson, Kari %A Munroe, Patricia B %A Arking, Dan E %A Lo, Cecilia W %A Jamshidi, Yalda %X

BACKGROUND: Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear.

RESULTS: Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874 individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction.

CONCLUSIONS: Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes.

%B Genome Biol %V 19 %P 87 %8 2018 07 17 %G eng %N 1 %R 10.1186/s13059-018-1457-6 %0 Journal Article %J Circ Genom Precis Med %D 2018 %T ExomeChip-Wide Analysis of 95 626 Individuals Identifies 10 Novel Loci Associated With QT and JT Intervals. %A Bihlmeyer, Nathan A %A Brody, Jennifer A %A Smith, Albert Vernon %A Warren, Helen R %A Lin, Honghuang %A Isaacs, Aaron %A Liu, Ching-Ti %A Marten, Jonathan %A Radmanesh, Farid %A Hall, Leanne M %A Grarup, Niels %A Mei, Hao %A Müller-Nurasyid, Martina %A Huffman, Jennifer E %A Verweij, Niek %A Guo, Xiuqing %A Yao, Jie %A Li-Gao, Ruifang %A van den Berg, Marten %A Weiss, Stefan %A Prins, Bram P %A van Setten, Jessica %A Haessler, Jeffrey %A Lyytikäinen, Leo-Pekka %A Li, Man %A Alonso, Alvaro %A Soliman, Elsayed Z %A Bis, Joshua C %A Austin, Tom %A Chen, Yii-Der Ida %A Psaty, Bruce M %A Harrris, Tamara B %A Launer, Lenore J %A Padmanabhan, Sandosh %A Dominiczak, Anna %A Huang, Paul L %A Xie, Zhijun %A Ellinor, Patrick T %A Kors, Jan A %A Campbell, Archie %A Murray, Alison D %A Nelson, Christopher P %A Tobin, Martin D %A Bork-Jensen, Jette %A Hansen, Torben %A Pedersen, Oluf %A Linneberg, Allan %A Sinner, Moritz F %A Peters, Annette %A Waldenberger, Melanie %A Meitinger, Thomas %A Perz, Siegfried %A Kolcic, Ivana %A Rudan, Igor %A de Boer, Rudolf A %A van der Meer, Peter %A Lin, Henry J %A Taylor, Kent D %A de Mutsert, Renée %A Trompet, Stella %A Jukema, J Wouter %A Maan, Arie C %A Stricker, Bruno H C %A Rivadeneira, Fernando %A Uitterlinden, Andre %A Völker, Uwe %A Homuth, Georg %A Völzke, Henry %A Felix, Stephan B %A Mangino, Massimo %A Spector, Timothy D %A Bots, Michiel L %A Perez, Marco %A Raitakari, Olli T %A Kähönen, Mika %A Mononen, Nina %A Gudnason, Vilmundur %A Munroe, Patricia B %A Lubitz, Steven A %A van Duijn, Cornelia M %A Newton-Cheh, Christopher H %A Hayward, Caroline %A Rosand, Jonathan %A Samani, Nilesh J %A Kanters, Jørgen K %A Wilson, James G %A Kääb, Stefan %A Polasek, Ozren %A van der Harst, Pim %A Heckbert, Susan R %A Rotter, Jerome I %A Mook-Kanamori, Dennis O %A Eijgelsheim, Mark %A Dörr, Marcus %A Jamshidi, Yalda %A Asselbergs, Folkert W %A Kooperberg, Charles %A Lehtimäki, Terho %A Arking, Dan E %A Sotoodehnia, Nona %X

BACKGROUND: QT interval, measured through a standard ECG, captures the time it takes for the cardiac ventricles to depolarize and repolarize. JT interval is the component of the QT interval that reflects ventricular repolarization alone. Prolonged QT interval has been linked to higher risk of sudden cardiac arrest.

METHODS AND RESULTS: We performed an ExomeChip-wide analysis for both QT and JT intervals, including 209 449 variants, both common and rare, in 17 341 genes from the Illumina Infinium HumanExome BeadChip. We identified 10 loci that modulate QT and JT interval duration that have not been previously reported in the literature using single-variant statistical models in a meta-analysis of 95 626 individuals from 23 cohorts (comprised 83 884 European ancestry individuals, 9610 blacks, 1382 Hispanics, and 750 Asians). This brings the total number of ventricular repolarization associated loci to 45. In addition, our approach of using coding variants has highlighted the role of 17 specific genes for involvement in ventricular repolarization, 7 of which are in novel loci.

CONCLUSIONS: Our analyses show a role for myocyte internal structure and interconnections in modulating QT interval duration, adding to previous known roles of potassium, sodium, and calcium ion regulation, as well as autonomic control. We anticipate that these discoveries will open new paths to the goal of making novel remedies for the prevention of lethal ventricular arrhythmias and sudden cardiac arrest.

%B Circ Genom Precis Med %V 11 %P e001758 %8 2018 Jan %G eng %N 1 %R 10.1161/CIRCGEN.117.001758 %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 Nat Genet %D 2018 %T Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits. %A Evangelou, Evangelos %A Warren, Helen R %A Mosen-Ansorena, David %A Mifsud, Borbala %A Pazoki, Raha %A Gao, He %A Ntritsos, Georgios %A Dimou, Niki %A Cabrera, Claudia P %A Karaman, Ibrahim %A Ng, Fu Liang %A Evangelou, Marina %A Witkowska, Katarzyna %A Tzanis, Evan %A Hellwege, Jacklyn N %A Giri, Ayush %A Velez Edwards, Digna R %A Sun, Yan V %A Cho, Kelly %A Gaziano, J Michael %A Wilson, Peter W F %A Tsao, Philip S %A Kovesdy, Csaba P %A Esko, Tõnu %A Mägi, Reedik %A Milani, Lili %A Almgren, Peter %A Boutin, Thibaud %A Debette, Stephanie %A Ding, Jun %A Giulianini, Franco %A Holliday, Elizabeth G %A Jackson, Anne U %A Li-Gao, Ruifang %A Lin, Wei-Yu %A Luan, Jian'an %A Mangino, Massimo %A Oldmeadow, Christopher %A Prins, Bram Peter %A Qian, Yong %A Sargurupremraj, Muralidharan %A Shah, Nabi %A Surendran, Praveen %A Thériault, Sébastien %A Verweij, Niek %A Willems, Sara M %A Zhao, Jing-Hua %A Amouyel, Philippe %A Connell, John %A de Mutsert, Renée %A Doney, Alex S F %A Farrall, Martin %A Menni, Cristina %A Morris, Andrew D %A Noordam, Raymond %A Paré, Guillaume %A Poulter, Neil R %A Shields, Denis C %A Stanton, Alice %A Thom, Simon %A Abecasis, Goncalo %A Amin, Najaf %A Arking, Dan E %A Ayers, Kristin L %A Barbieri, Caterina M %A Batini, Chiara %A Bis, Joshua C %A Blake, Tineka %A Bochud, Murielle %A Boehnke, Michael %A Boerwinkle, Eric %A Boomsma, Dorret I %A Bottinger, Erwin P %A Braund, Peter S %A Brumat, Marco %A Campbell, Archie %A Campbell, Harry %A Chakravarti, Aravinda %A Chambers, John C %A Chauhan, Ganesh %A Ciullo, Marina %A Cocca, Massimiliano %A Collins, Francis %A Cordell, Heather J %A Davies, Gail %A Borst, Martin H de %A Geus, Eco J de %A Deary, Ian J %A Deelen, Joris %A del Greco M, Fabiola %A Demirkale, Cumhur Yusuf %A Dörr, Marcus %A Ehret, Georg B %A Elosua, Roberto %A Enroth, Stefan %A Erzurumluoglu, A Mesut %A Ferreira, Teresa %A Frånberg, Mattias %A Franco, Oscar H %A Gandin, Ilaria %A Gasparini, Paolo %A Giedraitis, Vilmantas %A Gieger, Christian %A Girotto, Giorgia %A Goel, Anuj %A Gow, Alan J %A Gudnason, Vilmundur %A Guo, Xiuqing %A Gyllensten, Ulf %A Hamsten, Anders %A Harris, Tamara B %A Harris, Sarah E %A Hartman, Catharina A %A Havulinna, Aki S %A Hicks, Andrew A %A Hofer, Edith %A Hofman, Albert %A Hottenga, Jouke-Jan %A Huffman, Jennifer E %A Hwang, Shih-Jen %A Ingelsson, Erik %A James, Alan %A Jansen, Rick %A Jarvelin, Marjo-Riitta %A Joehanes, Roby %A Johansson, Asa %A Johnson, Andrew D %A Joshi, Peter K %A Jousilahti, Pekka %A Jukema, J Wouter %A Jula, Antti %A Kähönen, Mika %A Kathiresan, Sekar %A Keavney, Bernard D %A Khaw, Kay-Tee %A Knekt, Paul %A Knight, Joanne %A Kolcic, Ivana %A Kooner, Jaspal S %A Koskinen, Seppo %A Kristiansson, Kati %A Kutalik, Zoltán %A Laan, Maris %A Larson, Marty %A Launer, Lenore J %A Lehne, Benjamin %A Lehtimäki, Terho %A Liewald, David C M %A Lin, Li %A Lind, Lars %A Lindgren, Cecilia M %A Liu, Yongmei %A Loos, Ruth J F %A Lopez, Lorna M %A Lu, Yingchang %A Lyytikäinen, Leo-Pekka %A Mahajan, Anubha %A Mamasoula, Chrysovalanto %A Marrugat, Jaume %A Marten, Jonathan %A Milaneschi, Yuri %A Morgan, Anna %A Morris, Andrew P %A Morrison, Alanna C %A Munson, Peter J %A Nalls, Mike A %A Nandakumar, Priyanka %A Nelson, Christopher P %A Niiranen, Teemu %A Nolte, Ilja M %A Nutile, Teresa %A Oldehinkel, Albertine J %A Oostra, Ben A %A O'Reilly, Paul F %A Org, Elin %A Padmanabhan, Sandosh %A Palmas, Walter %A Palotie, Aarno %A Pattie, Alison %A Penninx, Brenda W J H %A Perola, Markus %A Peters, Annette %A Polasek, Ozren %A Pramstaller, Peter P %A Nguyen, Quang Tri %A Raitakari, Olli T %A Ren, Meixia %A Rettig, Rainer %A Rice, Kenneth %A Ridker, Paul M %A Ried, Janina S %A Riese, Harriëtte %A Ripatti, Samuli %A Robino, Antonietta %A Rose, Lynda M %A Rotter, Jerome I %A Rudan, Igor %A Ruggiero, Daniela %A Saba, Yasaman %A Sala, Cinzia F %A Salomaa, Veikko %A Samani, Nilesh J %A Sarin, Antti-Pekka %A Schmidt, Reinhold %A Schmidt, Helena %A Shrine, Nick %A Siscovick, David %A Smith, Albert V %A Snieder, Harold %A Sõber, Siim %A Sorice, Rossella %A Starr, John M %A Stott, David J %A Strachan, David P %A Strawbridge, Rona J %A Sundström, Johan %A Swertz, Morris A %A Taylor, Kent D %A Teumer, Alexander %A Tobin, Martin D %A Tomaszewski, Maciej %A Toniolo, Daniela %A Traglia, Michela %A Trompet, Stella %A Tuomilehto, Jaakko %A Tzourio, Christophe %A Uitterlinden, André G %A Vaez, Ahmad %A van der Most, Peter J %A van Duijn, Cornelia M %A Vergnaud, Anne-Claire %A Verwoert, Germaine C %A Vitart, Veronique %A Völker, Uwe %A Vollenweider, Peter %A Vuckovic, Dragana %A Watkins, Hugh %A Wild, Sarah H %A Willemsen, Gonneke %A Wilson, James F %A Wright, Alan F %A Yao, Jie %A Zemunik, Tatijana %A Zhang, Weihua %A Attia, John R %A Butterworth, Adam S %A Chasman, Daniel I %A Conen, David %A Cucca, Francesco %A Danesh, John %A Hayward, Caroline %A Howson, Joanna M M %A Laakso, Markku %A Lakatta, Edward G %A Langenberg, Claudia %A Melander, Olle %A Mook-Kanamori, Dennis O %A Palmer, Colin N A %A Risch, Lorenz %A Scott, Robert A %A Scott, Rodney J %A Sever, Peter %A Spector, Tim D %A van der Harst, Pim %A Wareham, Nicholas J %A Zeggini, Eleftheria %A Levy, Daniel %A Munroe, Patricia B %A Newton-Cheh, Christopher %A Brown, Morris J %A Metspalu, Andres %A Hung, Adriana M %A O'Donnell, Christopher J %A Edwards, Todd L %A Psaty, Bruce M %A Tzoulaki, Ioanna %A Barnes, Michael R %A Wain, Louise V %A Elliott, Paul %A Caulfield, Mark J %X

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.

%B Nat Genet %V 50 %P 1412-1425 %8 2018 Oct %G eng %N 10 %R 10.1038/s41588-018-0205-x %0 Journal Article %J Dement Geriatr Cogn Disord %D 2018 %T Genetic Variation in Genes Underlying Diverse Dementias May Explain a Small Proportion of Cases in the Alzheimer's Disease Sequencing Project. %A Blue, Elizabeth E %A Bis, Joshua C %A Dorschner, Michael O %A Tsuang, Debby W %A Barral, Sandra M %A Beecham, Gary %A Below, Jennifer E %A Bush, William S %A Butkiewicz, Mariusz %A Cruchaga, Carlos %A DeStefano, Anita %A Farrer, Lindsay A %A Goate, Alison %A Haines, Jonathan %A Jaworski, Jim %A Jun, Gyungah %A Kunkle, Brian %A Kuzma, Amanda %A Lee, Jenny J %A Lunetta, Kathryn L %A Ma, Yiyi %A Martin, Eden %A Naj, Adam %A Nato, Alejandro Q %A Navas, Patrick %A Nguyen, Hiep %A Reitz, Christiane %A Reyes, Dolly %A Salerno, William %A Schellenberg, Gerard D %A Seshadri, Sudha %A Sohi, Harkirat %A Thornton, Timothy A %A Valadares, Otto %A van Duijn, Cornelia %A Vardarajan, Badri N %A Wang, Li-San %A Boerwinkle, Eric %A Dupuis, Josée %A Pericak-Vance, Margaret A %A Mayeux, Richard %A Wijsman, Ellen M %X

BACKGROUND/AIMS: The Alzheimer's Disease Sequencing Project (ADSP) aims to identify novel genes influencing Alzheimer's disease (AD). Variants within genes known to cause dementias other than AD have previously been associated with AD risk. We describe evidence of co-segregation and associations between variants in dementia genes and clinically diagnosed AD within the ADSP.

METHODS: We summarize the properties of known pathogenic variants within dementia genes, describe the co-segregation of variants annotated as "pathogenic" in ClinVar and new candidates observed in ADSP families, and test for associations between rare variants in dementia genes in the ADSP case-control study. The participants were clinically evaluated for AD, and they represent European, Caribbean Hispanic, and isolate Dutch populations.

RESULTS/CONCLUSIONS: Pathogenic variants in dementia genes were predominantly rare and conserved coding changes. Pathogenic variants within ARSA, CSF1R, and GRN were observed, and candidate variants in GRN and CHMP2B were nominated in ADSP families. An independent case-control study provided evidence of an association between variants in TREM2, APOE, ARSA, CSF1R, PSEN1, and MAPT and risk of AD. Variants in genes which cause dementing disorders may influence the clinical diagnosis of AD in a small proportion of cases within the ADSP.

%B Dement Geriatr Cogn Disord %V 45 %P 1-17 %8 2018 %G eng %N 1-2 %R 10.1159/000485503 %0 Journal Article %J Am J Hum Genet %D 2018 %T Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders. %A Ligthart, Symen %A Vaez, Ahmad %A Võsa, Urmo %A Stathopoulou, Maria G %A de Vries, Paul S %A Prins, Bram P %A van der Most, Peter J %A Tanaka, Toshiko %A Naderi, Elnaz %A Rose, Lynda M %A Wu, Ying %A Karlsson, Robert %A Barbalic, Maja %A Lin, Honghuang %A Pool, Rene %A Zhu, Gu %A Mace, Aurelien %A Sidore, Carlo %A Trompet, Stella %A Mangino, Massimo %A Sabater-Lleal, Maria %A Kemp, John P %A Abbasi, Ali %A Kacprowski, Tim %A Verweij, Niek %A Smith, Albert V %A Huang, Tao %A Marzi, Carola %A Feitosa, Mary F %A Lohman, Kurt K %A Kleber, Marcus E %A Milaneschi, Yuri %A Mueller, Christian %A Huq, Mahmudul %A Vlachopoulou, Efthymia %A Lyytikäinen, Leo-Pekka %A Oldmeadow, Christopher %A Deelen, Joris %A Perola, Markus %A Zhao, Jing Hua %A Feenstra, Bjarke %A Amini, Marzyeh %A Lahti, Jari %A Schraut, Katharina E %A Fornage, Myriam %A Suktitipat, Bhoom %A Chen, Wei-Min %A Li, Xiaohui %A Nutile, Teresa %A Malerba, Giovanni %A Luan, Jian'an %A Bak, Tom %A Schork, Nicholas %A del Greco M, Fabiola %A Thiering, Elisabeth %A Mahajan, Anubha %A Marioni, Riccardo E %A Mihailov, Evelin %A Eriksson, Joel %A Ozel, Ayse Bilge %A Zhang, Weihua %A Nethander, Maria %A Cheng, Yu-Ching %A Aslibekyan, Stella %A Ang, Wei %A Gandin, Ilaria %A Yengo, Loic %A Portas, Laura %A Kooperberg, Charles %A Hofer, Edith %A Rajan, Kumar B %A Schurmann, Claudia %A den Hollander, Wouter %A Ahluwalia, Tarunveer S %A Zhao, Jing %A Draisma, Harmen H M %A Ford, Ian %A Timpson, Nicholas %A Teumer, Alexander %A Huang, Hongyan %A Wahl, Simone %A Liu, Yongmei %A Huang, Jie %A Uh, Hae-Won %A Geller, Frank %A Joshi, Peter K %A Yanek, Lisa R %A Trabetti, Elisabetta %A Lehne, Benjamin %A Vozzi, Diego %A Verbanck, Marie %A Biino, Ginevra %A Saba, Yasaman %A Meulenbelt, Ingrid %A O'Connell, Jeff R %A Laakso, Markku %A Giulianini, Franco %A Magnusson, Patrik K E %A Ballantyne, Christie M %A Hottenga, Jouke Jan %A Montgomery, Grant W %A Rivadineira, Fernando %A Rueedi, Rico %A Steri, Maristella %A Herzig, Karl-Heinz %A Stott, David J %A Menni, Cristina %A Frånberg, Mattias %A St Pourcain, Beate %A Felix, Stephan B %A Pers, Tune H %A Bakker, Stephan J L %A Kraft, Peter %A Peters, Annette %A Vaidya, Dhananjay %A Delgado, Graciela %A Smit, Johannes H %A Großmann, Vera %A Sinisalo, Juha %A Seppälä, Ilkka %A Williams, Stephen R %A Holliday, Elizabeth G %A Moed, Matthijs %A Langenberg, Claudia %A Räikkönen, Katri %A Ding, Jingzhong %A Campbell, Harry %A Sale, Michèle M %A Chen, Yii-der I %A James, Alan L %A Ruggiero, Daniela %A Soranzo, Nicole %A Hartman, Catharina A %A Smith, Erin N %A Berenson, Gerald S %A Fuchsberger, Christian %A Hernandez, Dena %A Tiesler, Carla M T %A Giedraitis, Vilmantas %A Liewald, David %A Fischer, Krista %A Mellström, Dan %A Larsson, Anders %A Wang, Yunmei %A Scott, William R %A Lorentzon, Matthias %A Beilby, John %A Ryan, Kathleen A %A Pennell, Craig E %A Vuckovic, Dragana %A Balkau, Beverly %A Concas, Maria Pina %A Schmidt, Reinhold %A Mendes de Leon, Carlos F %A Bottinger, Erwin P %A Kloppenburg, Margreet %A Paternoster, Lavinia %A Boehnke, Michael %A Musk, A W %A Willemsen, Gonneke %A Evans, David M %A Madden, Pamela A F %A Kähönen, Mika %A Kutalik, Zoltán %A Zoledziewska, Magdalena %A Karhunen, Ville %A Kritchevsky, Stephen B %A Sattar, Naveed %A Lachance, Genevieve %A Clarke, Robert %A Harris, Tamara B %A Raitakari, Olli T %A Attia, John R %A van Heemst, Diana %A Kajantie, Eero %A Sorice, Rossella %A Gambaro, Giovanni %A Scott, Robert A %A Hicks, Andrew A %A Ferrucci, Luigi %A Standl, Marie %A Lindgren, Cecilia M %A Starr, John M %A Karlsson, Magnus %A Lind, Lars %A Li, Jun Z %A Chambers, John C %A Mori, Trevor A %A de Geus, Eco J C N %A Heath, Andrew C %A Martin, Nicholas G %A Auvinen, Juha %A Buckley, Brendan M %A de Craen, Anton J M %A Waldenberger, Melanie %A Strauch, Konstantin %A Meitinger, Thomas %A Scott, Rodney J %A McEvoy, Mark %A Beekman, Marian %A Bombieri, Cristina %A Ridker, Paul M %A Mohlke, Karen L %A Pedersen, Nancy L %A Morrison, Alanna C %A Boomsma, Dorret I %A Whitfield, John B %A Strachan, David P %A Hofman, Albert %A Vollenweider, Peter %A Cucca, Francesco %A Jarvelin, Marjo-Riitta %A Jukema, J Wouter %A Spector, Tim D %A Hamsten, Anders %A Zeller, Tanja %A Uitterlinden, André G %A Nauck, Matthias %A Gudnason, Vilmundur %A Qi, Lu %A Grallert, Harald %A Borecki, Ingrid B %A Rotter, Jerome I %A März, Winfried %A Wild, Philipp S %A Lokki, Marja-Liisa %A Boyle, Michael %A Salomaa, Veikko %A Melbye, Mads %A Eriksson, Johan G %A Wilson, James F %A Penninx, Brenda W J H %A Becker, Diane M %A Worrall, Bradford B %A Gibson, Greg %A Krauss, Ronald M %A Ciullo, Marina %A Zaza, Gianluigi %A Wareham, Nicholas J %A Oldehinkel, Albertine J %A Palmer, Lyle J %A Murray, Sarah S %A Pramstaller, Peter P %A Bandinelli, Stefania %A Heinrich, Joachim %A Ingelsson, Erik %A Deary, Ian J %A Mägi, Reedik %A Vandenput, Liesbeth %A van der Harst, Pim %A Desch, Karl C %A Kooner, Jaspal S %A Ohlsson, Claes %A Hayward, Caroline %A Lehtimäki, Terho %A Shuldiner, Alan R %A Arnett, Donna K %A Beilin, Lawrence J %A Robino, Antonietta %A Froguel, Philippe %A Pirastu, Mario %A Jess, Tine %A Koenig, Wolfgang %A Loos, Ruth J F %A Evans, Denis A %A Schmidt, Helena %A Smith, George Davey %A Slagboom, P Eline %A Eiriksdottir, Gudny %A Morris, Andrew P %A Psaty, Bruce M %A Tracy, Russell P %A Nolte, Ilja M %A Boerwinkle, Eric %A Visvikis-Siest, Sophie %A Reiner, Alex P %A Gross, Myron %A Bis, Joshua C %A Franke, Lude %A Franco, Oscar H %A Benjamin, Emelia J %A Chasman, Daniel I %A Dupuis, Josée %A Snieder, Harold %A Dehghan, Abbas %A Alizadeh, Behrooz Z %X

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

%B Am J Hum Genet %V 103 %P 691-706 %8 2018 Nov 01 %G eng %N 5 %R 10.1016/j.ajhg.2018.09.009 %0 Journal Article %J Nat Commun %D 2018 %T Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation. %A Teumer, Alexander %A Chaker, Layal %A Groeneweg, Stefan %A Li, Yong %A Di Munno, Celia %A Barbieri, Caterina %A Schultheiss, Ulla T %A Traglia, Michela %A Ahluwalia, Tarunveer S %A Akiyama, Masato %A Appel, Emil Vincent R %A Arking, Dan E %A Arnold, Alice %A Astrup, Arne %A Beekman, Marian %A Beilby, John P %A Bekaert, Sofie %A Boerwinkle, Eric %A Brown, Suzanne J %A De Buyzere, Marc %A Campbell, Purdey J %A Ceresini, Graziano %A Cerqueira, Charlotte %A Cucca, Francesco %A Deary, Ian J %A Deelen, Joris %A Eckardt, Kai-Uwe %A Ekici, Arif B %A Eriksson, Johan G %A Ferrrucci, Luigi %A Fiers, Tom %A Fiorillo, Edoardo %A Ford, Ian %A Fox, Caroline S %A Fuchsberger, Christian %A Galesloot, Tessel E %A Gieger, Christian %A Gögele, Martin %A De Grandi, Alessandro %A Grarup, Niels %A Greiser, Karin Halina %A Haljas, Kadri %A Hansen, Torben %A Harris, Sarah E %A van Heemst, Diana %A den Heijer, Martin %A Hicks, Andrew A %A den Hollander, Wouter %A Homuth, Georg %A Hui, Jennie %A Ikram, M Arfan %A Ittermann, Till %A Jensen, Richard A %A Jing, Jiaojiao %A Jukema, J Wouter %A Kajantie, Eero %A Kamatani, Yoichiro %A Kasbohm, Elisa %A Kaufman, Jean-Marc %A Kiemeney, Lambertus A %A Kloppenburg, Margreet %A Kronenberg, Florian %A Kubo, Michiaki %A Lahti, Jari %A Lapauw, Bruno %A Li, Shuo %A Liewald, David C M %A Lim, Ee Mun %A Linneberg, Allan %A Marina, Michela %A Mascalzoni, Deborah %A Matsuda, Koichi %A Medenwald, Daniel %A Meisinger, Christa %A Meulenbelt, Ingrid %A De Meyer, Tim %A Meyer zu Schwabedissen, Henriette E %A Mikolajczyk, Rafael %A Moed, Matthijs %A Netea-Maier, Romana T %A Nolte, Ilja M %A Okada, Yukinori %A Pala, Mauro %A Pattaro, Cristian %A Pedersen, Oluf %A Petersmann, Astrid %A Porcu, Eleonora %A Postmus, Iris %A Pramstaller, Peter P %A Psaty, Bruce M %A Ramos, Yolande F M %A Rawal, Rajesh %A Redmond, Paul %A Richards, J Brent %A Rietzschel, Ernst R %A Rivadeneira, Fernando %A Roef, Greet %A Rotter, Jerome I %A Sala, Cinzia F %A Schlessinger, David %A Selvin, Elizabeth %A Slagboom, P Eline %A Soranzo, Nicole %A Sørensen, Thorkild I A %A Spector, Timothy D %A Starr, John M %A Stott, David J %A Taes, Youri %A Taliun, Daniel %A Tanaka, Toshiko %A Thuesen, Betina %A Tiller, Daniel %A Toniolo, Daniela %A Uitterlinden, André G %A Visser, W Edward %A Walsh, John P %A Wilson, Scott G %A Wolffenbuttel, Bruce H R %A Yang, Qiong %A Zheng, Hou-Feng %A Cappola, Anne %A Peeters, Robin P %A Naitza, Silvia %A Völzke, Henry %A Sanna, Serena %A Köttgen, Anna %A Visser, Theo J %A Medici, Marco %X

Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves' disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.

%B Nat Commun %V 9 %P 4455 %8 2018 10 26 %G eng %N 1 %R 10.1038/s41467-018-06356-1 %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 Nat Commun %D 2018 %T Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels. %A Jiang, Xia %A O'Reilly, Paul F %A Aschard, Hugues %A Hsu, Yi-Hsiang %A Richards, J Brent %A Dupuis, Josée %A Ingelsson, Erik %A Karasik, David %A Pilz, Stefan %A Berry, Diane %A Kestenbaum, Bryan %A Zheng, Jusheng %A Luan, Jianan %A Sofianopoulou, Eleni %A Streeten, Elizabeth A %A Albanes, Demetrius %A Lutsey, Pamela L %A Yao, Lu %A Tang, Weihong %A Econs, Michael J %A Wallaschofski, Henri %A Völzke, Henry %A Zhou, Ang %A Power, Chris %A McCarthy, Mark I %A Michos, Erin D %A Boerwinkle, Eric %A Weinstein, Stephanie J %A Freedman, Neal D %A Huang, Wen-Yi %A van Schoor, Natasja M %A van der Velde, Nathalie %A Groot, Lisette C P G M de %A Enneman, Anke %A Cupples, L Adrienne %A Booth, Sarah L %A Vasan, Ramachandran S %A Liu, Ching-Ti %A Zhou, Yanhua %A Ripatti, Samuli %A Ohlsson, Claes %A Vandenput, Liesbeth %A Lorentzon, Mattias %A Eriksson, Johan G %A Shea, M Kyla %A Houston, Denise K %A Kritchevsky, Stephen B %A Liu, Yongmei %A Lohman, Kurt K %A Ferrucci, Luigi %A Peacock, Munro %A Gieger, Christian %A Beekman, Marian %A Slagboom, Eline %A Deelen, Joris %A Heemst, Diana van %A Kleber, Marcus E %A März, Winfried %A de Boer, Ian H %A Wood, Alexis C %A Rotter, Jerome I %A Rich, Stephen S %A Robinson-Cohen, Cassianne %A den Heijer, Martin %A Jarvelin, Marjo-Riitta %A Cavadino, Alana %A Joshi, Peter K %A Wilson, James F %A Hayward, Caroline %A Lind, Lars %A Michaëlsson, Karl %A Trompet, Stella %A Zillikens, M Carola %A Uitterlinden, André G %A Rivadeneira, Fernando %A Broer, Linda %A Zgaga, Lina %A Campbell, Harry %A Theodoratou, Evropi %A Farrington, Susan M %A Timofeeva, Maria %A Dunlop, Malcolm G %A Valdes, Ana M %A Tikkanen, Emmi %A Lehtimäki, Terho %A Lyytikäinen, Leo-Pekka %A Kähönen, Mika %A Raitakari, Olli T %A Mikkilä, Vera %A Ikram, M Arfan %A Sattar, Naveed %A Jukema, J Wouter %A Wareham, Nicholas J %A Langenberg, Claudia %A Forouhi, Nita G %A Gundersen, Thomas E %A Khaw, Kay-Tee %A Butterworth, Adam S %A Danesh, John %A Spector, Timothy %A Wang, Thomas J %A Hyppönen, Elina %A Kraft, Peter %A Kiel, Douglas P %X

Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10 at rs8018720 in SEC23A, and P = 1.9×10 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.

%B Nat Commun %V 9 %P 260 %8 2018 Jan 17 %G eng %N 1 %R 10.1038/s41467-017-02662-2 %0 Journal Article %J Circulation %D 2018 %T Genome-Wide Association Trans-Ethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels. %A Sabater-Lleal, Maria %A Huffman, Jennifer E %A de Vries, Paul S %A Marten, Jonathan %A Mastrangelo, Michael A %A Song, Ci %A Pankratz, Nathan %A Ward-Caviness, Cavin K %A Yanek, Lisa R %A Trompet, Stella %A Delgado, Graciela E %A Guo, Xiuqing %A Bartz, Traci M %A Martinez-Perez, Angel %A Germain, Marine %A de Haan, Hugoline G %A Ozel, Ayse B %A Polasek, Ozren %A Smith, Albert V %A Eicher, John D %A Reiner, Alex P %A Tang, Weihong %A Davies, Neil M %A Stott, David J %A Rotter, Jerome I %A Tofler, Geoffrey H %A Boerwinkle, Eric %A de Maat, Moniek P M %A Kleber, Marcus E %A Welsh, Paul %A Brody, Jennifer A %A Chen, Ming-Huei %A Vaidya, Dhananjay %A Soria, José Manuel %A Suchon, Pierre %A van Hylckama Vlieg, Astrid %A Desch, Karl C %A Kolcic, Ivana %A Joshi, Peter K %A Launer, Lenore J %A Harris, Tamara B %A Campbell, Harry %A Rudan, Igor %A Becker, Diane M %A Li, Jun Z %A Rivadeneira, Fernando %A Uitterlinden, André G %A Hofman, Albert %A Franco, Oscar H %A Cushman, Mary %A Psaty, Bruce M %A Morange, Pierre-Emmanuel %A McKnight, Barbara %A Chong, Michael R %A Fernandez-Cadenas, Israel %A Rosand, Jonathan %A Lindgren, Arne %A Gudnason, Vilmundur %A Wilson, James F %A Hayward, Caroline %A Ginsburg, David %A Fornage, Myriam %A Rosendaal, Frits R %A Souto, Juan Carlos %A Becker, Lewis C %A Jenny, Nancy S %A März, Winfried %A Jukema, J Wouter %A Dehghan, Abbas %A Trégouët, David-Alexandre %A Morrison, Alanna C %A Johnson, Andrew D %A O'Donnell, Christopher J %A Strachan, David P %A Lowenstein, Charles J %A Smith, Nicholas L %X

BACKGROUND: Factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are associated with risk of arterial and venous thrombosis and with hemorrhagic disorders. We aimed to identify and functionally test novel genetic associations regulating plasma FVIII and VWF.

METHODS: We meta-analyzed genome-wide association results from 46,354 individuals of European, African, East Asian, and Hispanic ancestry. All studies performed linear regression analysis using an additive genetic model and associated approximately 35 million imputed variants with natural-log transformed phenotype levels. In vitro gene silencing in cultured endothelial cells was performed for candidate genes to provide additional evidence on association and function. Two-sample Mendelian randomization (MR) analyses were applied to test the causal role of FVIII and VWF plasma levels on the risk of arterial and venous thrombotic events.

RESULTS: We identified 13 novel genome-wide significant (p≤2.5x10) associations; 7 with FVIII levels ( FCHO2/TMEM171/TNPO1, HLA, SOX17/RP1, LINC00583/NFIB, RAB5C-KAT2A, RPL3/TAB1/SYNGR1, and ARSA) and 11 with VWF levels ( PDHB/PXK/KCTD6, SLC39A8, FCHO2/TMEM171/TNPO1, HLA, GIMAP7/GIMAP4, OR13C5/NIPSNAP, DAB2IP, C2CD4B, RAB5C-KAT2A, TAB1/SYNGR1, and ARSA), beyond 10 previously reported associations with these phenotypes. Functional validation provided further evidence of association for all loci on VWF except ARSA and DAB2IP. MR suggested causal effects of plasma FVIII activity levels on venous thrombosis and coronary artery disease risk and plasma VWF levels on ischemic stroke risk.

CONCLUSIONS: The meta-analysis identified 13 novel genetic loci regulating FVIII and VWF plasma levels, 10 of which we validated functionally. We provide some evidence for a causal role of these proteins in thrombotic events.

%B Circulation %8 2018 Nov 20 %G eng %R 10.1161/CIRCULATIONAHA.118.034532 %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 PLoS Genet %D 2018 %T Genome-wide meta-analysis of 158,000 individuals of European ancestry identifies three loci associated with chronic back pain. %A Suri, Pradeep %A Palmer, Melody R %A Tsepilov, Yakov A %A Freidin, Maxim B %A Boer, Cindy G %A Yau, Michelle S %A Evans, Daniel S %A Gelemanovic, Andrea %A Bartz, Traci M %A Nethander, Maria %A Arbeeva, Liubov %A Karssen, Lennart %A Neogi, Tuhina %A Campbell, Archie %A Mellström, Dan %A Ohlsson, Claes %A Marshall, Lynn M %A Orwoll, Eric %A Uitterlinden, Andre %A Rotter, Jerome I %A Lauc, Gordan %A Psaty, Bruce M %A Karlsson, Magnus K %A Lane, Nancy E %A Jarvik, Gail P %A Polasek, Ozren %A Hochberg, Marc %A Jordan, Joanne M %A van Meurs, Joyce B J %A Jackson, Rebecca %A Nielson, Carrie M %A Mitchell, Braxton D %A Smith, Blair H %A Hayward, Caroline %A Smith, Nicholas L %A Aulchenko, Yurii S %A Williams, Frances M K %X

Back pain is the #1 cause of years lived with disability worldwide, yet surprisingly little is known regarding the biology underlying this symptom. We conducted a genome-wide association study (GWAS) meta-analysis of chronic back pain (CBP). Adults of European ancestry were included from 15 cohorts in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and from the UK Biobank interim data release. CBP cases were defined as those reporting back pain present for ≥3-6 months; non-cases were included as comparisons ("controls"). Each cohort conducted genotyping using commercially available arrays followed by imputation. GWAS used logistic regression models with additive genetic effects, adjusting for age, sex, study-specific covariates, and population substructure. The threshold for genome-wide significance in the fixed-effect inverse-variance weighted meta-analysis was p<5×10-8. Suggestive (p<5×10-7) and genome-wide significant (p<5×10-8) variants were carried forward for replication or further investigation in the remaining UK Biobank participants not included in the discovery sample. The discovery sample comprised 158,025 individuals, including 29,531 CBP cases. A genome-wide significant association was found for the intronic variant rs12310519 in SOX5 (OR 1.08, p = 7.2×10-10). This was subsequently replicated in 283,752 UK Biobank participants not included in the discovery sample, including 50,915 cases (OR 1.06, p = 5.3×10-11), and exceeded genome-wide significance in joint meta-analysis (OR 1.07, p = 4.5×10-19). We found suggestive associations at three other loci in the discovery sample, two of which exceeded genome-wide significance in joint meta-analysis: an intergenic variant, rs7833174, located between CCDC26 and GSDMC (OR 1.05, p = 4.4×10-13), and an intronic variant, rs4384683, in DCC (OR 0.97, p = 2.4×10-10). In this first reported meta-analysis of GWAS for CBP, we identified and replicated a genetic locus associated with CBP (SOX5). We also identified 2 other loci that reached genome-wide significance in a 2-stage joint meta-analysis (CCDC26/GSDMC and DCC).

%B PLoS Genet %V 14 %P e1007601 %8 2018 Sep %G eng %N 9 %R 10.1371/journal.pgen.1007601 %0 Journal Article %J Nat Commun %D 2018 %T GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes. %A Franceschini, Nora %A Giambartolomei, Claudia %A de Vries, Paul S %A Finan, Chris %A Bis, Joshua C %A Huntley, Rachael P %A Lovering, Ruth C %A Tajuddin, Salman M %A Winkler, Thomas W %A Graff, Misa %A Kavousi, Maryam %A Dale, Caroline %A Smith, Albert V %A Hofer, Edith %A van Leeuwen, Elisabeth M %A Nolte, Ilja M %A Lu, Lingyi %A Scholz, Markus %A Sargurupremraj, Muralidharan %A Pitkänen, Niina %A Franzén, Oscar %A Joshi, Peter K %A Noordam, Raymond %A Marioni, Riccardo E %A Hwang, Shih-Jen %A Musani, Solomon K %A Schminke, Ulf %A Palmas, Walter %A Isaacs, Aaron %A Correa, Adolfo %A Zonderman, Alan B %A Hofman, Albert %A Teumer, Alexander %A Cox, Amanda J %A Uitterlinden, André G %A Wong, Andrew %A Smit, Andries J %A Newman, Anne B %A Britton, Annie %A Ruusalepp, Arno %A Sennblad, Bengt %A Hedblad, Bo %A Pasaniuc, Bogdan %A Penninx, Brenda W %A Langefeld, Carl D %A Wassel, Christina L %A Tzourio, Christophe %A Fava, Cristiano %A Baldassarre, Damiano %A O'Leary, Daniel H %A Teupser, Daniel %A Kuh, Diana %A Tremoli, Elena %A Mannarino, Elmo %A Grossi, Enzo %A Boerwinkle, Eric %A Schadt, Eric E %A Ingelsson, Erik %A Veglia, Fabrizio %A Rivadeneira, Fernando %A Beutner, Frank %A Chauhan, Ganesh %A Heiss, Gerardo %A Snieder, Harold %A Campbell, Harry %A Völzke, Henry %A Markus, Hugh S %A Deary, Ian J %A Jukema, J Wouter %A de Graaf, Jacqueline %A Price, Jacqueline %A Pott, Janne %A Hopewell, Jemma C %A Liang, Jingjing %A Thiery, Joachim %A Engmann, Jorgen %A Gertow, Karl %A Rice, Kenneth %A Taylor, Kent D %A Dhana, Klodian %A Kiemeney, Lambertus A L M %A Lind, Lars %A Raffield, Laura M %A Launer, Lenore J %A Holdt, Lesca M %A Dörr, Marcus %A Dichgans, Martin %A Traylor, Matthew %A Sitzer, Matthias %A Kumari, Meena %A Kivimaki, Mika %A Nalls, Mike A %A Melander, Olle %A Raitakari, Olli %A Franco, Oscar H %A Rueda-Ochoa, Oscar L %A Roussos, Panos %A Whincup, Peter H %A Amouyel, Philippe %A Giral, Philippe %A Anugu, Pramod %A Wong, Quenna %A Malik, Rainer %A Rauramaa, Rainer %A Burkhardt, Ralph %A Hardy, Rebecca %A Schmidt, Reinhold %A de Mutsert, Renée %A Morris, Richard W %A Strawbridge, Rona J %A Wannamethee, S Goya %A Hägg, Sara %A Shah, Sonia %A McLachlan, Stela %A Trompet, Stella %A Seshadri, Sudha %A Kurl, Sudhir %A Heckbert, Susan R %A Ring, Susan %A Harris, Tamara B %A Lehtimäki, Terho %A Galesloot, Tessel E %A Shah, Tina %A de Faire, Ulf %A Plagnol, Vincent %A Rosamond, Wayne D %A Post, Wendy %A Zhu, Xiaofeng %A Zhang, Xiaoling %A Guo, Xiuqing %A Saba, Yasaman %A Dehghan, Abbas %A Seldenrijk, Adrie %A Morrison, Alanna C %A Hamsten, Anders %A Psaty, Bruce M %A van Duijn, Cornelia M %A Lawlor, Deborah A %A Mook-Kanamori, Dennis O %A Bowden, Donald W %A Schmidt, Helena %A Wilson, James F %A Wilson, James G %A Rotter, Jerome I %A Wardlaw, Joanna M %A Deanfield, John %A Halcox, Julian %A Lyytikäinen, Leo-Pekka %A Loeffler, Markus %A Evans, Michele K %A Debette, Stephanie %A Humphries, Steve E %A Völker, Uwe %A Gudnason, Vilmundur %A Hingorani, Aroon D %A Björkegren, Johan L M %A Casas, Juan P %A O'Donnell, Christopher J %K ADAMTS9 Protein %K Amino Acid Oxidoreductases %K Carotid Intima-Media Thickness %K Coronary Disease %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Lod Score %K Plaque, Atherosclerotic %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Risk Factors %X

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

%B Nat Commun %V 9 %P 5141 %8 2018 12 03 %G eng %N 1 %R 10.1038/s41467-018-07340-5 %0 Journal Article %J Am J Epidemiol %D 2018 %T Harmonization of Respiratory Data From 9 US Population-Based Cohorts: The NHLBI Pooled Cohorts Study. %A Oelsner, Elizabeth C %A Balte, Pallavi P %A Cassano, Patricia A %A Couper, David %A Enright, Paul L %A Folsom, Aaron R %A Hankinson, John %A Jacobs, David R %A Kalhan, Ravi %A Kaplan, Robert %A Kronmal, Richard %A Lange, Leslie %A Loehr, Laura R %A London, Stephanie J %A Navas Acien, Ana %A Newman, Anne B %A O'Connor, George T %A Schwartz, Joseph E %A Smith, Lewis J %A Yeh, Fawn %A Zhang, Yiyi %A Moran, Andrew E %A Mwasongwe, Stanford %A White, Wendy B %A Yende, Sachin %A Barr, R Graham %X

Chronic lower respiratory diseases (CLRDs) are the fourth leading cause of death in the United States. To support investigations into CLRD risk determinants and new approaches to primary prevention, we aimed to harmonize and pool respiratory data from US general population-based cohorts. Data were obtained from prospective cohorts that performed prebronchodilator spirometry and were harmonized following 2005 ATS/ERS standards. In cohorts conducting follow-up for noncardiovascular events, CLRD events were defined as hospitalizations/deaths adjudicated as CLRD-related or assigned relevant administrative codes. Coding and variable names were applied uniformly. The pooled sample included 65,251 adults in 9 cohorts followed-up for CLRD-related mortality over 653,380 person-years during 1983-2016. Average baseline age was 52 years; 56% were female; 49% were never-smokers; and racial/ethnic composition was 44% white, 22% black, 28% Hispanic/Latino, and 5% American Indian. Over 96% had complete data on smoking, clinical CLRD diagnoses, and dyspnea. After excluding invalid spirometry examinations (13%), there were 105,696 valid examinations (median, 2 per participant). Of 29,351 participants followed for CLRD hospitalizations, median follow-up was 14 years; only 5% were lost to follow-up at 10 years. The NHLBI Pooled Cohorts Study provides a harmonization standard applied to a large, US population-based sample that may be used to advance epidemiologic research on CLRD.

%B Am J Epidemiol %V 187 %P 2265-2278 %8 2018 Nov 01 %G eng %N 11 %R 10.1093/aje/kwy139 %0 Journal Article %J SAGE Open Med %D 2018 %T Hospital and clinical care costs associated with atrial fibrillation for Medicare beneficiaries in the Cardiovascular Health Study and the Framingham Heart Study. %A Delaney, Joseph Ac %A Yin, Xiaoyan %A Fontes, João Daniel %A Wallace, Erin R %A Skinner, Asheley %A Wang, Na %A Hammill, Bradley G %A Benjamin, Emelia J %A Curtis, Lesley H %A Heckbert, Susan R %X

Background: Atrial fibrillation is increasingly prevalent as the US population ages and is associated with significant morbidity and mortality. Care for patients with atrial fibrillation can be costly, US health care costs are comparatively high, and there are few cost estimates available that incorporate detailed measurement of comorbidities and their effects on costs.

Methods and Results: In the Cardiovascular Health Study and the Framingham Heart Study, participants aged 65 years or older with newly diagnosed atrial fibrillation were matched on age and follow-up time to referents free of atrial fibrillation. The total clinical and hospital medical costs paid by Medicare Parts A and B (drug costs from Medicare Part D costs were not included) in the year prior to diagnosis (or matching) were compared with costs in the following year. Estimates were adjusted for other medical conditions and adjusted to 2009 dollars. In the Cardiovascular Health Study, 513 participants were diagnosed with new-onset atrial fibrillation and survived 30 days post-atrial fibrillation diagnosis, and 513 referents (as a control cohort) were identified, with a mean age of 77 years. In the Framingham Heart Study, we identified 336 participants diagnosed with atrial fibrillation, who survived 30 days post-atrial fibrillation diagnosis and matched these participants to 336 referents. We compared these new-onset atrial fibrillation participants with referents, using a difference in difference design to account for both time trends and differences between the two groups. The adjusted incremental cost for participants with atrial fibrillation, compared with referents, was US$18,060 (95% confidence interval: US$14,965-US$21,155) in the Cardiovascular Health Study and US$20,012 (95% confidence interval: US$15,057-US$24,966) in the Framingham Heart Study. The pooled estimate was US$18,601 (95% confidence interval: US$15,981-US$21,234).

Conclusion: Atrial fibrillation was associated with increased costs in the year after diagnosis in two community-based cohorts, even after careful accounting for age, time period, and systematically measured comorbidities.

%B SAGE Open Med %V 6 %P 2050312118759444 %8 2018 %G eng %R 10.1177/2050312118759444 %0 Journal Article %J Clin Cardiol %D 2018 %T Impact of lung-function measures on cardiovascular disease events in older adults with metabolic syndrome and diabetes. %A Lee, Hwa Mu %A Zhao, Yanglu %A Liu, Michael A %A Yanez, David %A Carnethon, Mercedes %A Graham Barr, R %A Wong, Nathan D %X

BACKGROUND: Individuals with metabolic syndrome (MetS) and diabetes (DM) are more likely to have decreased lung function and are at greater risk of cardiovascular disease (CVD).

HYPOTHESIS: Lung-function measures can predict CVD events in older persons with MetS, DM, and neither condition.

METHODS: We followed 4114 participants age ≥ 65 years with and without MetS or DM in the Cardiovascular Health Study. Cox regression examined the association of forced vital capacity (FVC) and 1-second forced expiratory volume (FEV ; percent of predicted values) with incident coronary heart disease and CVD events over 12.9 years.

RESULTS: DM was present in 537 (13.1%) and MetS in 1277 (31.0%) participants. Comparing fourth vs first quartiles for FVC, risk of CVD events was 16% (HR: 0.84, 95% CI: 0.59-1.18), 23% (HR: 0.77, 95% CI: 0.60-0.99), and 30% (HR: 0.70, 95% CI: 0.58-0.84) lower in DM, MetS, and neither disease groups, respectively. For FEV , CVD risk was lower by 2% (HR: 0.98, 95% CI: 0.70-1.37), 26% (HR: 0.74, 95% CI: 0.59-0.93), and 31% (HR: 0.69, 95% CI: 0.57-0.82) in DM. Findings were strongest for predicting congestive heart failure (CHF) in all disease groups. C-statistics increased significantly with addition of FEV or FVC over risk factors for CVD and CHF among those with neither MetS nor DM.

CONCLUSIONS: FEV and FVC are inversely related to CVD in older adults with and without MetS, but not DM (except for CHF); however, their value in incremental risk prediction beyond standard risk factors is limited mainly to metabolically healthier persons.

%B Clin Cardiol %V 41 %P 959-965 %8 2018 Jul %G eng %N 7 %R 10.1002/clc.22985 %0 Journal Article %J Am J Hum Genet %D 2018 %T A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure. %A Sung, Yun J %A Winkler, Thomas W %A de Las Fuentes, Lisa %A Bentley, Amy R %A Brown, Michael R %A Kraja, Aldi T %A Schwander, Karen %A Ntalla, Ioanna %A Guo, Xiuqing %A Franceschini, Nora %A Lu, Yingchang %A Cheng, Ching-Yu %A Sim, Xueling %A Vojinovic, Dina %A Marten, Jonathan %A Musani, Solomon K %A Li, Changwei %A Feitosa, Mary F %A Kilpeläinen, Tuomas O %A Richard, Melissa A %A Noordam, Raymond %A Aslibekyan, Stella %A Aschard, Hugues %A Bartz, Traci M %A Dorajoo, Rajkumar %A Liu, Yongmei %A Manning, Alisa K %A Rankinen, Tuomo %A Smith, Albert Vernon %A Tajuddin, Salman M %A Tayo, Bamidele O %A Warren, Helen R %A Zhao, Wei %A Zhou, Yanhua %A Matoba, Nana %A Sofer, Tamar %A Alver, Maris %A Amini, Marzyeh %A Boissel, Mathilde %A Chai, Jin Fang %A Chen, Xu %A Divers, Jasmin %A Gandin, Ilaria %A Gao, Chuan %A Giulianini, Franco %A Goel, Anuj %A Harris, Sarah E %A Hartwig, Fernando Pires %A Horimoto, Andrea R V R %A Hsu, Fang-Chi %A Jackson, Anne U %A Kähönen, Mika %A Kasturiratne, Anuradhani %A Kuhnel, Brigitte %A Leander, Karin %A Lee, Wen-Jane %A Lin, Keng-Hung %A 'an Luan, Jian %A McKenzie, Colin A %A Meian, He %A Nelson, Christopher P %A Rauramaa, Rainer %A Schupf, Nicole %A Scott, Robert A %A Sheu, Wayne H H %A Stančáková, Alena %A Takeuchi, Fumihiko %A van der Most, Peter J %A Varga, Tibor V %A Wang, Heming %A Wang, Yajuan %A Ware, Erin B %A Weiss, Stefan %A Wen, Wanqing %A Yanek, Lisa R %A Zhang, Weihua %A Zhao, Jing Hua %A Afaq, Saima %A Alfred, Tamuno %A Amin, Najaf %A Arking, Dan %A Aung, Tin %A Barr, R Graham %A Bielak, Lawrence F %A Boerwinkle, Eric %A Bottinger, Erwin P %A Braund, Peter S %A Brody, Jennifer A %A Broeckel, Ulrich %A Cabrera, Claudia P %A Cade, Brian %A Caizheng, Yu %A Campbell, Archie %A Canouil, Mickaël %A Chakravarti, Aravinda %A Chauhan, Ganesh %A Christensen, Kaare %A Cocca, Massimiliano %A Collins, Francis S %A Connell, John M %A de Mutsert, Renée %A de Silva, H Janaka %A Debette, Stephanie %A Dörr, Marcus %A Duan, Qing %A Eaton, Charles B %A Ehret, Georg %A Evangelou, Evangelos %A Faul, Jessica D %A Fisher, Virginia A %A Forouhi, Nita G %A Franco, Oscar H %A Friedlander, Yechiel %A Gao, He %A Gigante, Bruna %A Graff, Misa %A Gu, C Charles %A Gu, Dongfeng %A Gupta, Preeti %A Hagenaars, Saskia P %A Harris, Tamara B %A He, Jiang %A Heikkinen, Sami %A Heng, Chew-Kiat %A Hirata, Makoto %A Hofman, Albert %A Howard, Barbara V %A Hunt, Steven %A Irvin, Marguerite R %A Jia, Yucheng %A Joehanes, Roby %A Justice, Anne E %A Katsuya, Tomohiro %A Kaufman, Joel %A Kerrison, Nicola D %A Khor, Chiea Chuen %A Koh, Woon-Puay %A Koistinen, Heikki A %A Komulainen, Pirjo %A Kooperberg, Charles %A Krieger, Jose E %A Kubo, Michiaki %A Kuusisto, Johanna %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Lehne, Benjamin %A Lewis, Cora E %A Li, Yize %A Lim, Sing Hui %A Lin, Shiow %A Liu, Ching-Ti %A Liu, Jianjun %A Liu, Jingmin %A Liu, Kiang %A Liu, Yeheng %A Loh, Marie %A Lohman, Kurt K %A Long, Jirong %A Louie, Tin %A Mägi, Reedik %A Mahajan, Anubha %A Meitinger, Thomas %A Metspalu, Andres %A Milani, Lili %A Momozawa, Yukihide %A Morris, Andrew P %A Mosley, Thomas H %A Munson, Peter %A Murray, Alison D %A Nalls, Mike A %A Nasri, Ubaydah %A Norris, Jill M %A North, Kari %A Ogunniyi, Adesola %A Padmanabhan, Sandosh %A Palmas, Walter R %A Palmer, Nicholette D %A Pankow, James S %A Pedersen, Nancy L %A Peters, Annette %A Peyser, Patricia A %A Polasek, Ozren %A Raitakari, Olli T %A Renstrom, Frida %A Rice, Treva K %A Ridker, Paul M %A Robino, Antonietta %A Robinson, Jennifer G %A Rose, Lynda M %A Rudan, Igor %A Sabanayagam, Charumathi %A Salako, Babatunde L %A Sandow, Kevin %A Schmidt, Carsten O %A Schreiner, Pamela J %A Scott, William R %A Seshadri, Sudha %A Sever, Peter %A Sitlani, Colleen M %A Smith, Jennifer A %A Snieder, Harold %A Starr, John M %A Strauch, Konstantin %A Tang, Hua %A Taylor, Kent D %A Teo, Yik Ying %A Tham, Yih Chung %A Uitterlinden, André G %A Waldenberger, Melanie %A Wang, Lihua %A Wang, Ya X %A Wei, Wen Bin %A Williams, Christine %A Wilson, Gregory %A Wojczynski, Mary K %A Yao, Jie %A Yuan, Jian-Min %A Zonderman, Alan B %A Becker, Diane M %A Boehnke, Michael %A Bowden, Donald W %A Chambers, John C %A Chen, Yii-Der Ida %A de Faire, Ulf %A Deary, Ian J %A Esko, Tõnu %A Farrall, Martin %A Forrester, Terrence %A Franks, Paul W %A Freedman, Barry I %A Froguel, Philippe %A Gasparini, Paolo %A Gieger, Christian %A Horta, Bernardo Lessa %A Hung, Yi-Jen %A Jonas, Jost B %A Kato, Norihiro %A Kooner, Jaspal S %A Laakso, Markku %A Lehtimäki, Terho %A Liang, Kae-Woei %A Magnusson, Patrik K E %A Newman, Anne B %A Oldehinkel, Albertine J %A Pereira, Alexandre C %A Redline, Susan %A Rettig, Rainer %A Samani, Nilesh J %A Scott, James %A Shu, Xiao-Ou %A van der Harst, Pim %A Wagenknecht, Lynne E %A Wareham, Nicholas J %A Watkins, Hugh %A Weir, David R %A Wickremasinghe, Ananda R %A Wu, Tangchun %A Zheng, Wei %A Kamatani, Yoichiro %A Laurie, Cathy C %A Bouchard, Claude %A Cooper, Richard S %A Evans, Michele K %A Gudnason, Vilmundur %A Kardia, Sharon L R %A Kritchevsky, Stephen B %A Levy, Daniel %A O'Connell, Jeff R %A Psaty, Bruce M %A van Dam, Rob M %A Sims, Mario %A Arnett, Donna K %A Mook-Kanamori, Dennis O %A Kelly, Tanika N %A Fox, Ervin R %A Hayward, Caroline %A Fornage, Myriam %A Rotimi, Charles N %A Province, Michael A %A van Duijn, Cornelia M %A Tai, E Shyong %A Wong, Tien Yin %A Loos, Ruth J F %A Reiner, Alex P %A Rotter, Jerome I %A Zhu, Xiaofeng %A Bierut, Laura J %A Gauderman, W James %A Caulfield, Mark J %A Elliott, Paul %A Rice, Kenneth %A Munroe, Patricia B %A Morrison, Alanna C %A Cupples, L Adrienne %A Rao, Dabeeru C %A Chasman, Daniel I %X

Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).

%B Am J Hum Genet %V 102 %P 375-400 %8 2018 Mar 01 %G eng %N 3 %R 10.1016/j.ajhg.2018.01.015 %0 Journal Article %J Nat Commun %D 2018 %T Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels. %A Tin, Adrienne %A Li, Yong %A Brody, Jennifer A %A Nutile, Teresa %A Chu, Audrey Y %A Huffman, Jennifer E %A Yang, Qiong %A Chen, Ming-Huei %A Robinson-Cohen, Cassianne %A Mace, Aurelien %A Liu, Jun %A Demirkan, Ayse %A Sorice, Rossella %A Sedaghat, Sanaz %A Swen, Melody %A Yu, Bing %A Ghasemi, Sahar %A Teumer, Alexanda %A Vollenweider, Peter %A Ciullo, Marina %A Li, Meng %A Uitterlinden, André G %A Kraaij, Robert %A Amin, Najaf %A van Rooij, Jeroen %A Kutalik, Zoltán %A Dehghan, Abbas %A McKnight, Barbara %A van Duijn, Cornelia M %A Morrison, Alanna %A Psaty, Bruce M %A Boerwinkle, Eric %A Fox, Caroline S %A Woodward, Owen M %A Köttgen, Anna %K Exome %K Genetic Predisposition to Disease %K Glucose Transport Proteins, Facilitative %K Humans %K Kidney Function Tests %K Meta-Analysis as Topic %K Organic Anion Transporters %K Organic Cation Transport Proteins %K Protein Structure, Secondary %K Uric Acid %X

Elevated serum urate levels can cause gout, an excruciating disease with suboptimal treatment. Previous GWAS identified common variants with modest effects on serum urate. Here we report large-scale whole-exome sequencing association studies of serum urate and kidney function among ≤19,517 European ancestry and African-American individuals. We identify aggregate associations of low-frequency damaging variants in the urate transporters SLC22A12 (URAT1; p = 1.3 × 10) and SLC2A9 (p = 4.5 × 10). Gout risk in rare SLC22A12 variant carriers is halved (OR = 0.5, p = 4.9 × 10). Selected rare variants in SLC22A12 are validated in transport studies, confirming three as loss-of-function (R325W, R405C, and T467M) and illustrating the therapeutic potential of the new URAT1-blocker lesinurad. In SLC2A9, mapping of rare variants of large effects onto the predicted protein structure reveals new residues that may affect urate binding. These findings provide new insights into the genetic architecture of serum urate, and highlight molecular targets in SLC22A12 and SLC2A9 for lowering serum urate and preventing gout.

%B Nat Commun %V 9 %P 4228 %8 2018 10 12 %G eng %N 1 %R 10.1038/s41467-018-06620-4 %0 Journal Article %J Am J Hum Genet %D 2018 %T {Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects %A Medina-Gomez, C. %A Kemp, J. P. %A Trajanoska, K. %A Luan, J. %A Chesi, A. %A Ahluwalia, T. S. %A Mook-Kanamori, D. O. %A Ham, A. %A Hartwig, F. P. %A Evans, D. S. %A Joro, R. %A Nedeljkovic, I. %A Zheng, H. F. %A Zhu, K. %A Atalay, M. %A Liu, C. T. %A Nethander, M. %A Broer, L. %A Porleifsson, G. %A Mullin, B. H. %A Handelman, S. K. %A Nalls, M. A. %A Jessen, L. E. %A Heppe, D. H. M. %A Richards, J. B. %A Wang, C. %A Chawes, B. %A Schraut, K. E. %A Amin, N. %A Wareham, N. %A Karasik, D. %A Van der Velde, N. %A Ikram, M. A. %A Zemel, B. S. %A Zhou, Y. %A Carlsson, C. J. %A Liu, Y. %A McGuigan, F. E. %A Boer, C. G. %A B?nnelykke, K. %A Ralston, S. H. %A Robbins, J. A. %A Walsh, J. P. %A Zillikens, M. C. %A Langenberg, C. %A Li-Gao, R. %A Williams, F. M. K. %A Harris, T. B. %A Akesson, K. %A Jackson, R. D. %A Sigurdsson, G. %A den Heijer, M. %A van der Eerden, B. C. J. %A van de Peppel, J. %A Spector, T. D. %A Pennell, C. %A Horta, B. L. %A Felix, J. F. %A Zhao, J. H. %A Wilson, S. G. %A de Mutsert, R. %A Bisgaard, H. %A Styrk?rsd?ttir, U. %A Jaddoe, V. W. %A Orwoll, E. %A Lakka, T. A. %A Scott, R. %A Grant, S. F. A. %A Lorentzon, M. %A van Duijn, C. M. %A Wilson, J. F. %A Stefansson, K. %A Psaty, B. M. %A Kiel, D. P. %A Ohlsson, C. %A Ntzani, E. %A van Wijnen, A. J. %A Forgetta, V. %A Ghanbari, M. %A Logan, J. G. %A Williams, G. R. %A Bassett, J. H. D. %A Croucher, P. I. %A Evangelou, E. %A Uitterlinden, A. G. %A Ackert-Bicknell, C. L. %A Tobias, J. H. %A Evans, D. M. %A Rivadeneira, F. %X Bone mineral density (BMD) assessed by DXA is used to evaluate bone health. In children, total body (TB) measurements are commonly used; in older individuals, BMD at the lumbar spine (LS) and femoral neck (FN) is used to diagnose osteoporosis. To date, genetic variants in more than 60 loci have been identified as associated with BMD. To investigate the genetic determinants of TB-BMD variation along the life course and test for age-specific effects, we performed a meta-analysis of 30 genome-wide association studies (GWASs) of TB-BMD including 66,628 individuals overall and divided across five age strata, each spanning 15 years. We identified variants associated with TB-BMD at 80 loci, of which 36 have not been previously identified; overall, they explain approximately 10% of the TB-BMD variance when combining all age groups and influence the risk of fracture. Pathway and enrichment analysis of the association signals showed clustering within gene sets implicated in the regulation of cell growth and SMAD proteins, overexpressed in the musculoskeletal system, and enriched in enhancer and promoter regions. These findings reveal TB-BMD as a relevant trait for genetic studies of osteoporosis, enabling the identification of variants and pathways influencing different bone compartments. Only variants in ESR1 and close proximity to RANKL showed a clear effect dependency on age. This most likely indicates that the majority of genetic variants identified influence BMD early in life and that their effect can be captured throughout the life course. %B Am J Hum Genet %V 102 %P 88–102 %8 01 %G eng %0 Journal Article %J Circ Heart Fail %D 2018 %T Long-Term Cognitive Decline After Newly Diagnosed Heart Failure: Longitudinal Analysis in the CHS (Cardiovascular Health Study). %A Hammond, Christa A %A Blades, Natalie J %A Chaudhry, Sarwat I %A Dodson, John A %A Longstreth, W T %A Heckbert, Susan R %A Psaty, Bruce M %A Arnold, Alice M %A Dublin, Sascha %A Sitlani, Colleen M %A Gardin, Julius M %A Thielke, Stephen M %A Nanna, Michael G %A Gottesman, Rebecca F %A Newman, Anne B %A Thacker, Evan L %X

BACKGROUND: Heart failure (HF) is associated with cognitive impairment. However, we know little about the time course of cognitive change after HF diagnosis, the importance of comorbid atrial fibrillation, or the role of ejection fraction. We sought to determine the associations of incident HF with rates of cognitive decline and whether these differed by atrial fibrillation status or reduced versus preserved ejection fraction.

METHODS AND RESULTS: Participants were 4864 men and women aged ≥65 years without a history of HF and free of clinical stroke in the CHS (Cardiovascular Health Study)-a community-based prospective cohort study in the United States, with cognition assessed annually from 1989/1990 through 1998/1999. We identified 496 participants with incident HF by review of hospital discharge summaries and Medicare claims data, with adjudication according to standard criteria. Global cognitive ability was measured by the Modified Mini-Mental State Examination. In adjusted models, 5-year decline in model-predicted mean Modified Mini-Mental State Examination score was 10.2 points (95% confidence interval, 8.6-11.8) after incident HF diagnosed at 80 years of age, compared with a mean 5-year decline of 5.8 points (95% confidence interval, 5.3-6.2) from 80 to 85 years of age without HF. The association was stronger at older ages than at younger ages, did not vary significantly in the presence versus absence of atrial fibrillation (=0.084), and did not vary significantly by reduced versus preserved ejection fraction (=0.734).

CONCLUSIONS: Decline in global cognitive ability tends to be faster after HF diagnosis than without HF. Clinical and public health implications of this finding warrant further attention.

%B Circ Heart Fail %V 11 %P e004476 %8 2018 Mar %G eng %N 3 %R 10.1161/CIRCHEARTFAILURE.117.004476 %0 Journal Article %J Nephrol Dial Transplant %D 2018 %T Low thyroid function is not associated with an accelerated deterioration in renal function. %A Meuwese, Christiaan L %A van Diepen, Merel %A Cappola, Anne R %A Sarnak, Mark J %A Shlipak, Michael G %A Bauer, Douglas C %A Fried, Linda P %A Iacoviello, Massimo %A Vaes, Bert %A Degryse, Jean %A Khaw, Kay-Tee %A Luben, Robert N %A Asvold, Bjørn O %A Bjøro, Trine %A Vatten, Lars J %A de Craen, Anton J M %A Trompet, Stella %A Iervasi, Giorgio %A Molinaro, Sabrina %A Ceresini, Graziano %A Ferrucci, Luigi %A Dullaart, Robin P F %A Bakker, Stephan J L %A Jukema, J Wouter %A Kearney, Patricia M %A Stott, David J %A Peeters, Robin P %A Franco, Oscar H %A Völzke, Henry %A Walsh, John P %A Bremner, Alexandra %A Sgarbi, José A %A Maciel, Rui M B %A Imaizumi, Misa %A Ohishi, Waka %A Dekker, Friedo W %A Rodondi, Nicolas %A Gussekloo, Jacobijn %A den Elzen, Wendy P J %X

Background: Chronic kidney disease (CKD) is frequently accompanied by thyroid hormone dysfunction. It is currently unclear whether these alterations are the cause or consequence of CKD. This study aimed at studying the effect of thyroid hormone alterations on renal function in cross-sectional and longitudinal analyses in individuals from all adult age groups.

Methods: Individual participant data (IPD) from 16 independent cohorts having measured thyroid stimulating hormone, free thyroxine levels and creatinine levels were included. Thyroid hormone status was defined using clinical cut-off values. Estimated glomerular filtration rates (eGFR) were calculated by means of the four-variable Modification of Diet in Renal Disease (MDRD) formula. For this IPD meta-analysis, eGFR at baseline and eGFR change during follow-up were computed by fitting linear regression models and linear mixed models in each cohort separately. Effect estimates were pooled using random effects models.

Results: A total of 72 856 individuals from 16 different cohorts were included. At baseline, individuals with overt hypothyroidism (n = 704) and subclinical hypothyroidism (n = 3356) had a average (95% confidence interval) -4.07 (-6.37 to -1.78) and -2.40 (-3.78 to -1.02) mL/min/1.73 m2 lower eGFR as compared with euthyroid subjects (n = 66 542). In (subclinical) hyperthyroid subjects (n = 2254), average eGFR was 3.01 (1.50-4.52) mL/min/1.73 m2 higher. During 329 713 patient years of follow-up, eGFR did not decline more rapidly in individuals with low thyroid function compared with individuals with normal thyroid function.

Conclusions: Low thyroid function is not associated with a deterioration of renal function. The cross-sectional association may be explained by renal dysfunction causing thyroid hormone alterations.

%B Nephrol Dial Transplant %8 2018 Apr 18 %G eng %R 10.1093/ndt/gfy071 %0 Journal Article %J Br J Nutr %D 2018 %T Meta-analysis across Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium provides evidence for an association of serum vitamin D with pulmonary function. %A Xu, Jiayi %A Bartz, Traci M %A Chittoor, Geetha %A Eiriksdottir, Gudny %A Manichaikul, Ani W %A Sun, Fangui %A Terzikhan, Natalie %A Zhou, Xia %A Booth, Sarah L %A Brusselle, Guy G %A de Boer, Ian H %A Fornage, Myriam %A Frazier-Wood, Alexis C %A Graff, Mariaelisa %A Gudnason, Vilmundur %A Harris, Tamara B %A Hofman, Albert %A Hou, Ruixue %A Houston, Denise K %A Jacobs, David R %A Kritchevsky, Stephen B %A Latourelle, Jeanne %A Lemaitre, Rozenn N %A Lutsey, Pamela L %A O'Connor, George %A Oelsner, Elizabeth C %A Pankow, James S %A Psaty, Bruce M %A Rohde, Rebecca R %A Rich, Stephen S %A Rotter, Jerome I %A Smith, Lewis J %A Stricker, Bruno H %A Voruganti, V Saroja %A Wang, Thomas J %A Zillikens, M Carola %A Barr, R Graham %A Dupuis, Josée %A Gharib, Sina A %A Lahousse, Lies %A London, Stephanie J %A North, Kari E %A Smith, Albert V %A Steffen, Lyn M %A Hancock, Dana B %A Cassano, Patricia A %X

The role that vitamin D plays in pulmonary function remains uncertain. Epidemiological studies reported mixed findings for serum 25-hydroxyvitamin D (25(OH)D)-pulmonary function association. We conducted the largest cross-sectional meta-analysis of the 25(OH)D-pulmonary function association to date, based on nine European ancestry (EA) cohorts (n 22 838) and five African ancestry (AA) cohorts (n 4290) in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Data were analysed using linear models by cohort and ancestry. Effect modification by smoking status (current/former/never) was tested. Results were combined using fixed-effects meta-analysis. Mean serum 25(OH)D was 68 (sd 29) nmol/l for EA and 49 (sd 21) nmol/l for AA. For each 1 nmol/l higher 25(OH)D, forced expiratory volume in the 1st second (FEV1) was higher by 1·1 ml in EA (95 % CI 0·9, 1·3; P<0·0001) and 1·8 ml (95 % CI 1·1, 2·5; P<0·0001) in AA (P race difference=0·06), and forced vital capacity (FVC) was higher by 1·3 ml in EA (95 % CI 1·0, 1·6; P<0·0001) and 1·5 ml (95 % CI 0·8, 2·3; P=0·0001) in AA (P race difference=0·56). Among EA, the 25(OH)D-FVC association was stronger in smokers: per 1 nmol/l higher 25(OH)D, FVC was higher by 1·7 ml (95 % CI 1·1, 2·3) for current smokers and 1·7 ml (95 % CI 1·2, 2·1) for former smokers, compared with 0·8 ml (95 % CI 0·4, 1·2) for never smokers. In summary, the 25(OH)D associations with FEV1 and FVC were positive in both ancestries. In EA, a stronger association was observed for smokers compared with never smokers, which supports the importance of vitamin D in vulnerable populations.

%B Br J Nutr %P 1-12 %8 2018 Sep 12 %G eng %R 10.1017/S0007114518002180 %0 Journal Article %J Wellcome Open Res %D 2018 %T Meta-analysis of exome array data identifies six novel genetic loci for lung function. %A Jackson, Victoria E %A Latourelle, Jeanne C %A Wain, Louise V %A Smith, Albert V %A Grove, Megan L %A Bartz, Traci M %A Obeidat, Ma'en %A Province, Michael A %A Gao, Wei %A Qaiser, Beenish %A Porteous, David J %A Cassano, Patricia A %A Ahluwalia, Tarunveer S %A Grarup, Niels %A Li, Jin %A Altmaier, Elisabeth %A Marten, Jonathan %A Harris, Sarah E %A Manichaikul, Ani %A Pottinger, Tess D %A Li-Gao, Ruifang %A Lind-Thomsen, Allan %A Mahajan, Anubha %A Lahousse, Lies %A Imboden, Medea %A Teumer, Alexander %A Prins, Bram %A Lyytikäinen, Leo-Pekka %A Eiriksdottir, Gudny %A Franceschini, Nora %A Sitlani, Colleen M %A Brody, Jennifer A %A Bossé, Yohan %A Timens, Wim %A Kraja, Aldi %A Loukola, Anu %A Tang, Wenbo %A Liu, Yongmei %A Bork-Jensen, Jette %A Justesen, Johanne M %A Linneberg, Allan %A Lange, Leslie A %A Rawal, Rajesh %A Karrasch, Stefan %A Huffman, Jennifer E %A Smith, Blair H %A Davies, Gail %A Burkart, Kristin M %A Mychaleckyj, Josyf C %A Bonten, Tobias N %A Enroth, Stefan %A Lind, Lars %A Brusselle, Guy G %A Kumar, Ashish %A Stubbe, Beate %A Kähönen, Mika %A Wyss, Annah B %A Psaty, Bruce M %A Heckbert, Susan R %A Hao, Ke %A Rantanen, Taina %A Kritchevsky, Stephen B %A Lohman, Kurt %A Skaaby, Tea %A Pisinger, Charlotta %A Hansen, Torben %A Schulz, Holger %A Polasek, Ozren %A Campbell, Archie %A Starr, John M %A Rich, Stephen S %A Mook-Kanamori, Dennis O %A Johansson, Asa %A Ingelsson, Erik %A Uitterlinden, André G %A Weiss, Stefan %A Raitakari, Olli T %A Gudnason, Vilmundur %A North, Kari E %A Gharib, Sina A %A Sin, Don D %A Taylor, Kent D %A O'Connor, George T %A Kaprio, Jaakko %A Harris, Tamara B %A Pederson, Oluf %A Vestergaard, Henrik %A Wilson, James G %A Strauch, Konstantin %A Hayward, Caroline %A Kerr, Shona %A Deary, Ian J %A Barr, R Graham %A de Mutsert, Renée %A Gyllensten, Ulf %A Morris, Andrew P %A Ikram, M Arfan %A Probst-Hensch, Nicole %A Gläser, Sven %A Zeggini, Eleftheria %A Lehtimäki, Terho %A Strachan, David P %A Dupuis, Josée %A Morrison, Alanna C %A Hall, Ian P %A Tobin, Martin D %A London, Stephanie J %X

Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV ), forced vital capacity (FVC) and the ratio of FEV to FVC (FEV /FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. We identified significant (P<2·8x10 ) associations with six SNPs: a nonsynonymous variant in , which is predicted to be damaging, three intronic SNPs ( and ) and two intergenic SNPs near to and Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including and . Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.

%B Wellcome Open Res %V 3 %P 4 %8 2018 %G eng %R 10.12688/wellcomeopenres.12583.3 %0 Journal Article %J Nat Genet %D 2018 %T Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks. %A Demenais, Florence %A Margaritte-Jeannin, Patricia %A Barnes, Kathleen C %A Cookson, William O C %A Altmüller, Janine %A Ang, Wei %A Barr, R Graham %A Beaty, Terri H %A Becker, Allan B %A Beilby, John %A Bisgaard, Hans %A Bjornsdottir, Unnur Steina %A Bleecker, Eugene %A Bønnelykke, Klaus %A Boomsma, Dorret I %A Bouzigon, Emmanuelle %A Brightling, Christopher E %A Brossard, Myriam %A Brusselle, Guy G %A Burchard, Esteban %A Burkart, Kristin M %A Bush, Andrew %A Chan-Yeung, Moira %A Chung, Kian Fan %A Couto Alves, Alexessander %A Curtin, John A %A Custovic, Adnan %A Daley, Denise %A de Jongste, Johan C %A Del-Rio-Navarro, Blanca E %A Donohue, Kathleen M %A Duijts, Liesbeth %A Eng, Celeste %A Eriksson, Johan G %A Farrall, Martin %A Fedorova, Yuliya %A Feenstra, Bjarke %A Ferreira, Manuel A %A Freidin, Maxim B %A Gajdos, Zofia %A Gauderman, Jim %A Gehring, Ulrike %A Geller, Frank %A Genuneit, Jon %A Gharib, Sina A %A Gilliland, Frank %A Granell, Raquel %A Graves, Penelope E %A Gudbjartsson, Daniel F %A Haahtela, Tari %A Heckbert, Susan R %A Heederik, Dick %A Heinrich, Joachim %A Heliövaara, Markku %A Henderson, John %A Himes, Blanca E %A Hirose, Hiroshi %A Hirschhorn, Joel N %A Hofman, Albert %A Holt, Patrick %A Hottenga, Jouke %A Hudson, Thomas J %A Hui, Jennie %A Imboden, Medea %A Ivanov, Vladimir %A Jaddoe, Vincent W V %A James, Alan %A Janson, Christer %A Jarvelin, Marjo-Riitta %A Jarvis, Deborah %A Jones, Graham %A Jonsdottir, Ingileif %A Jousilahti, Pekka %A Kabesch, Michael %A Kähönen, Mika %A Kantor, David B %A Karunas, Alexandra S %A Khusnutdinova, Elza %A Koppelman, Gerard H %A Kozyrskyj, Anita L %A Kreiner, Eskil %A Kubo, Michiaki %A Kumar, Rajesh %A Kumar, Ashish %A Kuokkanen, Mikko %A Lahousse, Lies %A Laitinen, Tarja %A Laprise, Catherine %A Lathrop, Mark %A Lau, Susanne %A Lee, Young-Ae %A Lehtimäki, Terho %A Letort, Sébastien %A Levin, Albert M %A Li, Guo %A Liang, Liming %A Loehr, Laura R %A London, Stephanie J %A Loth, Daan W %A Manichaikul, Ani %A Marenholz, Ingo %A Martinez, Fernando J %A Matheson, Melanie C %A Mathias, Rasika A %A Matsumoto, Kenji %A Mbarek, Hamdi %A McArdle, Wendy L %A Melbye, Mads %A Melén, Erik %A Meyers, Deborah %A Michel, Sven %A Mohamdi, Hamida %A Musk, Arthur W %A Myers, Rachel A %A Nieuwenhuis, Maartje A E %A Noguchi, Emiko %A O'Connor, George T %A Ogorodova, Ludmila M %A Palmer, Cameron D %A Palotie, Aarno %A Park, Julie E %A Pennell, Craig E %A Pershagen, Göran %A Polonikov, Alexey %A Postma, Dirkje S %A Probst-Hensch, Nicole %A Puzyrev, Valery P %A Raby, Benjamin A %A Raitakari, Olli T %A Ramasamy, Adaikalavan %A Rich, Stephen S %A Robertson, Colin F %A Romieu, Isabelle %A Salam, Muhammad T %A Salomaa, Veikko %A Schlünssen, Vivi %A Scott, Robert %A Selivanova, Polina A %A Sigsgaard, Torben %A Simpson, Angela %A Siroux, Valérie %A Smith, Lewis J %A Solodilova, Maria %A Standl, Marie %A Stefansson, Kari %A Strachan, David P %A Stricker, Bruno H %A Takahashi, Atsushi %A Thompson, Philip J %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Tiesler, Carla M T %A Torgerson, Dara G %A Tsunoda, Tatsuhiko %A Uitterlinden, André G %A van der Valk, Ralf J P %A Vaysse, Amaury %A Vedantam, Sailaja %A von Berg, Andrea %A von Mutius, Erika %A Vonk, Judith M %A Waage, Johannes %A Wareham, Nick J %A Weiss, Scott T %A White, Wendy B %A Wickman, Magnus %A Widen, Elisabeth %A Willemsen, Gonneke %A Williams, L Keoki %A Wouters, Inge M %A Yang, James J %A Zhao, Jing Hua %A Moffatt, Miriam F %A Ober, Carole %A Nicolae, Dan L %X

We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms.

%B Nat Genet %V 50 %P 42-53 %8 2018 Jan %G eng %N 1 %R 10.1038/s41588-017-0014-7 %0 Journal Article %J Nat Genet %D 2018 %T Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. %A Malik, Rainer %A Chauhan, Ganesh %A Traylor, Matthew %A Sargurupremraj, Muralidharan %A Okada, Yukinori %A Mishra, Aniket %A Rutten-Jacobs, Loes %A Giese, Anne-Katrin %A van der Laan, Sander W %A Gretarsdottir, Solveig %A Anderson, Christopher D %A Chong, Michael %A Adams, Hieab H H %A Ago, Tetsuro %A Almgren, Peter %A Amouyel, Philippe %A Ay, Hakan %A Bartz, Traci M %A Benavente, Oscar R %A Bevan, Steve %A Boncoraglio, Giorgio B %A Brown, Robert D %A Butterworth, Adam S %A Carrera, Caty %A Carty, Cara L %A Chasman, Daniel I %A Chen, Wei-Min %A Cole, John W %A Correa, Adolfo %A Cotlarciuc, Ioana %A Cruchaga, Carlos %A Danesh, John %A de Bakker, Paul I W %A DeStefano, Anita L %A den Hoed, Marcel %A Duan, Qing %A Engelter, Stefan T %A Falcone, Guido J %A Gottesman, Rebecca F %A Grewal, Raji P %A Gudnason, Vilmundur %A Gustafsson, Stefan %A Haessler, Jeffrey %A Harris, Tamara B %A Hassan, Ahamad %A Havulinna, Aki S %A Heckbert, Susan R %A Holliday, Elizabeth G %A Howard, George %A Hsu, Fang-Chi %A Hyacinth, Hyacinth I %A Ikram, M Arfan %A Ingelsson, Erik %A Irvin, Marguerite R %A Jian, Xueqiu %A Jimenez-Conde, Jordi %A Johnson, Julie A %A Jukema, J Wouter %A Kanai, Masahiro %A Keene, Keith L %A Kissela, Brett M %A Kleindorfer, Dawn O %A Kooperberg, Charles %A Kubo, Michiaki %A Lange, Leslie A %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Lee, Jin-Moo %A Lemmens, Robin %A Leys, Didier %A Lewis, Cathryn M %A Lin, Wei-Yu %A Lindgren, Arne G %A Lorentzen, Erik %A Magnusson, Patrik K %A Maguire, Jane %A Manichaikul, Ani %A McArdle, Patrick F %A Meschia, James F %A Mitchell, Braxton D %A Mosley, Thomas H %A Nalls, Michael A %A Ninomiya, Toshiharu %A O'Donnell, Martin J %A Psaty, Bruce M %A Pulit, Sara L %A Rannikmae, Kristiina %A Reiner, Alexander P %A Rexrode, Kathryn M %A Rice, Kenneth %A Rich, Stephen S %A Ridker, Paul M %A Rost, Natalia S %A Rothwell, Peter M %A Rotter, Jerome I %A Rundek, Tatjana %A Sacco, Ralph L %A Sakaue, Saori %A Sale, Michèle M %A Salomaa, Veikko %A Sapkota, Bishwa R %A Schmidt, Reinhold %A Schmidt, Carsten O %A Schminke, Ulf %A Sharma, Pankaj %A Slowik, Agnieszka %A Sudlow, Cathie L M %A Tanislav, Christian %A Tatlisumak, Turgut %A Taylor, Kent D %A Thijs, Vincent N S %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Tiedt, Steffen %A Trompet, Stella %A Tzourio, Christophe %A van Duijn, Cornelia M %A Walters, Matthew %A Wareham, Nicholas J %A Wassertheil-Smoller, Sylvia %A Wilson, James G %A Wiggins, Kerri L %A Yang, Qiong %A Yusuf, Salim %A Bis, Joshua C %A Pastinen, Tomi %A Ruusalepp, Arno %A Schadt, Eric E %A Koplev, Simon %A Björkegren, Johan L M %A Codoni, Veronica %A Civelek, Mete %A Smith, Nicholas L %A Trégouët, David A %A Christophersen, Ingrid E %A Roselli, Carolina %A Lubitz, Steven A %A Ellinor, Patrick T %A Tai, E Shyong %A Kooner, Jaspal S %A Kato, Norihiro %A He, Jiang %A van der Harst, Pim %A Elliott, Paul %A Chambers, John C %A Takeuchi, Fumihiko %A Johnson, Andrew D %A Sanghera, Dharambir K %A Melander, Olle %A Jern, Christina %A Strbian, Daniel %A Fernandez-Cadenas, Israel %A Longstreth, W T %A Rolfs, Arndt %A Hata, Jun %A Woo, Daniel %A Rosand, Jonathan %A Paré, Guillaume %A Hopewell, Jemma C %A Saleheen, Danish %A Stefansson, Kari %A Worrall, Bradford B %A Kittner, Steven J %A Seshadri, Sudha %A Fornage, Myriam %A Markus, Hugh S %A Howson, Joanna M M %A Kamatani, Yoichiro %A Debette, Stephanie %A Dichgans, Martin %A Malik, Rainer %A Chauhan, Ganesh %A Traylor, Matthew %A Sargurupremraj, Muralidharan %A Okada, Yukinori %A Mishra, Aniket %A Rutten-Jacobs, Loes %A Giese, Anne-Katrin %A van der Laan, Sander W %A Gretarsdottir, Solveig %A Anderson, Christopher D %A Chong, Michael %A Adams, Hieab H H %A Ago, Tetsuro %A Almgren, Peter %A Amouyel, Philippe %A Ay, Hakan %A Bartz, Traci M %A Benavente, Oscar R %A Bevan, Steve %A Boncoraglio, Giorgio B %A Brown, Robert D %A Butterworth, Adam S %A Carrera, Caty %A Carty, Cara L %A Chasman, Daniel I %A Chen, Wei-Min %A Cole, John W %A Correa, Adolfo %A Cotlarciuc, Ioana %A Cruchaga, Carlos %A Danesh, John %A de Bakker, Paul I W %A DeStefano, Anita L %A Hoed, Marcel den %A Duan, Qing %A Engelter, Stefan T %A Falcone, Guido J %A Gottesman, Rebecca F %A Grewal, Raji P %A Gudnason, Vilmundur %A Gustafsson, Stefan %A Haessler, Jeffrey %A Harris, Tamara B %A Hassan, Ahamad %A Havulinna, Aki S %A Heckbert, Susan R %A Holliday, Elizabeth G %A Howard, George %A Hsu, Fang-Chi %A Hyacinth, Hyacinth I %A Ikram, M Arfan %A Ingelsson, Erik %A Irvin, Marguerite R %A Jian, Xueqiu %A Jimenez-Conde, Jordi %A Johnson, Julie A %A Jukema, J Wouter %A Kanai, Masahiro %A Keene, Keith L %A Kissela, Brett M %A Kleindorfer, Dawn O %A Kooperberg, Charles %A Kubo, Michiaki %A Lange, Leslie A %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Lee, Jin-Moo %A Lemmens, Robin %A Leys, Didier %A Lewis, Cathryn M %A Lin, Wei-Yu %A Lindgren, Arne G %A Lorentzen, Erik %A Magnusson, Patrik K %A Maguire, Jane %A Manichaikul, Ani %A McArdle, Patrick F %A Meschia, James F %A Mitchell, Braxton D %A Mosley, Thomas H %A Nalls, Michael A %A Ninomiya, Toshiharu %A O'Donnell, Martin J %A Psaty, Bruce M %A Pulit, Sara L %A Rannikmae, Kristiina %A Reiner, Alexander P %A Rexrode, Kathryn M %A Rice, Kenneth %A Rich, Stephen S %A Ridker, Paul M %A Rost, Natalia S %A Rothwell, Peter M %A Rotter, Jerome I %A Rundek, Tatjana %A Sacco, Ralph L %A Sakaue, Saori %A Sale, Michèle M %A Salomaa, Veikko %A Sapkota, Bishwa R %A Schmidt, Reinhold %A Schmidt, Carsten O %A Schminke, Ulf %A Sharma, Pankaj %A Slowik, Agnieszka %A Sudlow, Cathie L M %A Tanislav, Christian %A Tatlisumak, Turgut %A Taylor, Kent D %A Thijs, Vincent N S %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Tiedt, Steffen %A Trompet, Stella %A Tzourio, Christophe %A van Duijn, Cornelia M %A Walters, Matthew %A Wareham, Nicholas J %A Wassertheil-Smoller, Sylvia %A Wilson, James G %A Wiggins, Kerri L %A Yang, Qiong %A Yusuf, Salim %A Amin, Najaf %A Aparicio, Hugo S %A Arnett, Donna K %A Attia, John %A Beiser, Alexa S %A Berr, Claudine %A Buring, Julie E %A Bustamante, Mariana %A Caso, Valeria %A Cheng, Yu-Ching %A Choi, Seung Hoan %A Chowhan, Ayesha %A Cullell, Natalia %A Dartigues, Jean-François %A Delavaran, Hossein %A Delgado, Pilar %A Dörr, Marcus %A Engström, Gunnar %A Ford, Ian %A Gurpreet, Wander S %A Hamsten, Anders %A Heitsch, Laura %A Hozawa, Atsushi %A Ibanez, Laura %A Ilinca, Andreea %A Ingelsson, Martin %A Iwasaki, Motoki %A Jackson, Rebecca D %A Jood, Katarina %A Jousilahti, Pekka %A Kaffashian, Sara %A Kalra, Lalit %A Kamouchi, Masahiro %A Kitazono, Takanari %A Kjartansson, Olafur %A Kloss, Manja %A Koudstaal, Peter J %A Krupinski, Jerzy %A Labovitz, Daniel L %A Laurie, Cathy C %A Levi, Christopher R %A Li, Linxin %A Lind, Lars %A Lindgren, Cecilia M %A Lioutas, Vasileios %A Liu, Yong Mei %A Lopez, Oscar L %A Makoto, Hirata %A Martinez-Majander, Nicolas %A Matsuda, Koichi %A Minegishi, Naoko %A Montaner, Joan %A Morris, Andrew P %A Muiño, Elena %A Müller-Nurasyid, Martina %A Norrving, Bo %A Ogishima, Soichi %A Parati, Eugenio A %A Peddareddygari, Leema Reddy %A Pedersen, Nancy L %A Pera, Joanna %A Perola, Markus %A Pezzini, Alessandro %A Pileggi, Silvana %A Rabionet, Raquel %A Riba-Llena, Iolanda %A Ribasés, Marta %A Romero, Jose R %A Roquer, Jaume %A Rudd, Anthony G %A Sarin, Antti-Pekka %A Sarju, Ralhan %A Sarnowski, Chloe %A Sasaki, Makoto %A Satizabal, Claudia L %A Satoh, Mamoru %A Sattar, Naveed %A Sawada, Norie %A Sibolt, Gerli %A Sigurdsson, Ásgeir %A Smith, Albert %A Sobue, Kenji %A Soriano-Tárraga, Carolina %A Stanne, Tara %A Stine, O Colin %A Stott, David J %A Strauch, Konstantin %A Takai, Takako %A Tanaka, Hideo %A Tanno, Kozo %A Teumer, Alexander %A Tomppo, Liisa %A Torres-Aguila, Nuria P %A Touze, Emmanuel %A Tsugane, Shoichiro %A Uitterlinden, André G %A Valdimarsson, Einar M %A van der Lee, Sven J %A Völzke, Henry %A Wakai, Kenji %A Weir, David %A Williams, Stephen R %A Wolfe, Charles D A %A Wong, Quenna %A Xu, Huichun %A Yamaji, Taiki %A Sanghera, Dharambir K %A Melander, Olle %A Jern, Christina %A Strbian, Daniel %A Fernandez-Cadenas, Israel %A Longstreth, W T %A Rolfs, Arndt %A Hata, Jun %A Woo, Daniel %A Rosand, Jonathan %A Paré, Guillaume %A Hopewell, Jemma C %A Saleheen, Danish %A Stefansson, Kari %A Worrall, Bradford B %A Kittner, Steven J %A Seshadri, Sudha %A Fornage, Myriam %A Markus, Hugh S %A Howson, Joanna M M %A Kamatani, Yoichiro %A Debette, Stephanie %A Dichgans, Martin %X

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.

%B Nat Genet %V 50 %P 524-537 %8 2018 Apr %G eng %N 4 %R 10.1038/s41588-018-0058-3 %0 Journal Article %J Nat Genet %D 2018 %T Multi-ethnic genome-wide association study for atrial fibrillation. %A Roselli, Carolina %A Chaffin, Mark D %A Weng, Lu-Chen %A Aeschbacher, Stefanie %A Ahlberg, Gustav %A Albert, Christine M %A Almgren, Peter %A Alonso, Alvaro %A Anderson, Christopher D %A Aragam, Krishna G %A Arking, Dan E %A Barnard, John %A Bartz, Traci M %A Benjamin, Emelia J %A Bihlmeyer, Nathan A %A Bis, Joshua C %A Bloom, Heather L %A Boerwinkle, Eric %A Bottinger, Erwin B %A Brody, Jennifer A %A Calkins, Hugh %A Campbell, Archie %A Cappola, Thomas P %A Carlquist, John %A Chasman, Daniel I %A Chen, Lin Y %A Chen, Yii-Der Ida %A Choi, Eue-Keun %A Choi, Seung Hoan %A Christophersen, Ingrid E %A Chung, Mina K %A Cole, John W %A Conen, David %A Cook, James %A Crijns, Harry J %A Cutler, Michael J %A Damrauer, Scott M %A Daniels, Brian R %A Darbar, Dawood %A Delgado, Graciela %A Denny, Joshua C %A Dichgans, Martin %A Dörr, Marcus %A Dudink, Elton A %A Dudley, Samuel C %A Esa, Nada %A Esko, Tõnu %A Eskola, Markku %A Fatkin, Diane %A Felix, Stephan B %A Ford, Ian %A Franco, Oscar H %A Geelhoed, Bastiaan %A Grewal, Raji P %A Gudnason, Vilmundur %A Guo, Xiuqing %A Gupta, Namrata %A Gustafsson, Stefan %A Gutmann, Rebecca %A Hamsten, Anders %A Harris, Tamara B %A Hayward, Caroline %A Heckbert, Susan R %A Hernesniemi, Jussi %A Hocking, Lynne J %A Hofman, Albert %A Horimoto, Andrea R V R %A Huang, Jie %A Huang, Paul L %A Huffman, Jennifer %A Ingelsson, Erik %A Ipek, Esra Gucuk %A Ito, Kaoru %A Jimenez-Conde, Jordi %A Johnson, Renee %A Jukema, J Wouter %A Kääb, Stefan %A Kähönen, Mika %A Kamatani, Yoichiro %A Kane, John P %A Kastrati, Adnan %A Kathiresan, Sekar %A Katschnig-Winter, Petra %A Kavousi, Maryam %A Kessler, Thorsten %A Kietselaer, Bas L %A Kirchhof, Paulus %A Kleber, Marcus E %A Knight, Stacey %A Krieger, Jose E %A Kubo, Michiaki %A Launer, Lenore J %A Laurikka, Jari %A Lehtimäki, Terho %A Leineweber, Kirsten %A Lemaitre, Rozenn N %A Li, Man %A Lim, Hong Euy %A Lin, Henry J %A Lin, Honghuang %A Lind, Lars %A Lindgren, Cecilia M %A Lokki, Marja-Liisa %A London, Barry %A Loos, Ruth J F %A Low, Siew-Kee %A Lu, Yingchang %A Lyytikäinen, Leo-Pekka %A Macfarlane, Peter W %A Magnusson, Patrik K %A Mahajan, Anubha %A Malik, Rainer %A Mansur, Alfredo J %A Marcus, Gregory M %A Margolin, Lauren %A Margulies, Kenneth B %A März, Winfried %A McManus, David D %A Melander, Olle %A Mohanty, Sanghamitra %A Montgomery, Jay A %A Morley, Michael P %A Morris, Andrew P %A Müller-Nurasyid, Martina %A Natale, Andrea %A Nazarian, Saman %A Neumann, Benjamin %A Newton-Cheh, Christopher %A Niemeijer, Maartje N %A Nikus, Kjell %A Nilsson, Peter %A Noordam, Raymond %A Oellers, Heidi %A Olesen, Morten S %A Orho-Melander, Marju %A Padmanabhan, Sandosh %A Pak, Hui-Nam %A Paré, Guillaume %A Pedersen, Nancy L %A Pera, Joanna %A Pereira, Alexandre %A Porteous, David %A Psaty, Bruce M %A Pulit, Sara L %A Pullinger, Clive R %A Rader, Daniel J %A Refsgaard, Lena %A Ribasés, Marta %A Ridker, Paul M %A Rienstra, Michiel %A Risch, Lorenz %A Roden, Dan M %A Rosand, Jonathan %A Rosenberg, Michael A %A Rost, Natalia %A Rotter, Jerome I %A Saba, Samir %A Sandhu, Roopinder K %A Schnabel, Renate B %A Schramm, Katharina %A Schunkert, Heribert %A Schurman, Claudia %A Scott, Stuart A %A Seppälä, Ilkka %A Shaffer, Christian %A Shah, Svati %A Shalaby, Alaa A %A Shim, Jaemin %A Shoemaker, M Benjamin %A Siland, Joylene E %A Sinisalo, Juha %A Sinner, Moritz F %A Slowik, Agnieszka %A Smith, Albert V %A Smith, Blair H %A Smith, J Gustav %A Smith, Jonathan D %A Smith, Nicholas L %A Soliman, Elsayed Z %A Sotoodehnia, Nona %A Stricker, Bruno H %A Sun, Albert %A Sun, Han %A Svendsen, Jesper H %A Tanaka, Toshihiro %A Tanriverdi, Kahraman %A Taylor, Kent D %A Teder-Laving, Maris %A Teumer, Alexander %A Thériault, Sébastien %A Trompet, Stella %A Tucker, Nathan R %A Tveit, Arnljot %A Uitterlinden, André G %A van der Harst, Pim %A Van Gelder, Isabelle C %A Van Wagoner, David R %A Verweij, Niek %A Vlachopoulou, Efthymia %A Völker, Uwe %A Wang, Biqi %A Weeke, Peter E %A Weijs, Bob %A Weiss, Raul %A Weiss, Stefan %A Wells, Quinn S %A Wiggins, Kerri L %A Wong, Jorge A %A Woo, Daniel %A Worrall, Bradford B %A Yang, Pil-Sung %A Yao, Jie %A Yoneda, Zachary T %A Zeller, Tanja %A Zeng, Lingyao %A Lubitz, Steven A %A Lunetta, Kathryn L %A Ellinor, Patrick T %X

Atrial fibrillation (AF) affects more than 33 million individuals worldwide and has a complex heritability. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.

%B Nat Genet %V 50 %P 1225-1233 %8 2018 Sep %G eng %N 9 %R 10.1038/s41588-018-0133-9 %0 Journal Article %J Nat Commun %D 2018 %T Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function. %A Wyss, Annah B %A Sofer, Tamar %A Lee, Mi Kyeong %A Terzikhan, Natalie %A Nguyen, Jennifer N %A Lahousse, Lies %A Latourelle, Jeanne C %A Smith, Albert Vernon %A Bartz, Traci M %A Feitosa, Mary F %A Gao, Wei %A Ahluwalia, Tarunveer S %A Tang, Wenbo %A Oldmeadow, Christopher %A Duan, Qing %A de Jong, Kim %A Wojczynski, Mary K %A Wang, Xin-Qun %A Noordam, Raymond %A Hartwig, Fernando Pires %A Jackson, Victoria E %A Wang, Tianyuan %A Obeidat, Ma'en %A Hobbs, Brian D %A Huan, Tianxiao %A Gui, Hongsheng %A Parker, Margaret M %A Hu, Donglei %A Mogil, Lauren S %A Kichaev, Gleb %A Jin, Jianping %A Graff, Mariaelisa %A Harris, Tamara B %A Kalhan, Ravi %A Heckbert, Susan R %A Paternoster, Lavinia %A Burkart, Kristin M %A Liu, Yongmei %A Holliday, Elizabeth G %A Wilson, James G %A Vonk, Judith M %A Sanders, Jason L %A Barr, R Graham %A de Mutsert, Renée %A Menezes, Ana Maria Baptista %A Adams, Hieab H H %A van den Berge, Maarten %A Joehanes, Roby %A Levin, Albert M %A Liberto, Jennifer %A Launer, Lenore J %A Morrison, Alanna C %A Sitlani, Colleen M %A Celedón, Juan C %A Kritchevsky, Stephen B %A Scott, Rodney J %A Christensen, Kaare %A Rotter, Jerome I %A Bonten, Tobias N %A Wehrmeister, Fernando César %A Bossé, Yohan %A Xiao, Shujie %A Oh, Sam %A Franceschini, Nora %A Brody, Jennifer A %A Kaplan, Robert C %A Lohman, Kurt %A McEvoy, Mark %A Province, Michael A %A Rosendaal, Frits R %A Taylor, Kent D %A Nickle, David C %A Williams, L Keoki %A Burchard, Esteban G %A Wheeler, Heather E %A Sin, Don D %A Gudnason, Vilmundur %A North, Kari E %A Fornage, Myriam %A Psaty, Bruce M %A Myers, Richard H %A O'Connor, George %A Hansen, Torben %A Laurie, Cathy C %A Cassano, Patricia A %A Sung, Joohon %A Kim, Woo Jin %A Attia, John R %A Lange, Leslie %A Boezen, H Marike %A Thyagarajan, Bharat %A Rich, Stephen S %A Mook-Kanamori, Dennis O %A Horta, Bernardo Lessa %A Uitterlinden, André G %A Im, Hae Kyung %A Cho, Michael H %A Brusselle, Guy G %A Gharib, Sina A %A Dupuis, Josée %A Manichaikul, Ani %A London, Stephanie J %X

Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of lung function and clinical relevance of implicated loci.

%B Nat Commun %V 9 %P 2976 %8 2018 Jul 30 %G eng %N 1 %R 10.1038/s41467-018-05369-0 %0 Journal Article %J Am J Respir Cell Mol Biol %D 2018 %T Multiethnic Meta-Analysis Identifies RAI1 as a Possible Obstructive Sleep Apnea-related Quantitative Trait Locus in Men. %A Chen, Han %A Cade, Brian E %A Gleason, Kevin J %A Bjonnes, Andrew C %A Stilp, Adrienne M %A Sofer, Tamar %A Conomos, Matthew P %A Ancoli-Israel, Sonia %A Arens, Raanan %A Azarbarzin, Ali %A Bell, Graeme I %A Below, Jennifer E %A Chun, Sung %A Evans, Daniel S %A Ewert, Ralf %A Frazier-Wood, Alexis C %A Gharib, Sina A %A Haba-Rubio, José %A Hagen, Erika W %A Heinzer, Raphael %A Hillman, David R %A Johnson, W Craig %A Kutalik, Zoltán %A Lane, Jacqueline M %A Larkin, Emma K %A Lee, Seung Ku %A Liang, Jingjing %A Loredo, Jose S %A Mukherjee, Sutapa %A Palmer, Lyle J %A Papanicolaou, George J %A Penzel, Thomas %A Peppard, Paul E %A Post, Wendy S %A Ramos, Alberto R %A Rice, Ken %A Rotter, Jerome I %A Sands, Scott A %A Shah, Neomi A %A Shin, Chol %A Stone, Katie L %A Stubbe, Beate %A Sul, Jae Hoon %A Tafti, Mehdi %A Taylor, Kent D %A Teumer, Alexander %A Thornton, Timothy A %A Tranah, Gregory J %A Wang, Chaolong %A Wang, Heming %A Warby, Simon C %A Wellman, D Andrew %A Zee, Phyllis C %A Hanis, Craig L %A Laurie, Cathy C %A Gottlieb, Daniel J %A Patel, Sanjay R %A Zhu, Xiaofeng %A Sunyaev, Shamil R %A Saxena, Richa %A Lin, Xihong %A Redline, Susan %X

Obstructive sleep apnea (OSA) is a common heritable disorder displaying marked sexual dimorphism in disease prevalence and progression. Previous genetic association studies have identified a few genetic loci associated with OSA and related quantitative traits, but they have only focused on single ethnic groups, and a large proportion of the heritability remains unexplained. The apnea-hypopnea index (AHI) is a commonly used quantitative measure characterizing OSA severity. Because OSA differs by sex, and the pathophysiology of obstructive events differ in rapid eye movement (REM) and non-REM (NREM) sleep, we hypothesized that additional genetic association signals would be identified by analyzing the NREM/REM-specific AHI and by conducting sex-specific analyses in multiethnic samples. We performed genome-wide association tests for up to 19,733 participants of African, Asian, European, and Hispanic/Latino American ancestry in 7 studies. We identified rs12936587 on chromosome 17 as a possible quantitative trait locus for NREM AHI in men (N = 6,737; P = 1.7 × 10) but not in women (P = 0.77). The association with NREM AHI was replicated in a physiological research study (N = 67; P = 0.047). This locus overlapping the RAI1 gene and encompassing genes PEMT1, SREBF1, and RASD1 was previously reported to be associated with coronary artery disease, lipid metabolism, and implicated in Potocki-Lupski syndrome and Smith-Magenis syndrome, which are characterized by abnormal sleep phenotypes. We also identified gene-by-sex interactions in suggestive association regions, suggesting that genetic variants for AHI appear to vary by sex, consistent with the clinical observations of strong sexual dimorphism.

%B Am J Respir Cell Mol Biol %V 58 %P 391-401 %8 2018 Mar %G eng %N 3 %R 10.1165/rcmb.2017-0237OC %0 Journal Article %J PLoS One %D 2018 %T Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries. %A Feitosa, Mary F %A Kraja, Aldi T %A Chasman, Daniel I %A Sung, Yun J %A Winkler, Thomas W %A Ntalla, Ioanna %A Guo, Xiuqing %A Franceschini, Nora %A Cheng, Ching-Yu %A Sim, Xueling %A Vojinovic, Dina %A Marten, Jonathan %A Musani, Solomon K %A Li, Changwei %A Bentley, Amy R %A Brown, Michael R %A Schwander, Karen %A Richard, Melissa A %A Noordam, Raymond %A Aschard, Hugues %A Bartz, Traci M %A Bielak, Lawrence F %A Dorajoo, Rajkumar %A Fisher, Virginia %A Hartwig, Fernando P %A Horimoto, Andrea R V R %A Lohman, Kurt K %A Manning, Alisa K %A Rankinen, Tuomo %A Smith, Albert V %A Tajuddin, Salman M %A Wojczynski, Mary K %A Alver, Maris %A Boissel, Mathilde %A Cai, Qiuyin %A Campbell, Archie %A Chai, Jin Fang %A Chen, Xu %A Divers, Jasmin %A Gao, Chuan %A Goel, Anuj %A Hagemeijer, Yanick %A Harris, Sarah E %A He, Meian %A Hsu, Fang-Chi %A Jackson, Anne U %A Kähönen, Mika %A Kasturiratne, Anuradhani %A Komulainen, Pirjo %A Kuhnel, Brigitte %A Laguzzi, Federica %A Luan, Jian'an %A Matoba, Nana %A Nolte, Ilja M %A Padmanabhan, Sandosh %A Riaz, Muhammad %A Rueedi, Rico %A Robino, Antonietta %A Said, M Abdullah %A Scott, Robert A %A Sofer, Tamar %A Stančáková, Alena %A Takeuchi, Fumihiko %A Tayo, Bamidele O %A van der Most, Peter J %A Varga, Tibor V %A Vitart, Veronique %A Wang, Yajuan %A Ware, Erin B %A Warren, Helen R %A Weiss, Stefan %A Wen, Wanqing %A Yanek, Lisa R %A Zhang, Weihua %A Zhao, Jing Hua %A Afaq, Saima %A Amin, Najaf %A Amini, Marzyeh %A Arking, Dan E %A Aung, Tin %A Boerwinkle, Eric %A Borecki, Ingrid %A Broeckel, Ulrich %A Brown, Morris %A Brumat, Marco %A Burke, Gregory L %A Canouil, Mickaël %A Chakravarti, Aravinda %A Charumathi, Sabanayagam %A Ida Chen, Yii-Der %A Connell, John M %A Correa, Adolfo %A de Las Fuentes, Lisa %A de Mutsert, Renée %A de Silva, H Janaka %A Deng, Xuan %A Ding, Jingzhong %A Duan, Qing %A Eaton, Charles B %A Ehret, Georg %A Eppinga, Ruben N %A Evangelou, Evangelos %A Faul, Jessica D %A Felix, Stephan B %A Forouhi, Nita G %A Forrester, Terrence %A Franco, Oscar H %A Friedlander, Yechiel %A Gandin, Ilaria %A Gao, He %A Ghanbari, Mohsen %A Gigante, Bruna %A Gu, C Charles %A Gu, Dongfeng %A Hagenaars, Saskia P %A Hallmans, Göran %A Harris, Tamara B %A He, Jiang %A Heikkinen, Sami %A Heng, Chew-Kiat %A Hirata, Makoto %A Howard, Barbara V %A Ikram, M Arfan %A John, Ulrich %A Katsuya, Tomohiro %A Khor, Chiea Chuen %A Kilpeläinen, Tuomas O %A Koh, Woon-Puay %A Krieger, Jose E %A Kritchevsky, Stephen B %A Kubo, Michiaki %A Kuusisto, Johanna %A Lakka, Timo A %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Lehne, Benjamin %A Lewis, Cora E %A Li, Yize %A Lin, Shiow %A Liu, Jianjun %A Liu, Jingmin %A Loh, Marie %A Louie, Tin %A Mägi, Reedik %A McKenzie, Colin A %A Meitinger, Thomas %A Metspalu, Andres %A Milaneschi, Yuri %A Milani, Lili %A Mohlke, Karen L %A Momozawa, Yukihide %A Nalls, Mike A %A Nelson, Christopher P %A Sotoodehnia, Nona %A Norris, Jill M %A O'Connell, Jeff R %A Palmer, Nicholette D %A Perls, Thomas %A Pedersen, Nancy L %A Peters, Annette %A Peyser, Patricia A %A Poulter, Neil %A Raffel, Leslie J %A Raitakari, Olli T %A Roll, Kathryn %A Rose, Lynda M %A Rosendaal, Frits R %A Rotter, Jerome I %A Schmidt, Carsten O %A Schreiner, Pamela J %A Schupf, Nicole %A Scott, William R %A Sever, Peter S %A Shi, Yuan %A Sidney, Stephen %A Sims, Mario %A Sitlani, Colleen M %A Smith, Jennifer A %A Snieder, Harold %A Starr, John M %A Strauch, Konstantin %A Stringham, Heather M %A Tan, Nicholas Y Q %A Tang, Hua %A Taylor, Kent D %A Teo, Yik Ying %A Tham, Yih Chung %A Turner, Stephen T %A Uitterlinden, André G %A Vollenweider, Peter %A Waldenberger, Melanie %A Wang, Lihua %A Wang, Ya Xing %A Wei, Wen Bin %A Williams, Christine %A Yao, Jie %A Yu, Caizheng %A Yuan, Jian-Min %A Zhao, Wei %A Zonderman, Alan B %A Becker, Diane M %A Boehnke, Michael %A Bowden, Donald W %A Chambers, John C %A Deary, Ian J %A Esko, Tõnu %A Farrall, Martin %A Franks, Paul W %A Freedman, Barry I %A Froguel, Philippe %A Gasparini, Paolo %A Gieger, Christian %A Jonas, Jost Bruno %A Kamatani, Yoichiro %A Kato, Norihiro %A Kooner, Jaspal S %A Kutalik, Zoltán %A Laakso, Markku %A Laurie, Cathy C %A Leander, Karin %A Lehtimäki, Terho %A Study, Lifelines Cohort %A Magnusson, Patrik K E %A Oldehinkel, Albertine J %A Penninx, Brenda W J H %A Polasek, Ozren %A Porteous, David J %A Rauramaa, Rainer %A Samani, Nilesh J %A Scott, James %A Shu, Xiao-Ou %A van der Harst, Pim %A Wagenknecht, Lynne E %A Wareham, Nicholas J %A Watkins, Hugh %A Weir, David R %A Wickremasinghe, Ananda R %A Wu, Tangchun %A Zheng, Wei %A Bouchard, Claude %A Christensen, Kaare %A Evans, Michele K %A Gudnason, Vilmundur %A Horta, Bernardo L %A Kardia, Sharon L R %A Liu, Yongmei %A Pereira, Alexandre C %A Psaty, Bruce M %A Ridker, Paul M %A van Dam, Rob M %A Gauderman, W James %A Zhu, Xiaofeng %A Mook-Kanamori, Dennis O %A Fornage, Myriam %A Rotimi, Charles N %A Cupples, L Adrienne %A Kelly, Tanika N %A Fox, Ervin R %A Hayward, Caroline %A van Duijn, Cornelia M %A Tai, E Shyong %A Wong, Tien Yin %A Kooperberg, Charles %A Palmas, Walter %A Rice, Kenneth %A Morrison, Alanna C %A Elliott, Paul %A Caulfield, Mark J %A Munroe, Patricia B %A Rao, Dabeeru C %A Province, Michael A %A Levy, Daniel %X

Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.

%B PLoS One %V 13 %P e0198166 %8 2018 %G eng %N 6 %R 10.1371/journal.pone.0198166 %0 Journal Article %J Am J Respir Crit Care Med %D 2018 %T Omega-3 Fatty Acids and Genome-wide Interaction Analyses Reveal DPP10-Pulmonary Function Association. %A Xu, Jiayi %A Gaddis, Nathan C %A Bartz, Traci M %A Hou, Ruixue %A Manichaikul, Ani W %A Pankratz, Nathan %A Smith, Albert V %A Sun, Fangui %A Terzikhan, Natalie %A Markunas, Christina A %A Patchen, Bonnie K %A Schu, Matthew %A Beydoun, May A %A Brusselle, Guy G %A Eiriksdottir, Gudny %A Zhou, Xia %A Wood, Alexis C %A Graff, Mariaelisa %A Harris, Tamara B %A Ikram, M Arfan %A Jacobs, David R %A Launer, Lenore J %A Lemaitre, Rozenn N %A O'Connor, George %A Oelsner, Elizabeth C %A Psaty, Bruce M %A Ramachandran, Vasan S %A Rohde, Rebecca R %A Rich, Stephen S %A Rotter, Jerome I %A Seshadri, Sudha %A Smith, Lewis J %A Tiemeier, Henning %A Tsai, Michael Y %A Uitterlinden, André G %A Voruganti, V Saroja %A Xu, Hanfei %A Zilhão, Nuno R %A Fornage, Myriam %A Zillikens, M Carola %A London, Stephanie J %A Barr, R Graham %A Dupuis, Josée %A Gharib, Sina A %A Gudnason, Vilmundur %A Lahousse, Lies %A North, Kari E %A Steffen, Lyn M %A Cassano, Patricia A %A Hancock, Dana B %X

RATIONALE: Omega-3 poly-unsaturated fatty acids (n-3 PUFAs) have anti-inflammatory properties that could benefit adults with comprised pulmonary health.

OBJECTIVE: To investigate n-3 PUFA associations with spirometric measures of pulmonary function tests (PFTs) and determine underlying genetic susceptibility.

METHODS: Associations of n-3 PUFA biomarkers (alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid [DPA], and docosahexaenoic acid [DHA]) were evaluated with PFTs (forced expiratory volume in the first second [FEV], forced vital capacity [FVC], and [FEV/FVC]) in meta-analyses across seven cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (N=16,134 of European or African ancestry). PFT-associated n-3 PUFAs were carried forward to genome-wide interaction analyses in the four largest cohorts (N=11,962) and replicated in one cohort (N=1,687). Cohort-specific results were combined using joint 2 degree-of-freedom (2df) meta-analyses of single nucleotide polymorphism (SNP) associations and their interactions with n-3 PUFAs.

RESULTS: DPA and DHA were positively associated with FEV1 and FVC (P<0.025), with evidence for effect modification by smoking and by sex. Genome-wide analyses identified a novel association of rs11693320-an intronic DPP10 SNP-with FVC when incorporating an interaction with DHA, and the finding was replicated (P=9.4×10 across discovery and replication cohorts). The rs11693320-A allele (frequency~80%) was associated with lower FVC (P=2.1×10; β= -161.0mL), and the association was attenuated by higher DHA levels (P=2.1×10; β=36.2mL).

CONCLUSIONS: We corroborated beneficial effects of n-3 PUFAs on pulmonary function. By modeling genome-wide n-3 PUFA interactions, we identified a novel DPP10 SNP association with FVC that was not detectable in much larger studies ignoring this interaction.

%B Am J Respir Crit Care Med %8 2018 Sep 10 %G eng %R 10.1164/rccm.201802-0304OC %0 Journal Article %J Environ Int %D 2018 %T Outdoor air pollution and mosaic loss of chromosome Y in older men from the Cardiovascular Health Study. %A Wong, Jason Y Y %A Margolis, Helene G %A Machiela, Mitchell %A Zhou, Weiyin %A Odden, Michelle C %A Psaty, Bruce M %A Robbins, John %A Jones, Rena R %A Rotter, Jerome I %A Chanock, Stephen J %A Rothman, Nathaniel %A Lan, Qing %A Lee, Jennifer S %X

BACKGROUND: Mosaic loss of chromosome Y (mLOY) can occur in a fraction of cells as men age, which is potentially linked to increased mortality risk. Smoking is related to mLOY; however, the contribution of air pollution is unclear.

OBJECTIVE: We investigated whether exposure to outdoor air pollution, age, and smoking were associated with mLOY.

METHODS: We analyzed baseline (1989-1993) blood samples from 933 men ≥65 years of age from the prospective Cardiovascular Health Study. Particulate matter ≤10 μm (PM), carbon monoxide, nitrogen dioxide, sulfur dioxide, and ozone data were obtained from the U.S. EPA Aerometric Information Retrieval System for the year prior to baseline. Inverse-distance weighted air monitor data were used to estimate each participants' monthly residential exposure. mLOY was detected with standard methods using signal intensity (median log-R ratio (mLRR)) of the male-specific chromosome Y regions from Illumina array data. Linear regression models were used to evaluate relations between mean exposure in the prior year, age, smoking and continuous mLRR.

RESULTS: Increased PM was associated with mLOY, namely decreased mLRR (p-trend = 0.03). Compared with the lowest tertile (≤28.5 μg/m), the middle (28.5-31.0 μg/m; β = -0.0044, p = 0.09) and highest (≥31 μg/m; β = -0.0054, p = 0.04) tertiles had decreased mLRR, adjusted for age, clinic, race/cohort, smoking status and pack-years. Additionally, increasing age (β = -0.00035, p = 0.06) and smoking pack-years (β = -0.00011, p = 1.4E-3) were associated with decreased mLRR, adjusted for each other and race/cohort. No significant associations were found for other pollutants.

CONCLUSIONS: PM may increase leukocyte mLOY, a marker of genomic instability. The sample size was modest and replication is warranted.

%B Environ Int %V 116 %P 239-247 %8 2018 Apr 23 %G eng %R 10.1016/j.envint.2018.04.030 %0 Journal Article %J Nat Commun %D 2018 %T PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity. %A van Setten, Jessica %A Brody, Jennifer A %A Jamshidi, Yalda %A Swenson, Brenton R %A Butler, Anne M %A Campbell, Harry %A Del Greco, Fabiola M %A Evans, Daniel S %A Gibson, Quince %A Gudbjartsson, Daniel F %A Kerr, Kathleen F %A Krijthe, Bouwe P %A Lyytikäinen, Leo-Pekka %A Müller, Christian %A Müller-Nurasyid, Martina %A Nolte, Ilja M %A Padmanabhan, Sandosh %A Ritchie, Marylyn D %A Robino, Antonietta %A Smith, Albert V %A Steri, Maristella %A Tanaka, Toshiko %A Teumer, Alexander %A Trompet, Stella %A Ulivi, Sheila %A Verweij, Niek %A Yin, Xiaoyan %A Arnar, David O %A Asselbergs, Folkert W %A Bader, Joel S %A Barnard, John %A Bis, Josh %A Blankenberg, Stefan %A Boerwinkle, Eric %A Bradford, Yuki %A Buckley, Brendan M %A Chung, Mina K %A Crawford, Dana %A den Hoed, Marcel %A Denny, Josh C %A Dominiczak, Anna F %A Ehret, Georg B %A Eijgelsheim, Mark %A Ellinor, Patrick T %A Felix, Stephan B %A Franco, Oscar H %A Franke, Lude %A Harris, Tamara B %A Holm, Hilma %A Ilaria, Gandin %A Iorio, Annamaria %A Kähönen, Mika %A Kolcic, Ivana %A Kors, Jan A %A Lakatta, Edward G %A Launer, Lenore J %A Lin, Honghuang %A Lin, Henry J %A Loos, Ruth J F %A Lubitz, Steven A %A Macfarlane, Peter W %A Magnani, Jared W %A Leach, Irene Mateo %A Meitinger, Thomas %A Mitchell, Braxton D %A Münzel, Thomas %A Papanicolaou, George J %A Peters, Annette %A Pfeufer, Arne %A Pramstaller, Peter P %A Raitakari, Olli T %A Rotter, Jerome I %A Rudan, Igor %A Samani, Nilesh J %A Schlessinger, David %A Silva Aldana, Claudia T %A Sinner, Moritz F %A Smith, Jonathan D %A Snieder, Harold %A Soliman, Elsayed Z %A Spector, Timothy D %A Stott, David J %A Strauch, Konstantin %A Tarasov, Kirill V %A Thorsteinsdottir, Unnur %A Uitterlinden, André G %A Van Wagoner, David R %A Völker, Uwe %A Völzke, Henry %A Waldenberger, Melanie %A Jan Westra, Harm %A Wild, Philipp S %A Zeller, Tanja %A Alonso, Alvaro %A Avery, Christy L %A Bandinelli, Stefania %A Benjamin, Emelia J %A Cucca, Francesco %A Dörr, Marcus %A Ferrucci, Luigi %A Gasparini, Paolo %A Gudnason, Vilmundur %A Hayward, Caroline %A Heckbert, Susan R %A Hicks, Andrew A %A Jukema, J Wouter %A Kääb, Stefan %A Lehtimäki, Terho %A Liu, Yongmei %A Munroe, Patricia B %A Parsa, Afshin %A Polasek, Ozren %A Psaty, Bruce M %A Roden, Dan M %A Schnabel, Renate B %A Sinagra, Gianfranco %A Stefansson, Kari %A Stricker, Bruno H %A van der Harst, Pim %A van Duijn, Cornelia M %A Wilson, James F %A Gharib, Sina A %A de Bakker, Paul I W %A Isaacs, Aaron %A Arking, Dan E %A Sotoodehnia, Nona %X

Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.

%B Nat Commun %V 9 %P 2904 %8 2018 Jul 25 %G eng %N 1 %R 10.1038/s41467-018-04766-9 %0 Journal Article %J PLoS One %D 2018 %T Predictive value for cardiovascular events of common carotid intima media thickness and its rate of change in individuals at high cardiovascular risk - Results from the PROG-IMT collaboration. %A Lorenz, Matthias W %A Gao, Lu %A Ziegelbauer, Kathrin %A Norata, Giuseppe Danilo %A Empana, Jean Philippe %A Schmidtmann, Irene %A Lin, Hung-Ju %A McLachlan, Stela %A Bokemark, Lena %A Ronkainen, Kimmo %A Amato, Mauro %A Schminke, Ulf %A Srinivasan, Sathanur R %A Lind, Lars %A Okazaki, Shuhei %A Stehouwer, Coen D A %A Willeit, Peter %A Polak, Joseph F %A Steinmetz, Helmuth %A Sander, Dirk %A Poppert, Holger %A Desvarieux, Moïse %A Ikram, M Arfan %A Johnsen, Stein Harald %A Staub, Daniel %A Sirtori, Cesare R %A Iglseder, Bernhard %A Beloqui, Oscar %A Engström, Gunnar %A Friera, Alfonso %A Rozza, Francesco %A Xie, Wuxiang %A Parraga, Grace %A Grigore, Liliana %A Plichart, Matthieu %A Blankenberg, Stefan %A Su, Ta-Chen %A Schmidt, Caroline %A Tuomainen, Tomi-Pekka %A Veglia, Fabrizio %A Völzke, Henry %A Nijpels, Giel %A Willeit, Johann %A Sacco, Ralph L %A Franco, Oscar H %A Uthoff, Heiko %A Hedblad, Bo %A Suarez, Carmen %A Izzo, Raffaele %A Zhao, Dong %A Wannarong, Thapat %A Catapano, Alberico %A Ducimetiere, Pierre %A Espinola-Klein, Christine %A Chien, Kuo-Liong %A Price, Jackie F %A Bergström, Göran %A Kauhanen, Jussi %A Tremoli, Elena %A Dörr, Marcus %A Berenson, Gerald %A Kitagawa, Kazuo %A Dekker, Jacqueline M %A Kiechl, Stefan %A Sitzer, Matthias %A Bickel, Horst %A Rundek, Tatjana %A Hofman, Albert %A Mathiesen, Ellisiv B %A Castelnuovo, Samuela %A Landecho, Manuel F %A Rosvall, Maria %A Gabriel, Rafael %A de Luca, Nicola %A Liu, Jing %A Baldassarre, Damiano %A Kavousi, Maryam %A de Groot, Eric %A Bots, Michiel L %A Yanez, David N %A Thompson, Simon G %K Aged %K Cardiovascular Diseases %K Carotid Intima-Media Thickness %K Female %K Humans %K Intersectoral Collaboration %K Male %K Middle Aged %K Prognosis %K Risk Factors %X

AIMS: Carotid intima media thickness (CIMT) predicts cardiovascular (CVD) events, but the predictive value of CIMT change is debated. We assessed the relation between CIMT change and events in individuals at high cardiovascular risk.

METHODS AND RESULTS: From 31 cohorts with two CIMT scans (total n = 89070) on average 3.6 years apart and clinical follow-up, subcohorts were drawn: (A) individuals with at least 3 cardiovascular risk factors without previous CVD events, (B) individuals with carotid plaques without previous CVD events, and (C) individuals with previous CVD events. Cox regression models were fit to estimate the hazard ratio (HR) of the combined endpoint (myocardial infarction, stroke or vascular death) per standard deviation (SD) of CIMT change, adjusted for CVD risk factors. These HRs were pooled across studies. In groups A, B and C we observed 3483, 2845 and 1165 endpoint events, respectively. Average common CIMT was 0.79mm (SD 0.16mm), and annual common CIMT change was 0.01mm (SD 0.07mm), both in group A. The pooled HR per SD of annual common CIMT change (0.02 to 0.43mm) was 0.99 (95% confidence interval: 0.95-1.02) in group A, 0.98 (0.93-1.04) in group B, and 0.95 (0.89-1.04) in group C. The HR per SD of common CIMT (average of the first and the second CIMT scan, 0.09 to 0.75mm) was 1.15 (1.07-1.23) in group A, 1.13 (1.05-1.22) in group B, and 1.12 (1.05-1.20) in group C.

CONCLUSIONS: We confirm that common CIMT is associated with future CVD events in individuals at high risk. CIMT change does not relate to future event risk in high-risk individuals.

%B PLoS One %V 13 %P e0191172 %8 2018 %G eng %N 4 %R 10.1371/journal.pone.0191172 %0 Journal Article %J Gut %D 2018 %T Protein and glycomic plasma markers for early detection of adenoma and colon cancer. %A Rho, Jung-Hyun %A Ladd, Jon J %A Li, Christopher I %A Potter, John D %A Zhang, Yuzheng %A Shelley, David %A Shibata, David %A Coppola, Domenico %A Yamada, Hiroyuki %A Toyoda, Hidenori %A Tada, Toshifumi %A Kumada, Takashi %A Brenner, Dean E %A Hanash, Samir M %A Lampe, Paul D %K Adaptor Proteins, Signal Transducing %K Adenoma %K Adult %K Aged %K Aged, 80 and over %K Biomarkers, Tumor %K CA-19-9 Antigen %K Case-Control Studies %K Colonic Neoplasms %K Cytokine Receptor gp130 %K Early Detection of Cancer %K ErbB Receptors %K Female %K Humans %K Hyaluronan Receptors %K Lewis X Antigen %K Male %K Middle Aged %K Oligosaccharides %K Protein Array Analysis %K von Willebrand Factor %X

OBJECTIVE: To discover and confirm blood-based colon cancer early-detection markers.

DESIGN: We created a high-density antibody microarray to detect differences in protein levels in plasma from individuals diagnosed with colon cancer <3 years after blood was drawn (ie, prediagnostic) and cancer-free, matched controls. Potential markers were tested on plasma samples from people diagnosed with adenoma or cancer, compared with controls. Components of an optimal 5-marker panel were tested via immunoblotting using a third sample set, Luminex assay in a large fourth sample set and immunohistochemistry (IHC) on tissue microarrays.

RESULTS: In the prediagnostic samples, we found 78 significantly (t-test) increased proteins, 32 of which were confirmed in the diagnostic samples. From these 32, optimal 4-marker panels of BAG family molecular chaperone regulator 4 (BAG4), interleukin-6 receptor subunit beta (IL6ST), von Willebrand factor (VWF) and CD44 or epidermal growth factor receptor (EGFR) were established. Each panel member and the panels also showed increases in the diagnostic adenoma and cancer samples in independent third and fourth sample sets via immunoblot and Luminex, respectively. IHC results showed increased levels of BAG4, IL6ST and CD44 in adenoma and cancer tissues. Inclusion of EGFR and CD44 sialyl Lewis-A and Lewis-X content increased the panel performance. The protein/glycoprotein panel was statistically significantly higher in colon cancer samples, characterised by a range of area under the curves from 0.90 (95% CI 0.82 to 0.98) to 0.86 (95% CI 0.83 to 0.88), for the larger second and fourth sets, respectively.

CONCLUSIONS: A panel including BAG4, IL6ST, VWF, EGFR and CD44 protein/glycomics performed well for detection of early stages of colon cancer and should be further examined in larger studies.

%B Gut %V 67 %P 473-484 %8 2018 03 %G eng %N 3 %R 10.1136/gutjnl-2016-312794 %0 Journal Article %J Nat Genet %D 2018 %T Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes. %A Mahajan, Anubha %A Wessel, Jennifer %A Willems, Sara M %A Zhao, Wei %A Robertson, Neil R %A Chu, Audrey Y %A Gan, Wei %A Kitajima, Hidetoshi %A Taliun, Daniel %A Rayner, N William %A Guo, Xiuqing %A Lu, Yingchang %A Li, Man %A Jensen, Richard A %A Hu, Yao %A Huo, Shaofeng %A Lohman, Kurt K %A Zhang, Weihua %A Cook, James P %A Prins, Bram Peter %A Flannick, Jason %A Grarup, Niels %A Trubetskoy, Vassily Vladimirovich %A Kravic, Jasmina %A Kim, Young Jin %A Rybin, Denis V %A Yaghootkar, Hanieh %A Müller-Nurasyid, Martina %A Meidtner, Karina %A Li-Gao, Ruifang %A Varga, Tibor V %A Marten, Jonathan %A Li, Jin %A Smith, Albert Vernon %A An, Ping %A Ligthart, Symen %A Gustafsson, Stefan %A Malerba, Giovanni %A Demirkan, Ayse %A Tajes, Juan Fernandez %A Steinthorsdottir, Valgerdur %A Wuttke, Matthias %A Lecoeur, Cécile %A Preuss, Michael %A Bielak, Lawrence F %A Graff, Marielisa %A Highland, Heather M %A Justice, Anne E %A Liu, Dajiang J %A Marouli, Eirini %A Peloso, Gina Marie %A Warren, Helen R %A Afaq, Saima %A Afzal, Shoaib %A Ahlqvist, Emma %A Almgren, Peter %A Amin, Najaf %A Bang, Lia B %A Bertoni, Alain G %A Bombieri, Cristina %A Bork-Jensen, Jette %A Brandslund, Ivan %A Brody, Jennifer A %A Burtt, Noel P %A Canouil, Mickaël %A Chen, Yii-Der Ida %A Cho, Yoon Shin %A Christensen, Cramer %A Eastwood, Sophie V %A Eckardt, Kai-Uwe %A Fischer, Krista %A Gambaro, Giovanni %A Giedraitis, Vilmantas %A Grove, Megan L %A de Haan, Hugoline G %A Hackinger, Sophie %A Hai, Yang %A Han, Sohee %A Tybjærg-Hansen, Anne %A Hivert, Marie-France %A Isomaa, Bo %A Jäger, Susanne %A Jørgensen, Marit E %A Jørgensen, Torben %A Käräjämäki, AnneMari %A Kim, Bong-Jo %A Kim, Sung Soo %A Koistinen, Heikki A %A Kovacs, Peter %A Kriebel, Jennifer %A Kronenberg, Florian %A Läll, Kristi %A Lange, Leslie A %A Lee, Jung-Jin %A Lehne, Benjamin %A Li, Huaixing %A Lin, Keng-Hung %A Linneberg, Allan %A Liu, Ching-Ti %A Liu, Jun %A Loh, Marie %A Mägi, Reedik %A Mamakou, Vasiliki %A McKean-Cowdin, Roberta %A Nadkarni, Girish %A Neville, Matt %A Nielsen, Sune F %A Ntalla, Ioanna %A Peyser, Patricia A %A Rathmann, Wolfgang %A Rice, Kenneth %A Rich, Stephen S %A Rode, Line %A Rolandsson, Olov %A Schönherr, Sebastian %A Selvin, Elizabeth %A Small, Kerrin S %A Stančáková, Alena %A Surendran, Praveen %A Taylor, Kent D %A Teslovich, Tanya M %A Thorand, Barbara %A Thorleifsson, Gudmar %A Tin, Adrienne %A Tönjes, Anke %A Varbo, Anette %A Witte, Daniel R %A Wood, Andrew R %A Yajnik, Pranav %A Yao, Jie %A Yengo, Loic %A Young, Robin %A Amouyel, Philippe %A Boeing, Heiner %A Boerwinkle, Eric %A Bottinger, Erwin P %A Chowdhury, Rajiv %A Collins, Francis S %A Dedoussis, George %A Dehghan, Abbas %A Deloukas, Panos %A Ferrario, Marco M %A Ferrieres, Jean %A Florez, Jose C %A Frossard, Philippe %A Gudnason, Vilmundur %A Harris, Tamara B %A Heckbert, Susan R %A Howson, Joanna M M %A Ingelsson, Martin %A Kathiresan, Sekar %A Kee, Frank %A Kuusisto, Johanna %A Langenberg, Claudia %A Launer, Lenore J %A Lindgren, Cecilia M %A Männistö, Satu %A Meitinger, Thomas %A Melander, Olle %A Mohlke, Karen L %A Moitry, Marie %A Morris, Andrew D %A Murray, Alison D %A de Mutsert, Renée %A Orho-Melander, Marju %A Owen, Katharine R %A Perola, Markus %A Peters, Annette %A Province, Michael A %A Rasheed, Asif %A Ridker, Paul M %A Rivadineira, Fernando %A Rosendaal, Frits R %A Rosengren, Anders H %A Salomaa, Veikko %A Sheu, Wayne H-H %A Sladek, Rob %A Smith, Blair H %A Strauch, Konstantin %A Uitterlinden, André G %A Varma, Rohit %A Willer, Cristen J %A Blüher, Matthias %A Butterworth, Adam S %A Chambers, John Campbell %A Chasman, Daniel I %A Danesh, John %A van Duijn, Cornelia %A Dupuis, Josée %A Franco, Oscar H %A Franks, Paul W %A Froguel, Philippe %A Grallert, Harald %A Groop, Leif %A Han, Bok-Ghee %A Hansen, Torben %A Hattersley, Andrew T %A Hayward, Caroline %A Ingelsson, Erik %A Kardia, Sharon L R %A Karpe, Fredrik %A Kooner, Jaspal Singh %A Köttgen, Anna %A Kuulasmaa, Kari %A Laakso, Markku %A Lin, Xu %A Lind, Lars %A Liu, Yongmei %A Loos, Ruth J F %A Marchini, Jonathan %A Metspalu, Andres %A Mook-Kanamori, Dennis %A Nordestgaard, Børge G %A Palmer, Colin N A %A Pankow, James S %A Pedersen, Oluf %A Psaty, Bruce M %A Rauramaa, Rainer %A Sattar, Naveed %A Schulze, Matthias B %A Soranzo, Nicole %A Spector, Timothy D %A Stefansson, Kari %A Stumvoll, Michael %A Thorsteinsdottir, Unnur %A Tuomi, Tiinamaija %A Tuomilehto, Jaakko %A Wareham, Nicholas J %A Wilson, James G %A Zeggini, Eleftheria %A Scott, Robert A %A Barroso, Inês %A Frayling, Timothy M %A Goodarzi, Mark O %A Meigs, James B %A Boehnke, Michael %A Saleheen, Danish %A Morris, Andrew P %A Rotter, Jerome I %A McCarthy, Mark I %X

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.

%B Nat Genet %V 50 %P 559-571 %8 2018 Apr %G eng %N 4 %R 10.1038/s41588-018-0084-1 %0 Journal Article %J J Clin Endocrinol Metab %D 2018 %T The relation between thyroid function and anemia: a pooled analysis of individual participant data. %A Wopereis, Daisy M %A Du Puy, Robert S %A van Heemst, Diana %A Walsh, John P %A Bremner, Alexandra %A Bakker, Stephan J L %A Bauer, Douglas C %A Cappola, Anne R %A Ceresini, Graziano %A Degryse, Jean %A Dullaart, Robin P F %A Feller, Martin %A Ferrucci, Luigi %A Floriani, Carmen %A Franco, Oscar H %A Iacoviello, Massimo %A Iervasi, Georgio %A Imaizumi, Misa %A Jukema, J Wouter %A Khaw, Kay-Tee %A Luben, Robert N %A Molinaro, Sabrina %A Nauck, Matthias %A Patel, Kushang V %A Peeters, Robin P %A Psaty, Bruce M %A Razvi, Salman %A Schindhelm, Roger K %A van Schoor, Natasja M %A Stott, David J %A Vaes, Bert %A Vanderpump, Mark P J %A Völzke, Henry %A Westendorp, Rudi G J %A Rodondi, Nicolas %A Cobbaert, Christa M %A Gussekloo, Jacobijn %A den Elzen, Wendy P J %X

Context: Anemia and thyroid dysfunction often co-occur and both increase with age. Human data on the relationship between thyroid disease and anemia are scarce.

Objective: To investigate the cross-sectional and longitudinal associations between clinical thyroid status and anemia.

Design: Individual participant data meta-analysis.

Setting: Sixteen cohorts participating in the Thyroid Studies Collaboration (n=42 162).

Main outcome measures: Primary outcome measure was anemia (hemoglobin <130 g/L in men and <120 g/L in women).

Results: Cross-sectionally, participants with abnormal thyroid status had an increased risk of having anemia compared with euthyroid participants (overt hypothyroidism, pooled odds ratio 1.84 [95% CI: 1.35-2.50], subclinical hypothyroidism 1.21 [1.02-1.43], subclinical hyperthyroidism 1.27 [1.03-1.57], overt hyperthyroidism 1.69 [1.00-2.87]). Hemoglobin levels were lower in all groups compared to participants with euthyroidism. In the longitudinal analyses (n=25,466 from 14 cohorts), the pooled hazard ratio for the risk of development of anemia was 1.38 [95% CI: 0.86-2.20] for overt hypothyroidism, 1.18 [1.00-1.38] for subclinical hypothyroidism, 1.15 [0.94-1.42] for subclinical hyperthyroidism and 1.47 [0.91-2.38] for overt hyperthyroidism. Sensitivity analyses excluding thyroid medication or high levels of C-reactive protein yielded similar results. No differences in mean annual change in hemoglobin levels were observed between the thyroid hormone status groups.

Conclusion: Higher odds of having anemia were observed in both participants with hypothyroid function and hyperthyroid function. In addition, reduced thyroid function at baseline showed a trend of increased risk of developing anemia during follow-up. It remains to be assessed in a randomized controlled trial whether treatment is effective in reducing anemia.

%B J Clin Endocrinol Metab %8 2018 Aug 02 %G eng %R 10.1210/jc.2018-00481 %0 Journal Article %J Am J Kidney Dis %D 2018 %T Relationship of Estimated GFR and Albuminuria to Concurrent Laboratory Abnormalities: An Individual Participant Data Meta-analysis in a Global Consortium. %A Inker, Lesley A %A Grams, Morgan E %A Levey, Andrew S %A Coresh, Josef %A Cirillo, Massimo %A Collins, John F %A Gansevoort, Ron T %A Gutierrez, Orlando M %A Hamano, Takayuki %A Heine, Gunnar H %A Ishikawa, Shizukiyo %A Jee, Sun Ha %A Kronenberg, Florian %A Landray, Martin J %A Miura, Katsuyuki %A Nadkarni, Girish N %A Peralta, Carmen A %A Rothenbacher, Dietrich %A Schaeffner, Elke %A Sedaghat, Sanaz %A Shlipak, Michael G %A Zhang, Luxia %A van Zuilen, Arjan D %A Hallan, Stein I %A Kovesdy, Csaba P %A Woodward, Mark %A Levin, Adeera %X

RATIONALE & OBJECTIVE: Chronic kidney disease (CKD) is complicated by abnormalities that reflect disruption in filtration, tubular, and endocrine functions of the kidney. Our aim was to explore the relationship of specific laboratory result abnormalities and hypertension with the estimated glomerular filtration rate (eGFR) and albuminuria CKD staging framework.

STUDY DESIGN: Cross-sectional individual participant-level analyses in a global consortium.

SETTING & STUDY POPULATIONS: 17 CKD and 38 general population and high-risk cohorts.

SELECTION CRITERIA FOR STUDIES: Cohorts in the CKD Prognosis Consortium with data for eGFR and albuminuria, as well as a measurement of hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, or calcium, or hypertension.

DATA EXTRACTION: Data were obtained and analyzed between July 2015 and January 2018.

ANALYTICAL APPROACH: We modeled the association of eGFR and albuminuria with hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, and calcium values using linear regression and with hypertension and categorical definitions of each abnormality using logistic regression. Results were pooled using random-effects meta-analyses.

RESULTS: The CKD cohorts (n=254,666 participants) were 27% women and 10% black, with a mean age of 69 (SD, 12) years. The general population/high-risk cohorts (n=1,758,334) were 50% women and 2% black, with a mean age of 50 (16) years. There was a strong graded association between lower eGFR and all laboratory result abnormalities (ORs ranging from 3.27 [95% CI, 2.68-3.97] to 8.91 [95% CI, 7.22-10.99] comparing eGFRs of 15 to 29 with eGFRs of 45 to 59mL/min/1.73m), whereas albuminuria had equivocal or weak associations with abnormalities (ORs ranging from 0.77 [95% CI, 0.60-0.99] to 1.92 [95% CI, 1.65-2.24] comparing urinary albumin-creatinine ratio > 300 vs < 30mg/g).

LIMITATIONS: Variations in study era, health care delivery system, typical diet, and laboratory assays.

CONCLUSIONS: Lower eGFR was strongly associated with higher odds of multiple laboratory result abnormalities. Knowledge of risk associations might help guide management in the heterogeneous group of patients with CKD.

%B Am J Kidney Dis %8 2018 Oct 19 %G eng %R 10.1053/j.ajkd.2018.08.013 %0 Journal Article %J J Am Heart Assoc %D 2018 %T Reversal of Aging-Induced Increases in Aortic Stiffness by Targeting Cytoskeletal Protein-Protein Interfaces. %A Nicholson, Christopher J %A Singh, Kuldeep %A Saphirstein, Robert J %A Gao, Yuan Z %A Li, Qian %A Chiu, Joanna G %A Leavis, Paul %A Verwoert, Germaine C %A Mitchell, G F %A Porter, Tyrone %A Morgan, Kathleen G %X

BACKGROUND: The proximal aorta normally functions as a critical shock absorber that protects small downstream vessels from damage by pressure and flow pulsatility generated by the heart during systole. This shock absorber function is impaired with age because of aortic stiffening.

METHODS AND RESULTS: We examined the contribution of common genetic variation to aortic stiffness in humans by interrogating results from the AortaGen Consortium genome-wide association study of carotid-femoral pulse wave velocity. Common genetic variation in the N-WASP () locus is associated with carotid-femoral pulse wave velocity (rs600420, =0.0051). Thus, we tested the hypothesis that decoy proteins designed to disrupt the interaction of cytoskeletal proteins such as N-WASP with its binding partners in the vascular smooth muscle cytoskeleton could decrease ex vivo stiffness of aortas from a mouse model of aging. A synthetic decoy peptide construct of N-WASP significantly reduced activated stiffness in ex vivo aortas of aged mice. Two other cytoskeletal constructs targeted to VASP and talin-vinculin interfaces similarly decreased aging-induced ex vivo active stiffness by on-target specific actions. Furthermore, packaging these decoy peptides into microbubbles enables the peptides to be ultrasound-targeted to the wall of the proximal aorta to attenuate ex vivo active stiffness.

CONCLUSIONS: We conclude that decoy peptides targeted to vascular smooth muscle cytoskeletal protein-protein interfaces and microbubble packaged can decrease aortic stiffness ex vivo. Our results provide proof of concept at the ex vivo level that decoy peptides targeted to cytoskeletal protein-protein interfaces may lead to substantive dynamic modulation of aortic stiffness.

%B J Am Heart Assoc %V 7 %8 2018 Jul 18 %G eng %N 15 %R 10.1161/JAHA.118.008926 %0 Journal Article %J Lancet %D 2018 %T Risk thresholds for alcohol consumption: combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies. %A Wood, Angela M %A Kaptoge, Stephen %A Butterworth, Adam S %A Willeit, Peter %A Warnakula, Samantha %A Bolton, Thomas %A Paige, Ellie %A Paul, Dirk S %A Sweeting, Michael %A Burgess, Stephen %A Bell, Steven %A Astle, William %A Stevens, David %A Koulman, Albert %A Selmer, Randi M %A Verschuren, W M Monique %A Sato, Shinichi %A Njølstad, Inger %A Woodward, Mark %A Salomaa, Veikko %A Nordestgaard, Børge G %A Yeap, Bu B %A Fletcher, Astrid %A Melander, Olle %A Kuller, Lewis H %A Balkau, Beverley %A Marmot, Michael %A Koenig, Wolfgang %A Casiglia, Edoardo %A Cooper, Cyrus %A Arndt, Volker %A Franco, Oscar H %A Wennberg, Patrik %A Gallacher, John %A de la Cámara, Agustin Gómez %A Völzke, Henry %A Dahm, Christina C %A Dale, Caroline E %A Bergmann, Manuela M %A Crespo, Carlos J %A van der Schouw, Yvonne T %A Kaaks, Rudolf %A Simons, Leon A %A Lagiou, Pagona %A Schoufour, Josje D %A Boer, Jolanda M A %A Key, Timothy J %A Rodriguez, Beatriz %A Moreno-Iribas, Conchi %A Davidson, Karina W %A Taylor, James O %A Sacerdote, Carlotta %A Wallace, Robert B %A Quiros, J Ramon %A Tumino, Rosario %A Blazer, Dan G %A Linneberg, Allan %A Daimon, Makoto %A Panico, Salvatore %A Howard, Barbara %A Skeie, Guri %A Strandberg, Timo %A Weiderpass, Elisabete %A Nietert, Paul J %A Psaty, Bruce M %A Kromhout, Daan %A Salamanca-Fernandez, Elena %A Kiechl, Stefan %A Krumholz, Harlan M %A Grioni, Sara %A Palli, Domenico %A Huerta, José M %A Price, Jackie %A Sundström, Johan %A Arriola, Larraitz %A Arima, Hisatomi %A Travis, Ruth C %A Panagiotakos, Demosthenes B %A Karakatsani, Anna %A Trichopoulou, Antonia %A Kühn, Tilman %A Grobbee, Diederick E %A Barrett-Connor, Elizabeth %A van Schoor, Natasja %A Boeing, Heiner %A Overvad, Kim %A Kauhanen, Jussi %A Wareham, Nick %A Langenberg, Claudia %A Forouhi, Nita %A Wennberg, Maria %A Després, Jean-Pierre %A Cushman, Mary %A Cooper, Jackie A %A Rodriguez, Carlos J %A Sakurai, Masaru %A Shaw, Jonathan E %A Knuiman, Matthew %A Voortman, Trudy %A Meisinger, Christa %A Tjønneland, Anne %A Brenner, Hermann %A Palmieri, Luigi %A Dallongeville, Jean %A Brunner, Eric J %A Assmann, Gerd %A Trevisan, Maurizio %A Gillum, Richard F %A Ford, Ian %A Sattar, Naveed %A Lazo, Mariana %A Thompson, Simon G %A Ferrari, Pietro %A Leon, David A %A Smith, George Davey %A Peto, Richard %A Jackson, Rod %A Banks, Emily %A Di Angelantonio, Emanuele %A Danesh, John %X

BACKGROUND: Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease.

METHODS: We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose-response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th-95th percentile 1·04-13·5]) from 71 011 participants from 37 studies.

FINDINGS: In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1·14, 95% CI, 1·10-1·17), coronary disease excluding myocardial infarction (1·06, 1·00-1·11), heart failure (1·09, 1·03-1·15), fatal hypertensive disease (1·24, 1·15-1·33); and fatal aortic aneurysm (1·15, 1·03-1·28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0·94, 0·91-0·97). In comparison to those who reported drinking >0-≤100 g per week, those who reported drinking >100-≤200 g per week, >200-≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1-2 years, or 4-5 years, respectively.

INTERPRETATION: In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines.

FUNDING: UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Union Framework 7, and European Research Council.

%B Lancet %V 391 %P 1513-1523 %8 2018 04 14 %G eng %N 10129 %R 10.1016/S0140-6736(18)30134-X %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 Heart Rhythm %D 2018 %T Sleep characteristics that predict atrial fibrillation. %A Christensen, Matthew A %A Dixit, Shalini %A Dewland, Thomas A %A Whitman, Isaac R %A Nah, Gregory %A Vittinghoff, Eric %A Mukamal, Kenneth J %A Redline, Susan %A Robbins, John A %A Newman, Anne B %A Patel, Sanjay R %A Magnani, Jared W %A Psaty, Bruce M %A Olgin, Jeffrey E %A Pletcher, Mark J %A Heckbert, Susan R %A Marcus, Gregory M %X

BACKGROUND: The relationship between sleep disruption, independent of obstructive sleep apnea (OSA), and atrial fibrillation (AF) is unknown.

OBJECTIVE: The purpose of this study was to determine whether poor sleep itself is a risk factor for AF.

METHODS: We first performed an analysis of participants in the Health eHeart Study and validated those findings in the longitudinal Cardiovascular Health Study, including a subset of patients undergoing polysomnography. To determine whether the observed relationships readily translated to medical practice, we examined 2005-2009 data from the California Healthcare Cost and Utilization Project.

RESULTS: Among 4553 Health eHeart participants, the 526 with AF exhibited more frequent nighttime awakening (odd ratio [OR] 1.47; 95% confidence interval [CI] 1.14-1.89; P = .003). In 5703 Cardiovascular Health Study participants followed for a median 11.6 years, frequent nighttime awakening predicted a 33% greater risk of AF (hazard ratio [HR] 1.33; 95% CI 1.17-1.51; P <.001). In patients with polysomnography (N = 1127), every standard deviation percentage decrease in rapid eye movement (REM) sleep was associated with a 18% higher risk of developing AF (HR 1.18; 95% CI 1.00-1.38; P = .047). Among 14,330,651 California residents followed for a median 3.9 years, an insomnia diagnosis predicted a 36% increased risk of new AF (HR 1.36; 95% CI 1.30-1.42; P <.001).

CONCLUSION: Sleep disruption consistently predicted AF before and after adjustment for OSA and other potential confounders across several different populations. Sleep quality itself may be important in the pathogenesis of AF, potentially representing a novel target for prevention.

%B Heart Rhythm %V 15 %P 1289-1295 %8 2018 Sep %G eng %N 9 %R 10.1016/j.hrthm.2018.05.008 %0 Journal Article %J J Am Heart Assoc %D 2018 %T Social Network Trajectories in Myocardial Infarction Versus Ischemic Stroke. %A Dhand, Amar %A Longstreth, W T %A Chaves, Paulo H M %A Dhamoon, Mandip S %X

BACKGROUND: Changes in social networks are rarely examined before and after various diseases because of insufficient data. CHS (The Cardiovascular Health Study) offers an opportunity to compare social network trajectories surrounding well-adjudicated myocardial infarction (MI) or stroke events. We tested the hypothesis that social networks will be stable after MI and decrease after stroke.

METHODS AND RESULTS: We examined trajectories of the Lubben Social Network Scale score (LSNS, range 0-50) before and after vascular events over 11 years. The LSNS assesses engagement in family networks, friends' networks, and social supports. We used a linear mixed model with repeated measures and fixed effects to compare the change in social network score before and after events in 395 people with MI and 382 with ischemic stroke. Over a mean of 12.4 years of follow-up for MI and 11.1 years for stroke, we examined an average of 4 social network scores for each participant. We controlled for sociodemographics, baseline cognitive function, and comorbidities. The participants' mean age was 73.5, 51% were women, and 88% were non-Hispanic white. After MI, the social network trajectory remained stable compared with the baseline trajectory (-0.06 points per year, adjusted =0.2356). After stroke, the social network trajectory declined compared with the baseline trajectory (-0.14 points per year, adjusted =0.0364).

CONCLUSIONS: Social networks remained stable after MI and declined after stroke. This small and persistent decline after adjustment for potential confounders is notable because it deviates from stable network trajectories found in CHS participants and is specific to stroke.

%B J Am Heart Assoc %V 7 %8 2018 Apr 13 %G eng %N 8 %R 10.1161/JAHA.117.008029 %0 Journal Article %J Aging (Albany NY) %D 2018 %T Strong impact of natural-selection-free heterogeneity in genetics of age-related phenotypes. %A Kulminski, Alexander M %A Huang, Jian %A Loika, Yury %A Arbeev, Konstantin G %A Bagley, Olivia %A Yashkin, Arseniy %A Duan, Matt %A Culminskaya, Irina %K Aging %K Computational Biology %K Gene Expression Regulation %K Genome-Wide Association Study %K Genotype %K Humans %K Polymorphism, Single Nucleotide %X

A conceptual difficulty in genetics of age-related phenotypes that make individuals vulnerable to disease in post-reproductive life is genetic heterogeneity attributed to an undefined role of evolution in establishing their molecular mechanisms. Here, we performed univariate and pleiotropic genome-wide meta-analyses of 20 age-related phenotypes leveraging longitudinal information in a sample of 33,431 individuals and dealing with the natural-selection-free genetic heterogeneity. We identified 142 non-proxy single nucleotide polymorphisms (SNPs) with phenotype-specific (18 SNPs) and pleiotropic (124 SNPs) associations at genome-wide level. Univariate meta-analysis identified two novel (11.1%) and replicated 16 SNPs whereas pleiotropic meta-analysis identified 115 novel (92.7%) and nine replicated SNPs. Pleiotropic associations for most novel (93.9%) and all replicated SNPs were strongly impacted by the natural-selection-free genetic heterogeneity in its unconventional form of antagonistic heterogeneity, implying antagonistic directions of genetic effects for directly correlated phenotypes. Our results show that the common genome-wide approach is well adapted to handle homogeneous univariate associations within Mendelian framework whereas most associations with age-related phenotypes are more complex and well beyond that framework. Dissecting the natural-selection-free genetic heterogeneity is critical for gaining insights into genetics of age-related phenotypes and has substantial and unexplored yet potential for improving efficiency of genome-wide analysis.

%B Aging (Albany NY) %V 10 %P 492-514 %8 2018 03 29 %G eng %N 3 %R 10.18632/aging.101407 %0 Journal Article %J Nat Commun %D 2018 %T Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function. %A Davies, Gail %A Lam, Max %A Harris, Sarah E %A Trampush, Joey W %A Luciano, Michelle %A Hill, W David %A Hagenaars, Saskia P %A Ritchie, Stuart J %A Marioni, Riccardo E %A Fawns-Ritchie, Chloe %A Liewald, David C M %A Okely, Judith A %A Ahola-Olli, Ari V %A Barnes, Catriona L K %A Bertram, Lars %A Bis, Joshua C %A Burdick, Katherine E %A Christoforou, Andrea %A DeRosse, Pamela %A Djurovic, Srdjan %A Espeseth, Thomas %A Giakoumaki, Stella %A Giddaluru, Sudheer %A Gustavson, Daniel E %A Hayward, Caroline %A Hofer, Edith %A Ikram, M Arfan %A Karlsson, Robert %A Knowles, Emma %A Lahti, Jari %A Leber, Markus %A Li, Shuo %A Mather, Karen A %A Melle, Ingrid %A Morris, Derek %A Oldmeadow, Christopher %A Palviainen, Teemu %A Payton, Antony %A Pazoki, Raha %A Petrovic, Katja %A Reynolds, Chandra A %A Sargurupremraj, Muralidharan %A Scholz, Markus %A Smith, Jennifer A %A Smith, Albert V %A Terzikhan, Natalie %A Thalamuthu, Anbupalam %A Trompet, Stella %A van der Lee, Sven J %A Ware, Erin B %A Windham, B Gwen %A Wright, Margaret J %A Yang, Jingyun %A Yu, Jin %A Ames, David %A Amin, Najaf %A Amouyel, Philippe %A Andreassen, Ole A %A Armstrong, Nicola J %A Assareh, Amelia A %A Attia, John R %A Attix, Deborah %A Avramopoulos, Dimitrios %A Bennett, David A %A Böhmer, Anne C %A Boyle, Patricia A %A Brodaty, Henry %A Campbell, Harry %A Cannon, Tyrone D %A Cirulli, Elizabeth T %A Congdon, Eliza %A Conley, Emily Drabant %A Corley, Janie %A Cox, Simon R %A Dale, Anders M %A Dehghan, Abbas %A Dick, Danielle %A Dickinson, Dwight %A Eriksson, Johan G %A Evangelou, Evangelos %A Faul, Jessica D %A Ford, Ian %A Freimer, Nelson A %A Gao, He %A Giegling, Ina %A Gillespie, Nathan A %A Gordon, Scott D %A Gottesman, Rebecca F %A Griswold, Michael E %A Gudnason, Vilmundur %A Harris, Tamara B %A Hartmann, Annette M %A Hatzimanolis, Alex %A Heiss, Gerardo %A Holliday, Elizabeth G %A Joshi, Peter K %A Kähönen, Mika %A Kardia, Sharon L R %A Karlsson, Ida %A Kleineidam, Luca %A Knopman, David S %A Kochan, Nicole A %A Konte, Bettina %A Kwok, John B %A Le Hellard, Stephanie %A Lee, Teresa %A Lehtimäki, Terho %A Li, Shu-Chen %A Liu, Tian %A Koini, Marisa %A London, Edythe %A Longstreth, Will T %A Lopez, Oscar L %A Loukola, Anu %A Luck, Tobias %A Lundervold, Astri J %A Lundquist, Anders %A Lyytikäinen, Leo-Pekka %A Martin, Nicholas G %A Montgomery, Grant W %A Murray, Alison D %A Need, Anna C %A Noordam, Raymond %A Nyberg, Lars %A Ollier, William %A Papenberg, Goran %A Pattie, Alison %A Polasek, Ozren %A Poldrack, Russell A %A Psaty, Bruce M %A Reppermund, Simone %A Riedel-Heller, Steffi G %A Rose, Richard J %A Rotter, Jerome I %A Roussos, Panos %A Rovio, Suvi P %A Saba, Yasaman %A Sabb, Fred W %A Sachdev, Perminder S %A Satizabal, Claudia L %A Schmid, Matthias %A Scott, Rodney J %A Scult, Matthew A %A Simino, Jeannette %A Slagboom, P Eline %A Smyrnis, Nikolaos %A Soumaré, Aïcha %A Stefanis, Nikos C %A Stott, David J %A Straub, Richard E %A Sundet, Kjetil %A Taylor, Adele M %A Taylor, Kent D %A Tzoulaki, Ioanna %A Tzourio, Christophe %A Uitterlinden, Andre %A Vitart, Veronique %A Voineskos, Aristotle N %A Kaprio, Jaakko %A Wagner, Michael %A Wagner, Holger %A Weinhold, Leonie %A Wen, K Hoyan %A Widen, Elisabeth %A Yang, Qiong %A Zhao, Wei %A Adams, Hieab H H %A Arking, Dan E %A Bilder, Robert M %A Bitsios, Panos %A Boerwinkle, Eric %A Chiba-Falek, Ornit %A Corvin, Aiden %A De Jager, Philip L %A Debette, Stephanie %A Donohoe, Gary %A Elliott, Paul %A Fitzpatrick, Annette L %A Gill, Michael %A Glahn, David C %A Hägg, Sara %A Hansell, Narelle K %A Hariri, Ahmad R %A Ikram, M Kamran %A Jukema, J Wouter %A Vuoksimaa, Eero %A Keller, Matthew C %A Kremen, William S %A Launer, Lenore %A Lindenberger, Ulman %A Palotie, Aarno %A Pedersen, Nancy L %A Pendleton, Neil %A Porteous, David J %A Räikkönen, Katri %A Raitakari, Olli T %A Ramirez, Alfredo %A Reinvang, Ivar %A Rudan, Igor %A Schmidt, Reinhold %A Schmidt, Helena %A Schofield, Peter W %A Schofield, Peter R %A Starr, John M %A Steen, Vidar M %A Trollor, Julian N %A Turner, Steven T %A van Duijn, Cornelia M %A Villringer, Arno %A Weinberger, Daniel R %A Weir, David R %A Wilson, James F %A Malhotra, Anil %A McIntosh, Andrew M %A Gale, Catharine R %A Seshadri, Sudha %A Mosley, Thomas H %A Bressler, Jan %A Lencz, Todd %A Deary, Ian J %X

General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.

%B Nat Commun %V 9 %P 2098 %8 2018 May 29 %G eng %N 1 %R 10.1038/s41467-018-04362-x %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 Neuroimage %D 2018 %T Systemic inflammation as a predictor of brain aging: Contributions of physical activity, metabolic risk, and genetic risk. %A Corlier, Fabian %A Hafzalla, George %A Faskowitz, Joshua %A Kuller, Lewis H %A Becker, James T %A Lopez, Oscar L %A Thompson, Paul M %A Braskie, Meredith N %X

Inflammatory processes may contribute to risk for Alzheimer's disease (AD) and age-related brain degeneration. Metabolic and genetic risk factors, and physical activity may, in turn, influence these inflammatory processes. Some of these risk factors are modifiable, and interact with each other. Understanding how these processes together relate to brain aging will help to inform future interventions to treat or prevent cognitive decline. We used brain magnetic resonance imaging (MRI) to scan 335 older adult humans (mean age 77.3 ± 3.4 years) who remained non-demented for the duration of the 9-year longitudinal study. We used structural equation modeling (SEM) in a subset of 226 adults to evaluate whether measures of baseline peripheral inflammation (serum C-reactive protein levels; CRP), mediated the baseline contributions of genetic and metabolic risk, and physical activity, to regional cortical thickness in AD-relevant brain regions at study year 9. We found that both baseline metabolic risk and AD risk variant apolipoprotein E ε4 (APOE4), modulated baseline serum CRP. Higher baseline CRP levels, in turn, predicted thinner regional cortex at year 9, and mediated an effect between higher metabolic risk and thinner cortex in those regions. A higher polygenic risk score composed of variants in immune-associated AD risk genes (other than APOE) was associated with thinner regional cortex. However, CRP levels did not mediate this effect, suggesting that other mechanisms may be responsible for the elevated AD risk. We found interactions between genetic and environmental factors and structural brain health. Our findings support the role of metabolic risk and peripheral inflammation in age-related brain decline.

%B Neuroimage %V 172 %P 118-129 %8 2018 May 15 %G eng %R 10.1016/j.neuroimage.2017.12.027 %0 Journal Article %J Int J Obes (Lond) %D 2018 %T Trans-ethnic analysis of metabochip data identifies two new loci associated with BMI. %A Gong, J %A Nishimura, K K %A Fernandez-Rhodes, L %A Haessler, J %A Bien, S %A Graff, M %A Lim, U %A Lu, Y %A Gross, M %A Fornage, M %A Yoneyama, S %A Isasi, C R %A Bůžková, P %A Daviglus, M %A Lin, D-Y %A Tao, R %A Goodloe, R %A Bush, W S %A Farber-Eger, E %A Boston, J %A Dilks, H H %A Ehret, G %A Gu, C C %A Lewis, C E %A Nguyen, K-D H %A Cooper, R %A Leppert, M %A Irvin, M R %A Bottinger, E P %A Wilkens, L R %A Haiman, C A %A Park, L %A Monroe, K R %A Cheng, I %A Stram, D O %A Carlson, C S %A Jackson, R %A Kuller, L %A Houston, D %A Kooperberg, C %A Buyske, S %A Hindorff, L A %A Crawford, D C %A Loos, R J F %A Le Marchand, L %A Matise, T C %A North, K E %A Peters, U %X

OBJECTIVE: Body mass index (BMI) is commonly used to assess obesity, which is associated with numerous diseases and negative health outcomes. BMI has been shown to be a heritable, polygenic trait, with close to 100 loci previously identified and replicated in multiple populations. We aim to replicate known BMI loci and identify novel associations in a trans-ethnic study population.

SUBJECTS: Using eligible participants from the Population Architecture using Genomics and Epidemiology consortium, we conducted a trans-ethnic meta-analysis of 102 514 African Americans, Hispanics, Asian/Native Hawaiian, Native Americans and European Americans. Participants were genotyped on over 200 000 SNPs on the Illumina Metabochip custom array, or imputed into the 1000 Genomes Project (Phase I). Linear regression of the natural log of BMI, adjusting for age, sex, study site (if applicable), and ancestry principal components, was conducted for each race/ethnicity within each study cohort. Race/ethnicity-specific, and combined meta-analyses used fixed-effects models.

RESULTS: We replicated 15 of 21 BMI loci included on the Metabochip, and identified two novel BMI loci at 1q41 (rs2820436) and 2q31.1 (rs10930502) at the Metabochip-wide significance threshold (P<2.5 × 10). Bioinformatic functional investigation of SNPs at these loci suggests a possible impact on pathways that regulate metabolism and adipose tissue.

CONCLUSION: Conducting studies in genetically diverse populations continues to be a valuable strategy for replicating known loci and uncovering novel BMI associations.

%B Int J Obes (Lond) %V 42 %P 384-390 %8 2018 Mar %G eng %N 3 %R 10.1038/ijo.2017.304 %0 Journal Article %J J Clin Endocrinol Metab %D 2018 %T Trans-ethnic Evaluation Identifies Novel Low Frequency Loci Associated with 25-Hydroxyvitamin D Concentrations. %A Hong, Jaeyoung %A Hatchell, Kathryn E %A Bradfield, Jonathan P %A Andrew, Bjonnes %A Alessandra, Chesi %A Chao-Qiang, Lai %A Langefeld, Carl D %A Lu, Lingyi %A Lu, Yingchang %A Lutsey, Pamela L %A Musani, Solomon K %A Nalls, Mike A %A Robinson-Cohen, Cassianne %A Roizen, Jeffery D %A Saxena, Richa %A Tucker, Katherine L %A Ziegler, Julie T %A Arking, Dan E %A Bis, Joshua C %A Boerwinkle, Eric %A Bottinger, Erwin P %A Bowden, Donald W %A Gilsanz, Vincente %A Houston, Denise K %A Kalkwarf, Heidi J %A Kelly, Andrea %A Lappe, Joan M %A Liu, Yongmei %A Michos, Erin D %A Oberfield, Sharon E %A Palmer, Nicholette D %A Rotter, Jerome I %A Sapkota, Bishwa %A Shepherd, John A %A Wilson, James G %A Basu, Saonli %A de Boer, Ian H %A Divers, Jasmin %A Freedman, Barry I %A Grant, Struan F A %A Hakanarson, Hakon %A Harris, Tamara B %A Kestenbaum, Bryan R %A Kritchevsky, Stephen B %A Loos, Ruth J F %A Norris, Jill M %A Norwood, Arnita F %A Ordovas, Jose M %A Pankow, James S %A Psaty, Bruce M %A Sanhgera, Dharambir K %A Wagenknecht, Lynne E %A Zemel, Babette S %A Meigs, James %A Dupuis, Josée %A Florez, Jose C %A Wang, Thomas %A Liu, Ching-Ti %A Engelman, Corinne D %A Billings, Liana K %X

Context: Vitamin D inadequacy is common in the adult population of the United States. While the genetic determinants underlying vitamin D inadequacy have been studied in people of European ancestry, less is known in Hispanic or African ancestry populations.

Objective: The TRANSCEN-D (TRANS-ethniC Evaluation of vitamiN D GWAS) consortium was assembled to replicate genetic associations with 25-hydroxyvitamin D (25(OH)D) concentrations from the meta-analyses of European ancestry (SUNLIGHT) and to identify novel genetic variants related to vitamin D concentrations in African and Hispanic ancestries.

Design: Ancestry-specific (Hispanic and African) and trans-ethnic (Hispanic, African and European) meta-analyses were performed using the METAL software.

Patients or Other Participants: In total, 8,541 African-American and 3,485 Hispanic-American (from North America) participants from twelve cohorts, and 16,124 European participants from SUNLIGHT were included in the study.

Main Outcome Measure(s): Blood concentrations of 25(OH)D were measured for all participants.

Results: Ancestry-specific analyses in African and Hispanic Americans replicated SNPs in GC (2 and 4 SNPs, respectively). A potentially novel SNP (rs79666294) near the KIF4B gene was identified in the African-American cohort. Trans-ethnic evaluation replicated GC and DHCR7 region SNPs. Additionally, the trans-ethnic analyses revealed novel SNPs rs719700 and rs1410656 near the ANO6/ARID2 and HTR2A genes, respectively.

Conclusions: Ancestry-specific and trans-ethnic GWAS of 25(OH)D confirmed findings in GC and DHCR7 for African and Hispanic American samples and revealed novel findings near KIF4B, ANO6/ARID2, and HTR2A. The biological mechanisms that link these regions with 25(OH)D metabolism require further investigation.

%B J Clin Endocrinol Metab %8 2018 Jan 09 %G eng %R 10.1210/jc.2017-01802 %0 Journal Article %J Mol Psychiatry %D 2018 %T Whole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation. %A Bis, Joshua C %A Jian, Xueqiu %A Kunkle, Brian W %A Chen, Yuning %A Hamilton-Nelson, Kara L %A Bush, William S %A Salerno, William J %A Lancour, Daniel %A Ma, Yiyi %A Renton, Alan E %A Marcora, Edoardo %A Farrell, John J %A Zhao, Yi %A Qu, Liming %A Ahmad, Shahzad %A Amin, Najaf %A Amouyel, Philippe %A Beecham, Gary W %A Below, Jennifer E %A Campion, Dominique %A Charbonnier, Camille %A Chung, Jaeyoon %A Crane, Paul K %A Cruchaga, Carlos %A Cupples, L Adrienne %A Dartigues, Jean-François %A Debette, Stephanie %A Deleuze, Jean-Francois %A Fulton, Lucinda %A Gabriel, Stacey B %A Genin, Emmanuelle %A Gibbs, Richard A %A Goate, Alison %A Grenier-Boley, Benjamin %A Gupta, Namrata %A Haines, Jonathan L %A Havulinna, Aki S %A Helisalmi, Seppo %A Hiltunen, Mikko %A Howrigan, Daniel P %A Ikram, M Arfan %A Kaprio, Jaakko %A Konrad, Jan %A Kuzma, Amanda %A Lander, Eric S %A Lathrop, Mark %A Lehtimäki, Terho %A Lin, Honghuang %A Mattila, Kari %A Mayeux, Richard %A Muzny, Donna M %A Nasser, Waleed %A Neale, Benjamin %A Nho, Kwangsik %A Nicolas, Gaël %A Patel, Devanshi %A Pericak-Vance, Margaret A %A Perola, Markus %A Psaty, Bruce M %A Quenez, Olivier %A Rajabli, Farid %A Redon, Richard %A Reitz, Christiane %A Remes, Anne M %A Salomaa, Veikko %A Sarnowski, Chloe %A Schmidt, Helena %A Schmidt, Michael %A Schmidt, Reinhold %A Soininen, Hilkka %A Thornton, Timothy A %A Tosto, Giuseppe %A Tzourio, Christophe %A van der Lee, Sven J %A van Duijn, Cornelia M %A Vardarajan, Badri %A Wang, Weixin %A Wijsman, Ellen %A Wilson, Richard K %A Witten, Daniela %A Worley, Kim C %A Zhang, Xiaoling %A Bellenguez, Céline %A Lambert, Jean-Charles %A Kurki, Mitja I %A Palotie, Aarno %A Daly, Mark %A Boerwinkle, Eric %A Lunetta, Kathryn L %A DeStefano, Anita L %A Dupuis, Josée %A Martin, Eden R %A Schellenberg, Gerard D %A Seshadri, Sudha %A Naj, Adam C %A Fornage, Myriam %A Farrer, Lindsay A %X

The Alzheimer's Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls). The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes: IGHG3 (p = 9.8 × 10), an immunoglobulin gene whose antibodies interact with β-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 × 10), and a zinc-finger protein ZNF655 (gene-based p = 5.0 × 10). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.

%B Mol Psychiatry %8 2018 Aug 14 %G eng %R 10.1038/s41380-018-0112-7 %0 Journal Article %J Hum Mol Genet %D 2019 %T Admixture mapping identifies novel loci for obstructive sleep apnea in Hispanic/Latino Americans. %A Wang, Heming %A Cade, Brian E %A Sofer, Tamar %A Sands, Scott A %A Chen, Han %A Browning, Sharon R %A Stilp, Adrienne M %A Louie, Tin L %A Thornton, Timothy A %A Johnson, W Craig %A Below, Jennifer E %A Conomos, Matthew P %A Evans, Daniel S %A Gharib, Sina A %A Guo, Xiuqing %A Wood, Alexis C %A Mei, Hao %A Yaffe, Kristine %A Loredo, Jose S %A Ramos, Alberto R %A Barrett-Connor, Elizabeth %A Ancoli-Israel, Sonia %A Zee, Phyllis C %A Arens, Raanan %A Shah, Neomi A %A Taylor, Kent D %A Tranah, Gregory J %A Stone, Katie L %A Hanis, Craig L %A Wilson, James G %A Gottlieb, Daniel J %A Patel, Sanjay R %A Rice, Ken %A Post, Wendy S %A Rotter, Jerome I %A Sunyaev, Shamil R %A Cai, Jianwen %A Lin, Xihong %A Purcell, Shaun M %A Laurie, Cathy C %A Saxena, Richa %A Redline, Susan %A Zhu, Xiaofeng %X

Obstructive sleep apnea (OSA) is a common disorder associated with increased risk of cardiovascular disease and mortality. Its prevalence and severity vary across ancestral background. Although OSA traits are heritable, few genetic associations have been identified. To identify genetic regions associated with OSA and improve statistical power, we applied admixture mapping on three primary OSA traits [the apnea hypopnea index (AHI), overnight average oxyhemoglobin saturation (SaO2) and percentage time SaO2 < 90%] and a secondary trait (respiratory event duration) in a Hispanic/Latino American population study of 11 575 individuals with significant variation in ancestral background. Linear mixed models were performed using previously inferred African, European and Amerindian local genetic ancestry markers. Global African ancestry was associated with a lower AHI, higher SaO2 and shorter event duration. Admixture mapping analysis of the primary OSA traits identified local African ancestry at the chromosomal region 2q37 as genome-wide significantly associated with AHI (P < 5.7 × 10-5), and European and Amerindian ancestries at 18q21 suggestively associated with both AHI and percentage time SaO2 < 90% (P < 10-3). Follow-up joint ancestry-SNP association analyses identified novel variants in ferrochelatase (FECH), significantly associated with AHI and percentage time SaO2 < 90% after adjusting for multiple tests (P < 8 × 10-6). These signals contributed to the admixture mapping associations and were replicated in independent cohorts. In this first admixture mapping study of OSA, novel associations with variants in the iron/heme metabolism pathway suggest a role for iron in influencing respiratory traits underlying OSA.

%B Hum Mol Genet %V 28 %P 675-687 %8 2019 02 15 %G eng %N 4 %R 10.1093/hmg/ddy387 %0 Journal Article %J Am J Respir Crit Care Med %D 2019 %T Albuminuria, Lung Function Decline, and Risk of Incident Chronic Obstructive Pulmonary Disease. The NHLBI Pooled Cohorts Study. %A Oelsner, Elizabeth C %A Balte, Pallavi P %A Grams, Morgan E %A Cassano, Patricia A %A Jacobs, David R %A Barr, R Graham %A Burkart, Kristin M %A Kalhan, Ravi %A Kronmal, Richard %A Loehr, Laura R %A O'Connor, George T %A Schwartz, Joseph E %A Shlipak, Michael %A Tracy, Russell P %A Tsai, Michael Y %A White, Wendy %A Yende, Sachin %X

RATIONALE: Chronic lower respiratory diseases (CLRDs), including chronic obstructive pulmonary disease (COPD) and asthma, are the fourth leading cause of death. Prior studies suggest that albuminuria, a biomarker of endothelial injury, is increased in patients with COPD.

OBJECTIVES: To test whether albuminuria was associated with lung function decline and incident CLRDs.

METHODS: Six U.S. population-based cohorts were harmonized and pooled. Participants with prevalent clinical lung disease were excluded. Albuminuria (urine albumin-to-creatinine ratio) was measured in spot samples. Lung function was assessed by spirometry. Incident CLRD-related hospitalizations and deaths were classified via adjudication and/or administrative criteria. Mixed and proportional hazards models were used to test individual-level associations adjusted for age, height, weight, sex, race/ethnicity, education, birth year, cohort, smoking status, pack-years of smoking, renal function, hypertension, diabetes, and medications.

MEASUREMENTS AND MAIN RESULTS: Among 10,961 participants with preserved lung function, mean age at albuminuria measurement was 60 years, 51% were never-smokers, median albuminuria was 5.6 mg/g, and mean FEV decline was 31.5 ml/yr. For each SD increase in log-transformed albuminuria, there was 2.81% greater FEV decline (95% confidence interval [CI], 0.86-4.76%; P = 0.0047), 11.02% greater FEV/FVC decline (95% CI, 4.43-17.62%; P = 0.0011), and 15% increased hazard of incident spirometry-defined moderate-to-severe COPD (95% CI, 2-31%, P = 0.0021). Each SD log-transformed albuminuria increased hazards of incident COPD-related hospitalization/mortality by 26% (95% CI, 18-34%, P < 0.0001) among 14,213 participants followed for events. Asthma events were not significantly associated. Associations persisted in participants without current smoking, diabetes, hypertension, or cardiovascular disease.

CONCLUSIONS: Albuminuria was associated with greater lung function decline, incident spirometry-defined COPD, and incident COPD-related events in a U.S. population-based sample.

%B Am J Respir Crit Care Med %V 199 %P 321-332 %8 2019 Feb 01 %G eng %N 3 %R 10.1164/rccm.201803-0402OC %0 Journal Article %J JAMA Cardiol %D 2019 %T Assessment of the Relationship Between Genetic Determinants of Thyroid Function and Atrial Fibrillation: A Mendelian Randomization Study. %A Ellervik, Christina %A Roselli, Carolina %A Christophersen, Ingrid E %A Alonso, Alvaro %A Pietzner, Maik %A Sitlani, Collen M %A Trompet, Stella %A Arking, Dan E %A Geelhoed, Bastiaan %A Guo, Xiuqing %A Kleber, Marcus E %A Lin, Henry J %A Lin, Honghuang %A Macfarlane, Peter %A Selvin, Elizabeth %A Shaffer, Christian %A Smith, Albert V %A Verweij, Niek %A Weiss, Stefan %A Cappola, Anne R %A Dörr, Marcus %A Gudnason, Vilmundur %A Heckbert, Susan %A Mooijaart, Simon %A März, Winfried %A Psaty, Bruce M %A Ridker, Paul M %A Roden, Dan %A Stott, David J %A Völzke, Henry %A Benjamin, Emelia J %A Delgado, Graciela %A Ellinor, Patrick %A Homuth, Georg %A Köttgen, Anna %A Jukema, Johan W %A Lubitz, Steven A %A Mora, Samia %A Rienstra, Michiel %A Rotter, Jerome I %A Shoemaker, M Benjamin %A Sotoodehnia, Nona %A Taylor, Kent D %A van der Harst, Pim %A Albert, Christine M %A Chasman, Daniel I %X

Importance: Increased free thyroxine (FT4) and decreased thyrotropin are associated with increased risk of atrial fibrillation (AF) in observational studies, but direct involvement is unclear.

Objective: To evaluate the potential direct involvement of thyroid traits on AF.

Design, Setting, and Participants: Study-level mendelian randomization (MR) included 11 studies, and summary-level MR included 55 114 AF cases and 482 295 referents, all of European ancestry.

Exposures: Genomewide significant variants were used as instruments for standardized FT4 and thyrotropin levels within the reference range, standardized triiodothyronine (FT3):FT4 ratio, hypothyroidism, standardized thyroid peroxidase antibody levels, and hyperthyroidism. Mendelian randomization used genetic risk scores in study-level analysis or individual single-nucleotide polymorphisms in 2-sample MR for the summary-level data.

Main Outcomes and Measures: Prevalent and incident AF.

Results: The study-level analysis included 7679 individuals with AF and 49 233 referents (mean age [standard error], 62 [3] years; 15 859 men [29.7%]). In study-level random-effects meta-analysis, the pooled hazard ratio of FT4 levels (nanograms per deciliter) for incident AF was 1.55 (95% CI, 1.09-2.20; P = .02; I2 = 76%) and the pooled odds ratio (OR) for prevalent AF was 2.80 (95% CI, 1.41-5.54; P = .003; I2 = 64%) in multivariable-adjusted analyses. The FT4 genetic risk score was associated with an increase in FT4 by 0.082 SD (standard error, 0.007; P < .001) but not with incident AF (risk ratio, 0.84; 95% CI, 0.62-1.14; P = .27) or prevalent AF (OR, 1.32; 95% CI, 0.64-2.73; P = .46). Similarly, in summary-level inverse-variance weighted random-effects MR, gene-based FT4 within the reference range was not associated with AF (OR, 1.01; 95% CI, 0.89-1.14; P = .88). However, gene-based increased FT3:FT4 ratio, increased thyrotropin within the reference range, and hypothyroidism were associated with AF with inverse-variance weighted random-effects OR of 1.33 (95% CI, 1.08-1.63; P = .006), 0.88 (95% CI, 0.84-0.92; P < .001), and 0.94 (95% CI, 0.90-0.99; P = .009), respectively, and robust to tests of horizontal pleiotropy. However, the subset of hypothyroidism single-nucleotide polymorphisms involved in autoimmunity and thyroid peroxidase antibodies levels were not associated with AF. Gene-based hyperthyroidism was associated with AF with MR-Egger OR of 1.31 (95% CI, 1.05-1.63; P = .02) with evidence of horizontal pleiotropy (P = .045).

Conclusions and Relevance: Genetically increased FT3:FT4 ratio and hyperthyroidism, but not FT4 within the reference range, were associated with increased AF, and increased thyrotropin within the reference range and hypothyroidism were associated with decreased AF, supporting a pathway involving the pituitary-thyroid-cardiac axis.

%B JAMA Cardiol %8 2019 Jan 23 %G eng %R 10.1001/jamacardio.2018.4635 %0 Journal Article %J Calcif Tissue Int %D 2019 %T The Association of Aromatic Amino Acids with Incident Hip Fracture, aBMD, and Body Composition from the Cardiovascular Health Study. %A Le, Brian %A Bůzková, Petra %A Robbins, John A %A Fink, Howard A %A Raiford, Mattie %A Isales, Carlos M %A Shikany, James M %A Coughlin, Steven S %A Carbone, Laura D %X

In 5187 persons from the Cardiovascular Health Study, there was no significant association of dietary intakes of aromatic amino acids (AAA) with areal BMD of the hip or body composition. However, those who had the lowest dietary intakes of AAA were at increased risk for incident hip fractures. Prior studies of the association of protein intake with osteoporosis are conflicting and have not directly examined the relationship of aromatic amino acids (AAA) with fractures, areal bone mineral density (aBMD), and body composition. We sought to determine the relationship of dietary intakes of AAA with osteoporosis parameters in elderly men and women. 5187 men and women aged ≥ 65 years from the Cardiovascular Health Study (CHS) with dietary intakes of AAA (tryptophan, phenylalanine, tyrosine) estimated by food frequency questionnaire (FFQ) were included. We examined the relationship between a one-time estimate of daily dietary AAA intake with risk of incident hip fractures over a median of 13.2 years of fracture follow-up. A subset (n = 1336) who had dual energy X-ray absorptiometry (DXA) performed were included in a cross-sectional analysis of the association of dietary AAA intake with aBMD of the total hip and measurements of body composition. In multivariable models adjusted for demographic and clinical variables, medication use, and diet, higher dietary AAA intake was not significantly associated with incident hip fractures. All hazard ratios (HR) were less than one (tryptophan, HR 0.14, 95% CI 0.01 to 1.89; phenylalanine, HR 0.60, 95% CI 0.23 to 1.55; tyrosine, HR 0.59, 95% CI 0.27 to 1.32), but confidence intervals were wide and included no difference. However, in post hoc analyses, the lowest quartile of intake for each AAA was associated with an increased risk for hip fracture compared to higher quartiles (p ≤ 0.047 for all). Dietary AAA intakes were not significantly associated with total hip aBMD or any measurements of body composition. Overall, there was no significant association of dietary AAA intake with hip fractures, aBMD of the hip, or body composition. However, there may be a subset of elderly individuals with low dietary intakes of AAA who are at increased for hip fractures.

%B Calcif Tissue Int %V 105 %P 161-172 %8 2019 Aug %G eng %N 2 %R 10.1007/s00223-019-00562-9 %0 Journal Article %J Bone %D 2019 %T {Association of bone mineral density with hemoglobin and change in hemoglobin among older men and women: The Cardiovascular Health Study %A Valderr?bano, R. J. %A Buzkova, P. %A Chang, P. Y. %A Zakai, N. A. %A Fink, H. A. %A Robbins, J. A. %A Lee, J. S. %A Wu, J. Y. %X Osteoblasts and their precursors support hematopoiesis in the bone marrow. We hypothesized that declines in Hgb levels are associated with bone mineral density (BMD).\ The Cardiovascular Health Study is a prospective longitudinal study that enrolled 5888 community-dwelling adults aged >65 years and measured hemoglobin twice, in 1989-90 and 1992-93, as well as BMD by dual-energy X-ray absorptiometry (DXA) in 1994-95. In a subset of 1513 men and women with a Hgb in 1992-93 and BMD, we used linear regression to estimate associations of Hgb (per standard deviation (SD)) with total hip (TH), lumbar spine (LS) and total body (TB) BMD, and used Poisson regression to estimate associations of anemia (in 1992-93; Hgb <13 g/dL in men; <12 g/dL in women) with "low BMD" defined as T-score less than -1 at the TH. In 1277 participants with Hgb measured on average 2.9 years apart and BMD, we used linear regression to estimate the associations of annualized change in Hgb with TH, LS and TB BMD. All models included age, sex, study-site, race, smoking, alcohol use, weight, height, steroid use, physical activity score, self-reported health, previous cardiovascular disease and prior anti-fracture medication use.\ No significant association was observed between Hgb, measured a mean 2.2 years prior to BMD, and BMD at the TH and LS in men (TH beta = -0.60 [x 10-2 g/cm2per 1.1 g/dL Hgb], 95% CI: -1.88 to 0.68; LS beta = -1.69, 95% CI: -3.83 to 0.45) or women (TH beta = -0.49 [x 10-2 g/cm2per 1.3 g/dL Hgb], 95% CI: -1.57 to 0.59; LS beta = -0.40, 95% CI: -2.57 to 1.76). Anemia was not observed to be significantly associated with low BMD in men (RR = 0.99, 95% CI: 0.72-1.40) nor women (RR = 0.98, 95% CI: 0.82-1.17). The mean change in Hgb was a loss of 0.06 g/dL/year (SD = 0.32). Change in Hgb was not observed to be significantly associated with BMD in men (TH beta = -0.55[x 10-2 g/cm2per 1 g/dL annualized Hgb change], 95% CI: -4.28 to 3.19; LS beta = 0.63, 95% CI: -5.38 to 6.65) or women (TH beta = 0.92, 95% CI: -1.96 to 3.79; LS beta = -1.77, 95% CI: -7.52 to 3.98). No significant association was observed between anemia and low bone density by T-score in men and women.\ These findings support neither the hypothesis that low Hgb prior to bone density or decreases in Hgb are associated with bone density in older community-dwelling adults nor the use of Hgb level as a case-finding tool to prompt BMD measurement. %B Bone %V 120 %P 321–326 %8 03 %G eng %0 Journal Article %J Am J Clin Nutr %D 2019 %T {Association of dietary folate and vitamin B-12 intake with genome-wide DNA methylation in blood: a large-scale epigenome-wide association analysis in 5841 individuals %A Mandaviya, P. R. %A Joehanes, R. %A Brody, J. %A Castillo-Fernandez, J. E. %A Dekkers, K. F. %A Do, A. N. %A Graff, M. %A H?nninen, I. K. %A Tanaka, T. %A de Jonge, E. A. L. %A Kiefte-de Jong, J. C. %A Absher, D. M. %A Aslibekyan, S. %A de Rijke, Y. B. %A Fornage, M. %A Hernandez, D. G. %A Hurme, M. A. %A Ikram, M. A. %A Jacques, P. F. %A Justice, A. E. %A Kiel, D. P. %A Lemaitre, R. N. %A Mendelson, M. M. %A Mikkil?, V. %A Moore, A. Z. %A Pallister, T. %A Raitakari, O. T. %A Schalkwijk, C. G. %A Sha, J. %A Slagboom, E. P. E. %A Smith, C. E. %A Stehouwer, C. D. A. %A Tsai, P. C. %A Uitterlinden, A. G. %A van der Kallen, C. J. H. %A van Heemst, D. %A Arnett, D. K. %A Bandinelli, S. %A Bell, J. T. %A Heijmans, B. T. %A Lehtim?ki, T. %A Levy, D. %A North, K. E. %A Sotoodehnia, N. %A van Greevenbroek, M. M. J. %A van Meurs, J. B. J. %A Heil, S. G. %X Folate and vitamin B-12 are essential micronutrients involved in the donation of methyl groups in cellular metabolism. However, associations between intake of these nutrients and genome-wide DNA methylation levels have not been studied comprehensively in humans.\ The aim of this study was to assess whether folate and/or vitamin B-12 intake are asssociated with genome-wide changes in DNA methylation in leukocytes.\ A large-scale epigenome-wide association study of folate and vitamin B-12 intake was performed on DNA from 5841 participants from 10 cohorts using Illumina 450k arrays. Folate and vitamin B-12 intakes were calculated from food-frequency questionnaires (FFQs). Continuous and categorical (low compared with high intake) linear regression mixed models were applied per cohort, controlling for confounders. A meta-analysis was performed to identify significant differentially methylated positions (DMPs) and regions (DMRs), and a pathway analysis was performed on the DMR annotated genes.\ The categorical model resulted in 6 DMPs, which are all negatively associated with folate intake, annotated to FAM64A, WRAP73, FRMD8, CUX1, and LCN8 genes, which have a role in cellular processes including centrosome localization, cell proliferation, and tumorigenesis. Regional analysis showed 74 folate-associated DMRs, of which 73 were negatively associated with folate intake. The most significant folate-associated DMR was a 400-base pair (bp) spanning region annotated to the LGALS3BP gene. In the categorical model, vitamin B-12 intake was associated with 29 DMRs annotated to 48 genes, of which the most significant was a 1100-bp spanning region annotated to the calcium-binding tyrosine phosphorylation-regulated gene (CABYR). Vitamin B-12 intake was not associated with DMPs.\ We identified novel epigenetic loci that are associated with folate and vitamin B-12 intake. Interestingly, we found a negative association between folate and DNA methylation. Replication of these methylation loci is necessary in future studies. %B Am J Clin Nutr %V 110 %P 437–450 %8 08 %G eng %0 Journal Article %J J Bone Miner Res %D 2019 %T Association of Dietary Niacin Intake With Incident Hip Fracture, BMD, and Body Composition: The Cardiovascular Health Study. %A Carbone, Laura D %A Bůzková, Petra %A Fink, Howard A %A Raiford, Mattie %A Le, Brian %A Isales, Carlos M %A Shikany, James M %A Coughlin, Steven S %A Robbins, John A %X

Interest in niacin has increased in the setting of reports suggesting that niacin plays a role in diseases of aging. No study to date has examined the association of dietary niacin intake with multiple skeletal health parameters including bone mineral density (BMD), hip fractures, and body composition, and none have included both African American and white men and women. Participants included 5187 men and women ≥65 years from the Cardiovascular Health Study (CHS). Mean daily dietary niacin intake was 32.6 mg, with quartiles 1 through 4 defined as 3.6 to 21.8 mg/day, 21.9 to 30.2 mg/day, 30.3 to 40.9 mg/day, and 41.0 to 102.4 mg/day, respectively. Risk of incident hip fracture per 10 mg increment of daily dietary niacin intake was estimated using proportional hazards models. During a median follow-up of 13 years, 725 participants had an incident hip fracture. In models adjusted for demographic and clinical characteristics and diet, dietary niacin intake was significantly associated with an increased risk of hip fractures (hazard ratio [HR] 1.12; 95% CI, 1.01 to 1.24) with spline models suggesting a U-shaped association. In post hoc analyses, both the lowest (HR 1.31; 95% CI, 1.04 to 1.66) and highest (HR 1.53; 95% CI, 1.20 to 1.95) quartiles of niacin intake were associated with an increased risk of incident hip fracture versus quartiles 2 and 3. There was a trend for a significant inverse association of dietary niacin intake with hip BMD (p = 0.06), but no significant association with total body BMD or any body composition measures. In this cohort of elderly, community-dwelling African American and white men and women, both high and low dietary niacin intakes were associated with a significantly increased risk of subsequent hip fracture, suggesting a possible U-shaped association. By comparison, dietary niacin may have an inverse linear association with hip BMD. © 2018 American Society for Bone and Mineral Research.

%B J Bone Miner Res %8 2019 Jan 19 %G eng %R 10.1002/jbmr.3639 %0 Journal Article %J Nephrology (Carlton) %D 2019 %T Association of serum and urinary uromodulin and their correlates in older adults-The Cardiovascular Health Study. %A Steubl, Dominik %A Bůzková, Petra %A Ix, Joachim H %A Devarajan, Prasad %A Bennett, Michael R %A Chaves, Paolo H M %A Shlipak, Michael G %A Bansal, Nisha %A Sarnak, Mark J %A Garimella, Pranav S %X

Uromodulin is released into serum (sUMOD) and urine (uUMOD) exclusively by renal tubular cells. Both sUMOD and uUMOD are correlated with estimated glomerular filtration rate (eGFR), and associated with mortality and cardiovascular disease (CVD). However, no study to our knowledge has measured both sUMOD and uUMOD in the same population, thus the relationship of sUMOD with uUMOD with one another, and their respective correlates have not been evaluated simultaneously. We evaluated the correlations of sUMOD, uUMOD with eGFR in a random sub-cohort (n = 933) of the Cardiovascular Health Study and their associations with demographic and laboratory parameters and CVD risk factors using multi-variable linear regression analysis. The mean age of the cohort was 78 years, 40% were male and 15% were Black. The mean sUMOD level was 127 ng/mL, uUMOD was 30 500 ng/mL and eGFR was 63 mL/min/1.73 m . Correlation between sUMOD and uUMOD, adjusted for eGFR was moderate (r = 0.27 [95% confidence interval = 0.21-0.33]). The correlation of eGFR with sUMOD (r = 0.44 [0.39-0.49]) was stronger than with uUMOD (r = 0.21 [0.15-0.27]). In multi-variable analysis adjusting sUMOD for uUMOD and vice versa, sUMOD was independently associated with eGFR (β = 1.3 [1.1-1.6]), log2 C-reactive protein (β = -4.2 [-6.8 to -1.6]) and male sex (β = -13.6 [-22.7 to -4.5]). In contrast, male sex was associated with higher uUMOD (β = 3700 [400-7000]), while diabetes (β = -6400 [-10 600 to -2100]) and hypertension (-4300 [-7500 to -1100]) were associated with lower uUMOD levels. We conclude that sUMOD is more strongly associated with eGFR compared with uUMOD. Correlates of sUMOD and uUMOD differ substantially, suggesting that apical and basolateral secretion may be differentially regulated.

%B Nephrology (Carlton) %8 2019 Dec 17 %G eng %R 10.1111/nep.13688 %0 Journal Article %J Nephrol Dial Transplant %D 2019 %T Association of serum uromodulin with mortality and cardiovascular disease in the elderly-the Cardiovascular Health Study. %A Steubl, Dominik %A Bůzková, Petra %A Garimella, Pranav S %A Ix, Joachim H %A Devarajan, Prasad %A Bennett, Michael R %A Chaves, Paulo H M %A Shlipak, Michael G %A Bansal, Nisha %A Sarnak, Mark J %X

BACKGROUND: Uromodulin (UMOD) is released by renal tubular cells into the serum (sUMOD) and urine. Lower urine UMOD has been linked to mortality and cardiovascular disease but much less is known about sUMOD. We evaluated the association of sUMOD with these outcomes in community-dwelling older adults.

METHODS: We measured sUMOD in a random subcohort of 933 participants enrolled in the Cardiovascular Health Study. The associations of sUMOD with all-cause mortality, incident heart failure (HF) and incident cardiovascular disease (CVD; myocardial infarction, stroke and mortality due to coronary disease or stroke) were evaluated using multivariable Cox regression, adjusting for study participants' demographics, estimated glomerular filtration rate (eGFR), albuminuria and CVD risk factors. Generalized additive models with splines were used to address the functional form of sUMOD with outcomes. Due to nonlinear associations of sUMOD with all outcomes, 2.5% of the values on either end of the sUMOD distribution were excluded from the analyses, limiting the range of sUMOD to 34.3-267.1 ng/mL.

RESULTS: The mean age was 78 ± 5 years, 40% were male, sUMOD level was 127 ± 64 ng/mL, eGFR was 63 mL/min/1.73 m2 and 42% had CKD defined as eGFR <60 mL/min/1.73 m2. Patients in the lower sUMOD quartiles had lower eGFR and higher albuminuria (P < 0.01, respectively). During a median follow-up of 9.9 years, 805 patients died, 283 developed HF and 274 developed CVD. In multivariable analysis, higher sUMOD was significantly associated with a lower hazard for mortality {hazard ratio [HR] 0.89 [95% confidence interval (CI) 0.80-0.99] per 1 standard deviation (SD) higher sUMOD}, CVD [HR 0.80 (95% CI 0.67-0.96)] and the composite endpoint [HR 0.88 (95% CI 0.78-0.99)]; the association with HF was not statistically significant [HR 0.84 (95% CI 0.70-1.01)].

CONCLUSION: Higher sUMOD is independently associated with a lower risk for mortality and CVD in older adults.

%B Nephrol Dial Transplant %8 2019 Mar 21 %G eng %R 10.1093/ndt/gfz008 %0 Journal Article %J Brain %D 2019 %T Association of variants in HTRA1 and NOTCH3 with MRI-defined extremes of cerebral small vessel disease in older subjects. %A Mishra, Aniket %A Chauhan, Ganesh %A Violleau, Marie-Helene %A Vojinovic, Dina %A Jian, Xueqiu %A Bis, Joshua C %A Li, Shuo %A Saba, Yasaman %A Grenier-Boley, Benjamin %A Yang, Qiong %A Bartz, Traci M %A Hofer, Edith %A Soumaré, Aïcha %A Peng, Fen %A Duperron, Marie-Gabrielle %A Foglio, Mario %A Mosley, Thomas H %A Schmidt, Reinhold %A Psaty, Bruce M %A Launer, Lenore J %A Boerwinkle, Eric %A Zhu, Yicheng %A Mazoyer, Bernard %A Lathrop, Mark %A Bellenguez, Céline %A van Duijn, Cornelia M %A Ikram, M Arfan %A Schmidt, Helena %A Longstreth, W T %A Fornage, Myriam %A Seshadri, Sudha %A Joutel, Anne %A Tzourio, Christophe %A Debette, Stephanie %X

We report a composite extreme phenotype design using distribution of white matter hyperintensities and brain infarcts in a population-based cohort of older persons for gene-mapping of cerebral small vessel disease. We demonstrate its application in the 3C-Dijon whole exome sequencing (WES) study (n = 1924, nWESextremes = 512), with both single variant and gene-based association tests. We used other population-based cohort studies participating in the CHARGE consortium for replication, using whole exome sequencing (nWES = 2,868, nWESextremes = 956) and genome-wide genotypes (nGW = 9924, nGWextremes = 3308). We restricted our study to candidate genes known to harbour mutations for Mendelian small vessel disease: NOTCH3, HTRA1, COL4A1, COL4A2 and TREX1. We identified significant associations of a common intronic variant in HTRA1, rs2293871 using single variant association testing (Pdiscovery = 8.21 × 10-5, Preplication = 5.25 × 10-3, Pcombined = 4.72 × 10-5) and of NOTCH3 using gene-based tests (Pdiscovery = 1.61 × 10-2, Preplication = 3.99 × 10-2, Pcombined = 5.31 × 10-3). Follow-up analysis identified significant association of rs2293871 with small vessel ischaemic stroke, and two blood expression quantitative trait loci of HTRA1 in linkage disequilibrium. Additionally, we identified two participants in the 3C-Dijon cohort (0.4%) carrying heterozygote genotypes at known pathogenic variants for familial small vessel disease within NOTCH3 and HTRA1. In conclusion, our proof-of-concept study provides strong evidence that using a novel composite MRI-derived phenotype for extremes of small vessel disease can facilitate the identification of genetic variants underlying small vessel disease, both common variants and those with rare and low frequency. The findings demonstrate shared mechanisms and a continuum between genes underlying Mendelian small vessel disease and those contributing to the common, multifactorial form of the disease.

%B Brain %8 2019 Mar 11 %G eng %R 10.1093/brain/awz024 %0 Journal Article %J Nat Commun %D 2019 %T Associations of autozygosity with a broad range of human phenotypes. %A Clark, David W %A Okada, Yukinori %A Moore, Kristjan H S %A Mason, Dan %A Pirastu, Nicola %A Gandin, Ilaria %A Mattsson, Hannele %A Barnes, Catriona L K %A Lin, Kuang %A Zhao, Jing Hua %A Deelen, Patrick %A Rohde, Rebecca %A Schurmann, Claudia %A Guo, Xiuqing %A Giulianini, Franco %A Zhang, Weihua %A Medina-Gómez, Carolina %A Karlsson, Robert %A Bao, Yanchun %A Bartz, Traci M %A Baumbach, Clemens %A Biino, Ginevra %A Bixley, Matthew J %A Brumat, Marco %A Chai, Jin-Fang %A Corre, Tanguy %A Cousminer, Diana L %A Dekker, Annelot M %A Eccles, David A %A van Eijk, Kristel R %A Fuchsberger, Christian %A Gao, He %A Germain, Marine %A Gordon, Scott D %A de Haan, Hugoline G %A Harris, Sarah E %A Hofer, Edith %A Huerta-Chagoya, Alicia %A Igartua, Catherine %A Jansen, Iris E %A Jia, Yucheng %A Kacprowski, Tim %A Karlsson, Torgny %A Kleber, Marcus E %A Li, Shengchao Alfred %A Li-Gao, Ruifang %A Mahajan, Anubha %A Matsuda, Koichi %A Meidtner, Karina %A Meng, Weihua %A Montasser, May E %A van der Most, Peter J %A Munz, Matthias %A Nutile, Teresa %A Palviainen, Teemu %A Prasad, Gauri %A Prasad, Rashmi B %A Priyanka, Tallapragada Divya Sri %A Rizzi, Federica %A Salvi, Erika %A Sapkota, Bishwa R %A Shriner, Daniel %A Skotte, Line %A Smart, Melissa C %A Smith, Albert Vernon %A van der Spek, Ashley %A Spracklen, Cassandra N %A Strawbridge, Rona J %A Tajuddin, Salman M %A Trompet, Stella %A Turman, Constance %A Verweij, Niek %A Viberti, Clara %A Wang, Lihua %A Warren, Helen R %A Wootton, Robyn E %A Yanek, Lisa R %A Yao, Jie %A Yousri, Noha A %A Zhao, Wei %A Adeyemo, Adebowale A %A Afaq, Saima %A Aguilar-Salinas, Carlos Alberto %A Akiyama, Masato %A Albert, Matthew L %A Allison, Matthew A %A Alver, Maris %A Aung, Tin %A Azizi, Fereidoun %A Bentley, Amy R %A Boeing, Heiner %A Boerwinkle, Eric %A Borja, Judith B %A de Borst, Gert J %A Bottinger, Erwin P %A Broer, Linda %A Campbell, Harry %A Chanock, Stephen %A Chee, Miao-Li %A Chen, Guanjie %A Chen, Yii-der I %A Chen, Zhengming %A Chiu, Yen-Feng %A Cocca, Massimiliano %A Collins, Francis S %A Concas, Maria Pina %A Corley, Janie %A Cugliari, Giovanni %A van Dam, Rob M %A Damulina, Anna %A Daneshpour, Maryam S %A Day, Felix R %A Delgado, Graciela E %A Dhana, Klodian %A Doney, Alexander S F %A Dörr, Marcus %A Doumatey, Ayo P %A Dzimiri, Nduna %A Ebenesersdóttir, S Sunna %A Elliott, Joshua %A Elliott, Paul %A Ewert, Ralf %A Felix, Janine F %A Fischer, Krista %A Freedman, Barry I %A Girotto, Giorgia %A Goel, Anuj %A Gögele, Martin %A Goodarzi, Mark O %A Graff, Mariaelisa %A Granot-Hershkovitz, Einat %A Grodstein, Francine %A Guarrera, Simonetta %A Gudbjartsson, Daniel F %A Guity, Kamran %A Gunnarsson, Bjarni %A Guo, Yu %A Hagenaars, Saskia P %A Haiman, Christopher A %A Halevy, Avner %A Harris, Tamara B %A Hedayati, Mehdi %A van Heel, David A %A Hirata, Makoto %A Höfer, Imo %A Hsiung, Chao Agnes %A Huang, Jinyan %A Hung, Yi-Jen %A Ikram, M Arfan %A Jagadeesan, Anuradha %A Jousilahti, Pekka %A Kamatani, Yoichiro %A Kanai, Masahiro %A Kerrison, Nicola D %A Kessler, Thorsten %A Khaw, Kay-Tee %A Khor, Chiea Chuen %A de Kleijn, Dominique P V %A Koh, Woon-Puay %A Kolcic, Ivana %A Kraft, Peter %A Krämer, Bernhard K %A Kutalik, Zoltán %A Kuusisto, Johanna %A Langenberg, Claudia %A Launer, Lenore J %A Lawlor, Deborah A %A Lee, I-Te %A Lee, Wen-Jane %A Lerch, Markus M %A Li, Liming %A Liu, Jianjun %A Loh, Marie %A London, Stephanie J %A Loomis, Stephanie %A Lu, Yingchang %A Luan, Jian'an %A Mägi, Reedik %A Manichaikul, Ani W %A Manunta, Paolo %A Másson, Gísli %A Matoba, Nana %A Mei, Xue W %A Meisinger, Christa %A Meitinger, Thomas %A Mezzavilla, Massimo %A Milani, Lili %A Millwood, Iona Y %A Momozawa, Yukihide %A Moore, Amy %A Morange, Pierre-Emmanuel %A Moreno-Macias, Hortensia %A Mori, Trevor A %A Morrison, Alanna C %A Muka, Taulant %A Murakami, Yoshinori %A Murray, Alison D %A de Mutsert, Renée %A Mychaleckyj, Josyf C %A Nalls, Mike A %A Nauck, Matthias %A Neville, Matt J %A Nolte, Ilja M %A Ong, Ken K %A Orozco, Lorena %A Padmanabhan, Sandosh %A Pálsson, Gunnar %A Pankow, James S %A Pattaro, Cristian %A Pattie, Alison %A Polasek, Ozren %A Poulter, Neil %A Pramstaller, Peter P %A Quintana-Murci, Lluis %A Räikkönen, Katri %A Ralhan, Sarju %A Rao, Dabeeru C %A van Rheenen, Wouter %A Rich, Stephen S %A Ridker, Paul M %A Rietveld, Cornelius A %A Robino, Antonietta %A van Rooij, Frank J A %A Ruggiero, Daniela %A Saba, Yasaman %A Sabanayagam, Charumathi %A Sabater-Lleal, Maria %A Sala, Cinzia Felicita %A Salomaa, Veikko %A Sandow, Kevin %A Schmidt, Helena %A Scott, Laura J %A Scott, William R %A Sedaghati-Khayat, Bahareh %A Sennblad, Bengt %A van Setten, Jessica %A Sever, Peter J %A Sheu, Wayne H-H %A Shi, Yuan %A Shrestha, Smeeta %A Shukla, Sharvari Rahul %A Sigurdsson, Jon K %A Sikka, Timo Tonis %A Singh, Jai Rup %A Smith, Blair H %A Stančáková, Alena %A Stanton, Alice %A Starr, John M %A Stefansdottir, Lilja %A Straker, Leon %A Sulem, Patrick %A Sveinbjornsson, Gardar %A Swertz, Morris A %A Taylor, Adele M %A Taylor, Kent D %A Terzikhan, Natalie %A Tham, Yih-Chung %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Tillander, Annika %A Tracy, Russell P %A Tusié-Luna, Teresa %A Tzoulaki, Ioanna %A Vaccargiu, Simona %A Vangipurapu, Jagadish %A Veldink, Jan H %A Vitart, Veronique %A Völker, Uwe %A Vuoksimaa, Eero %A Wakil, Salma M %A Waldenberger, Melanie %A Wander, Gurpreet S %A Wang, Ya Xing %A Wareham, Nicholas J %A Wild, Sarah %A Yajnik, Chittaranjan S %A Yuan, Jian-Min %A Zeng, Lingyao %A Zhang, Liang %A Zhou, Jie %A Amin, Najaf %A Asselbergs, Folkert W %A Bakker, Stephan J L %A Becker, Diane M %A Lehne, Benjamin %A Bennett, David A %A van den Berg, Leonard H %A Berndt, Sonja I %A Bharadwaj, Dwaipayan %A Bielak, Lawrence F %A Bochud, Murielle %A Boehnke, Mike %A Bouchard, Claude %A Bradfield, Jonathan P %A Brody, Jennifer A %A Campbell, Archie %A Carmi, Shai %A Caulfield, Mark J %A Cesarini, David %A Chambers, John C %A Chandak, Giriraj Ratan %A Cheng, Ching-Yu %A Ciullo, Marina %A Cornelis, Marilyn %A Cusi, Daniele %A Smith, George Davey %A Deary, Ian J %A Dorajoo, Rajkumar %A van Duijn, Cornelia M %A Ellinghaus, David %A Erdmann, Jeanette %A Eriksson, Johan G %A Evangelou, Evangelos %A Evans, Michele K %A Faul, Jessica D %A Feenstra, Bjarke %A Feitosa, Mary %A Foisy, Sylvain %A Franke, Andre %A Friedlander, Yechiel %A Gasparini, Paolo %A Gieger, Christian %A Gonzalez, Clicerio %A Goyette, Philippe %A Grant, Struan F A %A Griffiths, Lyn R %A Groop, Leif %A Gudnason, Vilmundur %A Gyllensten, Ulf %A Hakonarson, Hakon %A Hamsten, Anders %A van der Harst, Pim %A Heng, Chew-Kiat %A Hicks, Andrew A %A Hochner, Hagit %A Huikuri, Heikki %A Hunt, Steven C %A Jaddoe, Vincent W V %A De Jager, Philip L %A Johannesson, Magnus %A Johansson, Asa %A Jonas, Jost B %A Jukema, J Wouter %A Junttila, Juhani %A Kaprio, Jaakko %A Kardia, Sharon L R %A Karpe, Fredrik %A Kumari, Meena %A Laakso, Markku %A van der Laan, Sander W %A Lahti, Jari %A Laudes, Matthias %A Lea, Rodney A %A Lieb, Wolfgang %A Lumley, Thomas %A Martin, Nicholas G %A März, Winfried %A Matullo, Giuseppe %A McCarthy, Mark I %A Medland, Sarah E %A Merriman, Tony R %A Metspalu, Andres %A Meyer, Brian F %A Mohlke, Karen L %A Montgomery, Grant W %A Mook-Kanamori, Dennis %A Munroe, Patricia B %A North, Kari E %A Nyholt, Dale R %A O'Connell, Jeffery R %A Ober, Carole %A Oldehinkel, Albertine J %A Palmas, Walter %A Palmer, Colin %A Pasterkamp, Gerard G %A Patin, Etienne %A Pennell, Craig E %A Perusse, Louis %A Peyser, Patricia A %A Pirastu, Mario %A Polderman, Tinca J C %A Porteous, David J %A Posthuma, Danielle %A Psaty, Bruce M %A Rioux, John D %A Rivadeneira, Fernando %A Rotimi, Charles %A Rotter, Jerome I %A Rudan, Igor %A den Ruijter, Hester M %A Sanghera, Dharambir K %A Sattar, Naveed %A Schmidt, Reinhold %A Schulze, Matthias B %A Schunkert, Heribert %A Scott, Robert A %A Shuldiner, Alan R %A Sim, Xueling %A Small, Neil %A Smith, Jennifer A %A Sotoodehnia, Nona %A Tai, E-Shyong %A Teumer, Alexander %A Timpson, Nicholas J %A Toniolo, Daniela %A Trégouët, David-Alexandre %A Tuomi, Tiinamaija %A Vollenweider, Peter %A Wang, Carol A %A Weir, David R %A Whitfield, John B %A Wijmenga, Cisca %A Wong, Tien-Yin %A Wright, John %A Yang, Jingyun %A Yu, Lei %A Zemel, Babette S %A Zonderman, Alan B %A Perola, Markus %A Magnusson, Patrik K E %A Uitterlinden, André G %A Kooner, Jaspal S %A Chasman, Daniel I %A Loos, Ruth J F %A Franceschini, Nora %A Franke, Lude %A Haley, Chris S %A Hayward, Caroline %A Walters, Robin G %A Perry, John R B %A Esko, Tõnu %A Helgason, Agnar %A Stefansson, Kari %A Joshi, Peter K %A Kubo, Michiaki %A Wilson, James F %X

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F) for >1.4 million individuals, we show that F is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F are confirmed within full-sibling pairs, where the variation in F is independent of all environmental confounding.

%B Nat Commun %V 10 %P 4957 %8 2019 Oct 31 %G eng %N 1 %R 10.1038/s41467-019-12283-6 %0 Journal Article %J Am. J. Clin. Nutr. %D 2019 %T {Associations of circulating very-long-chain saturated fatty acids and incident type 2 diabetes: a pooled analysis of prospective cohort studies %A Fretts, A. M. %A Imamura, F. %A Marklund, M. %A Micha, R. %A Wu, J. H. Y. %A Murphy, R. A. %A Chien, K. L. %A McKnight, B. %A Tintle, N. %A Forouhi, N. G. %A Qureshi, W. T. %A Virtanen, J. K. %A Wong, K. %A Wood, A. C. %A Lankinen, M. %A Rajaobelina, K. %A Harris, T. B. %A Djouss?, L. %A Harris, B. %A Wareham, N. J. %A Steffen, L. M. %A Laakso, M. %A Veenstra, J. %A Samieri, C. %A Brouwer, I. A. %A Yu, C. I. %A Koulman, A. %A Steffen, B. T. %A Helmer, C. %A Sotoodehnia, N. %A Siscovick, D. %A Gudnason, V. %A Wagenknecht, L. %A Voutilainen, S. %A Tsai, M. Y. %A Uusitupa, M. %A Kalsbeek, A. %A Berr, C. %A Mozaffarian, D. %A Lemaitre, R. N. %X Saturated fatty acids (SFAs) of different chain lengths have unique metabolic and biological effects, and a small number of recent studies suggest that higher circulating concentrations of the very-long-chain SFAs (VLSFAs) arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0) are associated with a lower risk of diabetes. Confirmation of these findings in a large and diverse population is needed.\ We investigated the associations of circulating VLSFAs 20:0, 22:0, and 24:0 with incident type 2 diabetes in prospective studies.\ Twelve studies that are part of the Fatty Acids and Outcomes Research Consortium participated in the analysis. Using Cox or logistic regression within studies and an inverse-variance-weighted meta-analysis across studies, we examined the associations of VLSFAs 20:0, 22:0, and 24:0 with incident diabetes among 51,431 participants.\ There were 14,276 cases of incident diabetes across participating studies. Higher circulating concentrations of 20:0, 22:0, and 24:0 were each associated with a lower risk of incident diabetes. Pooling across cohorts, the RR (95% CI) for incident diabetes comparing the 90th percentile to the 10th percentile was 0.78 (0.70, 0.87) for 20:0, 0.84 (0.77, 0.91) for 22:0, and 0.75 (0.69, 0.83) for 24:0 after adjustment for demographic, lifestyle, adiposity, and other health factors. Results were fully attenuated in exploratory models that adjusted for circulating 16:0 and triglycerides.\ Results from this pooled analysis indicate that higher concentrations of circulating VLSFAs 20:0, 22:0, and 24:0 are each associated with a lower risk of diabetes. %B Am. J. Clin. Nutr. %V 109 %P 1216–1223 %8 04 %G eng %0 Journal Article %J PLoS Genet %D 2019 %T Associations of variants In the hexokinase 1 and interleukin 18 receptor regions with oxyhemoglobin saturation during sleep. %A Cade, Brian E %A Chen, Han %A Stilp, Adrienne M %A Louie, Tin %A Ancoli-Israel, Sonia %A Arens, Raanan %A Barfield, Richard %A Below, Jennifer E %A Cai, Jianwen %A Conomos, Matthew P %A Evans, Daniel S %A Frazier-Wood, Alexis C %A Gharib, Sina A %A Gleason, Kevin J %A Gottlieb, Daniel J %A Hillman, David R %A Johnson, W Craig %A Lederer, David J %A Lee, Jiwon %A Loredo, Jose S %A Mei, Hao %A Mukherjee, Sutapa %A Patel, Sanjay R %A Post, Wendy S %A Purcell, Shaun M %A Ramos, Alberto R %A Reid, Kathryn J %A Rice, Ken %A Shah, Neomi A %A Sofer, Tamar %A Taylor, Kent D %A Thornton, Timothy A %A Wang, Heming %A Yaffe, Kristine %A Zee, Phyllis C %A Hanis, Craig L %A Palmer, Lyle J %A Rotter, Jerome I %A Stone, Katie L %A Tranah, Gregory J %A Wilson, James G %A Sunyaev, Shamil R %A Laurie, Cathy C %A Zhu, Xiaofeng %A Saxena, Richa %A Lin, Xihong %A Redline, Susan %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Cell Adhesion Molecules, Neuronal %K Computational Biology %K Extracellular Matrix Proteins %K Female %K Gene Regulatory Networks %K Genetic Variation %K Genome-Wide Association Study %K Hexokinase %K Humans %K Hypoxia %K Interleukin-18 Receptor alpha Subunit %K Male %K Middle Aged %K Nerve Tissue Proteins %K NLR Family, Pyrin Domain-Containing 3 Protein %K Oxygen %K Oxyhemoglobins %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Serine Endopeptidases %K Sleep %K Sleep Apnea Syndromes %K Young Adult %X

Sleep disordered breathing (SDB)-related overnight hypoxemia is associated with cardiometabolic disease and other comorbidities. Understanding the genetic bases for variations in nocturnal hypoxemia may help understand mechanisms influencing oxygenation and SDB-related mortality. We conducted genome-wide association tests across 10 cohorts and 4 populations to identify genetic variants associated with three correlated measures of overnight oxyhemoglobin saturation: average and minimum oxyhemoglobin saturation during sleep and the percent of sleep with oxyhemoglobin saturation under 90%. The discovery sample consisted of 8,326 individuals. Variants with p < 1 × 10(-6) were analyzed in a replication group of 14,410 individuals. We identified 3 significantly associated regions, including 2 regions in multi-ethnic analyses (2q12, 10q22). SNPs in the 2q12 region associated with minimum SpO2 (rs78136548 p = 2.70 × 10(-10)). SNPs at 10q22 were associated with all three traits including average SpO2 (rs72805692 p = 4.58 × 10(-8)). SNPs in both regions were associated in over 20,000 individuals and are supported by prior associations or functional evidence. Four additional significant regions were detected in secondary sex-stratified and combined discovery and replication analyses, including a region overlapping Reelin, a known marker of respiratory complex neurons.These are the first genome-wide significant findings reported for oxyhemoglobin saturation during sleep, a phenotype of high clinical interest. Our replicated associations with HK1 and IL18R1 suggest that variants in inflammatory pathways, such as the biologically-plausible NLRP3 inflammasome, may contribute to nocturnal hypoxemia.

%B PLoS Genet %V 15 %P e1007739 %8 2019 04 %G eng %N 4 %R 10.1371/journal.pgen.1007739 %0 Journal Article %J Circulation %D 2019 %T Biomarkers of Dietary Omega-6 Fatty Acids and Incident Cardiovascular Disease and Mortality. %A Marklund, Matti %A Wu, Jason H Y %A Imamura, Fumiaki %A Del Gobbo, Liana C %A Fretts, Amanda %A de Goede, Janette %A Shi, Peilin %A Tintle, Nathan %A Wennberg, Maria %A Aslibekyan, Stella %A Chen, Tzu-An %A de Oliveira Otto, Marcia C %A Hirakawa, Yoichiro %A Eriksen, Helle Højmark %A Kröger, Janine %A Laguzzi, Federica %A Lankinen, Maria %A Murphy, Rachel A %A Prem, Kiesha %A Samieri, Cecilia %A Virtanen, Jyrki %A Wood, Alexis C %A Wong, Kerry %A Yang, Wei-Sin %A Zhou, Xia %A Baylin, Ana %A Boer, Jolanda M A %A Brouwer, Ingeborg A %A Campos, Hannia %A Chaves, Paulo H M %A Chien, Kuo-Liong %A de Faire, Ulf %A Djoussé, Luc %A Eiriksdottir, Gudny %A El-Abbadi, Naglaa %A Forouhi, Nita G %A Michael Gaziano, J %A Geleijnse, Johanna M %A Gigante, Bruna %A Giles, Graham %A Guallar, Eliseo %A Gudnason, Vilmundur %A Harris, Tamara %A Harris, William S %A Helmer, Catherine %A Hellenius, Mai-Lis %A Hodge, Allison %A Hu, Frank B %A Jacques, Paul F %A Jansson, Jan-Håkan %A Kalsbeek, Anya %A Khaw, Kay-Tee %A Koh, Woon-Puay %A Laakso, Markku %A Leander, Karin %A Lin, Hung-Ju %A Lind, Lars %A Luben, Robert %A Luo, Juhua %A McKnight, Barbara %A Mursu, Jaakko %A Ninomiya, Toshiharu %A Overvad, Kim %A Psaty, Bruce M %A Rimm, Eric %A Schulze, Matthias B %A Siscovick, David %A Skjelbo Nielsen, Michael %A Smith, Albert V %A Steffen, Brian T %A Steffen, Lyn %A Sun, Qi %A Sundström, Johan %A Tsai, Michael Y %A Tunstall-Pedoe, Hugh %A Uusitupa, Matti I J %A van Dam, Rob M %A Veenstra, Jenna %A Monique Verschuren, W M %A Wareham, Nick %A Willett, Walter %A Woodward, Mark %A Yuan, Jian-Min %A Micha, Renata %A Lemaitre, Rozenn N %A Mozaffarian, Dariush %A Riserus, Ulf %X

BACKGROUND: Global dietary recommendations for and cardiovascular effects of linoleic acid, the major dietary omega-6 fatty acid, and its major metabolite, arachidonic acid, remain controversial. To address this uncertainty and inform international recommendations, we evaluated how in vivo circulating and tissue levels of linoleic acid (LA) and arachidonic acid (AA) relate to incident cardiovascular disease (CVD) across multiple international studies.

METHODS: We performed harmonized, de novo, individual-level analyses in a global consortium of 30 prospective observational studies from 13 countries. Multivariable-adjusted associations of circulating and adipose tissue LA and AA biomarkers with incident total CVD and subtypes (coronary heart disease, ischemic stroke, cardiovascular mortality) were investigated according to a prespecified analytic plan. Levels of LA and AA, measured as the percentage of total fatty acids, were evaluated linearly according to their interquintile range (ie, the range between the midpoint of the first and fifth quintiles), and categorically by quintiles. Study-specific results were pooled using inverse-variance-weighted meta-analysis. Heterogeneity was explored by age, sex, race, diabetes mellitus, statin use, aspirin use, omega-3 levels, and fatty acid desaturase 1 genotype (when available).

RESULTS: In 30 prospective studies with medians of follow-up ranging 2.5 to 31.9 years, 15 198 incident cardiovascular events occurred among 68 659 participants. Higher levels of LA were significantly associated with lower risks of total CVD, cardiovascular mortality, and ischemic stroke, with hazard ratios per interquintile range of 0.93 (95% CI, 0.88-0.99), 0.78 (0.70-0.85), and 0.88 (0.79-0.98), respectively, and nonsignificantly with lower coronary heart disease risk (0.94; 0.88-1.00). Relationships were similar for LA evaluated across quintiles. AA levels were not associated with higher risk of cardiovascular outcomes; in a comparison of extreme quintiles, higher levels were associated with lower risk of total CVD (0.92; 0.86-0.99). No consistent heterogeneity by population subgroups was identified in the observed relationships.

CONCLUSIONS: In pooled global analyses, higher in vivo circulating and tissue levels of LA and possibly AA were associated with lower risk of major cardiovascular events. These results support a favorable role for LA in CVD prevention.

%B Circulation %V 139 %P 2422-2436 %8 2019 May 21 %G eng %N 21 %R 10.1161/CIRCULATIONAHA.118.038908 %0 Journal Article %J Circulation %D 2019 %T Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease. %A Agha, Golareh %A Mendelson, Michael M %A Ward-Caviness, Cavin K %A Joehanes, Roby %A Huan, Tianxiao %A Gondalia, Rahul %A Salfati, Elias %A Brody, Jennifer A %A Fiorito, Giovanni %A Bressler, Jan %A Chen, Brian H %A Ligthart, Symen %A Guarrera, Simonetta %A Colicino, Elena %A Just, Allan C %A Wahl, Simone %A Gieger, Christian %A Vandiver, Amy R %A Tanaka, Toshiko %A Hernandez, Dena G %A Pilling, Luke C %A Singleton, Andrew B %A Sacerdote, Carlotta %A Krogh, Vittorio %A Panico, Salvatore %A Tumino, Rosario %A Li, Yun %A Zhang, Guosheng %A Stewart, James D %A Floyd, James S %A Wiggins, Kerri L %A Rotter, Jerome I %A Multhaup, Michael %A Bakulski, Kelly %A Horvath, Steven %A Tsao, Philip S %A Absher, Devin M %A Vokonas, Pantel %A Hirschhorn, Joel %A Fallin, M Daniele %A Liu, Chunyu %A Bandinelli, Stefania %A Boerwinkle, Eric %A Dehghan, Abbas %A Schwartz, Joel D %A Psaty, Bruce M %A Feinberg, Andrew P %A Hou, Lifang %A Ferrucci, Luigi %A Sotoodehnia, Nona %A Matullo, Giuseppe %A Peters, Annette %A Fornage, Myriam %A Assimes, Themistocles L %A Whitsel, Eric A %A Levy, Daniel %A Baccarelli, Andrea A %K Adult %K Aged %K Cohort Studies %K Coronary Disease %K CpG Islands %K DNA Methylation %K Europe %K Female %K Genome-Wide Association Study %K Humans %K Incidence %K Leukocytes %K Male %K Middle Aged %K Myocardial Infarction %K Population Groups %K Prognosis %K Prospective Studies %K Risk %K United States %X

BACKGROUND: DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts.

METHODS: Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts.

RESULTS: Among 11 461 individuals (mean age 64 years, 67% women, 35% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate<0.05). These CpGs map to genes with key roles in calcium regulation (ATP2B2, CASR, GUCA1B, HPCAL1), and genes identified in genome- and epigenome-wide studies of serum calcium (CASR), serum calcium-related risk of CHD (CASR), coronary artery calcified plaque (PTPRN2), and kidney function (CDH23, HPCAL1), among others. Mendelian randomization analyses supported a causal effect of DNA methylation on incident CHD; these CpGs map to active regulatory regions proximal to long non-coding RNA transcripts.

CONCLUSION: Methylation of blood-derived DNA is associated with risk of future CHD across diverse populations and may serve as an informative tool for gaining further insight on the development of CHD.

%B Circulation %V 140 %P 645-657 %8 2019 08 20 %G eng %N 8 %R 10.1161/CIRCULATIONAHA.118.039357 %0 Journal Article %J Nat Genet %D 2019 %T A catalog of genetic loci associated with kidney function from analyses of a million individuals. %A Wuttke, Matthias %A Li, Yong %A Li, Man %A Sieber, Karsten B %A Feitosa, Mary F %A Gorski, Mathias %A Tin, Adrienne %A Wang, Lihua %A Chu, Audrey Y %A Hoppmann, Anselm %A Kirsten, Holger %A Giri, Ayush %A Chai, Jin-Fang %A Sveinbjornsson, Gardar %A Tayo, Bamidele O %A Nutile, Teresa %A Fuchsberger, Christian %A Marten, Jonathan %A Cocca, Massimiliano %A Ghasemi, Sahar %A Xu, Yizhe %A Horn, Katrin %A Noce, Damia %A van der Most, Peter J %A Sedaghat, Sanaz %A Yu, Zhi %A Akiyama, Masato %A Afaq, Saima %A Ahluwalia, Tarunveer S %A Almgren, Peter %A Amin, Najaf %A Arnlöv, Johan %A Bakker, Stephan J L %A Bansal, Nisha %A Baptista, Daniela %A Bergmann, Sven %A Biggs, Mary L %A Biino, Ginevra %A Boehnke, Michael %A Boerwinkle, Eric %A Boissel, Mathilde %A Bottinger, Erwin P %A Boutin, Thibaud S %A Brenner, Hermann %A Brumat, Marco %A Burkhardt, Ralph %A Butterworth, Adam S %A Campana, Eric %A Campbell, Archie %A Campbell, Harry %A Canouil, Mickaël %A Carroll, Robert J %A Catamo, Eulalia %A Chambers, John C %A Chee, Miao-Ling %A Chee, Miao-Li %A Chen, Xu %A Cheng, Ching-Yu %A Cheng, Yurong %A Christensen, Kaare %A Cifkova, Renata %A Ciullo, Marina %A Concas, Maria Pina %A Cook, James P %A Coresh, Josef %A Corre, Tanguy %A Sala, Cinzia Felicita %A Cusi, Daniele %A Danesh, John %A Daw, E Warwick %A de Borst, Martin H %A De Grandi, Alessandro %A de Mutsert, Renée %A de Vries, Aiko P J %A Degenhardt, Frauke %A Delgado, Graciela %A Demirkan, Ayse %A Di Angelantonio, Emanuele %A Dittrich, Katalin %A Divers, Jasmin %A Dorajoo, Rajkumar %A Eckardt, Kai-Uwe %A Ehret, Georg %A Elliott, Paul %A Endlich, Karlhans %A Evans, Michele K %A Felix, Janine F %A Foo, Valencia Hui Xian %A Franco, Oscar H %A Franke, Andre %A Freedman, Barry I %A Freitag-Wolf, Sandra %A Friedlander, Yechiel %A Froguel, Philippe %A Gansevoort, Ron T %A Gao, He %A Gasparini, Paolo %A Gaziano, J Michael %A Giedraitis, Vilmantas %A Gieger, Christian %A Girotto, Giorgia %A Giulianini, Franco %A Gögele, Martin %A Gordon, Scott D %A Gudbjartsson, Daniel F %A Gudnason, Vilmundur %A Haller, Toomas %A Hamet, Pavel %A Harris, Tamara B %A Hartman, Catharina A %A Hayward, Caroline %A Hellwege, Jacklyn N %A Heng, Chew-Kiat %A Hicks, Andrew A %A Hofer, Edith %A Huang, Wei %A Hutri-Kähönen, Nina %A Hwang, Shih-Jen %A Ikram, M Arfan %A Indridason, Olafur S %A Ingelsson, Erik %A Ising, Marcus %A Jaddoe, Vincent W V %A Jakobsdottir, Johanna %A Jonas, Jost B %A Joshi, Peter K %A Josyula, Navya Shilpa %A Jung, Bettina %A Kähönen, Mika %A Kamatani, Yoichiro %A Kammerer, Candace M %A Kanai, Masahiro %A Kastarinen, Mika %A Kerr, Shona M %A Khor, Chiea-Chuen %A Kiess, Wieland %A Kleber, Marcus E %A Koenig, Wolfgang %A Kooner, Jaspal S %A Körner, Antje %A Kovacs, Peter %A Kraja, Aldi T %A Krajcoviechova, Alena %A Kramer, Holly %A Krämer, Bernhard K %A Kronenberg, Florian %A Kubo, Michiaki %A Kuhnel, Brigitte %A Kuokkanen, Mikko %A Kuusisto, Johanna %A La Bianca, Martina %A Laakso, Markku %A Lange, Leslie A %A Langefeld, Carl D %A Lee, Jeannette Jen-Mai %A Lehne, Benjamin %A Lehtimäki, Terho %A Lieb, Wolfgang %A Lim, Su-Chi %A Lind, Lars %A Lindgren, Cecilia M %A Liu, Jun %A Liu, Jianjun %A Loeffler, Markus %A Loos, Ruth J F %A Lucae, Susanne %A Lukas, Mary Ann %A Lyytikäinen, Leo-Pekka %A Mägi, Reedik %A Magnusson, Patrik K E %A Mahajan, Anubha %A Martin, Nicholas G %A Martins, Jade %A März, Winfried %A Mascalzoni, Deborah %A Matsuda, Koichi %A Meisinger, Christa %A Meitinger, Thomas %A Melander, Olle %A Metspalu, Andres %A Mikaelsdottir, Evgenia K %A Milaneschi, Yuri %A Miliku, Kozeta %A Mishra, Pashupati P %A Mohlke, Karen L %A Mononen, Nina %A Montgomery, Grant W %A Mook-Kanamori, Dennis O %A Mychaleckyj, Josyf C %A Nadkarni, Girish N %A Nalls, Mike A %A Nauck, Matthias %A Nikus, Kjell %A Ning, Boting %A Nolte, Ilja M %A Noordam, Raymond %A O'Connell, Jeffrey %A O'Donoghue, Michelle L %A Olafsson, Isleifur %A Oldehinkel, Albertine J %A Orho-Melander, Marju %A Ouwehand, Willem H %A Padmanabhan, Sandosh %A Palmer, Nicholette D %A Palsson, Runolfur %A Penninx, Brenda W J H %A Perls, Thomas %A Perola, Markus %A Pirastu, Mario %A Pirastu, Nicola %A Pistis, Giorgio %A Podgornaia, Anna I %A Polasek, Ozren %A Ponte, Belen %A Porteous, David J %A Poulain, Tanja %A Pramstaller, Peter P %A Preuss, Michael H %A Prins, Bram P %A Province, Michael A %A Rabelink, Ton J %A Raffield, Laura M %A Raitakari, Olli T %A Reilly, Dermot F %A Rettig, Rainer %A Rheinberger, Myriam %A Rice, Kenneth M %A Ridker, Paul M %A Rivadeneira, Fernando %A Rizzi, Federica %A Roberts, David J %A Robino, Antonietta %A Rossing, Peter %A Rudan, Igor %A Rueedi, Rico %A Ruggiero, Daniela %A Ryan, Kathleen A %A Saba, Yasaman %A Sabanayagam, Charumathi %A Salomaa, Veikko %A Salvi, Erika %A Saum, Kai-Uwe %A Schmidt, Helena %A Schmidt, Reinhold %A Schöttker, Ben %A Schulz, Christina-Alexandra %A Schupf, Nicole %A Shaffer, Christian M %A Shi, Yuan %A Smith, Albert V %A Smith, Blair H %A Soranzo, Nicole %A Spracklen, Cassandra N %A Strauch, Konstantin %A Stringham, Heather M %A Stumvoll, Michael %A Svensson, Per O %A Szymczak, Silke %A Tai, E-Shyong %A Tajuddin, Salman M %A Tan, Nicholas Y Q %A Taylor, Kent D %A Teren, Andrej %A Tham, Yih-Chung %A Thiery, Joachim %A Thio, Chris H L %A Thomsen, Hauke %A Thorleifsson, Gudmar %A Toniolo, Daniela %A Tönjes, Anke %A Tremblay, Johanne %A Tzoulaki, Ioanna %A Uitterlinden, André G %A Vaccargiu, Simona %A van Dam, Rob M %A van der Harst, Pim %A van Duijn, Cornelia M %A Velez Edward, Digna R %A Verweij, Niek %A Vogelezang, Suzanne %A Völker, Uwe %A Vollenweider, Peter %A Waeber, Gérard %A Waldenberger, Melanie %A Wallentin, Lars %A Wang, Ya Xing %A Wang, Chaolong %A Waterworth, Dawn M %A Bin Wei, Wen %A White, Harvey %A Whitfield, John B %A Wild, Sarah H %A Wilson, James F %A Wojczynski, Mary K %A Wong, Charlene %A Wong, Tien-Yin %A Xu, Liang %A Yang, Qiong %A Yasuda, Masayuki %A Yerges-Armstrong, Laura M %A Zhang, Weihua %A Zonderman, Alan B %A Rotter, Jerome I %A Bochud, Murielle %A Psaty, Bruce M %A Vitart, Veronique %A Wilson, James G %A Dehghan, Abbas %A Parsa, Afshin %A Chasman, Daniel I %A Ho, Kevin %A Morris, Andrew P %A Devuyst, Olivier %A Akilesh, Shreeram %A Pendergrass, Sarah A %A Sim, Xueling %A Böger, Carsten A %A Okada, Yukinori %A Edwards, Todd L %A Snieder, Harold %A Stefansson, Kari %A Hung, Adriana M %A Heid, Iris M %A Scholz, Markus %A Teumer, Alexander %A Köttgen, Anna %A Pattaro, Cristian %K Chromosome Mapping %K European Continental Ancestry Group %K Genetic Association Studies %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Glomerular Filtration Rate %K Humans %K Inheritance Patterns %K Kidney Function Tests %K Phenotype %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Quantitative Trait, Heritable %K Renal Insufficiency, Chronic %K Uromodulin %X

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

%B Nat Genet %V 51 %P 957-972 %8 2019 06 %G eng %N 6 %R 10.1038/s41588-019-0407-x %0 Journal Article %J Clin Chem %D 2019 %T Dairy Intake and Body Composition and Cardiometabolic Traits among Adults: Mendelian Randomization Analysis of 182041 Individuals from 18 Studies. %X

BACKGROUND: Associations between dairy intake and body composition and cardiometabolic traits have been inconsistently observed in epidemiological studies, and the causal relationship remains ill-defined.

METHODS: We performed Mendelian randomization analysis using an established genetic variant located upstream of the lactase gene (-13910 C/T, rs4988235) associated with dairy intake as an instrumental variable (IV). The causal effects of dairy intake on body composition and cardiometabolic traits (lipids, glycemic traits, and inflammatory factors) were quantified by IV estimators among 182041 participants from 18 studies.

RESULTS: Each 1 serving/day higher dairy intake was associated with higher lean mass [β (SE) = 0.117 kg (0.035); = 0.001], higher hemoglobin A [0.009% (0.002); < 0.001], lower LDL [-0.014 mmol/L (0.006); = 0.013], total cholesterol (TC) [-0.012 mmol/L (0.005); = 0.023], and non-HDL [-0.012 mmol/L (0.005); = 0.028]. The -13910 C/T CT + TT genotype was associated with 0.214 more dairy servings/day (SE = 0.047; < 0.001), 0.284 cm higher waist circumference (SE = 0.118; = 0.017), 0.112 kg higher lean mass (SE = 0.027; = 3.8 × 10), 0.032 mmol/L lower LDL (SE = 0.009; = 0.001), and 0.032 mmol/L lower TC (SE = 0.010; = 0.001). Genetically higher dairy intake was associated with increased lean mass [0.523 kg per serving/day (0.170); = 0.002] after correction for multiple testing (0.05/18). However, we find that genetically higher dairy intake was not associated with lipids and glycemic traits.

CONCLUSIONS: The present study provides evidence to support a potential causal effect of higher dairy intake on increased lean mass among adults. Our findings suggest that the observational associations of dairy intake with lipids and glycemic traits may be the result of confounding.

%B Clin Chem %V 65 %P 751-760 %8 2019 Jun %G eng %N 6 %R 10.1373/clinchem.2018.300335 %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2019 %T Discrepancy in Frailty Identification: Move beyond Predictive Validity. %A Xue, Qian-Li %A Tian, Jing %A Walston, Jeremy D %A Chaves, Paulo H M %A Newman, Anne B %A Bandeen-Roche, Karen %X

BACKGROUND: To evaluate the discordance in frailty classification between the frailty index (FI) and the physical frailty phenotype (PFP) and identify factors discriminating those with discordant frailty classification from each other and from those for whom the assessments agree.

METHODS: A prospective observational study of older adults aged 65 and older selected from Medicare eligibility lists in four US communities (n=5,362). The PFP was measured by the Cardiovascular Health Study PFP. Subjects meeting ≥3 of the 5 criteria were deemed frail. The FI was calculated as the proportion of deficits in an a priori selected set of 48 measures and subjects were classified as frail if FI>0.35.

RESULTS: The prevalence of frailty was 7.0% by the PFP and 8.3% by the FI. Of the 730 deemed frail by either instrument, only 12% were in agreement; whereas 39% were classified as frail by PFP but not FI; and 48% were classified as frail by FI but not PFP. Participants aged 65-72 or greater disease burden were mostly likely to be characterized as being FI-frail but not PFP-frail. The associations of frailty with age and mortality was stronger when frailty was measured by the PFP rather than the FI.

CONCLUSIONS: Despite comparable frailty prevalence between the PFP and the FI, there was substantial discordance in individual-level classification, with highest agreement existing only in the most vulnerable subset. These findings suggest that there are clinically important contexts in which PFP and FI cannot be used interchangeably.

%B J Gerontol A Biol Sci Med Sci %8 2019 Feb 21 %G eng %R 10.1093/gerona/glz052 %0 Journal Article %J JAMA %D 2019 %T Discriminative Accuracy of FEV1:FVC Thresholds for COPD-Related Hospitalization and Mortality. %A Bhatt, Surya P %A Balte, Pallavi P %A Schwartz, Joseph E %A Cassano, Patricia A %A Couper, David %A Jacobs, David R %A Kalhan, Ravi %A O'Connor, George T %A Yende, Sachin %A Sanders, Jason L %A Umans, Jason G %A Dransfield, Mark T %A Chaves, Paulo H %A White, Wendy B %A Oelsner, Elizabeth C %K Aged %K Aged, 80 and over %K Cohort Studies %K Female %K Forced Expiratory Volume %K Hospitalization %K Humans %K Male %K Middle Aged %K Prognosis %K Proportional Hazards Models %K Pulmonary Disease, Chronic Obstructive %K Risk Assessment %K Vital Capacity %X

Importance: According to numerous current guidelines, the diagnosis of chronic obstructive pulmonary disease (COPD) requires a ratio of the forced expiratory volume in the first second to the forced vital capacity (FEV1:FVC) of less than 0.70, yet this fixed threshold is based on expert opinion and remains controversial.

Objective: To determine the discriminative accuracy of various FEV1:FVC fixed thresholds for predicting COPD-related hospitalization and mortality.

Design, Setting, and Participants: The National Heart, Lung, and Blood Institute (NHLBI) Pooled Cohorts Study harmonized and pooled data from 4 US general population-based cohorts (Atherosclerosis Risk in Communities Study; Cardiovascular Health Study; Health, Aging, and Body Composition Study; and Multi-Ethnic Study of Atherosclerosis). Participants aged 45 to 102 years were enrolled from 1987 to 2000 and received follow-up longitudinally through 2016.

Exposures: Presence of airflow obstruction, which was defined by a baseline FEV1:FVC less than a range of fixed thresholds (0.75 to 0.65) or less than the lower limit of normal as defined by Global Lung Initiative reference equations (LLN).

Main Outcomes and Measures: The primary outcome was a composite of COPD hospitalization and COPD-related mortality, defined by adjudication or administrative criteria. The optimal fixed FEV1:FVC threshold was defined by the best discrimination for these COPD-related events as indexed using the Harrell C statistic from unadjusted Cox proportional hazards models. Differences in C statistics were compared with respect to less than 0.70 and less than LLN thresholds using a nonparametric approach.

Results: Among 24 207 adults in the pooled cohort (mean [SD] age at enrollment, 63 [10.5] years; 12 990 [54%] women; 16 794 [69%] non-Hispanic white; 15 181 [63%] ever smokers), complete follow-up was available for 11 077 (77%) at 15 years. During a median follow-up of 15 years, 3925 participants experienced COPD-related events over 340 757 person-years of follow-up (incidence density rate, 11.5 per 1000 person-years), including 3563 COPD-related hospitalizations and 447 COPD-related deaths. With respect to discrimination of COPD-related events, the optimal fixed threshold (0.71; C statistic for optimal fixed threshold, 0.696) was not significantly different from the 0.70 threshold (difference, 0.001 [95% CI, -0.002 to 0.004]) but was more accurate than the LLN threshold (difference, 0.034 [95% CI, 0.028 to 0.041]). The 0.70 threshold provided optimal discrimination in the subgroup analysis of ever smokers and in adjusted models.

Conclusions and Relevance: Defining airflow obstruction as FEV1:FVC less than 0.70 provided discrimination of COPD-related hospitalization and mortality that was not significantly different or was more accurate than other fixed thresholds and the LLN. These results support the use of FEV1:FVC less than 0.70 to identify individuals at risk of clinically significant COPD.

%B JAMA %V 321 %P 2438-2447 %8 2019 06 25 %G eng %N 24 %R 10.1001/jama.2019.7233 %0 Journal Article %J Am J Clin Nutr %D 2019 %T Disentangling the genetics of lean mass. %A Karasik, David %A Zillikens, M Carola %A Hsu, Yi-Hsiang %A Aghdassi, Ali %A Åkesson, Kristina %A Amin, Najaf %A Barroso, Inês %A Bennett, David A %A Bertram, Lars %A Bochud, Murielle %A Borecki, Ingrid B %A Broer, Linda %A Buchman, Aron S %A Byberg, Liisa %A Campbell, Harry %A Campos-Obando, Natalia %A Cauley, Jane A %A Cawthon, Peggy M %A Chambers, John C %A Chen, Zhao %A Cho, Nam H %A Choi, Hyung Jin %A Chou, Wen-Chi %A Cummings, Steven R %A de Groot, Lisette C P G M %A De Jager, Phillip L %A Demuth, Ilja %A Diatchenko, Luda %A Econs, Michael J %A Eiriksdottir, Gudny %A Enneman, Anke W %A Eriksson, Joel %A Eriksson, Johan G %A Estrada, Karol %A Evans, Daniel S %A Feitosa, Mary F %A Fu, Mao %A Gieger, Christian %A Grallert, Harald %A Gudnason, Vilmundur %A Lenore, Launer J %A Hayward, Caroline %A Hofman, Albert %A Homuth, Georg %A Huffman, Kim M %A Husted, Lise B %A Illig, Thomas %A Ingelsson, Erik %A Ittermann, Till %A Jansson, John-Olov %A Johnson, Toby %A Biffar, Reiner %A Jordan, Joanne M %A Jula, Antti %A Karlsson, Magnus %A Khaw, Kay-Tee %A Kilpeläinen, Tuomas O %A Klopp, Norman %A Kloth, Jacqueline S L %A Koller, Daniel L %A Kooner, Jaspal S %A Kraus, William E %A Kritchevsky, Stephen %A Kutalik, Zoltán %A Kuulasmaa, Teemu %A Kuusisto, Johanna %A Laakso, Markku %A Lahti, Jari %A Lang, Thomas %A Langdahl, Bente L %A Lerch, Markus M %A Lewis, Joshua R %A Lill, Christina %A Lind, Lars %A Lindgren, Cecilia %A Liu, Yongmei %A Livshits, Gregory %A Ljunggren, Osten %A Loos, Ruth J F %A Lorentzon, Mattias %A Luan, Jian'an %A Luben, Robert N %A Malkin, Ida %A McGuigan, Fiona E %A Medina-Gómez, Carolina %A Meitinger, Thomas %A Melhus, Håkan %A Mellström, Dan %A Michaëlsson, Karl %A Mitchell, Braxton D %A Morris, Andrew P %A Mosekilde, Leif %A Nethander, Maria %A Newman, Anne B %A O'Connell, Jeffery R %A Oostra, Ben A %A Orwoll, Eric S %A Palotie, Aarno %A Peacock, Munro %A Perola, Markus %A Peters, Annette %A Prince, Richard L %A Psaty, Bruce M %A Räikkönen, Katri %A Ralston, Stuart H %A Ripatti, Samuli %A Rivadeneira, Fernando %A Robbins, John A %A Rotter, Jerome I %A Rudan, Igor %A Salomaa, Veikko %A Satterfield, Suzanne %A Schipf, Sabine %A Shin, Chan Soo %A Smith, Albert V %A Smith, Shad B %A Soranzo, Nicole %A Spector, Timothy D %A Stančáková, Alena %A Stefansson, Kari %A Steinhagen-Thiessen, Elisabeth %A Stolk, Lisette %A Streeten, Elizabeth A %A Styrkarsdottir, Unnur %A Swart, Karin M A %A Thompson, Patricia %A Thomson, Cynthia A %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Tikkanen, Emmi %A Tranah, Gregory J %A Uitterlinden, André G %A van Duijn, Cornelia M %A van Schoor, Natasja M %A Vandenput, Liesbeth %A Vollenweider, Peter %A Völzke, Henry %A Wactawski-Wende, Jean %A Walker, Mark %A J Wareham, Nicholas %A Waterworth, Dawn %A Weedon, Michael N %A Wichmann, H-Erich %A Widen, Elisabeth %A Williams, Frances M K %A Wilson, James F %A Wright, Nicole C %A Yerges-Armstrong, Laura M %A Yu, Lei %A Zhang, Weihua %A Zhao, Jing Hua %A Zhou, Yanhua %A Nielson, Carrie M %A Harris, Tamara B %A Demissie, Serkalem %A Kiel, Douglas P %A Ohlsson, Claes %X

Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass.

Objectives: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci.

Methods: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms).

Results: Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection.

Conclusions: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.

%B Am J Clin Nutr %V 109 %P 276-287 %8 2019 Feb 01 %G eng %N 2 %R 10.1093/ajcn/nqy272 %0 Journal Article %J Sleep %D 2019 %T Epigenome-wide association analysis of daytime sleepiness in the Multi-Ethnic Study of Atherosclerosis reveals African-American-specific associations. %A Barfield, Richard %A Wang, Heming %A Liu, Yongmei %A Brody, Jennifer A %A Swenson, Brenton %A Li, Ruitong %A Bartz, Traci M %A Sotoodehnia, Nona %A Chen, Yii-der I %A Cade, Brian E %A Chen, Han %A Patel, Sanjay R %A Zhu, Xiaofeng %A Gharib, Sina A %A Johnson, W Craig %A Rotter, Jerome I %A Saxena, Richa %A Purcell, Shaun %A Lin, Xihong %A Redline, Susan %A Sofer, Tamar %X

STUDY OBJECTIVES: Daytime sleepiness is a consequence of inadequate sleep, sleep-wake control disorder, or other medical conditions. Population variability in prevalence of daytime sleepiness is likely due to genetic and biological factors as well as social and environmental influences. DNA methylation (DNAm) potentially influences multiple health outcomes. Here, we explored the association between DNAm and daytime sleepiness quantified by the Epworth Sleepiness Scale (ESS).

METHODS: We performed multi-ethnic and ethnic-specific epigenome-wide association studies for DNAm and ESS in the Multi-Ethnic Study of Atherosclerosis (MESA; n = 619) and the Cardiovascular Health Study (n = 483), with cross-study replication and meta-analysis. Genetic variants near ESS-associated DNAm were analyzed for methylation quantitative trait loci and followed with replication of genotype-sleepiness associations in the UK Biobank.

RESULTS: In MESA only, we detected four DNAm-ESS associations: one across all race/ethnic groups; three in African-Americans (AA) only. Two of the MESA AA associations, in genes KCTD5 and RXRA, nominally replicated in CHS (p-value < 0.05). In the AA meta-analysis, we detected 14 DNAm-ESS associations (FDR q-value < 0.05, top association p-value = 4.26 × 10-8). Three DNAm sites mapped to genes (CPLX3, GFAP, and C7orf50) with biological relevance. We also found evidence for associations with DNAm sites in RAI1, a gene associated with sleep and circadian phenotypes. UK Biobank follow-up analyses detected SNPs in RAI1, RXRA, and CPLX3 with nominal sleepiness associations.

CONCLUSIONS: We identified methylation sites in multiple genes possibly implicated in daytime sleepiness. Most significant DNAm-ESS associations were specific to AA. Future work is needed to identify mechanisms driving ancestry-specific methylation effects.

%B Sleep %8 2019 May 29 %G eng %R 10.1093/sleep/zsz101 %0 Journal Article %J Eur Heart J %D 2019 %T {Equalization of four cardiovascular risk algorithms after systematic recalibration: individual-participant meta-analysis of 86 prospective studies %A Pennells, L. %A Kaptoge, S. %A Wood, A. %A Sweeting, M. %A Zhao, X. %A White, I. %A Burgess, S. %A Willeit, P. %A Bolton, T. %A Moons, K. G. M. %A van der Schouw, Y. T. %A Selmer, R. %A Khaw, K. T. %A Gudnason, V. %A Assmann, G. %A Amouyel, P. %A Salomaa, V. %A Kivimaki, M. %A Nordestgaard, B. G. %A Blaha, M. J. %A Kuller, L. H. %A Brenner, H. %A Gillum, R. F. %A Meisinger, C. %A Ford, I. %A Knuiman, M. W. %A Rosengren, A. %A Lawlor, D. A. %A V?lzke, H. %A Cooper, C. %A Mar?n Iba?ez, A. %A Casiglia, E. %A Kauhanen, J. %A Cooper, J. A. %A Rodriguez, B. %A Sundstr?m, J. %A Barrett-Connor, E. %A Dankner, R. %A Nietert, P. J. %A Davidson, K. W. %A Wallace, R. B. %A Blazer, D. G. %A Bj?rkelund, C. %A Donfrancesco, C. %A Krumholz, H. M. %A Nissinen, A. %A Davis, B. R. %A Coady, S. %A Whincup, P. H. %A J?rgensen, T. %A Ducimetiere, P. %A Trevisan, M. %A Engstr?m, G. %A Crespo, C. J. %A Meade, T. W. %A Visser, M. %A Kromhout, D. %A Kiechl, S. %A Daimon, M. %A Price, J. F. %A G?mez de la C?mara, A. %A Wouter Jukema, J. %A Lamarche, B. %A Onat, A. %A Simons, L. A. %A Kavousi, M. %A Ben-Shlomo, Y. %A Gallacher, J. %A Dekker, J. M. %A Arima, H. %A Shara, N. %A Tipping, R. W. %A Roussel, R. %A Brunner, E. J. %A Koenig, W. %A Sakurai, M. %A Pavlovic, J. %A Gansevoort, R. T. %A Nagel, D. %A Goldbourt, U. %A Barr, E. L. M. %A Palmieri, L. %A Nj?lstad, I. %A Sato, S. %A Monique Verschuren, W. M. %A Varghese, C. V. %A Graham, I. %A Onuma, O. %A Greenland, P. %A Woodward, M. %A Ezzati, M. %A Psaty, B. M. %A Sattar, N. %A Jackson, R. %A Ridker, P. M. %A Cook, N. R. %A D'Agostino, R. B. %A Thompson, S. G. %A Danesh, J. %A Di Angelantonio, E. %A Tipping, R. W. %A Simpson, L. M. %A Pressel, S. L. %A Couper, D. J. %A Nambi, V. %A Matsushita, K. %A Folsom, A. R. %A Shaw, J. E. %A Magliano, D. J. %A Zimmet, P. Z. %A Knuiman, M. W. %A Whincup, P. H. %A Wannamethee, S. G. %A Willeit, J. %A Santer, P. %A Egger, G. %A Casas, J. P. %A Amuzu, A. %A Ben-Shlomo, Y. %A Gallacher, J. %A Tikhonoff, V. %A Casiglia, E. %A Sutherland, S. E. %A Nietert, P. J. %A Cushman, M. %A Psaty, B. M. %A S?gaard, A. J. %A H?heim, L. L. %A Ariansen, I. %A Tybj?rg-Hansen, A. %A Jensen, G. B. %A Schnohr, P. %A Giampaoli, S. %A Vanuzzo, D. %A Panico, S. %A Palmieri, L. %A Balkau, B. %A Bonnet, F. %A Marre, M. %A de la C?mara, A. G. %A Rubio Herrera, M. A. %A Friedlander, Y. %A McCallum, J. %A McLachlan, S. %A Guralnik, J. %A Phillips, C. L. %A Khaw, K. T. %A Wareham, N. %A Sch?ttker, B. %A Saum, K. U. %A Holleczek, B. %A Nissinen, A. %A Tolonen, H. %A Giampaoli, S. %A Donfrancesco, C. %A Vartiainen, E. %A Jousilahti, P. %A Harald, K. %A D?Agostino, R. B. %A Massaro, J. M. %A Pencina, M. %A Vasan, R. %A Kayama, T. %A Kato, T. %A Oizumi, T. %A Jespersen, J. %A M?ller, L. %A Bladbjerg, E. M. %A Chetrit, A. %A Rosengren, A. %A Wilhelmsen, L. %A Bj?rkelund, C. %A Lissner, L. %A Nagel, D. %A Dennison, E. %A Kiyohara, Y. %A Ninomiya, T. %A Doi, Y. %A Rodriguez, B. %A Nijpels, G. %A Stehouwer, C. D. A. %A Sato, S. %A Kazumasa, Y. %A Iso, H. %A Goldbourt, U. %A Salomaa, V. %A Vartiainen, E. %A Kurl, S. %A Tuomainen, T. P. %A Salonen, J. T. %A Visser, M. %A Deeg, D. J. H. %A Meade, T. W. %A Nilsson, P. M. %A Hedblad, B. %A Melander, O. %A De Boer, I. H. %A DeFilippis, A. P. %A Verschuren, W. M. M. %A Sattar, N. %A Watt, G. %A Meisinger, C. %A Koenig, W. %A Rosengren, A. %A Kuller, L. H. %A Tverdal, A. %A Gillum, R. F. %A Cooper, J. A. %A Kirkland, S. %A Shimbo, D. %A Shaffer, J. %A Sato, S. %A Kazumasa, Y. %A Iso, H. %A Ducimetiere, P. %A Bakker, S. J. L. %A van der Harst, P. %A Hillege, H. L. %A Crespo, C. J. %A Amouyel, P. %A Dallongeville, J. %A Assmann, G. %A Schulte, H. %A Trompet, S. %A Smit, R. A. J. %A Stott, D. J. %A van der Schouw, Y. T. %A Despr?s, J. P. %A Cantin, B. %A Dagenais, G. R. %A Laughlin, G. %A Wingard, D. %A Trevisan, M. %A Aspelund, T. %A Eiriksdottir, G. %A Gudmundsson, E. F. %A Ikram, A. %A van Rooij, F. J. A. %A Franco, O. H. %A Rueda-Ochoa, O. L. %A Muka, T. %A Glisic, M. %A Tunstall-Pedoe, H. %A V?lzke, H. %A Howard, B. V. %A Zhang, Y. %A Jolly, S. %A Gallacher, J. %A Davey-Smith, G. %A Can, G. %A Y?ksel, H. %A Nakagawa, H. %A Morikawa, Y. %A Miura, K. %A Nj?lstad, I. %A Ingelsson, M. %A Giedraitis, V. %A Ridker, P. M. %A Gaziano, J. M. %A Kivimaki, M. %A Shipley, M. %A Brunner, E. J. %A Arndt, V. %A Brenner, H. %A Cook, N. %A Ridker, P. M. %A Ford, I. %A Sattar, N. %A Iba?ez, A. M. %A Geleijnse, J. M. %X There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after 'recalibration', a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied.\ Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at 'high' 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over-predicted CVD risk on average by 10%, 52%, and 41%, respectively, whereas RRS under-predicted by 10%. Original versions of algorithms classified 29-39% of individuals aged ≥40 years as high risk. By contrast, recalibration reduced this proportion to 22-24% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44-51 such individuals using original algorithms, in contrast to 37-39 individuals with recalibrated algorithms.\ Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need. %B Eur Heart J %V 40 %P 621–631 %8 02 %G eng %0 Journal Article %J Nature %D 2019 %T {Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls %A Flannick, J. %A Mercader, J. M. %A Fuchsberger, C. %A Udler, M. S. %A Mahajan, A. %A Wessel, J. %A Teslovich, T. M. %A Caulkins, L. %A Koesterer, R. %A Barajas-Olmos, F. %A Blackwell, T. W. %A Boerwinkle, E. %A Brody, J. A. %A Centeno-Cruz, F. %A Chen, L. %A Chen, S. %A Contreras-Cubas, C. %A C?rdova, E. %A Correa, A. %A Cortes, M. %A DeFronzo, R. A. %A Dolan, L. %A Drews, K. L. %A Elliott, A. %A Floyd, J. S. %A Gabriel, S. %A Garay-Sevilla, M. E. %A Garc?a-Ortiz, H. %A Gross, M. %A Han, S. %A Heard-Costa, N. L. %A Jackson, A. U. %A J?rgensen, M. E. %A Kang, H. M. %A Kelsey, M. %A Kim, B. J. %A Koistinen, H. A. %A Kuusisto, J. %A Leader, J. B. %A Linneberg, A. %A Liu, C. T. %A Liu, J. %A Lyssenko, V. %A Manning, A. K. %A Marcketta, A. %A Malacara-Hernandez, J. M. %A Mart?nez-Hern?ndez, A. %A Matsuo, K. %A Mayer-Davis, E. %A Mendoza-Caamal, E. %A Mohlke, K. L. %A Morrison, A. C. %A Ndungu, A. %A Ng, M. C. Y. %A O'Dushlaine, C. %A Payne, A. J. %A Pihoker, C. %A Post, W. S. %A Preuss, M. %A Psaty, B. M. %A Vasan, R. S. %A Rayner, N. W. %A Reiner, A. P. %A Revilla-Monsalve, C. %A Robertson, N. R. %A Santoro, N. %A Schurmann, C. %A So, W. Y. %A Sober?n, X. %A Stringham, H. M. %A Strom, T. M. %A Tam, C. H. T. %A Thameem, F. %A Tomlinson, B. %A Torres, J. M. %A Tracy, R. P. %A van Dam, R. M. %A Vujkovic, M. %A Wang, S. %A Welch, R. P. %A Witte, D. R. %A Wong, T. Y. %A Atzmon, G. %A Barzilai, N. %A Blangero, J. %A Bonnycastle, L. L. %A Bowden, D. W. %A Chambers, J. C. %A Chan, E. %A Cheng, C. Y. %A Cho, Y. S. %A Collins, F. S. %A de Vries, P. S. %A Duggirala, R. %A Glaser, B. %A Gonzalez, C. %A Gonzalez, M. E. %A Groop, L. %A Kooner, J. S. %A Kwak, S. H. %A Laakso, M. %A Lehman, D. M. %A Nilsson, P. %A Spector, T. D. %A Tai, E. S. %A Tuomi, T. %A Tuomilehto, J. %A Wilson, J. G. %A Aguilar-Salinas, C. A. %A Bottinger, E. %A Burke, B. %A Carey, D. J. %A Chan, J. C. N. %A Dupuis, J. %A Frossard, P. %A Heckbert, S. R. %A Hwang, M. Y. %A Kim, Y. J. %A Kirchner, H. L. %A Lee, J. Y. %A Lee, J. %A Loos, R. J. F. %A Ma, R. C. W. %A Morris, A. D. %A O'Donnell, C. J. %A Palmer, C. N. A. %A Pankow, J. %A Park, K. S. %A Rasheed, A. %A Saleheen, D. %A Sim, X. %A Small, K. S. %A Teo, Y. Y. %A Haiman, C. %A Hanis, C. L. %A Henderson, B. E. %A Orozco, L. %A Tusi?-Luna, T. %A Dewey, F. E. %A Baras, A. %A Gieger, C. %A Meitinger, T. %A Strauch, K. %A Lange, L. %A Grarup, N. %A Hansen, T. %A Pedersen, O. %A Zeitler, P. %A Dabelea, D. %A Abecasis, G. %A Bell, G. I. %A Cox, N. J. %A Seielstad, M. %A Sladek, R. %A Meigs, J. B. %A Rich, S. S. %A Rotter, J. I. %A Altshuler, D. %A Burtt, N. P. %A Scott, L. J. %A Morris, A. P. %A Florez, J. C. %A McCarthy, M. I. %A Boehnke, M. %X Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and in 12 gene sets, including those corresponding to T2D drug targets (P = 6.1 × 10-3) and candidate genes from knockout mice (P = 5.2 × 10-3). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000-185,000 sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts. %B Nature %V 570 %P 71–76 %8 06 %G eng %0 Journal Article %J Am J Hum Genet %D 2019 %T {Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology %A Spracklen, C. N. %A Karaderi, T. %A Yaghootkar, H. %A Schurmann, C. %A Fine, R. S. %A Kutalik, Z. %A Preuss, M. H. %A Lu, Y. %A Wittemans, L. B. L. %A Adair, L. S. %A Allison, M. %A Amin, N. %A Auer, P. L. %A Bartz, T. M. %A her, M. %A Boehnke, M. %A Borja, J. B. %A Bork-Jensen, J. %A Broer, L. %A Chasman, D. I. %A Chen, Y. I. %A Chirstofidou, P. %A Demirkan, A. %A van Duijn, C. M. %A Feitosa, M. F. %A Garcia, M. E. %A Graff, M. %A Grallert, H. %A Grarup, N. %A Guo, X. %A Haesser, J. %A Hansen, T. %A Harris, T. B. %A Highland, H. M. %A Hong, J. %A Ikram, M. A. %A Ingelsson, E. %A Jackson, R. %A Jousilahti, P. %A nen, M. %A Kizer, J. R. %A Kovacs, P. %A Kriebel, J. %A Laakso, M. %A Lange, L. A. %A ki, T. %A Li, J. %A Li-Gao, R. %A Lind, L. %A Luan, J. %A inen, L. P. %A MacGregor, S. %A Mackey, D. A. %A Mahajan, A. %A Mangino, M. %A ö, S. %A McCarthy, M. I. %A McKnight, B. %A Medina-Gomez, C. %A Meigs, J. B. %A Molnos, S. %A Mook-Kanamori, D. %A Morris, A. P. %A de Mutsert, R. %A Nalls, M. A. %A Nedeljkovic, I. %A North, K. E. %A Pennell, C. E. %A Pradhan, A. D. %A Province, M. A. %A Raitakari, O. T. %A Raulerson, C. K. %A Reiner, A. P. %A Ridker, P. M. %A Ripatti, S. %A Roberston, N. %A Rotter, J. I. %A Salomaa, V. %A rate, A. A. %A Sitlani, C. M. %A Spector, T. D. %A Strauch, K. %A Stumvoll, M. %A Taylor, K. D. %A Thuesen, B. %A njes, A. %A Uitterlinden, A. G. %A Venturini, C. %A Walker, M. %A Wang, C. A. %A Wang, S. %A Wareham, N. J. %A Willems, S. M. %A Willems van Dijk, K. %A Wilson, J. G. %A Wu, Y. %A Yao, J. %A Young, K. L. %A Langenberg, C. %A Frayling, T. M. %A inen, T. O. %A Lindgren, C. M. %A Loos, R. J. F. %A Mohlke, K. L. %X ) with at least one obesity or lipid trait. Candidate genes include PRKAR2A, PTH1R, and HDAC9, which have been suggested to play roles in adipocyte differentiation or bone marrow adipose tissue. Taken together, these findings provide further insights into the processes that influence circulating adiponectin levels. %B Am J Hum Genet %V 105 %P 15–28 %8 Jul %G eng %0 Journal Article %J Am J Hum Genet %D 2019 %T {Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology %A Spracklen, C. N. %A Karaderi, T. %A Yaghootkar, H. %A Schurmann, C. %A Fine, R. S. %A Kutalik, Z. %A Preuss, M. H. %A Lu, Y. %A Wittemans, L. B. L. %A Adair, L. S. %A Allison, M. %A Amin, N. %A Auer, P. L. %A Bartz, T. M. %A her, M. %A Boehnke, M. %A Borja, J. B. %A Bork-Jensen, J. %A Broer, L. %A Chasman, D. I. %A Chen, Y. I. %A Chirstofidou, P. %A Demirkan, A. %A van Duijn, C. M. %A Feitosa, M. F. %A Garcia, M. E. %A Graff, M. %A Grallert, H. %A Grarup, N. %A Guo, X. %A Haesser, J. %A Hansen, T. %A Harris, T. B. %A Highland, H. M. %A Hong, J. %A Ikram, M. A. %A Ingelsson, E. %A Jackson, R. %A Jousilahti, P. %A nen, M. %A Kizer, J. R. %A Kovacs, P. %A Kriebel, J. %A Laakso, M. %A Lange, L. A. %A ki, T. %A Li, J. %A Li-Gao, R. %A Lind, L. %A Luan, J. %A inen, L. P. %A MacGregor, S. %A Mackey, D. A. %A Mahajan, A. %A Mangino, M. %A ö, S. %A McCarthy, M. I. %A McKnight, B. %A Medina-Gomez, C. %A Meigs, J. B. %A Molnos, S. %A Mook-Kanamori, D. %A Morris, A. P. %A de Mutsert, R. %A Nalls, M. A. %A Nedeljkovic, I. %A North, K. E. %A Pennell, C. E. %A Pradhan, A. D. %A Province, M. A. %A Raitakari, O. T. %A Raulerson, C. K. %A Reiner, A. P. %A Ridker, P. M. %A Ripatti, S. %A Roberston, N. %A Rotter, J. I. %A Salomaa, V. %A rate, A. A. %A Sitlani, C. M. %A Spector, T. D. %A Strauch, K. %A Stumvoll, M. %A Taylor, K. D. %A Thuesen, B. %A njes, A. %A Uitterlinden, A. G. %A Venturini, C. %A Walker, M. %A Wang, C. A. %A Wang, S. %A Wareham, N. J. %A Willems, S. M. %A Willems van Dijk, K. %A Wilson, J. G. %A Wu, Y. %A Yao, J. %A Young, K. L. %A Langenberg, C. %A Frayling, T. M. %A inen, T. O. %A Lindgren, C. M. %A Loos, R. J. F. %A Mohlke, K. L. %B Am J Hum Genet %V 105 %P 670–671 %8 Sep %G eng %0 Journal Article %J Nat Genet %D 2019 %T Genetic architecture of subcortical brain structures in 38,851 individuals. %A Satizabal, Claudia L %A Adams, Hieab H H %A Hibar, Derrek P %A White, Charles C %A Knol, Maria J %A Stein, Jason L %A Scholz, Markus %A Sargurupremraj, Muralidharan %A Jahanshad, Neda %A Roshchupkin, Gennady V %A Smith, Albert V %A Bis, Joshua C %A Jian, Xueqiu %A Luciano, Michelle %A Hofer, Edith %A Teumer, Alexander %A van der Lee, Sven J %A Yang, Jingyun %A Yanek, Lisa R %A Lee, Tom V %A Li, Shuo %A Hu, Yanhui %A Koh, Jia Yu %A Eicher, John D %A Desrivières, Sylvane %A Arias-Vasquez, Alejandro %A Chauhan, Ganesh %A Athanasiu, Lavinia %A Rentería, Miguel E %A Kim, Sungeun %A Hoehn, David %A Armstrong, Nicola J %A Chen, Qiang %A Holmes, Avram J %A den Braber, Anouk %A Kloszewska, Iwona %A Andersson, Micael %A Espeseth, Thomas %A Grimm, Oliver %A Abramovic, Lucija %A Alhusaini, Saud %A Milaneschi, Yuri %A 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Bernard, Manon %A Richards, Jennifer S %A Himali, Jayandra J %A Loeffler, Markus %A Rommelse, Nanda %A Hoffmann, Wolfgang %A Westlye, Lars T %A Valdés Hernández, Maria C %A Hansell, Narelle K %A van Erp, Theo G M %A Wolf, Christiane %A Kwok, John B J %A Vellas, Bruno %A Heinz, Andreas %A Olde Loohuis, Loes M %A Delanty, Norman %A Ho, Beng-Choon %A Ching, Christopher R K %A Shumskaya, Elena %A Singh, Baljeet %A Hofman, Albert %A van der Meer, Dennis %A Homuth, Georg %A Psaty, Bruce M %A Bastin, Mark E %A Montgomery, Grant W %A Foroud, Tatiana M %A Reppermund, Simone %A Hottenga, Jouke-Jan %A Simmons, Andrew %A Meyer-Lindenberg, Andreas %A Cahn, Wiepke %A Whelan, Christopher D %A van Donkelaar, Marjolein M J %A Yang, Qiong %A Hosten, Norbert %A Green, Robert C %A Thalamuthu, Anbupalam %A Mohnke, Sebastian %A Hulshoff Pol, Hilleke E %A Lin, Honghuang %A Jack, Clifford R %A Schofield, Peter R %A Mühleisen, Thomas W %A Maillard, Pauline %A Potkin, Steven G %A Wen, Wei %A Fletcher, Evan %A Toga, Arthur W %A Gruber, Oliver %A Huentelman, Matthew %A Davey Smith, George %A Launer, Lenore J %A Nyberg, Lars %A Jönsson, Erik G %A Crespo-Facorro, Benedicto %A Koen, Nastassja %A Greve, Douglas N %A Uitterlinden, André G %A Weinberger, Daniel R %A Steen, Vidar M %A Fedko, Iryna O %A Groenewold, Nynke A %A Niessen, Wiro J %A Toro, Roberto %A Tzourio, Christophe %A Longstreth, William T %A Ikram, M Kamran %A Smoller, Jordan W %A van Tol, Marie-Jose %A Sussmann, Jessika E %A Paus, Tomáš %A Lemaître, Hervé %A Schroeter, Matthias L %A Mazoyer, Bernard %A Andreassen, Ole A %A Holsboer, Florian %A Depondt, Chantal %A Veltman, Dick J %A Turner, Jessica A %A Pausova, Zdenka %A Schumann, Gunter %A van Rooij, Daan %A Djurovic, Srdjan %A Deary, Ian J %A McMahon, Katie L %A Müller-Myhsok, Bertram %A Brouwer, Rachel M %A Soininen, Hilkka %A Pandolfo, Massimo %A Wassink, Thomas H %A Cheung, Joshua W %A Wolfers, Thomas %A Martinot, Jean-Luc %A Zwiers, Marcel P %A Nauck, Matthias %A Melle, Ingrid %A Martin, Nicholas G %A Kanai, Ryota %A Westman, Eric %A Kahn, René S %A Sisodiya, Sanjay M %A White, Tonya %A Saremi, Arvin %A van Bokhoven, Hans %A Brunner, Han G %A Völzke, Henry %A Wright, Margaret J %A van 't Ent, Dennis %A Nöthen, Markus M %A Ophoff, Roel A %A Buitelaar, Jan K %A Fernández, Guillén %A Sachdev, Perminder S %A Rietschel, Marcella %A van Haren, Neeltje E M %A Fisher, Simon E %A Beiser, Alexa S %A Francks, Clyde %A Saykin, Andrew J %A Mather, Karen A %A Romanczuk-Seiferth, Nina %A Hartman, Catharina A %A DeStefano, Anita L %A Heslenfeld, Dirk J %A Weiner, Michael W %A Walter, Henrik %A Hoekstra, Pieter J %A Nyquist, Paul A %A Franke, Barbara %A Bennett, David A %A Grabe, Hans J %A Johnson, Andrew D %A Chen, Christopher %A van Duijn, Cornelia M %A Lopez, Oscar L %A Fornage, Myriam %A Wardlaw, Joanna M %A Schmidt, Reinhold %A DeCarli, Charles %A De Jager, Philip L %A Villringer, Arno %A Debette, Stephanie %A Gudnason, Vilmundur %A Medland, Sarah E %A Shulman, Joshua M %A Thompson, Paul M %A Seshadri, Sudha %A Ikram, M Arfan %X

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

%B Nat Genet %V 51 %P 1624-1636 %8 2019 Nov %G eng %N 11 %R 10.1038/s41588-019-0511-y %0 Journal Article %J Nat Genet %D 2019 %T Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. %A Kunkle, Brian W %A Grenier-Boley, Benjamin %A Sims, Rebecca %A Bis, Joshua C %A Damotte, Vincent %A Naj, Adam C %A Boland, Anne %A Vronskaya, Maria %A van der Lee, Sven J %A Amlie-Wolf, Alexandre %A Bellenguez, Céline %A Frizatti, Aura %A Chouraki, Vincent %A Martin, Eden R %A Sleegers, Kristel %A Badarinarayan, Nandini %A Jakobsdottir, Johanna %A Hamilton-Nelson, Kara L %A Moreno-Grau, Sonia %A Olaso, Robert %A Raybould, Rachel %A Chen, Yuning %A Kuzma, Amanda B %A Hiltunen, Mikko %A Morgan, Taniesha %A Ahmad, Shahzad %A Vardarajan, Badri N %A Epelbaum, Jacques %A Hoffmann, Per %A Boada, Merce %A Beecham, Gary W %A Garnier, Jean-Guillaume %A Harold, Denise %A Fitzpatrick, Annette L %A Valladares, Otto %A Moutet, Marie-Laure %A Gerrish, Amy %A Smith, Albert V %A Qu, Liming %A Bacq, Delphine %A Denning, Nicola %A Jian, Xueqiu %A Zhao, Yi %A Del Zompo, Maria %A Fox, Nick C %A Choi, Seung-Hoan %A Mateo, Ignacio %A Hughes, Joseph T %A Adams, Hieab H %A Malamon, John %A Sanchez-Garcia, Florentino %A Patel, Yogen %A Brody, Jennifer A %A Dombroski, Beth A %A Naranjo, Maria Candida Deniz %A Daniilidou, Makrina %A Eiriksdottir, Gudny %A Mukherjee, Shubhabrata %A Wallon, David %A Uphill, James %A Aspelund, Thor %A Cantwell, Laura B %A Garzia, Fabienne %A Galimberti, Daniela %A Hofer, Edith %A Butkiewicz, Mariusz %A Fin, Bertrand %A Scarpini, Elio %A Sarnowski, Chloe %A Bush, Will S %A Meslage, Stéphane %A Kornhuber, Johannes %A White, Charles C %A Song, Yuenjoo %A Barber, Robert C %A Engelborghs, Sebastiaan %A Sordon, Sabrina %A Voijnovic, Dina %A Adams, Perrie M %A Vandenberghe, Rik %A Mayhaus, Manuel %A Cupples, L Adrienne %A Albert, Marilyn S %A De Deyn, Peter P %A Gu, Wei %A Himali, Jayanadra J %A Beekly, Duane %A Squassina, Alessio %A Hartmann, Annette M %A Orellana, Adelina %A Blacker, Deborah %A Rodriguez-Rodriguez, Eloy %A Lovestone, Simon %A Garcia, Melissa E %A Doody, Rachelle S %A Munoz-Fernadez, Carmen %A Sussams, Rebecca %A Lin, Honghuang %A Fairchild, Thomas J %A Benito, Yolanda A %A Holmes, Clive %A Karamujić-Čomić, Hata %A Frosch, Matthew P %A Thonberg, Håkan %A Maier, Wolfgang %A Roschupkin, Gena %A Ghetti, Bernardino %A Giedraitis, Vilmantas %A Kawalia, Amit %A Li, Shuo %A Huebinger, Ryan M %A Kilander, Lena %A Moebus, Susanne %A Hernandez, Isabel %A Kamboh, M Ilyas %A Brundin, RoseMarie %A Turton, James %A Yang, Qiong %A Katz, Mindy J %A Concari, Letizia %A Lord, Jenny %A Beiser, Alexa S %A Keene, C Dirk %A Helisalmi, Seppo %A Kloszewska, Iwona %A Kukull, Walter A %A Koivisto, Anne Maria %A Lynch, Aoibhinn %A Tarraga, Lluis %A Larson, Eric B %A Haapasalo, Annakaisa %A Lawlor, Brian %A Mosley, Thomas H %A Lipton, Richard B %A Solfrizzi, Vincenzo %A Gill, Michael %A Longstreth, W T %A Montine, Thomas J %A Frisardi, Vincenza %A Diez-Fairen, Monica %A Rivadeneira, Fernando %A Petersen, Ronald C %A Deramecourt, Vincent %A Alvarez, Ignacio %A Salani, Francesca %A Ciaramella, Antonio %A Boerwinkle, Eric %A Reiman, Eric M %A Fiévet, Nathalie %A Rotter, Jerome I %A Reisch, Joan S %A Hanon, Olivier %A Cupidi, Chiara %A Andre Uitterlinden, A G %A Royall, Donald R %A Dufouil, Carole %A Maletta, Raffaele Giovanni %A de Rojas, Itziar %A Sano, Mary %A Brice, Alexis %A Cecchetti, Roberta %A George-Hyslop, Peter St %A Ritchie, Karen %A Tsolaki, Magda %A Tsuang, Debby W %A Dubois, Bruno %A Craig, David %A Wu, Chuang-Kuo %A Soininen, Hilkka %A Avramidou, Despoina %A Albin, Roger L %A Fratiglioni, Laura %A Germanou, Antonia %A Apostolova, Liana G %A Keller, Lina %A Koutroumani, Maria %A Arnold, Steven E %A Panza, Francesco %A Gkatzima, Olymbia %A Asthana, Sanjay %A Hannequin, Didier %A Whitehead, Patrice %A Atwood, Craig S %A Caffarra, Paolo %A Hampel, Harald %A Quintela, Inés %A Carracedo, Angel %A Lannfelt, Lars %A Rubinsztein, David C %A Barnes, Lisa L %A Pasquier, Florence %A Frölich, Lutz %A Barral, Sandra %A McGuinness, Bernadette %A Beach, Thomas G %A Johnston, Janet A %A Becker, James T %A Passmore, Peter %A Bigio, Eileen H %A Schott, Jonathan M %A Bird, Thomas D %A Warren, Jason D %A Boeve, Bradley F %A Lupton, Michelle K %A Bowen, James D %A Proitsi, Petra %A Boxer, Adam %A Powell, John F %A Burke, James R %A Kauwe, John S K %A Burns, Jeffrey M %A Mancuso, Michelangelo %A Buxbaum, Joseph D %A Bonuccelli, Ubaldo %A Cairns, Nigel J %A McQuillin, Andrew %A Cao, Chuanhai %A Livingston, Gill %A Carlson, Chris S %A Bass, Nicholas J %A Carlsson, Cynthia M %A Hardy, John %A Carney, Regina M %A Bras, Jose %A Carrasquillo, Minerva M %A Guerreiro, Rita %A Allen, Mariet %A Chui, Helena C %A Fisher, Elizabeth %A Masullo, Carlo %A Crocco, Elizabeth A %A DeCarli, Charles %A Bisceglio, Gina %A Dick, Malcolm %A Ma, Li %A Duara, Ranjan %A Graff-Radford, Neill R %A Evans, Denis A %A Hodges, Angela %A Faber, Kelley M %A Scherer, Martin %A Fallon, Kenneth B %A Riemenschneider, Matthias %A Fardo, David W %A Heun, Reinhard %A Farlow, Martin R %A Kölsch, Heike %A Ferris, Steven %A Leber, Markus %A Foroud, Tatiana M %A Heuser, Isabella %A Galasko, Douglas R %A Giegling, Ina %A Gearing, Marla %A Hüll, Michael %A Geschwind, Daniel H %A Gilbert, John R %A Morris, John %A Green, Robert C %A Mayo, Kevin %A Growdon, John H %A Feulner, Thomas %A Hamilton, Ronald L %A Harrell, Lindy E %A Drichel, Dmitriy %A Honig, Lawrence S %A Cushion, Thomas D %A Huentelman, Matthew J %A Hollingworth, Paul %A Hulette, Christine M %A Hyman, Bradley T %A Marshall, Rachel %A Jarvik, Gail P %A Meggy, Alun %A Abner, Erin %A Menzies, Georgina E %A Jin, Lee-Way %A Leonenko, Ganna %A Real, Luis M %A Jun, Gyungah R %A Baldwin, Clinton T %A Grozeva, Detelina %A Karydas, Anna %A Russo, Giancarlo %A Kaye, Jeffrey A %A Kim, Ronald %A Jessen, Frank %A Kowall, Neil W %A Vellas, Bruno %A Kramer, Joel H %A Vardy, Emma %A LaFerla, Frank M %A Jöckel, Karl-Heinz %A Lah, James J %A Dichgans, Martin %A Leverenz, James B %A Mann, David %A Levey, Allan I %A Pickering-Brown, Stuart %A Lieberman, Andrew P %A Klopp, Norman %A Lunetta, Kathryn L %A Wichmann, H-Erich %A Lyketsos, Constantine G %A Morgan, Kevin %A Marson, Daniel C %A Brown, Kristelle %A Martiniuk, Frank %A Medway, Christopher %A Mash, Deborah C %A Nöthen, Markus M %A Masliah, Eliezer %A Hooper, Nigel M %A McCormick, Wayne C %A Daniele, Antonio %A McCurry, Susan M %A Bayer, Anthony %A McDavid, Andrew N %A Gallacher, John %A McKee, Ann C %A van den Bussche, Hendrik %A Mesulam, Marsel %A Brayne, Carol %A Miller, Bruce L %A Riedel-Heller, Steffi %A Miller, Carol A %A Miller, Joshua W %A Al-Chalabi, Ammar %A Morris, John C %A Shaw, Christopher E %A Myers, Amanda J %A Wiltfang, Jens %A O'Bryant, Sid %A Olichney, John M %A Alvarez, Victoria %A Parisi, Joseph E %A Singleton, Andrew B %A Paulson, Henry L %A Collinge, John %A Perry, William R %A Mead, Simon %A Peskind, Elaine %A Cribbs, David H %A Rossor, Martin %A Pierce, Aimee %A Ryan, Natalie S %A Poon, Wayne W %A Nacmias, Benedetta %A Potter, Huntington %A Sorbi, Sandro %A Quinn, Joseph F %A Sacchinelli, Eleonora %A Raj, Ashok %A Spalletta, Gianfranco %A Raskind, Murray %A Caltagirone, Carlo %A Bossù, Paola %A Orfei, Maria Donata %A Reisberg, Barry %A Clarke, Robert %A Reitz, Christiane %A Smith, A David %A Ringman, John M %A Warden, Donald %A Roberson, Erik D %A Wilcock, Gordon %A Rogaeva, Ekaterina %A Bruni, Amalia Cecilia %A Rosen, Howard J %A Gallo, Maura %A Rosenberg, Roger N %A Ben-Shlomo, Yoav %A Sager, Mark A %A Mecocci, Patrizia %A Saykin, Andrew J %A Pastor, Pau %A Cuccaro, Michael L %A Vance, Jeffery M %A Schneider, Julie A %A Schneider, Lori S %A Slifer, Susan %A Seeley, William W %A Smith, Amanda G %A Sonnen, Joshua A %A Spina, Salvatore %A Stern, Robert A %A Swerdlow, Russell H %A Tang, Mitchell %A Tanzi, Rudolph E %A Trojanowski, John Q %A Troncoso, Juan C %A Van Deerlin, Vivianna M %A Van Eldik, Linda J %A Vinters, Harry V %A Vonsattel, Jean Paul %A Weintraub, Sandra %A Welsh-Bohmer, Kathleen A %A Wilhelmsen, Kirk C %A Williamson, Jennifer %A Wingo, Thomas S %A Woltjer, Randall L %A Wright, Clinton B %A Yu, Chang-En %A Yu, Lei %A Saba, Yasaman %A Pilotto, Alberto %A Bullido, María J %A Peters, Oliver %A Crane, Paul K %A Bennett, David %A Bosco, Paola %A Coto, Eliecer %A Boccardi, Virginia %A De Jager, Phil L %A Lleo, Alberto %A Warner, Nick %A Lopez, Oscar L %A Ingelsson, Martin %A Deloukas, Panagiotis %A Cruchaga, Carlos %A Graff, Caroline %A Gwilliam, Rhian %A Fornage, Myriam %A Goate, Alison M %A Sánchez-Juan, Pascual %A Kehoe, Patrick G %A Amin, Najaf %A Ertekin-Taner, Nilifur %A Berr, Claudine %A Debette, Stephanie %A Love, Seth %A Launer, Lenore J %A Younkin, Steven G %A Dartigues, Jean-François %A Corcoran, Chris %A Ikram, M Arfan %A Dickson, Dennis W %A Nicolas, Gaël %A Campion, Dominique %A Tschanz, JoAnn %A Schmidt, Helena %A Hakonarson, Hakon %A Clarimon, Jordi %A Munger, Ron %A Schmidt, Reinhold %A Farrer, Lindsay A %A Van Broeckhoven, Christine %A C O'Donovan, Michael %A DeStefano, Anita L %A Jones, Lesley %A Haines, Jonathan L %A Deleuze, Jean-Francois %A Owen, Michael J %A Gudnason, Vilmundur %A Mayeux, Richard %A Escott-Price, Valentina %A Psaty, Bruce M %A Ramirez, Alfredo %A Wang, Li-San %A Ruiz, Agustin %A van Duijn, Cornelia M %A Holmans, Peter A %A Seshadri, Sudha %A Williams, Julie %A Amouyel, Phillippe %A Schellenberg, Gerard D %A Lambert, Jean-Charles %A Pericak-Vance, Margaret A %X

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

%B Nat Genet %V 51 %P 414-430 %8 2019 Mar %G eng %N 3 %R 10.1038/s41588-019-0358-2 %0 Journal Article %J Sci Rep %D 2019 %T Genome Wide Meta-Analysis identifies common genetic signatures shared by heart function and Alzheimer's disease. %A Sáez, M E %A González-Pérez, A %A Hernández-Olasagarre, B %A Beà, A %A Moreno-Grau, S %A de Rojas, I %A Monté-Rubio, G %A Orellana, A %A Valero, S %A Comella, J X %A Sanchís, D %A Ruiz, A %X

Echocardiography has become an indispensable tool for the study of heart performance, improving the monitoring of individuals with cardiac diseases. Diverse genetic factors associated with echocardiographic measures have been previously reported. The impact of several apoptotic genes in heart development identified in experimental models prompted us to assess their potential association with human cardiac function. This study aimed at investigating the possible association of variants of apoptotic genes with echocardiographic traits and to identify new genetic markers associated with cardiac function. Genome wide data from different studies were obtained from public repositories. After quality control and imputation, a meta-analysis of individual association study results was performed. Our results confirmed the role of caspases and other apoptosis related genes with cardiac phenotypes. Moreover, enrichment analysis showed an over-representation of genes, including some apoptotic regulators, associated with Alzheimer's disease. We further explored this unexpected observation which was confirmed by genetic correlation analyses. Our findings show the association of apoptotic gene variants with echocardiographic indicators of heart function and reveal a novel potential genetic link between echocardiographic measures in healthy populations and cognitive decline later on in life. These findings may have important implications for preventative strategies combating Alzheimer's disease.

%B Sci Rep %V 9 %P 16665 %8 2019 Nov 13 %G eng %N 1 %R 10.1038/s41598-019-52724-2 %0 Journal Article %J Nat Commun %D 2019 %T {Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria %A Teumer, A. %A Li, Y. %A Ghasemi, S. %A Prins, B. P. %A Wuttke, M. %A Hermle, T. %A Giri, A. %A Sieber, K. B. %A Qiu, C. %A Kirsten, H. %A Tin, A. %A Chu, A. Y. %A Bansal, N. %A Feitosa, M. F. %A Wang, L. %A Chai, J. F. %A Cocca, M. %A Fuchsberger, C. %A Gorski, M. %A Hoppmann, A. %A Horn, K. %A Li, M. %A Marten, J. %A Noce, D. %A Nutile, T. %A Sedaghat, S. %A Sveinbjornsson, G. %A Tayo, B. O. %A van der Most, P. J. %A Xu, Y. %A Yu, Z. %A Gerstner, L. %A ?rnl?v, J. %A Bakker, S. J. L. %A Baptista, D. %A Biggs, M. L. %A Boerwinkle, E. %A Brenner, H. %A Burkhardt, R. %A Carroll, R. J. %A Chee, M. L. %A Chee, M. L. %A Chen, M. %A Cheng, C. Y. %A Cook, J. P. %A Coresh, J. %A Corre, T. %A Danesh, J. %A de Borst, M. H. %A De Grandi, A. %A de Mutsert, R. %A de Vries, A. P. J. %A Degenhardt, F. %A Dittrich, K. %A Divers, J. %A Eckardt, K. U. %A Ehret, G. %A Endlich, K. %A Felix, J. F. %A Franco, O. H. %A Franke, A. %A Freedman, B. I. %A Freitag-Wolf, S. %A Gansevoort, R. T. %A Giedraitis, V. %A G?gele, M. %A Grundner-Culemann, F. %A Gudbjartsson, D. F. %A Gudnason, V. %A Hamet, P. %A Harris, T. B. %A Hicks, A. A. %A Holm, H. %A Foo, V. H. X. %A Hwang, S. J. %A Ikram, M. A. %A Ingelsson, E. %A Jaddoe, V. W. V. %A Jakobsdottir, J. %A Josyula, N. S. %A Jung, B. %A K?h?nen, M. %A Khor, C. C. %A Kiess, W. %A Koenig, W. %A K?rner, A. %A Kovacs, P. %A Kramer, H. %A Kr?mer, B. K. %A Kronenberg, F. %A Lange, L. A. %A Langefeld, C. D. %A Lee, J. J. %A Lehtim?ki, T. %A Lieb, W. %A Lim, S. C. %A Lind, L. %A Lindgren, C. M. %A Liu, J. %A Loeffler, M. %A Lyytik?inen, L. P. %A Mahajan, A. %A Maranville, J. C. %A Mascalzoni, D. %A McMullen, B. %A Meisinger, C. %A Meitinger, T. %A Miliku, K. %A Mook-Kanamori, D. O. %A M?ller-Nurasyid, M. %A Mychaleckyj, J. C. %A Nauck, M. %A Nikus, K. %A Ning, B. %A Noordam, R. %A Connell, J. O. %A Olafsson, I. %A Palmer, N. D. %A Peters, A. %A Podgornaia, A. I. %A Ponte, B. %A Poulain, T. %A Pramstaller, P. P. %A Rabelink, T. J. %A Raffield, L. M. %A Reilly, D. F. %A Rettig, R. %A Rheinberger, M. %A Rice, K. M. %A Rivadeneira, F. %A Runz, H. %A Ryan, K. A. %A Sabanayagam, C. %A Saum, K. U. %A Sch?ttker, B. %A Shaffer, C. M. %A Shi, Y. %A Smith, A. V. %A Strauch, K. %A Stumvoll, M. %A Sun, B. B. %A Szymczak, S. %A Tai, E. S. %A Tan, N. Y. Q. %A Taylor, K. D. %A Teren, A. %A Tham, Y. C. %A Thiery, J. %A Thio, C. H. L. %A Thomsen, H. %A Thorsteinsdottir, U. %A T?njes, A. %A Tremblay, J. %A Uitterlinden, A. G. %A van der Harst, P. %A Verweij, N. %A Vogelezang, S. %A V?lker, U. %A Waldenberger, M. %A Wang, C. %A Wilson, O. D. %A Wong, C. %A Wong, T. Y. %A Yang, Q. %A Yasuda, M. %A Akilesh, S. %A Bochud, M. %A B?ger, C. A. %A Devuyst, O. %A Edwards, T. L. %A Ho, K. %A Morris, A. P. %A Parsa, A. %A Pendergrass, S. A. %A Psaty, B. M. %A Rotter, J. I. %A Stefansson, K. %A Wilson, J. G. %A Susztak, K. %A Snieder, H. %A Heid, I. M. %A Scholz, M. %A Butterworth, A. S. %A Hung, A. M. %A Pattaro, C. %A K?ttgen, A. %X Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria. %B Nat Commun %V 10 %P 4130 %8 09 %G eng %0 Journal Article %J Commun Biol %D 2019 %T {A genome-wide association study identifies genetic loci associated with specific lobar brain volumes %A van der Lee, S. J. %A Knol, M. J. %A Chauhan, G. %A Satizabal, C. L. %A Smith, A. V. %A Hofer, E. %A Bis, J. C. %A Hibar, D. P. %A Hilal, S. %A van den Akker, E. B. %A Arfanakis, K. %A Bernard, M. %A Yanek, L. R. %A Amin, N. %A Crivello, F. %A Cheung, J. W. %A Harris, T. B. %A Saba, Y. %A Lopez, O. L. %A Li, S. %A van der Grond, J. %A Yu, L. %A Paus, T. %A Roshchupkin, G. V. %A Amouyel, P. %A Jahanshad, N. %A Taylor, K. D. %A Yang, Q. %A Mathias, R. A. %A Boehringer, S. %A Mazoyer, B. %A Rice, K. %A Cheng, C. Y. %A Maillard, P. %A van Heemst, D. %A Wong, T. Y. %A Niessen, W. J. %A Beiser, A. S. %A Beekman, M. %A Zhao, W. %A Nyquist, P. A. %A Chen, C. %A Launer, L. J. %A Psaty, B. M. %A Ikram, M. K. %A Vernooij, M. W. %A Schmidt, H. %A Pausova, Z. %A Becker, D. M. %A De Jager, P. L. %A Thompson, P. M. %A van Duijn, C. M. %A Bennett, D. A. %A Slagboom, P. E. %A Schmidt, R. %A Longstreth, W. T. %A Ikram, M. A. %A Seshadri, S. %A Debette, S. %A Gudnason, V. %A Adams, H. H. H. %A DeCarli, C. %X Brain lobar volumes are heritable but genetic studies are limited. We performed genome-wide association studies of frontal, occipital, parietal and temporal lobe volumes in 16,016 individuals, and replicated our findings in 8,789 individuals. We identified six genetic loci associated with specific lobar volumes independent of intracranial volume. Two loci, associated with occipital (6q22.32) and temporal lobe volume (12q14.3), were previously reported to associate with intracranial and hippocampal volume, respectively. We identified four loci previously unknown to affect brain volumes: 3q24 for parietal lobe volume, and 1q22, 4p16.3 and 14q23.1 for occipital lobe volume. The associated variants were located in regions enriched for histone modifications (DAAM1 and THBS3), or close to genes causing Mendelian brain-related diseases (ZIC4 and FGFRL1). No genetic overlap between lobar volumes and neurological or psychiatric diseases was observed. Our findings reveal part of the complex genetics underlying brain development and suggest a role for regulatory regions in determining brain volumes. %B Commun Biol %V 2 %P 285 %G eng %0 Journal Article %J Blood %D 2019 %T A genome-wide association study identifies new loci for factor VII and implicates factor VII in ischemic stroke etiology. %A de Vries, Paul S %A Sabater-Lleal, Maria %A Huffman, Jennifer E %A Marten, Jonathan %A Song, Ci %A Pankratz, Nathan %A Bartz, Traci M %A de Haan, Hugoline G %A Delgado, Graciela E %A Eicher, John D %A Martinez-Perez, Angel %A Ward-Caviness, Cavin K %A Brody, Jennifer A %A Chen, Ming-Huei %A de Maat, Moniek P M %A Frånberg, Mattias %A Gill, Dipender %A Kleber, Marcus E %A Rivadeneira, Fernando %A Soria, José Manuel %A Tang, Weihong %A Tofler, Geoffrey H %A Uitterlinden, André G %A van Hylckama Vlieg, Astrid %A Seshadri, Sudha %A Boerwinkle, Eric %A Davies, Neil M %A Giese, Anne-Katrin %A Ikram, M Kamran %A Kittner, Steven J %A McKnight, Barbara %A Psaty, Bruce M %A Reiner, Alex P %A Sargurupremraj, Muralidharan %A Taylor, Kent D %A Fornage, Myriam %A Hamsten, Anders %A März, Winfried %A Rosendaal, Frits R %A Souto, Juan Carlos %A Dehghan, Abbas %A Johnson, Andrew D %A Morrison, Alanna C %A O'Donnell, Christopher J %A Smith, Nicholas L %X

Factor VII (FVII) is an important component of the coagulation cascade. Few genetic loci regulating FVII activity and/or levels have been discovered to date. We conducted a meta-analysis of 9 genome-wide association studies of plasma FVII levels (7 FVII activity and 2 FVII antigen) among 27 495 participants of European and African ancestry. Each study performed ancestry-specific association analyses. Inverse variance weighted meta-analysis was performed within each ancestry group and then combined for a -ancestry meta-analysis. Our primary analysis included the 7 studies that measured FVII activity, and a secondary analysis included all 9 studies. We provided functional genomic validation for newly identified significant loci by silencing candidate genes in a human liver cell line (HuH7) using small-interfering RNA and then measuring messenger RNA and FVII protein expression. Lastly, we used meta-analysis results to perform Mendelian randomization analysis to estimate the causal effect of FVII activity on coronary artery disease, ischemic stroke (IS), and venous thromboembolism. We identified 2 novel ( and ) and 6 known loci associated with FVII activity, explaining 19.0% of the phenotypic variance. Adding FVII antigen data to the meta-analysis did not result in the discovery of further loci. Silencing in HuH7 cells upregulated FVII, whereas silencing downregulated FVII. Mendelian randomization analyses suggest that FVII activity has a positive causal effect on the risk of IS. Variants at and contribute to FVII activity by regulating expression levels. FVII activity appears to contribute to the etiology of IS in the general population.

%B Blood %V 133 %P 967-977 %8 2019 Feb 28 %G eng %N 9 %R 10.1182/blood-2018-05-849240 %0 Journal Article %J Am J Hypertens %D 2019 %T {Genome-Wide Association Study of Apparent Treatment-Resistant Hypertension in the CHARGE Consortium: The CHARGE Pharmacogenetics Working Group %A Irvin, M. R. %A Sitlani, C. M. %A Floyd, J. S. %A Psaty, B. M. %A Bis, J. C. %A Wiggins, K. L. %A Whitsel, E. A. %A Sturmer, T. %A Stewart, J. %A Raffield, L. %A Sun, F. %A Liu, C. T. %A Xu, H. %A Cupples, A. L. %A Tanner, R. M. %A Rossing, P. %A Smith, A. %A Zilh?o, N. R. %A Launer, L. J. %A Noordam, R. %A Rotter, J. I. %A Yao, J. %A Li, X. %A Guo, X. %A Limdi, N. %A Sundaresan, A. %A Lange, L. %A Correa, A. %A Stott, D. J. %A Ford, I. %A Jukema, J. W. %A Gudnason, V. %A Mook-Kanamori, D. O. %A Trompet, S. %A Palmas, W. %A Warren, H. R. %A Hellwege, J. N. %A Giri, A. %A O'Donnell, C. %A Hung, A. M. %A Edwards, T. L. %A Ahluwalia, T. S. %A Arnett, D. K. %A Avery, C. L. %X {Only a handful of genetic discovery efforts in apparent treatment-resistant hypertension (aTRH) have been described.\ We conducted a case-control genome-wide association study of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg) or 4 or more medication classes regardless of BP control (nEA = 931 %B Am J Hypertens %V 32 %P 1146–1153 %8 11 %G eng %0 Journal Article %J Am J Hypertens %D 2019 %T Genome-Wide Association Study of Apparent Treatment-Resistant Hypertension in the CHARGE Consortium: The CHARGE Pharmacogenetics Working Group. %A Irvin, Marguerite R %A Sitlani, Colleen M %A Floyd, James S %A Psaty, Bruce M %A Bis, Joshua C %A Wiggins, Kerri L %A Whitsel, Eric A %A Stürmer, Til %A Stewart, James %A Raffield, Laura %A Sun, Fangui %A Liu, Ching-Ti %A Xu, Hanfei %A Cupples, Adrienne L %A Tanner, Rikki M %A Rossing, Peter %A Smith, Albert %A Zilhão, Nuno R %A Launer, Lenore J %A Noordam, Raymond %A Rotter, Jerome I %A Yao, Jie %A Li, Xiaohui %A Guo, Xiuqing %A Limdi, Nita %A Sundaresan, Aishwarya %A Lange, Leslie %A Correa, Adolfo %A Stott, David J %A Ford, Ian %A Jukema, J Wouter %A Gudnason, Vilmundur %A Mook-Kanamori, Dennis O %A Trompet, Stella %A Palmas, Walter %A Warren, Helen R %A Hellwege, Jacklyn N %A Giri, Ayush %A O'donnell, Christopher %A Hung, Adriana M %A Edwards, Todd L %A Ahluwalia, Tarunveer S %A Arnett, Donna K %A Avery, Christy L %K Aged %K Antihypertensive Agents %K Black or African American %K Blood Pressure %K Case-Control Studies %K DNA (Cytosine-5-)-Methyltransferases %K DNA Methyltransferase 3A %K DNA-Binding Proteins %K Drug Resistance %K Dystrophin-Associated Proteins %K Europe %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Hypertension %K Male %K Middle Aged %K Myosin Heavy Chains %K Myosin Type V %K Neuropeptides %K Pharmacogenetics %K Pharmacogenomic Variants %K Polymorphism, Single Nucleotide %K Risk Assessment %K Risk Factors %K Transcription Factors %K United States %K White People %X

BACKGROUND: Only a handful of genetic discovery efforts in apparent treatment-resistant hypertension (aTRH) have been described.

METHODS: We conducted a case-control genome-wide association study of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg) or 4 or more medication classes regardless of BP control (nEA = 931, nAA = 228). Both a normotensive control group and a treatment-responsive control group were considered in separate analyses. Normotensive controls were untreated (nEA = 14,210, nAA = 2,480) and had systolic BP/diastolic BP < 140/90 mm Hg. Treatment-responsive controls (nEA = 5,266, nAA = 1,817) had BP at goal (<140/90 mm Hg), while treated with one antihypertensive medication class. Individual cohorts used logistic regression with adjustment for age, sex, study site, and principal components for ancestry to examine the association of single-nucleotide polymorphisms with case-control status. Inverse variance-weighted fixed-effects meta-analyses were carried out using METAL.

RESULTS: The known hypertension locus, CASZ1, was a top finding among EAs (P = 1.1 × 10-8) and in the race-combined analysis (P = 1.5 × 10-9) using the normotensive control group (rs12046278, odds ratio = 0.71 (95% confidence interval: 0.6-0.8)). Single-nucleotide polymorphisms in this locus were robustly replicated in the Million Veterans Program (MVP) study in consideration of a treatment-responsive control group. There were no statistically significant findings for the discovery analyses including treatment-responsive controls.

CONCLUSION: This genomic discovery effort for aTRH identified CASZ1 as an aTRH risk locus.

%B Am J Hypertens %V 32 %P 1146-1153 %8 2019 Nov 15 %G eng %N 12 %R 10.1093/ajh/hpz150 %0 Journal Article %J Clin Pharmacol Ther %D 2019 %T Genomewide Association Study of Statin-Induced Myopathy in Patients Recruited Using the UK Clinical Practice Research Datalink. %A Carr, Daniel F %A Francis, Ben %A Jorgensen, Andrea L %A Zhang, Eunice %A Chinoy, Hector %A Heckbert, Susan R %A Bis, Joshua C %A Brody, Jennifer A %A Floyd, James S %A Psaty, Bruce M %A Molokhia, Mariam %A Lapeyre-Mestre, Maryse %A Conforti, Anita %A Alfirevic, Ana %A van Staa, Tjeerd %A Pirmohamed, Munir %K Adverse Drug Reaction Reporting Systems %K Case-Control Studies %K Databases, Factual %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Hydroxymethylglutaryl-CoA Reductase Inhibitors %K Liver-Specific Organic Anion Transporter 1 %K Muscular Diseases %K Pharmacogenomic Variants %K Polymorphism, Single Nucleotide %K Reproducibility of Results %K Risk Factors %K Severity of Illness Index %K United Kingdom %X

Statins can be associated with myopathy. We have undertaken a genomewide association study (GWAS) to discover and validate genetic risk factors for statin-induced myopathy in a "real-world" setting. One hundred thirty-five patients with statin myopathy recruited via the UK Clinical Practice Research Datalink were genotyped using the Illumina OmniExpress Exome version 1.0 Bead Chip and compared with the Wellcome Trust Case-Control Consortium (n = 2,501). Nominally statistically significant single nucleotide polymorphism (SNP) signals in the GWAS (P < 5 × 10 ) were further evaluated in several independent cohorts (comprising 332 cases and 449 drug-tolerant controls). Only one (rs4149056/c.521C>T in the SLCO1B1 gene) SNP was genomewide significant in the severe myopathy (creatine kinase > 10 × upper limit of normal or rhabdomyolysis) group (P = 2.55 × 10 ; odds ratio 5.15; 95% confidence interval 3.13-8.45). The association with SLCO1B1 was present for several statins and replicated in the independent validation cohorts. The data highlight the role of SLCO1B1 c.521C>T SNP as a replicable genetic risk factor for statin myopathy. No other novel genetic risk factors with a similar effect size were identified.

%B Clin Pharmacol Ther %V 106 %P 1353-1361 %8 2019 12 %G eng %N 6 %R 10.1002/cpt.1557 %0 Journal Article %J Circulation %D 2019 %T {Genome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels %A Sabater-Lleal, M. %A Huffman, J. E. %A de Vries, P. S. %A Marten, J. %A Mastrangelo, M. A. %A Song, C. %A Pankratz, N. %A Ward-Caviness, C. K. %A Yanek, L. R. %A Trompet, S. %A Delgado, G. E. %A Guo, X. %A Bartz, T. M. %A Martinez-Perez, A. %A Germain, M. %A de Haan, H. G. %A Ozel, A. B. %A Polasek, O. %A Smith, A. V. %A Eicher, J. D. %A Reiner, A. P. %A Tang, W. %A Davies, N. M. %A Stott, D. J. %A Rotter, J. I. %A Tofler, G. H. %A Boerwinkle, E. %A de Maat, M. P. M. %A Kleber, M. E. %A Welsh, P. %A Brody, J. A. %A Chen, M. H. %A Vaidya, D. %A Soria, J. M. %A Suchon, P. %A van Hylckama Vlieg, A. %A Desch, K. C. %A Kolcic, I. %A Joshi, P. K. %A Launer, L. J. %A Harris, T. B. %A Campbell, H. %A Rudan, I. %A Becker, D. M. %A Li, J. Z. %A Rivadeneira, F. %A Uitterlinden, A. G. %A Hofman, A. %A Franco, O. H. %A Cushman, M. %A Psaty, B. M. %A Morange, P. E. %A McKnight, B. %A Chong, M. R. %A Fernandez-Cadenas, I. %A Rosand, J. %A Lindgren, A. %A Gudnason, V. %A Wilson, J. F. %A Hayward, C. %A Ginsburg, D. %A Fornage, M. %A Rosendaal, F. R. %A Souto, J. C. %A Becker, L. C. %A Jenny, N. S. %A M?rz, W. %A Jukema, J. W. %A Dehghan, A. %A Tr?gou?t, D. A. %A Morrison, A. C. %A Johnson, A. D. %A O'Donnell, C. J. %A Strachan, D. P. %A Lowenstein, C. J. %A Smith, N. L. %X Factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are associated with risk of arterial and venous thrombosis and with hemorrhagic disorders. We aimed to identify and functionally test novel genetic associations regulating plasma FVIII and VWF.\ We meta-analyzed genome-wide association results from 46 354 individuals of European, African, East Asian, and Hispanic ancestry. All studies performed linear regression analysis using an additive genetic model and associated ≈35 million imputed variants with natural log-transformed phenotype levels. In vitro gene silencing in cultured endothelial cells was performed for candidate genes to provide additional evidence on association and function. Two-sample Mendelian randomization analyses were applied to test the causal role of FVIII and VWF plasma levels on the risk of arterial and venous thrombotic events.\ We identified 13 novel genome-wide significant ( P≤2.5×10-8) associations, 7 with FVIII levels ( FCHO2/TMEM171/TNPO1, HLA, SOX17/RP1, LINC00583/NFIB, RAB5C-KAT2A, RPL3/TAB1/SYNGR1, and ARSA) and 11 with VWF levels ( PDHB/PXK/KCTD6, SLC39A8, FCHO2/TMEM171/TNPO1, HLA, GIMAP7/GIMAP4, OR13C5/NIPSNAP, DAB2IP, C2CD4B, RAB5C-KAT2A, TAB1/SYNGR1, and ARSA), beyond 10 previously reported associations with these phenotypes. Functional validation provided further evidence of association for all loci on VWF except ARSA and DAB2IP. Mendelian randomization suggested causal effects of plasma FVIII activity levels on venous thrombosis and coronary artery disease risk and plasma VWF levels on ischemic stroke risk.\ The meta-analysis identified 13 novel genetic loci regulating FVIII and VWF plasma levels, 10 of which we validated functionally. We provide some evidence for a causal role of these proteins in thrombotic events. %B Circulation %V 139 %P 620–635 %8 01 %G eng %0 Journal Article %J Pharmacogenomics J %D 2019 %T Genome-wide meta-analysis of variant-by-diuretic interactions as modulators of lipid traits in persons of European and African ancestry. %A de Las Fuentes, L %A Sung, Y J %A Sitlani, C M %A Avery, C L %A Bartz, T M %A Keyser, C de %A Evans, D S %A Li, X %A Musani, S K %A Ruiter, R %A Smith, A V %A Sun, F %A Trompet, S %A Xu, H %A Arnett, D K %A Bis, J C %A Broeckel, U %A Busch, E L %A Chen, Y-D I %A Correa, A %A Cummings, S R %A Floyd, J S %A Ford, I %A Guo, X %A Harris, T B %A Ikram, M A %A Lange, L %A Launer, L J %A Reiner, A P %A Schwander, K %A Smith, N L %A Sotoodehnia, N %A Stewart, J D %A Stott, D J %A Stürmer, T %A Taylor, K D %A Uitterlinden, A %A Vasan, R S %A Wiggins, K L %A Cupples, L A %A Gudnason, V %A Heckbert, S R %A Jukema, J W %A Liu, Y %A Psaty, B M %A Rao, D C %A Rotter, J I %A Stricker, B %A Wilson, J G %A Whitsel, E A %X

Hypertension (HTN) is a significant risk factor for cardiovascular morbidity and mortality. Metabolic abnormalities, including adverse cholesterol and triglycerides (TG) profiles, are frequent comorbid findings with HTN and contribute to cardiovascular disease. Diuretics, which are used to treat HTN and heart failure, have been associated with worsening of fasting lipid concentrations. Genome-wide meta-analyses with 39,710 European-ancestry (EA) individuals and 9925 African-ancestry (AA) individuals were performed to identify genetic variants that modify the effect of loop or thiazide diuretic use on blood lipid concentrations. Both longitudinal and cross sectional data were used to compute cohort-specific interaction results, which were then combined through meta-analysis in each ancestry. These ancestry-specific results were further combined through trans-ancestry meta-analysis. Analysis of EA data identified two genome-wide significant (p < 5 × 10) loci with single nucleotide variant (SNV)-loop diuretic interaction on TG concentrations (including COL11A1). Analysis of AA data identified one genome-wide significant locus adjacent to BMP2 with SNV-loop diuretic interaction on TG concentrations. Trans-ancestry analysis strengthened evidence of association for SNV-loop diuretic interaction at two loci (KIAA1217 and BAALC). There were few significant SNV-thiazide diuretic interaction associations on TG concentrations and for either diuretic on cholesterol concentrations. Several promising loci were identified that may implicate biologic pathways that contribute to adverse metabolic side effects from diuretic therapy.

%B Pharmacogenomics J %8 2019 Dec 06 %G eng %R 10.1038/s41397-019-0132-y %0 Journal Article %J Blood %D 2019 %T Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism. %A Lindström, Sara %A Wang, Lu %A Smith, Erin N %A Gordon, William %A van Hylckama Vlieg, Astrid %A de Andrade, Mariza %A Brody, Jennifer A %A Pattee, Jack W %A Haessler, Jeffrey %A Brumpton, Ben M %A Chasman, Daniel I %A Suchon, Pierre %A Chen, Ming-Huei %A Turman, Constance %A Germain, Marine %A Wiggins, Kerri L %A MacDonald, James %A Braekkan, Sigrid K %A Armasu, Sebastian M %A Pankratz, Nathan %A Jackson, Rebecca D %A Nielsen, Jonas B %A Giulianini, Franco %A Puurunen, Marja K %A Ibrahim, Manal %A Heckbert, Susan R %A Damrauer, Scott M %A Natarajan, Pradeep %A Klarin, Derek %A de Vries, Paul S %A Sabater-Lleal, Maria %A Huffman, Jennifer E %A Bammler, Theo K %A Frazer, Kelly A %A McCauley, Bryan M %A Taylor, Kent %A Pankow, James S %A Reiner, Alexander P %A Gabrielsen, Maiken E %A Deleuze, Jean-Francois %A O'Donnell, Chris J %A Kim, Jihye %A McKnight, Barbara %A Kraft, Peter %A Hansen, John-Bjarne %A Rosendaal, Frits R %A Heit, John A %A Psaty, Bruce M %A Tang, Weihong %A Kooperberg, Charles %A Hveem, Kristian %A Ridker, Paul M %A Morange, Pierre-Emmanuel %A Johnson, Andrew D %A Kabrhel, Christopher %A Trégouët, David-Alexandre %A Smith, Nicholas L %X

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality. To advance our understanding of the biology contributing to VTE, we conducted a genome-wide association study (GWAS) of VTE and a transcriptome-wide association study (TWAS) based on imputed gene expression from whole blood and liver. We meta-analyzed GWAS data from 18 studies for 30 234 VTE cases and 172 122 controls and assessed the association between 12 923 718 genetic variants and VTE. We generated variant prediction scores of gene expression from whole blood and liver tissue and assessed them for association with VTE. Mendelian randomization analyses were conducted for traits genetically associated with novel VTE loci. We identified 34 independent genetic signals for VTE risk from GWAS meta-analysis, of which 14 are newly reported associations. This included 11 newly associated genetic loci (C1orf198, PLEK, OSMR-AS1, NUGGC/SCARA5, GRK5, MPHOSPH9, ARID4A, PLCG2, SMG6, EIF5A, and STX10) of which 6 replicated, and 3 new independent signals in 3 known genes. Further, TWAS identified 5 additional genetic loci with imputed gene expression levels differing between cases and controls in whole blood (SH2B3, SPSB1, RP11-747H7.3, RP4-737E23.2) and in liver (ERAP1). At some GWAS loci, we found suggestive evidence that the VTE association signal for novel and previously known regions colocalized with expression quantitative trait locus signals. Mendelian randomization analyses suggested that blood traits may contribute to the underlying risk of VTE. To conclude, we identified 16 novel susceptibility loci for VTE; for some loci, the association signals are likely mediated through gene expression of nearby genes.

%B Blood %V 134 %P 1645-1657 %8 2019 Nov 07 %G eng %N 19 %R 10.1182/blood.2019000435 %0 Journal Article %J Elife %D 2019 %T Genomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chances. %A Timmers, Paul Rhj %A Mounier, Ninon %A Läll, Kristi %A Fischer, Krista %A Ning, Zheng %A Feng, Xiao %A Bretherick, Andrew D %A Clark, David W %A Agbessi, M %A Ahsan, H %A Alves, I %A Andiappan, A %A Awadalla, P %A Battle, A %A Bonder, M J %A Boomsma, D %A Christiansen, M %A Claringbould, A %A Deelen, P %A van Dongen, J %A Esko, T %A Favé, M %A Franke, L %A Frayling, T %A Gharib, S A %A Gibson, G %A Hemani, G %A Jansen, R %A Kalnapenkis, A %A Kasela, S %A Kettunen, J %A Kim, Y %A Kirsten, H %A Kovacs, P %A Krohn, K %A Kronberg-Guzman, J %A Kukushkina, V %A Kutalik, Z %A Kähönen, M %A Lee, B %A Lehtimäki, T %A Loeffler, M %A Marigorta, U %A Metspalu, A %A van Meurs, J %A Milani, L %A Müller-Nurasyid, M %A Nauck, M %A Nivard, M %A Penninx, B %A Perola, M %A Pervjakova, N %A Pierce, B %A Powell, J %A Prokisch, H %A Psaty, B M %A Raitakari, O %A Ring, S %A Ripatti, S %A Rotzschke, O %A Ruëger, S %A Saha, A %A Scholz, M %A Schramm, K %A Seppälä, I %A Stumvoll, M %A Sullivan, P %A Teumer, A %A Thiery, J %A Tong, L %A Tönjes, A %A Verlouw, J %A Visscher, P M %A Võsa, U %A Völker, U %A Yaghootkar, H %A Yang, J %A Zeng, B %A Zhang, F %A Agbessi, M %A Ahsan, H %A Alves, I %A Andiappan, A %A Awadalla, P %A Battle, A %A Bonder, M J %A Boomsma, D %A Christiansen, M %A Claringbould, A %A Deelen, P %A van Dongen, J %A Esko, T %A Favé, M %A Franke, L %A Frayling, T %A Gharib, S A %A Gibson, G %A Hemani, G %A Jansen, R %A Kalnapenkis, A %A Kasela, S %A Kettunen, J %A Kim, Y %A Kirsten, H %A Kovacs, P %A Krohn, K %A Kronberg-Guzman, J %A Kukushkina, V %A Kutalik, Z %A Kähönen, M %A Lee, B %A Lehtimäki, T %A Loeffler, M %A Marigorta, U %A Metspalu, A %A van Meurs, J %A Milani, L %A Müller-Nurasyid, M %A Nauck, M %A Nivard, M %A Penninx, B %A Perola, M %A Pervjakova, N %A Pierce, B %A Powell, J %A Prokisch, H %A Psaty, B M %A Raitakari, O %A Ring, S %A Ripatti, S %A Rotzschke, O %A Ruëger, S %A Saha, A %A Scholz, M %A Schramm, K %A Seppälä, I %A Stumvoll, M %A Sullivan, P %A Teumer, A %A Thiery, J %A Tong, L %A Tönjes, A %A Verlouw, J %A Visscher, P M %A Võsa, U %A Völker, U %A Yaghootkar, H %A Yang, J %A Zeng, B %A Zhang, F %A Shen, Xia %A Esko, Tõnu %A Kutalik, Zoltán %A Wilson, James F %A Joshi, Peter K %X

We use a genome-wide association of 1 million parental lifespans of genotyped subjects and data on mortality risk factors to validate previously unreplicated findings near , , , , , and 13q21.31, and identify and replicate novel findings near , , and . We also validate previous findings near 5q33.3/ and , whilst finding contradictory evidence at other loci. Gene set and cell-specific analyses show that expression in foetal brain cells and adult dorsolateral prefrontal cortex is enriched for lifespan variation, as are gene pathways involving lipid proteins and homeostasis, vesicle-mediated transport, and synaptic function. Individual genetic variants that increase dementia, cardiovascular disease, and lung cancer - but not other cancers - explain the most variance. Resulting polygenic scores show a mean lifespan difference of around five years of life across the deciles.

Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

%B Elife %V 8 %8 2019 Jan 15 %G eng %R 10.7554/eLife.39856 %0 Journal Article %J Am J Epidemiol %D 2019 %T Heterogeneous Exposure Associations in Observational Cohort Studies: The Example of Blood Pressure in Older Adults. %A Odden, Michelle C %A Rawlings, Andreea M %A Khodadadi, Abtin %A Fern, Xiaoli %A Shlipak, Michael G %A Bibbins-Domingo, Kirsten %A Covinsky, Kenneth %A Kanaya, Alka M %A Lee, Anne %A Haan, Mary N %A Newman, Anne B %A Psaty, Bruce M %A Peralta, Carmen A %X

Heterogeneous exposure associations (HEAs) can be defined as differences in the association of a exposure with an outcome among subgroups that differ by a set of characteristics. This manuscript intends to foster discussion of HEAs in the epidemiological literature, and present a variant of the random forest algorithm that can be used to identify HEAs. We demonstrate the use of this algorithm in the setting of the association of systolic blood pressure and death in older adults. The training set included pooled data from the baseline examination of the Cardiovascular Health Study (1989-1993), the Health, Aging, and Body Composition study (1997-1998), and the Sacramento Area Latino Study on Aging (1998-1999). The test set included data from the National Health and Nutrition Examination Survey (1999-2002). The hazard ratios ranged from 1.25 (95% CI: 1.13, 1.37) per 10 mmHg higher systolic blood pressure in men aged ≤67 years with diastolic blood pressure >80 mmHg, to 1.00 (0.96, 1.03) in women with creatinine <0.7 mg/dL and a history of hypertension. HEAs have the potential to improve our understanding of disease mechanisms in diverse populations, and guide the design of randomized controlled trials to control exposures in heterogeneous populations.

%B Am J Epidemiol %8 2019 Oct 08 %G eng %R 10.1093/aje/kwz218 %0 Journal Article %J Clin Kidney J %D 2019 %T Higher albumin:creatinine ratio and lower estimated glomerular filtration rate are potential risk factors for decline of physical performance in the elderly: the Cardiovascular Health Study. %A Bůzková, Petra %A Barzilay, Joshua I %A Fink, Howard A %A Robbins, John A %A Cauley, Jane A %A Ix, Joachim H %A Mukamal, Kenneth J %X

Introduction: Mildly reduced renal function and elevated urine protein levels are each prospectively associated with hip fracture risk in older adults. Here we determine whether these markers are associated with reduced appendicular muscle performance.

Methods: We prospectively examined the associations of urine albumin:creatinine ratio (ACR) and reduced estimated glomerular filtration rate (eGFR) with longitudinal changes in grip strength and gait speed >2 years in 2317 older community-dwelling men and women (median age 77 years). The median ACR was 9.8 [interquartile range (IQR) 5.40-21.50] mg/g creatinine and the median eGFR was 71.6 (IQR 59.1-83.56) mL/min/1.73 m. Models were adjusted for demographic factors, clinical history and biochemical measures in four candidate pathways: diabetes, oxidative stress, inflammation and fibrosis.

Results: In demographic- and covariate-adjusted models, a 2-fold higher baseline urine ACR was associated with longitudinal changes of -0.17 kg [95% confidence interval (CI) -0.29 to -0.06) in grip strength and -1.10 cm/s (95% CI -1.67 to -0.53) gait speed per year. Corresponding estimates for a 10 mL/min/1.73 m lower baseline eGFR were -0.13 kg (95% CI -0.23 to -0.04) and -0.89 cm/s (95% CI -1.37 to -0.40), respectively. The associations of a 2-fold higher baseline ACR and a 10 mL/min/1.73 m lower baseline eGFR using cystatin C with grip strength and gait speed were equivalent to ∼1.2-1.9 additional years of age. Adjustment for covariates in candidate pathways did not attenuate these estimates.

Conclusions: In older adults, higher ACR and lower eGFR are potential risk factors for a decline of physical performance >2 years.

%B Clin Kidney J %V 12 %P 788-794 %8 2019 Dec %G eng %N 6 %R 10.1093/ckj/sfz024 %0 Journal Article %J Am J Hum Genet %D 2019 %T Impact of Rare and Common Genetic Variants on Diabetes Diagnosis by Hemoglobin A1c in Multi-Ancestry Cohorts: The Trans-Omics for Precision Medicine Program. %A Sarnowski, Chloe %A Leong, Aaron %A Raffield, Laura M %A Wu, Peitao %A de Vries, Paul S %A DiCorpo, Daniel %A Guo, Xiuqing %A Xu, Huichun %A Liu, Yongmei %A Zheng, Xiuwen %A Hu, Yao %A Brody, Jennifer A %A Goodarzi, Mark O %A Hidalgo, Bertha A %A Highland, Heather M %A Jain, Deepti %A Liu, Ching-Ti %A Naik, Rakhi P %A O'Connell, Jeffrey R %A Perry, James A %A Porneala, Bianca C %A Selvin, Elizabeth %A Wessel, Jennifer %A Psaty, Bruce M %A Curran, Joanne E %A Peralta, Juan M %A Blangero, John %A Kooperberg, Charles %A Mathias, Rasika %A Johnson, Andrew D %A Reiner, Alexander P %A Mitchell, Braxton D %A Cupples, L Adrienne %A Vasan, Ramachandran S %A Correa, Adolfo %A Morrison, Alanna C %A Boerwinkle, Eric %A Rotter, Jerome I %A Rich, Stephen S %A Manning, Alisa K %A Dupuis, Josée %A Meigs, James B %X

Hemoglobin A1c (HbA1c) is widely used to diagnose diabetes and assess glycemic control in individuals with diabetes. However, nonglycemic determinants, including genetic variation, may influence how accurately HbA1c reflects underlying glycemia. Analyzing the NHLBI Trans-Omics for Precision Medicine (TOPMed) sequence data in 10,338 individuals from five studies and four ancestries (6,158 Europeans, 3,123 African-Americans, 650 Hispanics, and 407 East Asians), we confirmed five regions associated with HbA1c (GCK in Europeans and African-Americans, HK1 in Europeans and Hispanics, FN3K and/or FN3KRP in Europeans, and G6PD in African-Americans and Hispanics) and we identified an African-ancestry-specific low-frequency variant (rs1039215 in HBG2 and HBE1, minor allele frequency (MAF) = 0.03). The most associated G6PD variant (rs1050828-T, p.Val98Met, MAF = 12% in African-Americans, MAF = 2% in Hispanics) lowered HbA1c (-0.88% in hemizygous males, -0.34% in heterozygous females) and explained 23% of HbA1c variance in African-Americans and 4% in Hispanics. Additionally, we identified a rare distinct G6PD coding variant (rs76723693, p.Leu353Pro, MAF = 0.5%; -0.98% in hemizygous males, -0.46% in heterozygous females) and detected significant association with HbA1c when aggregating rare missense variants in G6PD. We observed similar magnitude and direction of effects for rs1039215 (HBG2) and rs76723693 (G6PD) in the two largest TOPMed African American cohorts, and we replicated the rs76723693 association in the UK Biobank African-ancestry participants. These variants in G6PD and HBG2 were monomorphic in the European and Asian samples. African or Hispanic ancestry individuals carrying G6PD variants may be underdiagnosed for diabetes when screened with HbA1c. Thus, assessment of these variants should be considered for incorporation into precision medicine approaches for diabetes diagnosis.

%B Am J Hum Genet %V 105 %P 706-718 %8 2019 Oct 03 %G eng %N 4 %R 10.1016/j.ajhg.2019.08.010 %0 Journal Article %J Genet Epidemiol %D 2019 %T A large-scale exome array analysis of venous thromboembolism. %A Lindström, Sara %A Brody, Jennifer A %A Turman, Constance %A Germain, Marine %A Bartz, Traci M %A Smith, Erin N %A Chen, Ming-Huei %A Puurunen, Marja %A Chasman, Daniel %A Hassler, Jeffrey %A Pankratz, Nathan %A Basu, Saonli %A Guan, Weihua %A Gyorgy, Beata %A Ibrahim, Manal %A Empana, Jean-Philippe %A Olaso, Robert %A Jackson, Rebecca %A Braekkan, Sigrid K %A McKnight, Barbara %A Deleuze, Jean-Francois %A O'Donnell, Cristopher J %A Jouven, Xavier %A Frazer, Kelly A %A Psaty, Bruce M %A Wiggins, Kerri L %A Taylor, Kent %A Reiner, Alexander P %A Heckbert, Susan R %A Kooperberg, Charles %A Ridker, Paul %A Hansen, John-Bjarne %A Tang, Weihong %A Johnson, Andrew D %A Morange, Pierre-Emmanuel %A Trégouët, David A %A Kraft, Peter %A Smith, Nicholas L %A Kabrhel, Christopher %X

Although recent Genome-Wide Association Studies have identified novel associations for common variants, there has been no comprehensive exome-wide search for low-frequency variants that affect the risk of venous thromboembolism (VTE). We conducted a meta-analysis of 11 studies comprising 8,332 cases and 16,087 controls of European ancestry and 382 cases and 1,476 controls of African American ancestry genotyped with the Illumina HumanExome BeadChip. We used the seqMeta package in R to conduct single variant and gene-based rare variant tests. In the single variant analysis, we limited our analysis to the 64,794 variants with at least 40 minor alleles across studies (minor allele frequency [MAF] ~0.08%). We confirmed associations with previously identified VTE loci, including ABO, F5, F11, and FGA. After adjusting for multiple testing, we observed no novel significant findings in single variant or gene-based analysis. Given our sample size, we had greater than 80% power to detect minimum odds ratios greater than 1.5 and 1.8 for a single variant with MAF of 0.01 and 0.005, respectively. Larger studies and sequence data may be needed to identify novel low-frequency and rare variants associated with VTE risk.

%B Genet Epidemiol %8 2019 Jan 19 %G eng %R 10.1002/gepi.22187 %0 Journal Article %J Nephrol Dial Transplant %D 2019 %T {Low thyroid function is not associated with an accelerated deterioration in renal function %A Meuwese, C. L. %A van Diepen, M. %A Cappola, A. R. %A Sarnak, M. J. %A Shlipak, M. G. %A Bauer, D. C. %A Fried, L. P. %A Iacoviello, M. %A Vaes, B. %A Degryse, J. %A Khaw, K. T. %A Luben, R. N. %A ?svold, B. O. %A Bj?ro, T. %A Vatten, L. J. %A de Craen, A. J. M. %A Trompet, S. %A Iervasi, G. %A Molinaro, S. %A Ceresini, G. %A Ferrucci, L. %A Dullaart, R. P. F. %A Bakker, S. J. L. %A Jukema, J. W. %A Kearney, P. M. %A Stott, D. J. %A Peeters, R. P. %A Franco, O. H. %A V?lzke, H. %A Walsh, J. P. %A Bremner, A. %A Sgarbi, J. A. %A Maciel, R. M. B. %A Imaizumi, M. %A Ohishi, W. %A Dekker, F. W. %A Rodondi, N. %A Gussekloo, J. %A den Elzen, W. P. J. %X Chronic kidney disease (CKD) is frequently accompanied by thyroid hormone dysfunction. It is currently unclear whether these alterations are the cause or consequence of CKD. This study aimed at studying the effect of thyroid hormone alterations on renal function in cross-sectional and longitudinal analyses in individuals from all adult age groups.\ Individual participant data (IPD) from 16 independent cohorts having measured thyroid stimulating hormone, free thyroxine levels and creatinine levels were included. Thyroid hormone status was defined using clinical cut-off values. Estimated glomerular filtration rates (eGFR) were calculated by means of the four-variable Modification of Diet in Renal Disease (MDRD) formula. For this IPD meta-analysis, eGFR at baseline and eGFR change during follow-up were computed by fitting linear regression models and linear mixed models in each cohort separately. Effect estimates were pooled using random effects models.\ A total of 72 856 individuals from 16 different cohorts were included. At baseline, individuals with overt hypothyroidism (n = 704) and subclinical hypothyroidism (n = 3356) had a average (95% confidence interval) -4.07 (-6.37 to -1.78) and -2.40 (-3.78 to -1.02) mL/min/1.73 m2 lower eGFR as compared with euthyroid subjects (n = 66 542). In (subclinical) hyperthyroid subjects (n = 2254), average eGFR was 3.01 (1.50-4.52) mL/min/1.73 m2 higher. During 329 713 patient years of follow-up, eGFR did not decline more rapidly in individuals with low thyroid function compared with individuals with normal thyroid function.\ Low thyroid function is not associated with a deterioration of renal function. The cross-sectional association may be explained by renal dysfunction causing thyroid hormone alterations. %B Nephrol Dial Transplant %V 34 %P 650–659 %8 04 %G eng %0 Journal Article %J PLoS One %D 2019 %T Mendelian randomization evaluation of causal effects of fibrinogen on incident coronary heart disease. %A Ward-Caviness, Cavin K %A de Vries, Paul S %A Wiggins, Kerri L %A Huffman, Jennifer E %A Yanek, Lisa R %A Bielak, Lawrence F %A Giulianini, Franco %A Guo, Xiuqing %A Kleber, Marcus E %A Kacprowski, Tim %A Groß, Stefan %A Petersman, Astrid %A Davey Smith, George %A Hartwig, Fernando P %A Bowden, Jack %A Hemani, Gibran %A Müller-Nuraysid, Martina %A Strauch, Konstantin %A Koenig, Wolfgang %A Waldenberger, Melanie %A Meitinger, Thomas %A Pankratz, Nathan %A Boerwinkle, Eric %A Tang, Weihong %A Fu, Yi-Ping %A Johnson, Andrew D %A Song, Ci %A de Maat, Moniek P M %A Uitterlinden, André G %A Franco, Oscar H %A Brody, Jennifer A %A McKnight, Barbara %A Chen, Yii-Der Ida %A Psaty, Bruce M %A Mathias, Rasika A %A Becker, Diane M %A Peyser, Patricia A %A Smith, Jennifer A %A Bielinski, Suzette J %A Ridker, Paul M %A Taylor, Kent D %A Yao, Jie %A Tracy, Russell %A Delgado, Graciela %A Trompet, Stella %A Sattar, Naveed %A Jukema, J Wouter %A Becker, Lewis C %A Kardia, Sharon L R %A Rotter, Jerome I %A März, Winfried %A Dörr, Marcus %A Chasman, Daniel I %A Dehghan, Abbas %A O'Donnell, Christopher J %A Smith, Nicholas L %A Peters, Annette %A Morrison, Alanna C %X

BACKGROUND: Fibrinogen is an essential hemostatic factor and cardiovascular disease risk factor. Early attempts at evaluating the causal effect of fibrinogen on coronary heart disease (CHD) and myocardial infraction (MI) using Mendelian randomization (MR) used single variant approaches, and did not take advantage of recent genome-wide association studies (GWAS) or multi-variant, pleiotropy robust MR methodologies.

METHODS AND FINDINGS: We evaluated evidence for a causal effect of fibrinogen on both CHD and MI using MR. We used both an allele score approach and pleiotropy robust MR models. The allele score was composed of 38 fibrinogen-associated variants from recent GWAS. Initial analyses using the allele score used a meta-analysis of 11 European-ancestry prospective cohorts, free of CHD and MI at baseline, to examine incidence CHD and MI. We also applied 2 sample MR methods with data from a prevalent CHD and MI GWAS. Results are given in terms of the hazard ratio (HR) or odds ratio (OR), depending on the study design, and associated 95% confidence interval (CI). In single variant analyses no causal effect of fibrinogen on CHD or MI was observed. In multi-variant analyses using incidence CHD cases and the allele score approach, the estimated causal effect (HR) of a 1 g/L higher fibrinogen concentration was 1.62 (CI = 1.12, 2.36) when using incident cases and the allele score approach. In 2 sample MR analyses that accounted for pleiotropy, the causal estimate (OR) was reduced to 1.18 (CI = 0.98, 1.42) and 1.09 (CI = 0.89, 1.33) in the 2 most precise (smallest CI) models, out of 4 models evaluated. In the 2 sample MR analyses for MI, there was only very weak evidence of a causal effect in only 1 out of 4 models.

CONCLUSIONS: A small causal effect of fibrinogen on CHD is observed using multi-variant MR approaches which account for pleiotropy, but not single variant MR approaches. Taken together, results indicate that even with large sample sizes and multi-variant approaches MR analyses still cannot exclude the null when estimating the causal effect of fibrinogen on CHD, but that any potential causal effect is likely to be much smaller than observed in epidemiological studies.

%B PLoS One %V 14 %P e0216222 %8 2019 %G eng %N 5 %R 10.1371/journal.pone.0216222 %0 Journal Article %J Nat Commun %D 2019 %T {A meta-analysis of genome-wide association studies identifies multiple longevity genes %A Deelen, J. %A Evans, D. S. %A Arking, D. E. %A Tesi, N. %A Nygaard, M. %A Liu, X. %A Wojczynski, M. K. %A Biggs, M. L. %A van der Spek, A. %A Atzmon, G. %A Ware, E. B. %A Sarnowski, C. %A Smith, A. V. %A Sepp?l?, I. %A Cordell, H. J. %A Dose, J. %A Amin, N. %A Arnold, A. M. %A Ayers, K. L. %A Barzilai, N. %A Becker, E. J. %A Beekman, M. %A Blanch?, H. %A Christensen, K. %A Christiansen, L. %A Collerton, J. C. %A Cubaynes, S. %A Cummings, S. R. %A Davies, K. %A Debrabant, B. %A Deleuze, J. F. %A Duncan, R. %A Faul, J. D. %A Franceschi, C. %A Galan, P. %A Gudnason, V. %A Harris, T. B. %A Huisman, M. %A Hurme, M. A. %A Jagger, C. %A Jansen, I. %A Jylh?, M. %A K?h?nen, M. %A Karasik, D. %A Kardia, S. L. R. %A Kingston, A. %A Kirkwood, T. B. L. %A Launer, L. J. %A Lehtim?ki, T. %A Lieb, W. %A Lyytik?inen, L. P. %A Martin-Ruiz, C. %A Min, J. %A Nebel, A. %A Newman, A. B. %A Nie, C. %A Nohr, E. A. %A Orwoll, E. S. %A Perls, T. T. %A Province, M. A. %A Psaty, B. M. %A Raitakari, O. T. %A Reinders, M. J. T. %A Robine, J. M. %A Rotter, J. I. %A Sebastiani, P. %A Smith, J. %A S?rensen, T. I. A. %A Taylor, K. D. %A Uitterlinden, A. G. %A van der Flier, W. %A van der Lee, S. J. %A van Duijn, C. M. %A van Heemst, D. %A Vaupel, J. W. %A Weir, D. %A Ye, K. %A Zeng, Y. %A Zheng, W. %A Holstege, H. %A Kiel, D. P. %A Lunetta, K. L. %A Slagboom, P. E. %A Murabito, J. M. %X Human longevity is heritable, but genome-wide association (GWA) studies have had limited success. Here, we perform two meta-analyses of GWA studies of a rigorous longevity phenotype definition including 11,262/3484 cases surviving at or beyond the age corresponding to the 90th/99th survival percentile, respectively, and 25,483 controls whose age at death or at last contact was at or below the age corresponding to the 60th survival percentile. Consistent with previous reports, rs429358 (apolipoprotein E (ApoE) ε4) is associated with lower odds of surviving to the 90th and 99th percentile age, while rs7412 (ApoE ε2) shows the opposite. Moreover, rs7676745, located near GPR78, associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity. %B Nat Commun %V 10 %P 3669 %8 08 %G eng %0 Journal Article %J Nat Commun %D 2019 %T {A meta-analysis of genome-wide association studies identifies multiple longevity genes %A Deelen, J. %A Evans, D. S. %A Arking, D. E. %A Tesi, N. %A Nygaard, M. %A Liu, X. %A Wojczynski, M. K. %A Biggs, M. L. %A van der Spek, A. %A Atzmon, G. %A Ware, E. B. %A Sarnowski, C. %A Smith, A. V. %A ä, I. %A Cordell, H. J. %A Dose, J. %A Amin, N. %A Arnold, A. M. %A Ayers, K. L. %A Barzilai, N. %A Becker, E. J. %A Beekman, M. %A é, H. %A Christensen, K. %A Christiansen, L. %A Collerton, J. C. %A Cubaynes, S. %A Cummings, S. R. %A Davies, K. %A Debrabant, B. %A Deleuze, J. F. %A Duncan, R. %A Faul, J. D. %A Franceschi, C. %A Galan, P. %A Gudnason, V. %A Harris, T. B. %A Huisman, M. %A Hurme, M. A. %A Jagger, C. %A Jansen, I. %A ä, M. %A nen, M. %A Karasik, D. %A Kardia, S. L. R. %A Kingston, A. %A Kirkwood, T. B. L. %A Launer, L. J. %A ki, T. %A Lieb, W. %A inen, L. P. %A Martin-Ruiz, C. %A Min, J. %A Nebel, A. %A Newman, A. B. %A Nie, C. %A Nohr, E. A. %A Orwoll, E. S. %A Perls, T. T. %A Province, M. A. %A Psaty, B. M. %A Raitakari, O. T. %A Reinders, M. J. T. %A Robine, J. M. %A Rotter, J. I. %A Sebastiani, P. %A Smith, J. %A rensen, T. I. A. %A Taylor, K. D. %A Uitterlinden, A. G. %A van der Flier, W. %A van der Lee, S. J. %A van Duijn, C. M. %A van Heemst, D. %A Vaupel, J. W. %A Weir, D. %A Ye, K. %A Zeng, Y. %A Zheng, W. %A Holstege, H. %A Kiel, D. P. %A Lunetta, K. L. %A Slagboom, P. E. %A Murabito, J. M. %X 2) shows the opposite. Moreover, rs7676745, located near GPR78, associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity. %B Nat Commun %V 10 %P 3669 %8 Aug %G eng %0 Journal Article %J J Bone Miner Res %D 2019 %T {Meta-Analysis of Genomewide Association Studies Reveals Genetic Variants for Hip Bone Geometry %A Hsu, Y. H. %A Estrada, K. %A Evangelou, E. %A Ackert-Bicknell, C. %A Akesson, K. %A Beck, T. %A Brown, S. J. %A Capellini, T. %A Carbone, L. %A Cauley, J. %A Cheung, C. L. %A Cummings, S. R. %A Czerwinski, S. %A Demissie, S. %A Econs, M. %A Evans, D. %A Farber, C. %A Gautvik, K. %A Harris, T. %A Kammerer, C. %A Kemp, J. %A Koller, D. L. %A Kung, A. %A Lawlor, D. %A Lee, M. %A Lorentzon, M. %A McGuigan, F. %A Medina-Gomez, C. %A Mitchell, B. %A Newman, A. %A Nielson, C. %A Ohlsson, C. %A Peacock, M. %A Reppe, S. %A Richards, J. B. %A Robbins, J. %A Sigurdsson, G. %A Spector, T. D. %A Stefansson, K. %A Streeten, E. %A Styrkarsdottir, U. %A Tobias, J. %A Trajanoska, K. %A Uitterlinden, A. %A Vandenput, L. %A Wilson, S. G. %A Yerges-Armstrong, L. %A Young, M. %A Zillikens, M. C. %A Rivadeneira, F. %A Kiel, D. P. %A Karasik, D. %X Hip geometry is an important predictor of fracture. We performed a meta-analysis of GWAS studies in adults to identify genetic variants that are associated with proximal femur geometry phenotypes. We analyzed four phenotypes: (i) femoral neck length; (ii) neck-shaft angle; (iii) femoral neck width, and (iv) femoral neck section modulus, estimated from DXA scans using algorithms of hip structure analysis. In the Discovery stage, 10 cohort studies were included in the fixed-effect meta-analysis, with up to 18,719 men and women ages 16 to 93 years. Association analyses were performed with ∼2.5 million polymorphisms under an additive model adjusted for age, body mass index, and height. Replication analyses of meta-GWAS significant loci (at adjusted genomewide significance [GWS], threshold p ≤ 2.6 × 10-8 ) were performed in seven additional cohorts in silico. We looked up SNPs associated in our analysis, for association with height, bone mineral density (BMD), and fracture. In meta-analysis (combined Discovery and Replication stages), GWS associations were found at 5p15 (IRX1 and ADAMTS16); 5q35 near FGFR4; at 12p11 (in CCDC91); 11q13 (near LRP5 and PPP6R3 (rs7102273)). Several hip geometry signals overlapped with BMD, including LRP5 (chr. 11). Chr. 11 SNP rs7102273 was associated with any-type fracture (p = 7.5 × 10-5 ). We used bone transcriptome data and discovered several significant eQTLs, including rs7102273 and PPP6R3 expression (p = 0.0007), and rs6556301 (intergenic, chr.5 near FGFR4) and PDLIM7 expression (p = 0.005). In conclusion, we found associations between several genes and hip geometry measures that explained 12% to 22% of heritability at different sites. The results provide a defined set of genes related to biological pathways relevant to BMD and etiology of bone fragility. © 2019 American Society for Bone and Mineral Research. %B J Bone Miner Res %V 34 %P 1284–1296 %8 07 %G eng %0 Journal Article %J Am J Epidemiol %D 2019 %T Multi-Ancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions. %A de Vries, Paul S %A Brown, Michael R %A Bentley, Amy R %A Sung, Yun J %A Winkler, Thomas W %A Ntalla, Ioanna %A Schwander, Karen %A Kraja, Aldi T %A Guo, Xiuqing %A Franceschini, Nora %A Cheng, Ching-Yu %A Sim, Xueling %A Vojinovic, Dina %A Huffman, Jennifer E %A Musani, Solomon K %A Li, Changwei %A Feitosa, Mary F %A Richard, Melissa A %A Noordam, Raymond %A Aschard, Hugues %A Bartz, Traci M %A Bielak, Lawrence F %A Deng, Xuan %A Dorajoo, Rajkumar %A Lohman, Kurt K %A Manning, Alisa K %A Rankinen, Tuomo %A Smith, Albert V %A Tajuddin, Salman M %A Evangelou, Evangelos %A Graff, Mariaelisa %A Alver, Maris %A Boissel, Mathilde %A Chai, Jin Fang %A Chen, Xu %A Divers, Jasmin %A Gandin, Ilaria %A Gao, Chuan %A Goel, Anuj %A Hagemeijer, Yanick %A Harris, Sarah E %A Hartwig, Fernando P %A He, Meian %A Horimoto, Andrea R V R %A Hsu, Fang-Chi %A Jackson, Anne U %A Kasturiratne, Anuradhani %A Komulainen, Pirjo %A Kuhnel, Brigitte %A Laguzzi, Federica %A Lee, Joseph H %A Luan, Jian'an %A Lyytikäinen, Leo-Pekka %A Matoba, Nana %A Nolte, Ilja M %A Pietzner, Maik %A Riaz, Muhammad %A Said, M Abdullah %A Scott, Robert A %A Sofer, Tamar %A Stančáková, Alena %A Takeuchi, Fumihiko %A Tayo, Bamidele O %A van der Most, Peter J %A Varga, Tibor V %A Wang, Yajuan %A Ware, Erin B %A Wen, Wanqing %A Yanek, Lisa R %A Zhang, Weihua %A Zhao, Jing Hua %A Afaq, Saima %A Amin, Najaf %A Amini, Marzyeh %A Arking, Dan E %A Aung, Tin %A Ballantyne, Christie %A Boerwinkle, Eric %A Broeckel, Ulrich %A Campbell, Archie %A Canouil, Mickaël %A Charumathi, Sabanayagam %A Chen, Yii-Der Ida %A Connell, John M %A de Faire, Ulf %A de Las Fuentes, Lisa %A de Mutsert, Renée %A de Silva, H Janaka %A Ding, Jingzhong %A Dominiczak, Anna F %A Duan, Qing %A Eaton, Charles B %A Eppinga, Ruben N %A Faul, Jessica D %A Fisher, Virginia %A Forrester, Terrence %A Franco, Oscar H %A Friedlander, Yechiel %A Ghanbari, Mohsen %A Giulianini, Franco %A Grabe, Hans J %A Grove, Megan L %A Gu, C Charles %A Harris, Tamara B %A Heikkinen, Sami %A Heng, Chew-Kiat %A Hirata, Makoto %A Hixson, James E %A Howard, Barbara V %A Ikram, M Arfan %A Jacobs, David R %A Johnson, Craig %A Jonas, Jost Bruno %A Kammerer, Candace M %A Katsuya, Tomohiro %A Khor, Chiea Chuen %A Kilpeläinen, Tuomas O %A Koh, Woon-Puay %A Koistinen, Heikki A %A Kolcic, Ivana %A Kooperberg, Charles %A Krieger, Jose E %A Kritchevsky, Steve B %A Kubo, Michiaki %A Kuusisto, Johanna %A Lakka, Timo A %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Lehne, Benjamin %A Lemaitre, Rozenn N %A Li, Yize %A Liang, Jingjing %A Liu, Jianjun %A Liu, Kiang %A Loh, Marie %A Louie, Tin %A Mägi, Reedik %A Manichaikul, Ani W %A McKenzie, Colin A %A Meitinger, Thomas %A Metspalu, Andres %A Milaneschi, Yuri %A Milani, Lili %A Mohlke, Karen L %A Mosley, Thomas H %A Mukamal, Kenneth J %A Nalls, Mike A %A Nauck, Matthias %A Nelson, Christopher P %A Sotoodehnia, Nona %A O'Connell, Jeff R %A Palmer, Nicholette D %A Pazoki, Raha %A Pedersen, Nancy L %A Peters, Annette %A Peyser, Patricia A %A Polasek, Ozren %A Poulter, Neil %A Raffel, Leslie J %A Raitakari, Olli T %A Reiner, Alex P %A Rice, Treva K %A Rich, Stephen S %A Robino, Antonietta %A Robinson, Jennifer G %A Rose, Lynda M %A Rudan, Igor %A Schmidt, Carsten O %A Schreiner, Pamela J %A Scott, William R %A Sever, Peter %A Shi, Yuan %A Sidney, Stephen %A Sims, Mario %A Smith, Blair H %A Smith, Jennifer A %A Snieder, Harold %A Starr, John M %A Strauch, Konstantin %A Tan, Nicholas %A Taylor, Kent D %A Teo, Yik Ying %A Tham, Yih Chung %A Uitterlinden, André G %A van Heemst, Diana %A Vuckovic, Dragana %A Waldenberger, Melanie %A Wang, Lihua %A Wang, Yujie %A Wang, Zhe %A Wei, Wen Bin %A Williams, Christine %A Wilson, Gregory %A Wojczynski, Mary K %A Yao, Jie %A Yu, Bing %A Yu, Caizheng %A Yuan, Jian-Min %A Zhao, Wei %A Zonderman, Alan B %A Becker, Diane M %A Boehnke, Michael %A Bowden, Donald W %A Chambers, John C %A Deary, Ian J %A Esko, Tõnu %A Farrall, Martin %A Franks, Paul W %A Freedman, Barry I %A Froguel, Philippe %A Gasparini, Paolo %A Gieger, Christian %A Horta, Bernardo L %A Kamatani, Yoichiro %A Kato, Norihiro %A Kooner, Jaspal S %A Laakso, Markku %A Leander, Karin %A Lehtimäki, Terho %A Magnusson, Patrik K E %A Penninx, Brenda %A Pereira, Alexandre C %A Rauramaa, Rainer %A Samani, Nilesh J %A Scott, James %A Shu, Xiao-Ou %A van der Harst, Pim %A Wagenknecht, Lynne E %A Wang, Ya Xing %A Wareham, Nicholas J %A Watkins, Hugh %A Weir, David R %A Wickremasinghe, Ananda R %A Zheng, Wei %A Elliott, Paul %A North, Kari E %A Bouchard, Claude %A Evans, Michele K %A Gudnason, Vilmundur %A Liu, Ching-Ti %A Liu, Yongmei %A Psaty, Bruce M %A Ridker, Paul M %A van Dam, Rob M %A Kardia, Sharon L R %A Zhu, Xiaofeng %A Rotimi, Charles N %A Mook-Kanamori, Dennis O %A Fornage, Myriam %A Kelly, Tanika N %A Fox, Ervin R %A Hayward, Caroline %A van Duijn, Cornelia M %A Tai, E Shyong %A Wong, Tien Yin %A Liu, Jingmin %A Rotter, Jerome I %A Gauderman, W James %A Province, Michael A %A Munroe, Patricia B %A Rice, Kenneth %A Chasman, Daniel I %A Cupples, L Adrienne %A Rao, Dabeeru C %A Morrison, Alanna C %X

An individual's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multi-ancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in Stage 1 (genome-wide discovery) and 66 studies in Stage 2 (focused follow-up), for a total of 394,584 individuals from five ancestry groups. Genetic main and interaction effects were jointly assessed by a 2 degrees of freedom (DF) test, and a 1 DF test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in Stage 1 and were evaluated in Stage 2, followed by combined analyses of Stage 1 and Stage 2. In the combined analysis of Stage 1 and Stage 2, 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2 DF tests, of which 18 were novel. No genome-wide significant associations were found testing the interaction effect alone. The novel loci included several genes (PCSK5, VEGFB, and A1CF) with a putative role in lipid metabolism based on existing evidence from cellular and experimental models.

%B Am J Epidemiol %8 2019 Jan 29 %G eng %R 10.1093/aje/kwz005 %0 Journal Article %J Nat Genet %D 2019 %T Multi-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids. %A Bentley, Amy R %A Sung, Yun J %A Brown, Michael R %A Winkler, Thomas W %A Kraja, Aldi T %A Ntalla, Ioanna %A Schwander, Karen %A Chasman, Daniel I %A Lim, Elise %A Deng, Xuan %A Guo, Xiuqing %A Liu, Jingmin %A Lu, Yingchang %A Cheng, Ching-Yu %A Sim, Xueling %A Vojinovic, Dina %A Huffman, Jennifer E %A Musani, Solomon K %A Li, Changwei %A Feitosa, Mary F %A Richard, Melissa A %A Noordam, Raymond %A Baker, Jenna %A Chen, Guanjie %A Aschard, Hugues %A Bartz, Traci M %A Ding, Jingzhong %A Dorajoo, Rajkumar %A Manning, Alisa K %A Rankinen, Tuomo %A Smith, Albert V %A Tajuddin, Salman M %A Zhao, Wei %A Graff, Mariaelisa %A Alver, Maris %A Boissel, Mathilde %A Chai, Jin Fang %A Chen, Xu %A Divers, Jasmin %A Evangelou, Evangelos %A Gao, Chuan %A Goel, Anuj %A Hagemeijer, Yanick %A Harris, Sarah E %A Hartwig, Fernando P %A He, Meian %A Horimoto, Andrea R V R %A Hsu, Fang-Chi %A Hung, Yi-Jen %A Jackson, Anne U %A Kasturiratne, Anuradhani %A Komulainen, Pirjo %A Kuhnel, Brigitte %A Leander, Karin %A Lin, Keng-Hung %A Luan, Jian'an %A Lyytikäinen, Leo-Pekka %A Matoba, Nana %A Nolte, Ilja M %A Pietzner, Maik %A Prins, Bram %A Riaz, Muhammad %A Robino, Antonietta %A Said, M Abdullah %A Schupf, Nicole %A Scott, Robert A %A Sofer, Tamar %A Stančáková, Alena %A Takeuchi, Fumihiko %A Tayo, Bamidele O %A van der Most, Peter J %A Varga, Tibor V %A Wang, Tzung-Dau %A Wang, Yajuan %A Ware, Erin B %A Wen, Wanqing %A Xiang, Yong-Bing %A Yanek, Lisa R %A Zhang, Weihua %A Zhao, Jing Hua %A Adeyemo, Adebowale %A Afaq, Saima %A Amin, Najaf %A Amini, Marzyeh %A Arking, Dan E %A Arzumanyan, Zorayr %A Aung, Tin %A Ballantyne, Christie %A Barr, R Graham %A Bielak, Lawrence F %A Boerwinkle, Eric %A Bottinger, Erwin P %A Broeckel, Ulrich %A Brown, Morris %A Cade, Brian E %A Campbell, Archie %A Canouil, Mickaël %A Charumathi, Sabanayagam %A Chen, Yii-Der Ida %A Christensen, Kaare %A Concas, Maria Pina %A Connell, John M %A de Las Fuentes, Lisa %A de Silva, H Janaka %A de Vries, Paul S %A Doumatey, Ayo %A Duan, Qing %A Eaton, Charles B %A Eppinga, Ruben N %A Faul, Jessica D %A Floyd, James S %A Forouhi, Nita G %A Forrester, Terrence %A Friedlander, Yechiel %A Gandin, Ilaria %A Gao, He %A Ghanbari, Mohsen %A Gharib, Sina A %A Gigante, Bruna %A Giulianini, Franco %A Grabe, Hans J %A Gu, C Charles %A Harris, Tamara B %A Heikkinen, Sami %A Heng, Chew-Kiat %A Hirata, Makoto %A Hixson, James E %A Ikram, M Arfan %A Jia, Yucheng %A Joehanes, Roby %A Johnson, Craig %A Jonas, Jost Bruno %A Justice, Anne E %A Katsuya, Tomohiro %A Khor, Chiea Chuen %A Kilpeläinen, Tuomas O %A Koh, Woon-Puay %A Kolcic, Ivana %A Kooperberg, Charles %A Krieger, Jose E %A Kritchevsky, Stephen B %A Kubo, Michiaki %A Kuusisto, Johanna %A Lakka, Timo A %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Lehne, Benjamin %A Lewis, Cora E %A Li, Yize %A Liang, Jingjing %A Lin, Shiow %A Liu, Ching-Ti %A Liu, Jianjun %A Liu, Kiang %A Loh, Marie %A Lohman, Kurt K %A Louie, Tin %A Luzzi, Anna %A Mägi, Reedik %A Mahajan, Anubha %A Manichaikul, Ani W %A McKenzie, Colin A %A Meitinger, Thomas %A Metspalu, Andres %A Milaneschi, Yuri %A Milani, Lili %A Mohlke, Karen L %A Momozawa, Yukihide %A Morris, Andrew P %A Murray, Alison D %A Nalls, Mike A %A Nauck, Matthias %A Nelson, Christopher P %A North, Kari E %A O'Connell, Jeffrey R %A Palmer, Nicholette D %A Papanicolau, George J %A Pedersen, Nancy L %A Peters, Annette %A Peyser, Patricia A %A Polasek, Ozren %A Poulter, Neil %A Raitakari, Olli T %A Reiner, Alex P %A Renstrom, Frida %A Rice, Treva K %A Rich, Stephen S %A Robinson, Jennifer G %A Rose, Lynda M %A Rosendaal, Frits R %A Rudan, Igor %A Schmidt, Carsten O %A Schreiner, Pamela J %A Scott, William R %A Sever, Peter %A Shi, Yuan %A Sidney, Stephen %A Sims, Mario %A Smith, Jennifer A %A Snieder, Harold %A Starr, John M %A Strauch, Konstantin %A Stringham, Heather M %A Tan, Nicholas Y Q %A Tang, Hua %A Taylor, Kent D %A Teo, Yik Ying %A Tham, Yih Chung %A Tiemeier, Henning %A Turner, Stephen T %A Uitterlinden, André G %A van Heemst, Diana %A Waldenberger, Melanie %A Wang, Heming %A Wang, Lan %A Wang, Lihua %A Wei, Wen Bin %A Williams, Christine A %A Wilson, Gregory %A Wojczynski, Mary K %A Yao, Jie %A Young, Kristin %A Yu, Caizheng %A Yuan, Jian-Min %A Zhou, Jie %A Zonderman, Alan B %A Becker, Diane M %A Boehnke, Michael %A Bowden, Donald W %A Chambers, John C %A Cooper, Richard S %A de Faire, Ulf %A Deary, Ian J %A Elliott, Paul %A Esko, Tõnu %A Farrall, Martin %A Franks, Paul W %A Freedman, Barry I %A Froguel, Philippe %A Gasparini, Paolo %A Gieger, Christian %A Horta, Bernardo L %A Juang, Jyh-Ming Jimmy %A Kamatani, Yoichiro %A Kammerer, Candace M %A Kato, Norihiro %A Kooner, Jaspal S %A Laakso, Markku %A Laurie, Cathy C %A Lee, I-Te %A Lehtimäki, Terho %A Magnusson, Patrik K E %A Oldehinkel, Albertine J %A Penninx, Brenda W J H %A Pereira, Alexandre C %A Rauramaa, Rainer %A Redline, Susan %A Samani, Nilesh J %A Scott, James %A Shu, Xiao-Ou %A van der Harst, Pim %A Wagenknecht, Lynne E %A Wang, Jun-Sing %A Wang, Ya Xing %A Wareham, Nicholas J %A Watkins, Hugh %A Weir, David R %A Wickremasinghe, Ananda R %A Wu, Tangchun %A Zeggini, Eleftheria %A Zheng, Wei %A Bouchard, Claude %A Evans, Michele K %A Gudnason, Vilmundur %A Kardia, Sharon L R %A Liu, Yongmei %A Psaty, Bruce M %A Ridker, Paul M %A van Dam, Rob M %A Mook-Kanamori, Dennis O %A Fornage, Myriam %A Province, Michael A %A Kelly, Tanika N %A Fox, Ervin R %A Hayward, Caroline %A van Duijn, Cornelia M %A Tai, E Shyong %A Wong, Tien Yin %A Loos, Ruth J F %A Franceschini, Nora %A Rotter, Jerome I %A Zhu, Xiaofeng %A Bierut, Laura J %A Gauderman, W James %A Rice, Kenneth %A Munroe, Patricia B %A Morrison, Alanna C %A Rao, Dabeeru C %A Rotimi, Charles N %A Cupples, L Adrienne %X

The concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene-smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings.

%B Nat Genet %V 51 %P 636-648 %8 2019 Apr %G eng %N 4 %R 10.1038/s41588-019-0378-y %0 Journal Article %J Hum. Mol. Genet. %D 2019 %T {A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure %A Sung, Y. J. %A de Las Fuentes, L. %A Winkler, T. W. %A Chasman, D. I. %A Bentley, A. R. %A Kraja, A. T. %A Ntalla, I. %A Warren, H. R. %A Guo, X. %A Schwander, K. %A Manning, A. K. %A Brown, M. R. %A Aschard, H. %A Feitosa, M. F. %A Franceschini, N. %A Lu, Y. %A Cheng, C. Y. %A Sim, X. %A Vojinovic, D. %A Marten, J. %A Musani, S. K. %A Kilpel?inen, T. O. %A Richard, M. A. %A Aslibekyan, S. %A Bartz, T. M. %A Dorajoo, R. %A Li, C. %A Liu, Y. %A Rankinen, T. %A Smith, A. V. %A Tajuddin, S. M. %A Tayo, B. O. %A Zhao, W. %A Zhou, Y. %A Matoba, N. %A Sofer, T. %A Alver, M. %A Amini, M. %A Boissel, M. %A Chai, J. F. %A Chen, X. %A Divers, J. %A Gandin, I. %A Gao, C. %A Giulianini, F. %A Goel, A. %A Harris, S. E. %A Hartwig, F. P. %A He, M. %A Horimoto, A. R. V. R. %A Hsu, F. C. %A Jackson, A. U. %A Kammerer, C. M. %A Kasturiratne, A. %A Komulainen, P. %A K?hnel, B. %A Leander, K. %A Lee, W. J. %A Lin, K. H. %A Luan, J. %A Lyytik?inen, L. P. %A McKenzie, C. A. %A Nelson, C. P. %A Noordam, R. %A Scott, R. A. %A Sheu, W. H. H. %A Stan??kov?, A. %A Takeuchi, F. %A van der Most, P. J. %A Varga, T. V. %A Waken, R. J. %A Wang, H. %A Wang, Y. %A Ware, E. B. %A Weiss, S. %A Wen, W. %A Yanek, L. R. %A Zhang, W. %A Zhao, J. H. %A Afaq, S. %A Alfred, T. %A Amin, N. %A Arking, D. E. %A Aung, T. %A Barr, R. G. %A Bielak, L. F. %A Boerwinkle, E. %A Bottinger, E. P. %A Braund, P. S. %A Brody, J. A. %A Broeckel, U. %A Cade, B. %A Campbell, A. %A Canouil, M. %A Chakravarti, A. %A Cocca, M. %A Collins, F. S. %A Connell, J. M. %A de Mutsert, R. %A de Silva, H. J. %A D?rr, M. %A Duan, Q. %A Eaton, C. B. %A Ehret, G. %A Evangelou, E. %A Faul, J. D. %A Forouhi, N. G. %A Franco, O. H. %A Friedlander, Y. %A Gao, H. %A Gigante, B. %A Gu, C. C. %A Gupta, P. %A Hagenaars, S. P. %A Harris, T. B. %A He, J. %A Heikkinen, S. %A Heng, C. K. %A Hofman, A. %A Howard, B. V. %A Hunt, S. C. %A Irvin, M. R. %A Jia, Y. %A Katsuya, T. %A Kaufman, J. %A Kerrison, N. D. %A Khor, C. C. %A Koh, W. P. %A Koistinen, H. A. %A Kooperberg, C. B. %A Krieger, J. E. %A Kubo, M. %A Kutalik, Z. %A Kuusisto, J. %A Lakka, T. A. %A Langefeld, C. D. %A Langenberg, C. %A Launer, L. J. %A Lee, J. H. %A Lehne, B. %A Levy, D. %A Lewis, C. E. %A Li, Y. %A Lim, S. H. %A Liu, C. T. %A Liu, J. %A Liu, J. %A Liu, Y. %A Loh, M. %A Lohman, K. K. %A Louie, T. %A M?gi, R. %A Matsuda, K. %A Meitinger, T. %A Metspalu, A. %A Milani, L. %A Momozawa, Y. %A Mosley, T. H. %A Nalls, M. A. %A Nasri, U. %A O'Connell, J. R. %A Ogunniyi, A. %A Palmas, W. R. %A Palmer, N. D. %A Pankow, J. S. %A Pedersen, N. L. %A Peters, A. %A Peyser, P. A. %A Polasek, O. %A Porteous, D. %A Raitakari, O. T. %A Renstr?m, F. %A Rice, T. K. %A Ridker, P. M. %A Robino, A. %A Robinson, J. G. %A Rose, L. M. %A Rudan, I. %A Sabanayagam, C. %A Salako, B. L. %A Sandow, K. %A Schmidt, C. O. %A Schreiner, P. J. %A Scott, W. R. %A Sever, P. %A Sims, M. %A Sitlani, C. M. %A Smith, B. H. %A Smith, J. A. %A Snieder, H. %A Starr, J. M. %A Strauch, K. %A Tang, H. %A Taylor, K. D. %A Teo, Y. Y. %A Tham, Y. C. %A Uitterlinden, A. G. %A Waldenberger, M. %A Wang, L. %A Wang, Y. X. %A Wei, W. B. %A Wilson, G. %A Wojczynski, M. K. %A Xiang, Y. B. %A Yao, J. %A Yuan, J. M. %A Zonderman, A. B. %A Becker, D. M. %A Boehnke, M. %A Bowden, D. W. %A Chambers, J. C. %A Chen, Y. I. %A Weir, D. R. %A de Faire, U. %A Deary, I. J. %A Esko, T. %A Farrall, M. %A Forrester, T. %A Freedman, B. I. %A Froguel, P. %A Gasparini, P. %A Gieger, C. %A Horta, B. L. %A Hung, Y. J. %A Jonas, J. B. %A Kato, N. %A Kooner, J. S. %A Laakso, M. %A Lehtim?ki, T. %A Liang, K. W. %A Magnusson, P. K. E. %A Oldehinkel, A. J. %A Pereira, A. C. %A Perls, T. %A Rauramaa, R. %A Redline, S. %A Rettig, R. %A Samani, N. J. %A Scott, J. %A Shu, X. O. %A van der Harst, P. %A Wagenknecht, L. E. %A Wareham, N. J. %A Watkins, H. %A Wickremasinghe, A. R. %A Wu, T. %A Kamatani, Y. %A Laurie, C. C. %A Bouchard, C. %A Cooper, R. S. %A Evans, M. K. %A Gudnason, V. %A Hixson, J. %A Kardia, S. L. R. %A Kritchevsky, S. B. %A Psaty, B. M. %A van Dam, R. M. %A Arnett, D. K. %A Mook-Kanamori, D. O. %A Fornage, M. %A Fox, E. R. %A Hayward, C. %A van Duijn, C. M. %A Tai, E. S. %A Wong, T. Y. %A Loos, R. J. F. %A Reiner, A. P. %A Rotimi, C. N. %A Bierut, L. J. %A Zhu, X. %A Cupples, L. A. %A Province, M. A. %A Rotter, J. I. %A Franks, P. W. %A Rice, K. %A Elliott, P. %A Caulfield, M. J. %A Gauderman, W. J. %A Munroe, P. B. %A Rao, D. C. %A Morrison, A. C. %X Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene-smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene-smoking interaction analysis and 38 were newly identified (P < 5 × 10-8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings. %B Hum. Mol. Genet. %8 Apr %G eng %0 Journal Article %J Nat Commun %D 2019 %T Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration. %A Noordam, Raymond %A Bos, Maxime M %A Wang, Heming %A Winkler, Thomas W %A Bentley, Amy R %A Kilpeläinen, Tuomas O %A de Vries, Paul S %A Sung, Yun Ju %A Schwander, Karen %A Cade, Brian E %A Manning, Alisa %A Aschard, Hugues %A Brown, Michael R %A Chen, Han %A Franceschini, Nora %A Musani, Solomon K %A Richard, Melissa %A Vojinovic, Dina %A Aslibekyan, Stella %A Bartz, Traci M %A de Las Fuentes, Lisa %A Feitosa, Mary %A Horimoto, Andrea R %A Ilkov, Marjan %A Kho, Minjung %A Kraja, Aldi %A Li, Changwei %A Lim, Elise %A Liu, Yongmei %A Mook-Kanamori, Dennis O %A Rankinen, Tuomo %A Tajuddin, Salman M %A van der Spek, Ashley %A Wang, Zhe %A Marten, Jonathan %A Laville, Vincent %A Alver, Maris %A Evangelou, Evangelos %A Graff, Maria E %A He, Meian %A Kuhnel, Brigitte %A Lyytikäinen, Leo-Pekka %A Marques-Vidal, Pedro %A Nolte, Ilja M %A Palmer, Nicholette D %A Rauramaa, Rainer %A Shu, Xiao-Ou %A Snieder, Harold %A Weiss, Stefan %A Wen, Wanqing %A Yanek, Lisa R %A Adolfo, Correa %A Ballantyne, Christie %A Bielak, Larry %A Biermasz, Nienke R %A Boerwinkle, Eric %A Dimou, Niki %A Eiriksdottir, Gudny %A Gao, Chuan %A Gharib, Sina A %A Gottlieb, Daniel J %A Haba-Rubio, José %A Harris, Tamara B %A Heikkinen, Sami %A Heinzer, Raphael %A Hixson, James E %A Homuth, Georg %A Ikram, M Arfan %A Komulainen, Pirjo %A Krieger, Jose E %A Lee, Jiwon %A Liu, Jingmin %A Lohman, Kurt K %A Luik, Annemarie I %A Mägi, Reedik %A Martin, Lisa W %A Meitinger, Thomas %A Metspalu, Andres %A Milaneschi, Yuri %A Nalls, Mike A %A O'Connell, Jeff %A Peters, Annette %A Peyser, Patricia %A Raitakari, Olli T %A Reiner, Alex P %A Rensen, Patrick C N %A Rice, Treva K %A Rich, Stephen S %A Roenneberg, Till %A Rotter, Jerome I %A Schreiner, Pamela J %A Shikany, James %A Sidney, Stephen S %A Sims, Mario %A Sitlani, Colleen M %A Sofer, Tamar %A Strauch, Konstantin %A Swertz, Morris A %A Taylor, Kent D %A Uitterlinden, André G %A van Duijn, Cornelia M %A Völzke, Henry %A Waldenberger, Melanie %A Wallance, Robert B %A van Dijk, Ko Willems %A Yu, Caizheng %A Zonderman, Alan B %A Becker, Diane M %A Elliott, Paul %A Esko, Tõnu %A Gieger, Christian %A Grabe, Hans J %A Lakka, Timo A %A Lehtimäki, Terho %A North, Kari E %A Penninx, Brenda W J H %A Vollenweider, Peter %A Wagenknecht, Lynne E %A Wu, Tangchun %A Xiang, Yong-Bing %A Zheng, Wei %A Arnett, Donna K %A Bouchard, Claude %A Evans, Michele K %A Gudnason, Vilmundur %A Kardia, Sharon %A Kelly, Tanika N %A Kritchevsky, Stephen B %A Loos, Ruth J F %A Pereira, Alexandre C %A Province, Mike %A Psaty, Bruce M %A Rotimi, Charles %A Zhu, Xiaofeng %A Amin, Najaf %A Cupples, L Adrienne %A Fornage, Myriam %A Fox, Ervin F %A Guo, Xiuqing %A Gauderman, W James %A Rice, Kenneth %A Kooperberg, Charles %A Munroe, Patricia B %A Liu, Ching-Ti %A Morrison, Alanna C %A Rao, Dabeeru C %A van Heemst, Diana %A Redline, Susan %X

Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles.

%B Nat Commun %V 10 %P 5121 %8 2019 Nov 12 %G eng %N 1 %R 10.1038/s41467-019-12958-0 %0 Journal Article %J Nat Commun %D 2019 %T Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity. %A Kilpeläinen, Tuomas O %A Bentley, Amy R %A Noordam, Raymond %A Sung, Yun Ju %A Schwander, Karen %A Winkler, Thomas W %A Jakupović, Hermina %A Chasman, Daniel I %A Manning, Alisa %A Ntalla, Ioanna %A Aschard, Hugues %A Brown, Michael R %A de Las Fuentes, Lisa %A Franceschini, Nora %A Guo, Xiuqing %A Vojinovic, Dina %A Aslibekyan, Stella %A Feitosa, Mary F %A Kho, Minjung %A Musani, Solomon K %A Richard, Melissa %A Wang, Heming %A Wang, Zhe %A Bartz, Traci M %A Bielak, Lawrence F %A Campbell, Archie %A Dorajoo, Rajkumar %A Fisher, Virginia %A Hartwig, Fernando P %A Horimoto, Andrea R V R %A Li, Changwei %A Lohman, Kurt K %A Marten, Jonathan %A Sim, Xueling %A Smith, Albert V %A Tajuddin, Salman M %A Alver, Maris %A Amini, Marzyeh %A Boissel, Mathilde %A Chai, Jin Fang %A Chen, Xu %A Divers, Jasmin %A Evangelou, Evangelos %A Gao, Chuan %A Graff, Mariaelisa %A Harris, Sarah E %A He, Meian %A Hsu, Fang-Chi %A Jackson, Anne U %A Zhao, Jing Hua %A Kraja, Aldi T %A Kuhnel, Brigitte %A Laguzzi, Federica %A Lyytikäinen, Leo-Pekka %A Nolte, Ilja M %A Rauramaa, Rainer %A Riaz, Muhammad %A Robino, Antonietta %A Rueedi, Rico %A Stringham, Heather M %A Takeuchi, Fumihiko %A van der Most, Peter J %A Varga, Tibor V %A Verweij, Niek %A Ware, Erin B %A Wen, Wanqing %A Li, Xiaoyin %A Yanek, Lisa R %A Amin, Najaf %A Arnett, Donna K %A Boerwinkle, Eric %A Brumat, Marco %A Cade, Brian %A Canouil, Mickaël %A Chen, Yii-Der Ida %A Concas, Maria Pina %A Connell, John %A de Mutsert, Renée %A de Silva, H Janaka %A de Vries, Paul S %A Demirkan, Ayse %A Ding, Jingzhong %A Eaton, Charles B %A Faul, Jessica D %A Friedlander, Yechiel %A Gabriel, Kelley P %A Ghanbari, Mohsen %A Giulianini, Franco %A Gu, Chi Charles %A Gu, Dongfeng %A Harris, Tamara B %A He, Jiang %A Heikkinen, Sami %A Heng, Chew-Kiat %A Hunt, Steven C %A Ikram, M Arfan %A Jonas, Jost B %A Koh, Woon-Puay %A Komulainen, Pirjo %A Krieger, Jose E %A Kritchevsky, Stephen B %A Kutalik, Zoltán %A Kuusisto, Johanna %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Leander, Karin %A Lemaitre, Rozenn N %A Lewis, Cora E %A Liang, Jingjing %A Liu, Jianjun %A Mägi, Reedik %A Manichaikul, Ani %A Meitinger, Thomas %A Metspalu, Andres %A Milaneschi, Yuri %A Mohlke, Karen L %A Mosley, Thomas H %A Murray, Alison D %A Nalls, Mike A %A Nang, Ei-Ei Khaing %A Nelson, Christopher P %A Nona, Sotoodehnia %A Norris, Jill M %A Nwuba, Chiamaka Vivian %A O'Connell, Jeff %A Palmer, Nicholette D %A Papanicolau, George J %A Pazoki, Raha %A Pedersen, Nancy L %A Peters, Annette %A Peyser, Patricia A %A Polasek, Ozren %A Porteous, David J %A Poveda, Alaitz %A Raitakari, Olli T %A Rich, Stephen S %A Risch, Neil %A Robinson, Jennifer G %A Rose, Lynda M %A Rudan, Igor %A Schreiner, Pamela J %A Scott, Robert A %A Sidney, Stephen S %A Sims, Mario %A Smith, Jennifer A %A Snieder, Harold %A Sofer, Tamar %A Starr, John M %A Sternfeld, Barbara %A Strauch, Konstantin %A Tang, Hua %A Taylor, Kent D %A Tsai, Michael Y %A Tuomilehto, Jaakko %A Uitterlinden, André G %A van der Ende, M Yldau %A van Heemst, Diana %A Voortman, Trudy %A Waldenberger, Melanie %A Wennberg, Patrik %A Wilson, Gregory %A Xiang, Yong-Bing %A Yao, Jie %A Yu, Caizheng %A Yuan, Jian-Min %A Zhao, Wei %A Zonderman, Alan B %A Becker, Diane M %A Boehnke, Michael %A Bowden, Donald W %A de Faire, Ulf %A Deary, Ian J %A Elliott, Paul %A Esko, Tõnu %A Freedman, Barry I %A Froguel, Philippe %A Gasparini, Paolo %A Gieger, Christian %A Kato, Norihiro %A Laakso, Markku %A Lakka, Timo A %A Lehtimäki, Terho %A Magnusson, Patrik K E %A Oldehinkel, Albertine J %A Penninx, Brenda W J H %A Samani, Nilesh J %A Shu, Xiao-Ou %A van der Harst, Pim %A van Vliet-Ostaptchouk, Jana V %A Vollenweider, Peter %A Wagenknecht, Lynne E %A Wang, Ya X %A Wareham, Nicholas J %A Weir, David R %A Wu, Tangchun %A Zheng, Wei %A Zhu, Xiaofeng %A Evans, Michele K %A Franks, Paul W %A Gudnason, Vilmundur %A Hayward, Caroline %A Horta, Bernardo L %A Kelly, Tanika N %A Liu, Yongmei %A North, Kari E %A Pereira, Alexandre C %A Ridker, Paul M %A Tai, E Shyong %A van Dam, Rob M %A Fox, Ervin R %A Kardia, Sharon L R %A Liu, Ching-Ti %A Mook-Kanamori, Dennis O %A Province, Michael A %A Redline, Susan %A van Duijn, Cornelia M %A Rotter, Jerome I %A Kooperberg, Charles B %A Gauderman, W James %A Psaty, Bruce M %A Rice, Kenneth %A Munroe, Patricia B %A Fornage, Myriam %A Cupples, L Adrienne %A Rotimi, Charles N %A Morrison, Alanna C %A Rao, Dabeeru C %A Loos, Ruth J F %K Adolescent %K Adult %K African Continental Ancestry Group %K Aged %K Aged, 80 and over %K Asian Continental Ancestry Group %K Brazil %K Calcium-Binding Proteins %K Cholesterol %K Cholesterol, HDL %K Cholesterol, LDL %K European Continental Ancestry Group %K Exercise %K Female %K Genetic Loci %K Genome-Wide Association Study %K Genotype %K Hispanic Americans %K Humans %K LIM-Homeodomain Proteins %K Lipid Metabolism %K Lipids %K Male %K Membrane Proteins %K Microtubule-Associated Proteins %K Middle Aged %K Muscle Proteins %K Nerve Tissue Proteins %K Transcription Factors %K Triglycerides %K Young Adult %X

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

%B Nat Commun %V 10 %P 376 %8 2019 01 22 %G eng %N 1 %R 10.1038/s41467-018-08008-w %0 Journal Article %J Diabetes %D 2019 %T Multiethnic Genome-Wide Association Study of Diabetic Retinopathy Using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control. %A Pollack, Samuela %A Igo, Robert P %A Jensen, Richard A %A Christiansen, Mark %A Li, Xiaohui %A Cheng, Ching-Yu %A Ng, Maggie C Y %A Smith, Albert V %A Rossin, Elizabeth J %A Segrè, Ayellet V %A Davoudi, Samaneh %A Tan, Gavin S %A Chen, Yii-Der Ida %A Kuo, Jane Z %A Dimitrov, Latchezar M %A Stanwyck, Lynn K %A Meng, Weihua %A Hosseini, S Mohsen %A Imamura, Minako %A Nousome, Darryl %A Kim, Jihye %A Hai, Yang %A Jia, Yucheng %A Ahn, Jeeyun %A Leong, Aaron %A Shah, Kaanan %A Park, Kyu Hyung %A Guo, Xiuqing %A Ipp, Eli %A Taylor, Kent D %A Adler, Sharon G %A Sedor, John R %A Freedman, Barry I %A Lee, I-Te %A Sheu, Wayne H-H %A Kubo, Michiaki %A Takahashi, Atsushi %A Hadjadj, Samy %A Marre, Michel %A Trégouët, David-Alexandre %A McKean-Cowdin, Roberta %A Varma, Rohit %A McCarthy, Mark I %A Groop, Leif %A Ahlqvist, Emma %A Lyssenko, Valeriya %A Agardh, Elisabet %A Morris, Andrew %A Doney, Alex S F %A Colhoun, Helen M %A Toppila, Iiro %A Sandholm, Niina %A Groop, Per-Henrik %A Maeda, Shiro %A Hanis, Craig L %A Penman, Alan %A Chen, Ching J %A Hancock, Heather %A Mitchell, Paul %A Craig, Jamie E %A Chew, Emily Y %A Paterson, Andrew D %A Grassi, Michael A %A Palmer, Colin %A Bowden, Donald W %A Yaspan, Brian L %A Siscovick, David %A Cotch, Mary Frances %A Wang, Jie Jin %A Burdon, Kathryn P %A Wong, Tien Y %A Klein, Barbara E K %A Klein, Ronald %A Rotter, Jerome I %A Iyengar, Sudha K %A Price, Alkes L %A Sobrin, Lucia %X

To identify genetic variants associated with diabetic retinopathy (DR), we performed a large multiethnic genome-wide association study. Discovery included eight European cohorts ( = 3,246) and seven African American cohorts ( = 2,611). We meta-analyzed across cohorts using inverse-variance weighting, with and without liability threshold modeling of glycemic control and duration of diabetes. Variants with a value <1 × 10 were investigated in replication cohorts that included 18,545 European, 16,453 Asian, and 2,710 Hispanic subjects. After correction for multiple testing, the C allele of rs142293996 in an intron of nuclear VCP-like () was associated with DR in European discovery cohorts ( = 2.1 × 10), but did not reach genome-wide significance after meta-analysis with replication cohorts. We applied the Disease Association Protein-Protein Link Evaluator (DAPPLE) to our discovery results to test for evidence of risk being spread across underlying molecular pathways. One protein-protein interaction network built from genes in regions associated with proliferative DR was found to have significant connectivity ( = 0.0009) and corroborated with gene set enrichment analyses. These findings suggest that genetic variation in as well as variation within a protein-protein interaction network that includes genes implicated in inflammation, may influence risk for DR.

%B Diabetes %V 68 %P 441-456 %8 2019 Feb %G eng %N 2 %R 10.2337/db18-0567 %0 Journal Article %J Nat Hum Behav %D 2019 %T {New alcohol-related genes suggest shared genetic mechanisms with neuropsychiatric disorders %A Evangelou, E. %A Gao, H. %A Chu, C. %A Ntritsos, G. %A Blakeley, P. %A Butts, A. R. %A Pazoki, R. %A Suzuki, H. %A Koskeridis, F. %A Yiorkas, A. M. %A Karaman, I. %A Elliott, J. %A Luo, Q. %A Aeschbacher, S. %A Bartz, T. M. %A Baumeister, S. E. %A Braund, P. S. %A Brown, M. R. %A Brody, J. A. %A Clarke, T. K. %A Dimou, N. %A Faul, J. D. %A Homuth, G. %A Jackson, A. U. %A Kentistou, K. A. %A Joshi, P. K. %A Lemaitre, R. N. %A Lind, P. A. %A Lyytik?inen, L. P. %A Mangino, M. %A Milaneschi, Y. %A Nelson, C. P. %A Nolte, I. M. %A Per?l?, M. M. %A Polasek, O. %A Porteous, D. %A Ratliff, S. M. %A Smith, J. A. %A Stan??kov?, A. %A Teumer, A. %A Tuominen, S. %A Th?riault, S. %A Vangipurapu, J. %A Whitfield, J. B. %A Wood, A. %A Yao, J. %A Yu, B. %A Zhao, W. %A Arking, D. E. %A Auvinen, J. %A Liu, C. %A M?nnikk?, M. %A Risch, L. %A Rotter, J. I. %A Snieder, H. %A Veijola, J. %A Blakemore, A. I. %A Boehnke, M. %A Campbell, H. %A Conen, D. %A Eriksson, J. G. %A Grabe, H. J. %A Guo, X. %A van der Harst, P. %A Hartman, C. A. %A Hayward, C. %A Heath, A. C. %A Jarvelin, M. R. %A K?h?nen, M. %A Kardia, S. L. R. %A K?hne, M. %A Kuusisto, J. %A Laakso, M. %A Lahti, J. %A Lehtim?ki, T. %A McIntosh, A. M. %A Mohlke, K. L. %A Morrison, A. C. %A Martin, N. G. %A Oldehinkel, A. J. %A Penninx, B. W. J. H. %A Psaty, B. M. %A Raitakari, O. T. %A Rudan, I. %A Samani, N. J. %A Scott, L. J. %A Spector, T. D. %A Verweij, N. %A Weir, D. R. %A Wilson, J. F. %A Levy, D. %A Tzoulaki, I. %A Bell, J. D. %A Matthews, P. M. %A Rothenfluh, A. %A Desrivi?res, S. %A Schumann, G. %A Elliott, P. %X Excessive alcohol consumption is one of the main causes of death and disability worldwide. Alcohol consumption is a heritable complex trait. Here we conducted a meta-analysis of genome-wide association studies of alcohol consumption (g d-1) from the UK Biobank, the Alcohol Genome-Wide Consortium and the Cohorts for Heart and Aging Research in Genomic Epidemiology Plus consortia, collecting data from 480,842 people of European descent to decipher the genetic architecture of alcohol intake. We identified 46 new common loci and investigated their potential functional importance using magnetic resonance imaging data and gene expression studies. We identify genetic pathways associated with alcohol consumption and suggest genetic mechanisms that are shared with neuropsychiatric disorders such as schizophrenia. %B Nat Hum Behav %V 3 %P 950–961 %8 09 %G eng %0 Journal Article %J PLoS Med %D 2019 %T No causal effects of serum urate levels on the risk of chronic kidney disease: A Mendelian randomization study. %A Jordan, Daniel M %A Choi, Hyon K %A Verbanck, Marie %A Topless, Ruth %A Won, Hong-Hee %A Nadkarni, Girish %A Merriman, Tony R %A Do, Ron %K Adult %K Age Factors %K Female %K Genome-Wide Association Study %K Glomerular Filtration Rate %K Humans %K Male %K Mendelian Randomization Analysis %K Renal Insufficiency, Chronic %K Sex Factors %K Uric Acid %K Young Adult %X

BACKGROUND: Studies have shown strong positive associations between serum urate (SU) levels and chronic kidney disease (CKD) risk; however, whether the relation is causal remains uncertain. We evaluate whether genetic data are consistent with a causal impact of SU level on the risk of CKD and estimated glomerular filtration rate (eGFR).

METHODS AND FINDINGS: We used Mendelian randomization (MR) methods to evaluate the presence of a causal effect. We used aggregated genome-wide association data (N = 110,347 for SU, N = 69,374 for gout, N = 133,413 for eGFR, N = 117,165 for CKD), electronic-medical-record-linked UK Biobank data (N = 335,212), and population-based cohorts (N = 13,425), all in individuals of European ancestry, for SU levels and CKD. Our MR analysis showed that SU has a causal effect on neither eGFR level nor CKD risk across all MR analyses (all P > 0.05). These null associations contrasted with our epidemiological association findings from the 4 population-based cohorts (change in eGFR level per 1-mg/dl [59.48 μmol/l] increase in SU: -1.99 ml/min/1.73 m2; 95% CI -2.86 to -1.11; P = 8.08 × 10(-6); odds ratio [OR] for CKD: 1.48; 95% CI 1.32 to 1.65; P = 1.52 × 10(-11)). In contrast, the same MR approaches showed that SU has a causal effect on the risk of gout (OR estimates ranging from 3.41 to 6.04 per 1-mg/dl increase in SU, all P < 10-3), which served as a positive control of our approach. Overall, our MR analysis had >99% power to detect a causal effect of SU level on the risk of CKD of the same magnitude as the observed epidemiological association between SU and CKD. Limitations of this study include the lifelong effect of a genetic perturbation not being the same as an acute perturbation, the inability to study non-European populations, and some sample overlap between the datasets used in the study.

CONCLUSIONS: Evidence from our series of causal inference approaches using genetics does not support a causal effect of SU level on eGFR level or CKD risk. Reducing SU levels is unlikely to reduce the risk of CKD development.

%B PLoS Med %V 16 %P e1002725 %8 2019 01 %G eng %N 1 %R 10.1371/journal.pmed.1002725 %0 Journal Article %J J Am Heart Assoc %D 2019 %T NT -pro BNP as a Mediator of the Racial Difference in Incident Atrial Fibrillation and Heart Failure. %A Whitman, Isaac R %A Vittinghoff, Eric %A deFilippi, Christopher R %A Gottdiener, John S %A Alonso, Alvaro %A Psaty, Bruce M %A Heckbert, Susan R %A Hoogeveen, Ron C %A Arking, Dan E %A Selvin, Elizabeth %A Chen, Lin Y %A Dewland, Thomas A %A Marcus, Gregory M %X

Background Blacks harbor more cardiovascular risk factors than whites, but experience less atrial fibrillation ( AF ). Conversely, whites may have a lower risk of heart failure ( CHF ). N-terminal pro-B-type natriuretic peptide ( NT -pro BNP) levels are higher in whites, predict incident AF , and have diuretic effects in the setting of increased ventricular diastolic pressures, potentially providing a unifying explanation for these racial differences. Methods and Results We used data from the CHS (Cardiovascular Health Study) to determine the degree to which baseline NT -pro BNP levels mediate the relationships between race and incident AF and CHF by comparing beta estimates between models with and without NT -pro BNP . The ARIC (Atherosclerosis Risk in Communities) study was used to assess reproducibility. Among 4731 CHS (770 black) and 12 418 ARIC (3091 black) participants, there were 1277 and 1253 incident AF events, respectively. Whites had higher baseline NT -pro BNP ( CHS : 40% higher than blacks; 95% CI , 29-53; ARIC : 39% higher; 95% CI , 33-46) and had a greater risk of incident AF compared with blacks ( CHS : adjusted hazard ratio, 1.60; 95% CI , 1.31-1.93; ARIC : hazard ratio, 1.93; 95% CI , 1.57-2.27). NT -pro BNP levels explained a significant proportion of the racial difference in AF risk ( CHS : 36.2%; 95% CI , 23.2-69.2%; ARIC : 24.6%; 95% CI , 14.8-39.6%). Contrary to our hypothesis, given an increased risk of CHF among whites in CHS (adjusted hazard ratio, 1.20; 95% CI , 1.05-1.47) and the absence of a significant association between race and CHF in ARIC (adjusted hazard ratio, 1.07; 95% CI , 0.94-1.23), CHF -related mediation analyses were not performed. Conclusions A substantial portion of the relationship between race and AF was statistically explained by baseline NT -pro BNP levels. No consistent relationship between race and CHF was observed.

%B J Am Heart Assoc %V 8 %P e010868 %8 2019 Apr 02 %G eng %N 7 %R 10.1161/JAHA.118.010868 %0 Journal Article %J Am J Respir Crit Care Med %D 2019 %T {Omega-3 Fatty Acids and Genome-Wide Interaction Analyses Reveal DPP10-Pulmonary Function Association %A Xu, J. %A Gaddis, N. C. %A Bartz, T. M. %A Hou, R. %A Manichaikul, A. W. %A Pankratz, N. %A Smith, A. V. %A Sun, F. %A Terzikhan, N. %A Markunas, C. A. %A Patchen, B. K. %A Schu, M. %A Beydoun, M. A. %A Brusselle, G. G. %A Eiriksdottir, G. %A Zhou, X. %A Wood, A. C. %A Graff, M. %A Harris, T. B. %A Ikram, M. A. %A Jacobs, D. R. %A Launer, L. J. %A Lemaitre, R. N. %A O'Connor, G. T. %A Oelsner, E. C. %A Psaty, B. M. %A Vasan, R. S. %A Rohde, R. R. %A Rich, S. S. %A Rotter, J. I. %A Seshadri, S. %A Smith, L. J. %A Tiemeier, H. %A Tsai, M. Y. %A Uitterlinden, A. G. %A Voruganti, V. S. %A Xu, H. %A Zilh?o, N. R. %A Fornage, M. %A Zillikens, M. C. %A London, S. J. %A Barr, R. G. %A Dupuis, J. %A Gharib, S. A. %A Gudnason, V. %A Lahousse, L. %A North, K. E. %A Steffen, L. M. %A Cassano, P. A. %A Hancock, D. B. %X Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have anti-inflammatory properties that could benefit adults with comprised pulmonary health.\ To investigate n-3 PUFA associations with spirometric measures of pulmonary function tests (PFTs) and determine underlying genetic susceptibility.\ Associations of n-3 PUFA biomarkers (α-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid [DPA], and docosahexaenoic acid [DHA]) were evaluated with PFTs (FEV1, FVC, and FEV1/FVC) in meta-analyses across seven cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (N = 16,134 of European or African ancestry). PFT-associated n-3 PUFAs were carried forward to genome-wide interaction analyses in the four largest cohorts (N = 11,962) and replicated in one cohort (N = 1,687). Cohort-specific results were combined using joint 2 degree-of-freedom (2df) meta-analyses of SNP associations and their interactions with n-3 PUFAs.\ DPA and DHA were positively associated with FEV1 and FVC (P < 0.025), with evidence for effect modification by smoking and by sex. Genome-wide analyses identified a novel association of rs11693320-an intronic DPP10 SNP-with FVC when incorporating an interaction with DHA, and the finding was replicated (P2df = 9.4 × 10-9 across discovery and replication cohorts). The rs11693320-A allele (frequency, ∼80%) was associated with lower FVC (PSNP = 2.1 × 10-9; βSNP = -161.0 ml), and the association was attenuated by higher DHA levels (PSNP×DHA interaction = 2.1 × 10-7; βSNP×DHA interaction = 36.2 ml).\ We corroborated beneficial effects of n-3 PUFAs on pulmonary function. By modeling genome-wide n-3 PUFA interactions, we identified a novel DPP10 SNP association with FVC that was not detectable in much larger studies ignoring this interaction. %B Am J Respir Crit Care Med %V 199 %P 631–642 %8 03 %G eng %0 Journal Article %J PLoS One %D 2019 %T Pharmacogenomics of statin-related myopathy: Meta-analysis of rare variants from whole-exome sequencing. %A Floyd, James S %A Bloch, Katarzyna M %A Brody, Jennifer A %A Maroteau, Cyrielle %A Siddiqui, Moneeza K %A Gregory, Richard %A Carr, Daniel F %A Molokhia, Mariam %A Liu, Xiaoming %A Bis, Joshua C %A Ahmed, Ammar %A Liu, Xuan %A Hallberg, Pär %A Yue, Qun-Ying %A Magnusson, Patrik K E %A Brisson, Diane %A Wiggins, Kerri L %A Morrison, Alanna C %A Khoury, Etienne %A McKeigue, Paul %A Stricker, Bruno H %A Lapeyre-Mestre, Maryse %A Heckbert, Susan R %A Gallagher, Arlene M %A Chinoy, Hector %A Gibbs, Richard A %A Bondon-Guitton, Emmanuelle %A Tracy, Russell %A Boerwinkle, Eric %A Gaudet, Daniel %A Conforti, Anita %A van Staa, Tjeerd %A Sitlani, Colleen M %A Rice, Kenneth M %A Maitland-van der Zee, Anke-Hilse %A Wadelius, Mia %A Morris, Andrew P %A Pirmohamed, Munir %A Palmer, Colin A N %A Psaty, Bruce M %A Alfirevic, Ana %X

AIMS: Statin-related myopathy (SRM), which includes rhabdomyolysis, is an uncommon but important adverse drug reaction because the number of people prescribed statins world-wide is large. Previous association studies of common genetic variants have had limited success in identifying a genetic basis for this adverse drug reaction. We conducted a multi-site whole-exome sequencing study to investigate whether rare coding variants confer an increased risk of SRM.

METHODS AND RESULTS: SRM 3-5 cases (N = 505) and statin treatment-tolerant controls (N = 2047) were recruited from multiple sites in North America and Europe. SRM 3-5 was defined as symptoms consistent with muscle injury and an elevated creatine phosphokinase level >4 times upper limit of normal without another likely cause of muscle injury. Whole-exome sequencing and variant calling was coordinated from two analysis centres, and results of single-variant and gene-based burden tests were meta-analysed. No genome-wide significant associations were identified. Given the large number of cases, we had 80% power to identify a variant with minor allele frequency of 0.01 that increases the risk of SRM 6-fold at genome-wide significance.

CONCLUSIONS: In this large whole-exome sequencing study of severe statin-related muscle injury conducted to date, we did not find evidence that rare coding variants are responsible for this adverse drug reaction. Larger sample sizes would be required to identify rare variants with small effects, but it is unclear whether such findings would be clinically actionable.

%B PLoS One %V 14 %P e0218115 %8 2019 %G eng %N 6 %R 10.1371/journal.pone.0218115 %0 Journal Article %J BMJ %D 2019 %T {Quality of dietary fat and genetic risk of type 2 diabetes: individual participant data meta-analysis %A Merino, J. %A Guasch-Ferr?, M. %A Ellervik, C. %A Dashti, H. S. %A Sharp, S. J. %A Wu, P. %A Overvad, K. %A Sarnowski, C. %A Kuokkanen, M. %A Lemaitre, R. N. %A Justice, A. E. %A Ericson, U. %A Braun, K. V. E. %A Mahendran, Y. %A Frazier-Wood, A. C. %A Sun, D. %A Chu, A. Y. %A Tanaka, T. %A Luan, J. %A Hong, J. %A Tj?nneland, A. %A Ding, M. %A Lundqvist, A. %A Mukamal, K. %A Rohde, R. %A Schulz, C. A. %A Franco, O. H. %A Grarup, N. %A Chen, Y. I. %A Bazzano, L. %A Franks, P. W. %A Buring, J. E. %A Langenberg, C. %A Liu, C. T. %A Hansen, T. %A Jensen, M. K. %A S??ksj?rvi, K. %A Psaty, B. M. %A Young, K. L. %A Hindy, G. %A Sandholt, C. H. %A Ridker, P. M. %A Ordovas, J. M. %A Meigs, J. B. %A Pedersen, O. %A Kraft, P. %A Perola, M. %A North, K. E. %A Orho-Melander, M. %A Voortman, T. %A Toft, U. %A Rotter, J. I. %A Qi, L. %A Forouhi, N. G. %A Mozaffarian, D. %A S?rensen, T. I. A. %A Stampfer, M. J. %A M?nnist?, S. %A Selvin, E. %A Imamura, F. %A Salomaa, V. %A Hu, F. B. %A Wareham, N. J. %A Dupuis, J. %A Smith, C. E. %A Kilpel?inen, T. O. %A Chasman, D. I. %A Florez, J. C. %X {To investigate whether the genetic burden of type 2 diabetes modifies the association between the quality of dietary fat and the incidence of type 2 diabetes.\ Individual participant data meta-analysis.\ Eligible prospective cohort studies were systematically sourced from studies published between January 1970 and February 2017 through electronic searches in major medical databases (Medline, Embase, and Scopus) and discussion with investigators.\ Data from cohort studies or multicohort consortia with available genome-wide genetic data and information about the quality of dietary fat and the incidence of type 2 diabetes in participants of European descent was sought. Prospective cohorts that had accrued five or more years of follow-up were included. The type 2 diabetes genetic risk profile was characterized by a 68-variant polygenic risk score weighted by published effect sizes. Diet was recorded by using validated cohort-specific dietary assessment tools. Outcome measures were summary adjusted hazard ratios of incident type 2 diabetes for polygenic risk score, isocaloric replacement of carbohydrate (refined starch and sugars) with types of fat, and the interaction of types of fat with polygenic risk score.\ Of 102 305 participants from 15 prospective cohort studies, 20 015 type 2 diabetes cases were documented after a median follow-up of 12 years (interquartile range 9.4-14.2). The hazard ratio of type 2 diabetes per increment of 10 risk alleles in the polygenic risk score was 1.64 (95% confidence interval 1.54 to 1.75 %B BMJ %V 366 %P l4292 %8 07 %G eng %0 Journal Article %J Alzheimers Dement %D 2019 %T A rare missense variant of CASP7 is associated with familial late-onset Alzheimer's disease. %A Zhang, Xiaoling %A Zhu, Congcong %A Beecham, Gary %A Vardarajan, Badri N %A Ma, Yiyi %A Lancour, Daniel %A Farrell, John J %A Chung, Jaeyoon %A Mayeux, Richard %A Haines, Jonathan L %A Schellenberg, Gerard D %A Pericak-Vance, Margaret A %A Lunetta, Kathryn L %A Farrer, Lindsay A %X

INTRODUCTION: The genetic architecture of Alzheimer's disease (AD) is only partially understood.

METHODS: We conducted an association study for AD using whole sequence data from 507 genetically enriched AD cases (i.e., cases having close relatives affected by AD) and 4917 cognitively healthy controls of European ancestry (EA) and 172 enriched cases and 179 controls of Caribbean Hispanic ancestry. Confirmation of top findings from stage 1 was sought in two family-based genome-wide association study data sets and in a whole genome-sequencing data set comprising members from 42 EA and 115 Caribbean Hispanic families.

RESULTS: We identified associations in EAs with variants in 12 novel loci. The most robust finding is a rare CASP7 missense variant (rs116437863; P = 2.44 × 10) which improved when combined with results from stage 2 data sets (P = 1.92 × 10).

DISCUSSION: Our study demonstrated that an enriched case design can strengthen genetic signals, thus allowing detection of associations that would otherwise be missed in a traditional case-control study.

%B Alzheimers Dement %8 2019 Jan 03 %G eng %R 10.1016/j.jalz.2018.10.005 %0 Journal Article %J Am J Kidney Dis %D 2019 %T {Relationship of Estimated GFR and Albuminuria to Concurrent Laboratory Abnormalities: An Individual Participant Data Meta-analysis in a Global Consortium %A Inker, L. A. %A Grams, M. E. %A Levey, A. S. %A Coresh, J. %A Cirillo, M. %A Collins, J. F. %A Gansevoort, R. T. %A Gutierrez, O. M. %A Hamano, T. %A Heine, G. H. %A Ishikawa, S. %A Jee, S. H. %A Kronenberg, F. %A Landray, M. J. %A Miura, K. %A Nadkarni, G. N. %A Peralta, C. A. %A Rothenbacher, D. %A Schaeffner, E. %A Sedaghat, S. %A Shlipak, M. G. %A Zhang, L. %A van Zuilen, A. D. %A Hallan, S. I. %A Kovesdy, C. P. %A Woodward, M. %A Levin, A. %A Astor, B. %A Appel, L. %A Greene, T. %A Chen, T. %A Chalmers, J. %A Woodward, M. %A Arima, H. %A Perkovic, V. %A Yatsuya, H. %A Tamakoshi, K. %A Li, Y. %A Hirakawa, Y. %A Coresh, J. %A Matsushita, K. %A Grams, M. %A Sang, Y. %A Polkinghorne, K. %A Chadban, S. %A Atkins, R. %A Levin, A. %A Djurdjev, O. %A Zhang, L. %A Liu, L. %A Zhao, M. %A Wang, F. %A Wang, J. %A Schaeffner, E. %A Ebert, N. %A Martus, P. %A Levin, A. %A Djurdjev, O. %A Tang, M. %A Heine, G. %A Emrich, I. %A Seiler, S. %A Zawada, A. %A Nally, J. %A Navaneethan, S. %A Schold, J. %A Zhang, L. %A Zhao, M. %A Wang, F. %A Wang, J. %A Shlipak, M. %A Sarnak, M. %A Katz, R. %A Hiramoto, J. %A Iso, H. %A Yamagishi, K. %A Umesawa, M. %A Muraki, I. %A Fukagawa, M. %A Maruyama, S. %A Hamano, T. %A Hasegawa, T. %A Fujii, N. %A Wheeler, D. %A Emberson, J. %A Townend, J. %A Landray, M. %A Brenner, H. %A Sch?ttker, B. %A Saum, K. U. %A Rothenbacher, D. %A Fox, C. %A Hwang, S. J. %A K?ttgen, A. %A Kronenberg, F. %A Schneider, M. P. %A Eckardt, K. U. %A Green, J. %A Kirchner, H. L. %A Chang, A. R. %A Ho, K. %A Ito, S. %A Miyazaki, M. %A Nakayama, M. %A Yamada, G. %A Cirillo, M. %A Irie, F. %A Sairenchi, T. %A Ishikawa, S. %A Yano, Y. %A Kotani, K. %A Nakamura, T. %A Jee, S. H. %A Kimm, H. %A Mok, Y. %A Chodick, G. %A Shalev, V. %A Wetzels, J. F. M. %A Blankestijn, P. J. %A van Zuilen, A. D. %A van den Brand, J. %A Sarnak, M. %A Inker, L. %A Peralta, C. %A Hiramoto, J. %A Katz, R. %A Sarnak, M. %A Kronenberg, F. %A Kollerits, B. %A Ritz, E. %A Nitsch, D. %A Roderick, P. %A Fletcher, A. %A Bottinger, E. %A Nadkarni, G. N. %A Ellis, S. B. %A Nadukuru, R. %A Sang, Y. %A Ueshima, H. %A Okayama, A. %A Miura, K. %A Tanaka, S. %A Ueshima, H. %A Okamura, T. %A Miura, K. %A Tanaka, S. %A Miura, K. %A Okayama, A. %A Kadota, A. %A Tanaka, S. %A Kenealy, T. %A Elley, C. R. %A Collins, J. F. %A Drury, P. L. %A Ohkubo, T. %A Asayama, K. %A Metoki, H. %A Kikuya, M. %A Nakayama, M. %A Nelson, R. G. %A Knowler, W. C. %A Gansevoort, R. T. %A Bakker, S. J. %A Hak, E. %A Heerspink, H. J. L. %A Brunskill, N. %A Major, R. %A Shepherd, D. %A Medcalf, J. %A Jassal, S. K. %A Bergstrom, J. %A Ix, J. H. %A Barrett-Connor, E. %A Kovesdy, C. %A Kalantar-Zadeh, K. %A Sumida, K. %A Gutierrez, O. M. %A Muntner, P. %A Warnock, D. %A McClellan, W. %A Heerspink, H. J. L. %A de Zeeuw, D. %A Brenner, B. %A Sedaghat, S. %A Ikram, M. A. %A Hoorn, E. J. %A Dehghan, A. %A Carrero, J. J. %A Gasparini, A. %A Wettermark, B. %A Elinder, C. G. %A Wong, T. Y. %A Sabanayagam, C. %A Cheng, C. Y. %A Visseren, F. L. J. %A Evans, M. %A Segelmark, M. %A Stendahl, M. %A Sch?n, S. %A Tangri, N. %A Sud, M. %A Naimark, D. %A Wen, C. P. %A Tsao, C. K. %A Tsai, M. K. %A Chen, C. H. %A Konta, T. %A Hirayama, A. %A Ichikawa, K. %A Lannfelt, L. %A Larsson, A. %A ?rnl?v, J. %A Bilo, H. J. G. %A Landman, G. W. D. %A van Hateren, K. J. J. %A Kleefstra, N. %A Coresh Chair, J. %A Gansevoort, R. T. %A Grams, M. E. %A Hallan, S. %A Kovesdy, C. P. %A Levey, A. S. %A Matsushita, K. %A Shalev, V. %A Woodward, M. %A Ballew, S. H. %A Chen, J. %A Coresh, J. %A Grams, M. E. %A Kwak, L. %A Matsushita, K. %A Sang, Y. %A Surapaneni, A. %A Woodward, M. %X Chronic kidney disease (CKD) is complicated by abnormalities that reflect disruption in filtration, tubular, and endocrine functions of the kidney. Our aim was to explore the relationship of specific laboratory result abnormalities and hypertension with the estimated glomerular filtration rate (eGFR) and albuminuria CKD staging framework.\ Cross-sectional individual participant-level analyses in a global consortium.\ 17 CKD and 38 general population and high-risk cohorts.\ Cohorts in the CKD Prognosis Consortium with data for eGFR and albuminuria, as well as a measurement of hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, or calcium, or hypertension.\ Data were obtained and analyzed between July 2015 and January 2018.\ We modeled the association of eGFR and albuminuria with hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, and calcium values using linear regression and with hypertension and categorical definitions of each abnormality using logistic regression. Results were pooled using random-effects meta-analyses.\ The CKD cohorts (n=254,666 participants) were 27% women and 10% black, with a mean age of 69 (SD, 12) years. The general population/high-risk cohorts (n=1,758,334) were 50% women and 2% black, with a mean age of 50 (16) years. There was a strong graded association between lower eGFR and all laboratory result abnormalities (ORs ranging from 3.27 [95% CI, 2.68-3.97] to 8.91 [95% CI, 7.22-10.99] comparing eGFRs of 15 to 29 with eGFRs of 45 to 59mL/min/1.73m2), whereas albuminuria had equivocal or weak associations with abnormalities (ORs ranging from 0.77 [95% CI, 0.60-0.99] to 1.92 [95% CI, 1.65-2.24] comparing urinary albumin-creatinine ratio > 300 vs < 30mg/g).\ Variations in study era, health care delivery system, typical diet, and laboratory assays.\ Lower eGFR was strongly associated with higher odds of multiple laboratory result abnormalities. Knowledge of risk associations might help guide management in the heterogeneous group of patients with CKD. %B Am J Kidney Dis %V 73 %P 206–217 %8 02 %G eng %0 Journal Article %J Am J Hum Genet %D 2019 %T Sequencing Analysis at 8p23 Identifies Multiple Rare Variants in DLC1 Associated with Sleep-Related Oxyhemoglobin Saturation Level. %A Liang, Jingjing %A Cade, Brian E %A He, Karen Y %A Wang, Heming %A Lee, Jiwon %A Sofer, Tamar %A Williams, Stephanie %A Li, Ruitong %A Chen, Han %A Gottlieb, Daniel J %A Evans, Daniel S %A Guo, Xiuqing %A Gharib, Sina A %A Hale, Lauren %A Hillman, David R %A Lutsey, Pamela L %A Mukherjee, Sutapa %A Ochs-Balcom, Heather M %A Palmer, Lyle J %A Rhodes, Jessica %A Purcell, Shaun %A Patel, Sanjay R %A Saxena, Richa %A Stone, Katie L %A Tang, Weihong %A Tranah, Gregory J %A Boerwinkle, Eric %A Lin, Xihong %A Liu, Yongmei %A Psaty, Bruce M %A Vasan, Ramachandran S %A Cho, Michael H %A Manichaikul, Ani %A Silverman, Edwin K %A Barr, R Graham %A Rich, Stephen S %A Rotter, Jerome I %A Wilson, James G %A Redline, Susan %A Zhu, Xiaofeng %X

Average arterial oxyhemoglobin saturation during sleep (AvSpOS) is a clinically relevant measure of physiological stress associated with sleep-disordered breathing, and this measure predicts incident cardiovascular disease and mortality. Using high-depth whole-genome sequencing data from the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) project and focusing on genes with linkage evidence on chromosome 8p23, we observed that six coding and 51 noncoding variants in a gene that encodes the GTPase-activating protein (DLC1) are significantly associated with AvSpOS and replicated in independent subjects. The combined DLC1 association evidence of discovery and replication cohorts reaches genome-wide significance in European Americans (p = 7.9 × 10). A risk score for these variants, built on an independent dataset, explains 0.97% of the AvSpOS variation and contributes to the linkage evidence. The 51 noncoding variants are enriched in regulatory features in a human lung fibroblast cell line and contribute to DLC1 expression variation. Mendelian randomization analysis using these variants indicates a significant causal effect of DLC1 expression in fibroblasts on AvSpOS. Multiple sources of information, including genetic variants, gene expression, and methylation, consistently suggest that DLC1 is a gene associated with AvSpOS.

%B Am J Hum Genet %V 105 %P 1057-1068 %8 2019 Nov 07 %G eng %N 5 %R 10.1016/j.ajhg.2019.10.002 %0 Journal Article %J Pharmacogenomics J %D 2019 %T Statin-induced LDL cholesterol response and type 2 diabetes: a bidirectional two-sample Mendelian randomization study. %A Smit, Roelof A J %A Trompet, Stella %A Leong, Aaron %A Goodarzi, Mark O %A Postmus, Iris %A Warren, Helen %A Theusch, Elizabeth %A Barnes, Michael R %A Arsenault, Benoit J %A Li, Xiaohui %A Feng, QiPing %A Chasman, Daniel I %A Cupples, L Adrienne %A Hitman, Graham A %A Krauss, Ronald M %A Psaty, Bruce M %A Rotter, Jerome I %A Cessie, Saskia le %A Stein, C Michael %A Jukema, J Wouter %X

It remains unclear whether the increased risk of new-onset type 2 diabetes (T2D) seen in statin users is due to low LDL-C concentrations, or due to the statin-induced proportional change in LDL-C. In addition, genetic instruments have not been proposed before to examine whether liability to T2D might cause greater proportional statin-induced LDL-C lowering. Using summary-level statistics from the Genomic Investigation of Statin Therapy (GIST, n = 40,914) and DIAGRAM (n = 159,208) consortia, we found a positive genetic correlation between LDL-C statin response and T2D using LD score regression (r = 0.36, s.e. = 0.13). However, mendelian randomization analyses did not provide support for statin response having a causal effect on T2D risk (OR 1.00 (95% CI: 0.97, 1.03) per 10% increase in statin response), nor that liability to T2D has a causal effect on statin-induced LDL-C response (0.20% increase in response (95% CI: -0.40, 0.80) per doubling of odds of liability to T2D). Although we found no evidence to suggest that proportional statin response influences T2D risk, a definitive assessment should be made in populations comprised exclusively of statin users, as the presence of nonstatin users in the DIAGRAM dataset may have substantially diluted our effect estimate.

%B Pharmacogenomics J %8 2019 Dec 05 %G eng %R 10.1038/s41397-019-0125-x %0 Journal Article %J Genome Biol %D 2019 %T Systematic analysis of dark and camouflaged genes reveals disease-relevant genes hiding in plain sight. %A Ebbert, Mark T W %A Jensen, Tanner D %A Jansen-West, Karen %A Sens, Jonathon P %A Reddy, Joseph S %A Ridge, Perry G %A Kauwe, John S K %A Belzil, Veronique %A Pregent, Luc %A Carrasquillo, Minerva M %A Keene, Dirk %A Larson, Eric %A Crane, Paul %A Asmann, Yan W %A Ertekin-Taner, Nilufer %A Younkin, Steven G %A Ross, Owen A %A Rademakers, Rosa %A Petrucelli, Leonard %A Fryer, John D %K Genetic Predisposition to Disease %K Genome, Human %K Humans %K Mutation %X

BACKGROUND: The human genome contains "dark" gene regions that cannot be adequately assembled or aligned using standard short-read sequencing technologies, preventing researchers from identifying mutations within these gene regions that may be relevant to human disease. Here, we identify regions with few mappable reads that we call dark by depth, and others that have ambiguous alignment, called camouflaged. We assess how well long-read or linked-read technologies resolve these regions.

RESULTS: Based on standard whole-genome Illumina sequencing data, we identify 36,794 dark regions in 6054 gene bodies from pathways important to human health, development, and reproduction. Of these gene bodies, 8.7% are completely dark and 35.2% are ≥ 5% dark. We identify dark regions that are present in protein-coding exons across 748 genes. Linked-read or long-read sequencing technologies from 10x Genomics, PacBio, and Oxford Nanopore Technologies reduce dark protein-coding regions to approximately 50.5%, 35.6%, and 9.6%, respectively. We present an algorithm to resolve most camouflaged regions and apply it to the Alzheimer's Disease Sequencing Project. We rescue a rare ten-nucleotide frameshift deletion in CR1, a top Alzheimer's disease gene, found in disease cases but not in controls.

CONCLUSIONS: While we could not formally assess the association of the CR1 frameshift mutation with Alzheimer's disease due to insufficient sample-size, we believe it merits investigating in a larger cohort. There remain thousands of potentially important genomic regions overlooked by short-read sequencing that are largely resolved by long-read technologies.

%B Genome Biol %V 20 %P 97 %8 2019 05 20 %G eng %N 1 %R 10.1186/s13059-019-1707-2 %0 Journal Article %J Nat Genet %D 2019 %T Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels. %A Tin, Adrienne %A Marten, Jonathan %A Halperin Kuhns, Victoria L %A Li, Yong %A Wuttke, Matthias %A Kirsten, Holger %A Sieber, Karsten B %A Qiu, Chengxiang %A Gorski, Mathias %A Yu, Zhi %A Giri, Ayush %A Sveinbjornsson, Gardar %A Li, Man %A Chu, Audrey Y %A Hoppmann, Anselm %A O'Connor, Luke J %A Prins, Bram %A Nutile, Teresa %A Noce, Damia %A Akiyama, Masato %A Cocca, Massimiliano %A Ghasemi, Sahar %A van der Most, Peter J %A Horn, Katrin %A Xu, Yizhe %A Fuchsberger, Christian %A Sedaghat, Sanaz %A Afaq, Saima %A Amin, Najaf %A Arnlöv, Johan %A Bakker, Stephan J L %A Bansal, Nisha %A Baptista, Daniela %A Bergmann, Sven %A Biggs, Mary L %A Biino, Ginevra %A Boerwinkle, Eric %A Bottinger, Erwin P %A Boutin, Thibaud S %A Brumat, Marco %A Burkhardt, Ralph %A Campana, Eric %A Campbell, Archie %A Campbell, Harry %A Carroll, Robert J %A Catamo, Eulalia %A Chambers, John C %A Ciullo, Marina %A Concas, Maria Pina %A Coresh, Josef %A Corre, Tanguy %A Cusi, Daniele %A Felicita, Sala Cinzia %A de Borst, Martin H %A De Grandi, Alessandro %A de Mutsert, Renée %A de Vries, Aiko P J %A Delgado, Graciela %A Demirkan, Ayse %A Devuyst, Olivier %A Dittrich, Katalin %A Eckardt, Kai-Uwe %A Ehret, Georg %A Endlich, Karlhans %A Evans, Michele K %A Gansevoort, Ron T %A Gasparini, Paolo %A Giedraitis, Vilmantas %A Gieger, Christian %A Girotto, Giorgia %A Gögele, Martin %A Gordon, Scott D %A Gudbjartsson, Daniel F %A Gudnason, Vilmundur %A Haller, Toomas %A Hamet, Pavel %A Harris, Tamara B %A Hayward, Caroline %A Hicks, Andrew A %A Hofer, Edith %A Holm, Hilma %A Huang, Wei %A Hutri-Kähönen, Nina %A Hwang, Shih-Jen %A Ikram, M Arfan %A Lewis, Raychel M %A Ingelsson, Erik %A Jakobsdottir, Johanna %A Jonsdottir, Ingileif %A Jonsson, Helgi %A Joshi, Peter K %A Josyula, Navya Shilpa %A Jung, Bettina %A Kähönen, Mika %A Kamatani, Yoichiro %A Kanai, Masahiro %A Kerr, Shona M %A Kiess, Wieland %A Kleber, Marcus E %A Koenig, Wolfgang %A Kooner, Jaspal S %A Körner, Antje %A Kovacs, Peter %A Krämer, Bernhard K %A Kronenberg, Florian %A Kubo, Michiaki %A Kuhnel, Brigitte %A La Bianca, Martina %A Lange, Leslie A %A Lehne, Benjamin %A Lehtimäki, Terho %A Liu, Jun %A Loeffler, Markus %A Loos, Ruth J F %A Lyytikäinen, Leo-Pekka %A Mägi, Reedik %A Mahajan, Anubha %A Martin, Nicholas G %A März, Winfried %A Mascalzoni, Deborah %A Matsuda, Koichi %A Meisinger, Christa %A Meitinger, Thomas %A Metspalu, Andres %A Milaneschi, Yuri %A O'Donnell, Christopher J %A Wilson, Otis D %A Gaziano, J Michael %A Mishra, Pashupati P %A Mohlke, Karen L %A Mononen, Nina %A Montgomery, Grant W %A Mook-Kanamori, Dennis O %A Müller-Nurasyid, Martina %A Nadkarni, Girish N %A Nalls, Mike A %A Nauck, Matthias %A Nikus, Kjell %A Ning, Boting %A Nolte, Ilja M %A Noordam, Raymond %A O'Connell, Jeffrey R %A Olafsson, Isleifur %A Padmanabhan, Sandosh %A Penninx, Brenda W J H %A Perls, Thomas %A Peters, Annette %A Pirastu, Mario %A Pirastu, Nicola %A Pistis, Giorgio %A Polasek, Ozren %A Ponte, Belen %A Porteous, David J %A Poulain, Tanja %A Preuss, Michael H %A Rabelink, Ton J %A Raffield, Laura M %A Raitakari, Olli T %A Rettig, Rainer %A Rheinberger, Myriam %A Rice, Kenneth M %A Rizzi, Federica %A Robino, Antonietta %A Rudan, Igor %A Krajcoviechova, Alena %A Cifkova, Renata %A Rueedi, Rico %A Ruggiero, Daniela %A Ryan, Kathleen A %A Saba, Yasaman %A Salvi, Erika %A Schmidt, Helena %A Schmidt, Reinhold %A Shaffer, Christian M %A Smith, Albert V %A Smith, Blair H %A Spracklen, Cassandra N %A Strauch, Konstantin %A Stumvoll, Michael %A Sulem, Patrick %A Tajuddin, Salman M %A Teren, Andrej %A Thiery, Joachim %A Thio, Chris H L %A Thorsteinsdottir, Unnur %A Toniolo, Daniela %A Tönjes, Anke %A Tremblay, Johanne %A Uitterlinden, André G %A Vaccargiu, Simona %A van der Harst, Pim %A van Duijn, Cornelia M %A Verweij, Niek %A Völker, Uwe %A Vollenweider, Peter %A Waeber, Gérard %A Waldenberger, Melanie %A Whitfield, John B %A Wild, Sarah H %A Wilson, James F %A Yang, Qiong %A Zhang, Weihua %A Zonderman, Alan B %A Bochud, Murielle %A Wilson, James G %A Pendergrass, Sarah A %A Ho, Kevin %A Parsa, Afshin %A Pramstaller, Peter P %A Psaty, Bruce M %A Böger, Carsten A %A Snieder, Harold %A Butterworth, Adam S %A Okada, Yukinori %A Edwards, Todd L %A Stefansson, Kari %A Susztak, Katalin %A Scholz, Markus %A Heid, Iris M %A Hung, Adriana M %A Teumer, Alexander %A Pattaro, Cristian %A Woodward, Owen M %A Vitart, Veronique %A Köttgen, Anna %X

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.

%B Nat Genet %V 51 %P 1459-1474 %8 2019 Oct %G eng %N 10 %R 10.1038/s41588-019-0504-x %0 Journal Article %J Nat Genet %D 2019 %T Trans-ethnic association study of blood pressure determinants in over 750,000 individuals. %A Giri, Ayush %A Hellwege, Jacklyn N %A Keaton, Jacob M %A Park, Jihwan %A Qiu, Chengxiang %A Warren, Helen R %A Torstenson, Eric S %A Kovesdy, Csaba P %A Sun, Yan V %A Wilson, Otis D %A Robinson-Cohen, Cassianne %A Roumie, Christianne L %A Chung, Cecilia P %A Birdwell, Kelly A %A Damrauer, Scott M %A DuVall, Scott L %A Klarin, Derek %A Cho, Kelly %A Wang, Yu %A Evangelou, Evangelos %A Cabrera, Claudia P %A Wain, Louise V %A Shrestha, Rojesh %A Mautz, Brian S %A Akwo, Elvis A %A Sargurupremraj, Muralidharan %A Debette, Stephanie %A Boehnke, Michael %A Scott, Laura J %A Luan, Jian'an %A Zhao, Jing-Hua %A Willems, Sara M %A Thériault, Sébastien %A Shah, Nabi %A Oldmeadow, Christopher %A Almgren, Peter %A Li-Gao, Ruifang %A Verweij, Niek %A Boutin, Thibaud S %A Mangino, Massimo %A Ntalla, Ioanna %A Feofanova, Elena %A Surendran, Praveen %A Cook, James P %A Karthikeyan, Savita %A Lahrouchi, Najim %A Liu, Chunyu %A Sepúlveda, Nuno %A Richardson, Tom G %A Kraja, Aldi %A Amouyel, Philippe %A Farrall, Martin %A Poulter, Neil R %A Laakso, Markku %A Zeggini, Eleftheria %A Sever, Peter %A Scott, Robert A %A Langenberg, Claudia %A Wareham, Nicholas J %A Conen, David %A Palmer, Colin Neil Alexander %A Attia, John %A Chasman, Daniel I %A Ridker, Paul M %A Melander, Olle %A Mook-Kanamori, Dennis Owen %A Harst, Pim van der %A Cucca, Francesco %A Schlessinger, David %A Hayward, Caroline %A Spector, Tim D %A Jarvelin, Marjo-Riitta %A Hennig, Branwen J %A Timpson, Nicholas J %A Wei, Wei-Qi %A Smith, Joshua C %A Xu, Yaomin %A Matheny, Michael E %A Siew, Edward E %A Lindgren, Cecilia %A Herzig, Karl-Heinz %A Dedoussis, George %A Denny, Joshua C %A Psaty, Bruce M %A Howson, Joanna M M %A Munroe, Patricia B %A Newton-Cheh, Christopher %A Caulfield, Mark J %A Elliott, Paul %A Gaziano, J Michael %A Concato, John %A Wilson, Peter W F %A Tsao, Philip S %A Velez Edwards, Digna R %A Susztak, Katalin %A O'Donnell, Christopher J %A Hung, Adriana M %A Edwards, Todd L %X

In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.

%B Nat Genet %V 51 %P 51-62 %8 2019 Jan %G eng %N 1 %R 10.1038/s41588-018-0303-9 %0 Journal Article %J Sci Rep %D 2019 %T {Variants Associated with the Ankle Brachial Index Differ by Hispanic/Latino Ethnic Group: a genome-wide association study in the Hispanic Community Health Study/Study of Latinos %A Sofer, T. %A Emery, L. %A Jain, D. %A Ellis, A. M. %A Laurie, C. C. %A Allison, M. A. %A Lee, J. %A Kurniansyah, N. %A Kerr, K. F. %A Gonz?lez, H. M. %A Tarraf, W. %A Criqui, M. H. %A Lange, L. A. %A Palmas, W. R. %A Franceschini, N. %A Wassel, C. L. %X Lower extremity peripheral artery disease (PAD) burden differs by race/ethnicity. Although familial aggregation and heritability studies suggest a genetic basis, little is known about the genetic susceptibility to PAD, especially in non-European descent populations. Genome-wide association studies (GWAS) of the ankle brachial index (ABI) and PAD (defined as an ABI < 0.90) have not been conducted in Hispanics/Latinos. We performed a GWAS of PAD and the ABI in 7,589 participants aged >45 years from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). We also performed GWAS for ABI stratified by Hispanic/Latino ethnic subgroups: Central American, Mexican, and South American (Mainland group), and Cuban, Dominican, and Puerto Rican (Caribbean group). We detected two genome-wide significant associations for the ABI in COMMD10 in Puerto Ricans, and at SYBU in the Caribbean group. The lead SNP rs4466200 in the COMMD10 gene had a replication p = 0.02 for the ABI in Multi-Ethnic Study of Atherosclerosis (MESA) African Americans, but it did not replicate in African Americans from the Cardiovascular Health Study (CHS). In a regional look-up, a nearby SNP rs12520838 had Bonferroni adjusted p = 0.05 (unadjusted p = 7.5 × 10-5) for PAD in MESA Hispanics. Among three suggestive associations (p < 10-7) in subgroup-specific analyses, DMD on chromosome X, identified in Central Americans, replicated in MESA Hispanics (p = 2.2 × 10-4). None of the previously reported ABI and PAD associations in whites generalized to Hispanics/Latinos. %B Sci Rep %V 9 %P 11410 %8 08 %G eng %0 Journal Article %J BMJ Open %D 2020 %T {Androgens In Men Study (AIMS): protocol for meta-analyses of individual participant data investigating associations of androgens with health outcomes in men %A Yeap, B. B. %A Marriott, R. J. %A Adams, R. J. %A Antonio, L. %A Ballantyne, C. M. %A Bhasin, S. %A Cawthon, P. M. %A Couper, D. J. %A Dobs, A. S. %A Flicker, L. %A Karlsson, M. %A Martin, S. A. %A Matsumoto, A. M. %A Mellstr?m, D. %A Norman, P. E. %A Ohlsson, C. %A Orwoll, E. S. %A O'Neill, T. W. %A Shores, M. M. %A Travison, T. G. %A Vanderschueren, D. %A Wittert, G. A. %A Wu, F. C. W. %A Murray, K. %X This study aims to clarify the role(s) of endogenous sex hormones to influence health outcomes in men, specifically to define the associations of plasma testosterone with incidence of cardiovascular events, cancer, dementia and mortality risk, and to identify factors predicting testosterone concentrations. Data will be accrued from at least three Australian, two European and four North American population-based cohorts involving approximately 20 000 men.\ Eligible studies include prospective cohort studies with baseline testosterone concentrations measured using mass spectrometry and 5 years of follow-up data on incident cardiovascular events, mortality, cancer diagnoses or deaths, new-onset dementia or decline in cognitive function recorded. Data for men, who were not taking androgens or drugs suppressing testosterone production, metabolism or action; and had no prior orchidectomy, are eligible. Systematic literature searches were conducted from 14 June 2019 to 31 December 2019, with no date range set for searches. Aggregate level data will be sought where individual participant data (IPD) are not available. One-stage IPD random-effects meta-analyses will be performed, using linear mixed models, generalised linear mixed models and either stratified or frailty-augmented Cox regression models. Heterogeneity in estimates from different studies will be quantified and bias investigated using funnel plots. Effect size estimates will be presented in forest plots and non-negligible heterogeneity and bias investigated using subgroup or meta-regression analyses.\ Ethics approvals obtained for each of the participating cohorts state that participants have consented to have their data collected and used for research purposes. The Androgens In Men Study has been assessed as exempt from ethics review by the Human Ethics office at the University of Western Australia (file reference number RA/4/20/5014). Each of the component studies had obtained ethics approvals; please refer to respective component studies for details. Research findings will be disseminated to the scientific and broader community via the publication of four research articles, with each involving a separate set of IPD meta-analyses (articles will investigate different, distinct outcomes), at scientific conferences and meetings of relevant professional societies. Collaborating cohort studies will disseminate findings to study participants and local communities.\ CRD42019139668. %B BMJ Open %V 10 %P e034777 %8 05 %G eng %0 Journal Article %J JAMA Ophthalmol %D 2020 %T Association of Genetic Variation With Keratoconus. %A McComish, Bennet J %A Sahebjada, Srujana %A Bykhovskaya, Yelena %A Willoughby, Colin E %A Richardson, Andrea J %A Tenen, Abi %A Charlesworth, Jac C %A Macgregor, Stuart %A Mitchell, Paul %A Lucas, Sionne E M %A Mills, Richard A %A Mackey, David A %A Li, Xiaohui %A Wang, Jie Jin %A Jensen, Richard A %A Rotter, Jerome I %A Taylor, Kent D %A Hewitt, Alex W %A Rabinowitz, Yaron S %A Baird, Paul N %A Craig, Jamie E %A Burdon, Kathryn P %K Adult %K Female %K Fuchs' Endothelial Dystrophy %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Keratoconus %K Lipase %K Logistic Models %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %X

Importance: Keratoconus is a condition in which the cornea progressively thins and protrudes in a conical shape, severely affecting refraction and vision. It is a major indication for corneal transplant. To discover new genetic loci associated with keratoconus and better understand the causative mechanism of this disease, we performed a genome-wide association study on patients with keratoconus.

Objective: To identify genetic susceptibility regions for keratoconus in the human genome.

Design, Setting, and Participants: This study was conducted with data from eye clinics in Australia, the United States, and Northern Ireland. The discovery cohort of individuals with keratoconus and control participants from Australia was genotyped using the Illumina HumanCoreExome single-nucleotide polymorphism array. After quality control and data cleaning, genotypes were imputed against the 1000 Genomes Project reference panel (phase III; version 5), and association analyses were completed using PLINK version 1.90. Single-nucleotide polymorphisms with P < 1.00 × 10-6 were assessed for replication in 3 additional cohorts. Control participants were drawn from the cohorts of the Blue Mountains Eye Study and a previous study of glaucoma. Replication cohorts were from a previous keratoconus genome-wide association study data set from the United States, a cohort of affected and control participants from Australia and Northern Ireland, and a case-control cohort from Victoria, Australia. Data were collected from January 2006 to March 2019.

Main Outcomes and Measures: Associations between keratoconus and 6 252 612 genetic variants were estimated using logistic regression after adjusting for ancestry using the first 3 principal components.

Results: The discovery cohort included 522 affected individuals and 655 control participants, while the replication cohorts included 818 affected individuals (222 from the United States, 331 from Australia and Northern Ireland, and 265 from Victoria, Australia) and 3858 control participants (2927 from the United States, 229 from Australia and Northern Ireland, and 702 from Victoria, Australia). Two novel loci reached genome-wide significance (defined as P < 5.00 × 10-8), with a P value of 7.46 × 10-9 at rs61876744 in patatin-like phospholipase domain-containing 2 gene (PNPLA2) on chromosome 11 and a P value of 6.35 × 10-12 at rs138380, 2.2 kb upstream of casein kinase I isoform epsilon gene (CSNK1E) on chromosome 22. One additional locus was identified with a P value less than 1.00 × 10-6 in mastermind-like transcriptional coactivator 2 (MAML2) on chromosome 11 (P = 3.91 × 10-7). The novel locus in PNPLA2 reached genome-wide significance in an analysis of all 4 cohorts (P = 2.45 × 10-8).

Conclusions and Relevance: In this relatively large keratoconus genome-wide association study, we identified a genome-wide significant locus for keratoconus in the region of PNPLA2 on chromosome 11.

%B JAMA Ophthalmol %V 138 %P 174-181 %8 2020 02 01 %G eng %N 2 %R 10.1001/jamaophthalmol.2019.5293 %0 Journal Article %J JAMA Netw Open %D 2020 %T Association of Leukocyte Telomere Length With Mortality Among Adult Participants in 3 Longitudinal Studies. %A Arbeev, Konstantin G %A Verhulst, Simon %A Steenstrup, Troels %A Kark, Jeremy D %A Bagley, Olivia %A Kooperberg, Charles %A Reiner, Alexander P %A Hwang, Shih-Jen %A Levy, Daniel %A Fitzpatrick, Annette L %A Christensen, Kaare %A Yashin, Anatoliy I %A Aviv, Abraham %X

Importance: Leukocyte telomere length (LTL) is a trait associated with risk of cardiovascular disease and cancer, the 2 major disease categories that largely define longevity in the United States. However, it remains unclear whether LTL is associated with the human life span.

Objective: To examine whether LTL is associated with the life span of contemporary humans.

Design, Setting, and Participants: This cohort study included 3259 adults of European ancestry from the Cardiovascular Health Study (CHS), Framingham Heart Study (FHS), and Women's Health Initiative (WHI). Leukocyte telomere length was measured in 1992 and 1997 in the CHS, from 1995 to 1998 in the FHS, and from 1993 to 1998 in the WHI. Data analysis was conducted from February 2017 to December 2019.

Main Outcomes and Measures: Death and LTL, measured by Southern blots of the terminal restriction fragments, were the main outcomes. Cause of death was adjudicated by end point committees.

Results: The analyzed sample included 3259 participants (2342 [71.9%] women), with a median (range) age of 69.0 (50.0-98.0) years at blood collection. The median (range) follow-up until death was 10.9 (0.2-23.0) years in CHS, 19.7 (3.4-23.0) years in FHS, and 16.6 (0.5-20.0) years in WHI. During follow-up, there were 1525 deaths (482 [31.6%] of cardiovascular disease; 373 [24.5%] of cancer, and 670 [43.9%] of other or unknown causes). Short LTL, expressed in residual LTL, was associated with increased mortality risk. Overall, the hazard ratio for all-cause mortality for a 1-kilobase decrease in LTL was 1.34 (95% CI, 1.21-1.47). This association was stronger for noncancer causes of death (cardiovascular death: hazard ratio, 1.28; 95% CI, 1.08-1.52; cancer: hazard ratio, 1.13; 95% CI, 0.93-1.36; and other causes: hazard ratio, 1.53; 95% CI, 1.32-1.77).

Conclusions and Relevance: The results of this study indicate that LTL is associated with a natural life span limit in contemporary humans.

%B JAMA Netw Open %V 3 %P e200023 %8 2020 Feb 05 %G eng %N 2 %R 10.1001/jamanetworkopen.2020.0023 %0 Journal Article %J JAMA Intern Med %D 2020 %T Association of Nonobstructive Chronic Bronchitis With Respiratory Health Outcomes in Adults. %A Balte, Pallavi P %A Chaves, Paulo H M %A Couper, David J %A Enright, Paul %A Jacobs, David R %A Kalhan, Ravi %A Kronmal, Richard A %A Loehr, Laura R %A London, Stephanie J %A Newman, Anne B %A O'Connor, George T %A Schwartz, Joseph E %A Smith, Benjamin M %A Smith, Lewis J %A White, Wendy B %A Yende, Sachin %A Oelsner, Elizabeth C %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Asthma %K Bronchitis, Chronic %K Female %K Humans %K Lung %K Male %K Middle Aged %K Prospective Studies %K Respiratory Function Tests %K Smokers %K Smoking %K Young Adult %X

Importance: Chronic bronchitis has been associated with cigarette smoking as well as with e-cigarette use among young adults, but the association of chronic bronchitis in persons without airflow obstruction or clinical asthma, described as nonobstructive chronic bronchitis, with respiratory health outcomes remains uncertain.

Objective: To assess whether nonobstructive chronic bronchitis is associated with adverse respiratory health outcomes in adult ever smokers and never smokers.

Design, Setting, and Participants: This prospective cohort study included 22 325 adults without initial airflow obstruction (defined as the ratio of forced expiratory volume in the first second [FEV1] to forced vital capacity [FVC] of <0.70) or clinical asthma at baseline. The National Heart, Lung, and Blood Institute (NHLBI) Pooled Cohorts Study harmonized and pooled data from 9 US general population-based cohorts. Thus present study is based on data from 5 of these cohorts. Participants were enrolled from August 1971 through May 2007 and were followed up through December 2018.

Exposures: Nonobstructive chronic bronchitis was defined by questionnaire at baseline as both cough and phlegm for at least 3 months for at least 2 consecutive years.

Main Outcomes and Measures: Lung function was measured by prebronchodilator spirometry. Hospitalizations and deaths due to chronic lower respiratory disease and respiratory disease-related mortality were defined by events adjudication and administrative criteria. Models were stratified by smoking status and adjusted for anthropometric, sociodemographic, and smoking-related factors. The comparison group was participants without nonobstructive chronic bronchitis.

Results: Among 22 325 adults included in the analysis, mean (SD) age was 53.0 (16.3) years (range, 18.0-95.0 years), 58.2% were female, 65.9% were non-Hispanic white, and 49.6% were ever smokers. Among 11 082 ever smokers with 99 869 person-years of follow-up, participants with nonobstructive chronic bronchitis (300 [2.7%]) had accelerated decreases in FEV1 (4.1 mL/y; 95% CI, 2.1-6.1 mL/y) and FVC (4.7 mL/y; 95% CI, 2.2-7.2 mL/y), increased risks of chronic lower respiratory disease-related hospitalization or mortality (hazard ratio [HR], 2.2; 95% CI, 1.7-2.7), and greater respiratory disease-related (HR, 2.0; 95% CI, 1.1-3.8) and all-cause mortality (HR, 1.5; 95% CI, 1.3-1.8) compared with ever smokers without nonobstructive chronic bronchitis. Among 11 243 never smokers with 120 004 person-years of follow-up, participants with nonobstructive chronic bronchitis (151 [1.3%]) had greater rates of chronic lower respiratory disease-related hospitalization or mortality (HR, 3.1; 95% CI, 2.1-4.5) compared with never smokers without nonobstructive chronic bronchitis. Nonobstructive chronic bronchitis was not associated with FEV1:FVC decline or incident airflow obstruction. The presence of at least 1 of the component symptoms of nonobstructive chronic bronchitis (ie, chronic cough or phlegm), which was common in both ever smokers (11.0%) and never smokers (6.7%), was associated with adverse respiratory health outcomes.

Conclusions and Relevance: The findings suggest that nonobstructive chronic bronchitis is associated with adverse respiratory health outcomes, particularly in ever smokers, and may be a high-risk phenotype suitable for risk stratification and targeted therapies.

%B JAMA Intern Med %V 180 %P 676-686 %8 2020 05 01 %G eng %N 5 %R 10.1001/jamainternmed.2020.0104 %0 Journal Article %J Ann Epidemiol %D 2020 %T The association of prediagnosis social support with survival after heart failure in the Cardiovascular Health Study. %A Kaiser, Paulina %A Allen, Norrina %A Delaney, Joseph A C %A Hirsch, Calvin H %A Carnethon, Mercedes %A Arnold, Alice M %A Odden, Michelle C %X

PURPOSE: Although social support has been shown to be associated with survival among persons with cardiovascular disease, little research has focused on whether social support, measured before the onset of heart failure, can enhance survival after diagnosis. The objective of this study was to assess the association between prediagnosis social support and postdiagnosis survival among older adults with heart failure.

METHODS: We obtained the data from the Cardiovascular Health Study, which included noninstitutionalized adults aged 65 years or older from four sites in the United States with primary enrollment in 1989-1990. We used two measures of social support, the Lubben Social Network Scale and the Interpersonal Support Evaluation List. The analytic data set included 529 participants with a social support measure within two years before diagnosis of heart failure.

RESULTS: After adjustment for demographic covariates, cardiovascular risk factors, and general health status, mortality rates were lower among participants in the highest tertile of social network scores (HR 0.74, 95% CI: 0.59, 0.93) and the middle tertile (HR 0.73 [0.58, 0.90]), compared with the lowest tertile. Results with interpersonal support were null.

CONCLUSIONS: These findings suggest that prediagnosis structural social support may modestly buffer heart failure patients from mortality.

%B Ann Epidemiol %V 42 %P 73-77 %8 2020 Feb %G eng %R 10.1016/j.annepidem.2019.12.013 %0 Journal Article %J Alzheimers Dement %D 2020 %T Associations of body composition with incident dementia in older adults: Cardiovascular Health Study-Cognition Study. %A Cui, Chendi %A Mackey, Rachel H %A Shaaban, C Elizabeth %A Kuller, Lewis H %A Lopez, Oscar L %A Sekikawa, Akira %X

INTRODUCTION: A body of literature reported associations between late-life general adiposity measures (eg, body mass index) and dementia. Little is known about the association of late-life body composition with dementia risk.

METHODS: We determined this association among cognitively normal participants from the Cardiovascular Health Study- Cognition Study. Body composition was assessed by dual-energy x-ray absorptiometry in 1994-1995. Dementia was ascertained at annual follow-up from 1998-1999 to 2013. Associations of body composition with incident dementia were assessed by the Fine-Gray model.

RESULT: Among 344 participants (mean age 78, 62.2% women), body composition was significantly different between men and women, despite similar body mass indexes (BMIs). Increased dementia risk was significantly associated with lower lean mass in men and marginally with low appendicular lean mass in women.

DISCUSSION: Decreased lean mass was an indicator of increased dementia risk in older adults. Studies should test whether preventing lean mass loss in older adults reduces dementia risk.

%B Alzheimers Dement %8 2020 Aug 17 %G eng %R 10.1002/alz.12125 %0 Journal Article %J J Thromb Haemost %D 2020 %T Burden of rare exome sequence variants in PROC gene is associated with venous thromboembolism: a population-based study. %A Tang, Weihong %A Stimson, Mary Rachel %A Basu, Saonli %A Heckbert, Susan R %A Cushman, Mary %A Pankow, James S %A Folsom, Aaron R %A Pankratz, Nathan %X

BACKGROUND: Rare coding mutations underlying deficiencies of antithrombin and proteins C and S contribute to familial venous thromboembolism (VTE). It is uncertain whether rare variants play a role in the etiology of VTE in the general population.

OBJECTIVES: We conducted a deep whole-exome sequencing (WES) study to investigate the associations between rare coding variants and the risk of VTE in two population-based prospective cohorts.

PATIENTS/METHODS: Whole-exome sequencing was performed in the Longitudinal Investigation of Thromboembolism Etiology (LITE), which combines the Atherosclerosis Risk in Communities (ARIC) study (316 incident VTE events among 3159 African Americans [AAs] and 458 incident VTEs among 7772 European Americans [EAs]) and the Cardiovascular Healthy Study (CHS; 60 incident VTEs among 1751 EAs). We performed gene-based tests of rare variants (allele frequency < 1%, exome-wide significance P < 1.47 × 10 ) separately in each study and ancestry group, and meta-analyzed the results for the EAs in ARIC and CHS.

RESULTS: In the meta-analysis of EAs, we identified one gene, PROC, in which the burden of rare, coding variants was significantly associated with increased risk of VTE (HR = 5.42 [3.11, 9.42] for carriers versus non-carriers, P = 2.27 × 10 ). In ARIC EAs, carriers of the PROC rare variants had on average 0.75 standard deviation (SD) lower concentrations of plasma protein C and 0.28 SD higher D-dimer (P < .05) than non-carriers. Adjustment for low protein C status did not eliminate the association of PROC burden with VTE. In AAs, rare coding PROC variants were not associated with VTE.

CONCLUSIONS: Rare coding variants in PROC contribute to increased VTE risk in EAs in this general population sample.

%B J Thromb Haemost %V 18 %P 445-453 %8 2020 Feb %G eng %N 2 %R 10.1111/jth.14676 %0 Journal Article %J Nat Commun %D 2020 %T {Cerebral small vessel disease genomics and its implications across the lifespan %A Sargurupremraj, M. %A Suzuki, H. %A Jian, X. %A Sarnowski, C. %A Evans, T. E. %A Bis, J. C. %A Eiriksdottir, G. %A Sakaue, S. %A Terzikhan, N. %A Habes, M. %A Zhao, W. %A Armstrong, N. J. %A Hofer, E. %A Yanek, L. R. %A Hagenaars, S. P. %A Kumar, R. B. %A van den Akker, E. B. %A McWhirter, R. E. %A Trompet, S. %A Mishra, A. %A Saba, Y. %A Satizabal, C. L. %A Beaudet, G. %A Petit, L. %A Tsuchida, A. %A Zago, L. %A Schilling, S. %A Sigurdsson, S. %A Gottesman, R. F. %A Lewis, C. E. %A Aggarwal, N. T. %A Lopez, O. L. %A Smith, J. A. %A Vald?s Hern?ndez, M. C. %A van der Grond, J. %A Wright, M. J. %A Knol, M. J. %A D?rr, M. %A Thomson, R. J. %A Bordes, C. %A Le Grand, Q. %A Duperron, M. G. %A Smith, A. V. %A Knopman, D. S. %A Schreiner, P. J. %A Evans, D. A. %A Rotter, J. I. %A Beiser, A. S. %A Maniega, S. M. %A Beekman, M. %A Trollor, J. %A Stott, D. J. %A Vernooij, M. W. %A Wittfeld, K. %A Niessen, W. J. %A Soumar?, A. %A Boerwinkle, E. %A Sidney, S. %A Turner, S. T. %A Davies, G. %A Thalamuthu, A. %A V?lker, U. %A van Buchem, M. A. %A Bryan, R. N. %A Dupuis, J. %A Bastin, M. E. %A Ames, D. %A Teumer, A. %A Amouyel, P. %A Kwok, J. B. %A B?low, R. %A Deary, I. J. %A Schofield, P. R. %A Brodaty, H. %A Jiang, J. %A Tabara, Y. %A Setoh, K. %A Miyamoto, S. %A Yoshida, K. %A Nagata, M. %A Kamatani, Y. %A Matsuda, F. %A Psaty, B. M. %A Bennett, D. A. %A De Jager, P. L. %A Mosley, T. H. %A Sachdev, P. S. %A Schmidt, R. %A Warren, H. R. %A Evangelou, E. %A Tr?gou?t, D. A. %A Ikram, M. A. %A Wen, W. %A DeCarli, C. %A Srikanth, V. K. %A Jukema, J. W. %A Slagboom, E. P. %A Kardia, S. L. R. %A Okada, Y. %A Mazoyer, B. %A Wardlaw, J. M. %A Nyquist, P. A. %A Mather, K. A. %A Grabe, H. J. %A Schmidt, H. %A van Duijn, C. M. %A Gudnason, V. %A Longstreth, W. T. %A Launer, L. J. %A Lathrop, M. %A Seshadri, S. %A Tzourio, C. %A Adams, H. H. %A Matthews, P. M. %A Fornage, M. %A Debette, S. %A Amouyel, P. %A de Andrade, M. %A Basu, S. %A Berr, C. %A Brody, J. A. %A Chasman, D. I. %A Dartigues, J. F. %A Folsom, A. R. %A Germain, M. %A de Haan, H. %A Heit, J. %A Houwing-Duitermaat, J. %A Kabrhel, C. %A Kraft, P. %A Legal, G. %A Lindstr?m, S. %A Monajemi, R. %A Morange, P. E. %A Psaty, B. M. %A Reitsma, P. H. %A Ridker, P. M. %A Rose, L. M. %A Rosendaal, F. R. %A Saut, N. %A Slagboom, E. %A Smadja, D. %A Smith, N. L. %A Suchon, P. %A Tang, W. %A Taylor, K. D. %A Tr?gou?t, D. A. %A Tzourio, C. %A de Visser, M. C. H. %A van Hylckama Vlieg, A. %A Weng, L. C. %A Wiggins, K. L. %A Gormley, P. %A Anttila, V. %A Winsvold, B. S. %A Palta, P. %A Esko, T. %A Pers, T. H. %A Farh, K. H. %A Cuenca-Leon, E. %A Muona, M. %A Furlotte, N. A. %A Kurth, T. %A Ingason, A. %A McMahon, G. %A Ligthart, L. %A Terwindt, G. M. %A Kallela, M. %A Freilinger, T. M. %A Ran, C. %A Gordon, S. G. %A Stam, A. H. %A Steinberg, S. %A Borck, G. %A Koiranen, M. %A Quaye, L. %A Adams, H. H. H. %A Lehtim?ki, T. %A Sarin, A. P. %A Wedenoja, J. %A Hinds, D. A. %A Buring, J. E. %A Sch?rks, M. %A Ridker, P. M. %A Gudlaug Hrafnsdottir, M. %A Stefansson, H. %A Ring, S. M. %A Hottenga, J. J. %A Penninx, B. W. J. H. %A F?rkkil?, M. %A Artto, V. %A Kaunisto, M. %A Veps?l?inen, S. %A Malik, R. %A Heath, A. C. %A Madden, P. A. F. %A Martin, N. G. %A Montgomery, G. W. %A Kurki, M. %A Kals, M. %A M?gi, R. %A P?rn, K. %A H?m?l?inen, E. %A Huang, H. %A Byrnes, A. E. %A Franke, L. %A Huang, J. %A Stergiakouli, E. %A Lee, P. H. %A Sandor, C. %A Webber, C. %A Cader, Z. %A Muller-Myhsok, B. %A Schreiber, S. %A Meitinger, T. %A Eriksson, J. G. %A Salomaa, V. %A Heikkil?, K. %A Loehrer, E. %A Uitterlinden, A. G. %A Hofman, A. %A van Duijn, C. M. %A Cherkas, L. %A Pedersen, L. M. %A Stubhaug, A. %A Nielsen, C. S. %A M?nnikk?, M. %A Mihailov, E. %A Milani, L. %A G?bel, H. %A Esserlind, A. L. %A Francke Christensen, A. %A Folkmann Hansen, T. %A Werge, T. %A Kaprio, J. %A Aromaa, A. J. %A Raitakari, O. %A Ikram, M. A. %A Spector, T. %A J?rvelin, M. R. %A Metspalu, A. %A Kubisch, C. %A Strachan, D. P. %A Ferrari, M. D. %A Belin, A. C. %A Dichgans, M. %A Wessman, M. %A van den Maagdenberg, A. M. J. M. %A Zwart, J. A. %A Boomsma, D. I. %A Davey Smith, G. %A Stefansson, K. %A Eriksson, N. %A Daly, M. J. %A Neale, B. M. %A Olesen, J. %A Chasman, D. I. %A Nyholt, D. R. %A Palotie, A. %X White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials. %B Nat Commun %V 11 %P 6285 %8 12 %G eng %0 Journal Article %J JCI Insight %D 2020 %T Characterization of cardiac mechanics and incident atrial fibrillation in participants of the Cardiovascular Health Study. %A Patel, Ravi B %A Delaney, Joseph A %A Hu, Mo %A Patel, Harnish %A Cheng, Jeanette %A Gottdiener, John %A Kizer, Jorge R %A Marcus, Gregory M %A Turakhia, Mintu P %A Deo, Rajat %A Heckbert, Susan R %A Psaty, Bruce M %A Shah, Sanjiv J %X

BACKGROUND: Left atrial (LA) and left ventricular (LV) remodeling are associated with atrial fibrillation (AF). The prospective associations of impairment in cardiac mechanical function, as assessed by speckle-tracking echocardiography, with incident AF are less clear.

METHODS: In the Cardiovascular Health Study, a community-based cohort of older adults, participants free of AF with echocardiograms of adequate quality for speckle tracking were included. We evaluated the associations of indices of cardiac mechanics (LA reservoir strain, LV longitudinal strain, and LV early diastolic strain rate) with incident AF.

RESULTS: Of 4341 participants with strain imaging, participants with lower LA reservoir strain were older, had more cardiometabolic risk factors, and had lower renal function at baseline. Over a median follow-up of 10 years, 497 (11.4%) participants developed AF. Compared with the highest quartile of LA reservoir strain, the lowest quartile of LA reservoir strain was associated with higher risk of AF after covariate adjustment, including LA volume and LV longitudinal strain (heart rate [HR], 1.80; 95% CI, 1.31-2.45; P < 0.001). The association of LA reservoir strain and AF was stronger in subgroups with higher blood pressure, NT-proBNP, and LA volumes. There were no associations of LV longitudinal strain and LV early diastolic strain rate with incident AF after adjustment for LA reservoir strain.

CONCLUSION: Lower LA reservoir strain was associated with incident AF, independent of LV mechanics, and with stronger associations in high-risk subgroups. These findings suggest that LA mechanical dysfunction precedes the development of AF. Therapies targeting LA mechanical dysfunction may prevent progression to AF.

FUNDING: This research was supported by contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086 and grants KL2TR001424, R01HL107577, U01HL080295, and U01HL130114 from the NIH's National Center for Advancing Translational Sciences, and National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org.

%B JCI Insight %V 5 %8 2020 Oct 02 %G eng %N 19 %R 10.1172/jci.insight.141656 %0 Journal Article %J Lancet Respir Med %D 2020 %T Chronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts. %A Moll, Matthew %A Sakornsakolpat, Phuwanat %A Shrine, Nick %A Hobbs, Brian D %A DeMeo, Dawn L %A John, Catherine %A Guyatt, Anna L %A McGeachie, Michael J %A Gharib, Sina A %A Obeidat, Ma'en %A Lahousse, Lies %A Wijnant, Sara R A %A Brusselle, Guy %A Meyers, Deborah A %A Bleecker, Eugene R %A Li, Xingnan %A Tal-Singer, Ruth %A Manichaikul, Ani %A Rich, Stephen S %A Won, Sungho %A Kim, Woo Jin %A Do, Ah Ra %A Washko, George R %A Barr, R Graham %A Psaty, Bruce M %A Bartz, Traci M %A Hansel, Nadia N %A Barnes, Kathleen %A Hokanson, John E %A Crapo, James D %A Lynch, David %A Bakke, Per %A Gulsvik, Amund %A Hall, Ian P %A Wain, Louise %A Weiss, Scott T %A Silverman, Edwin K %A Dudbridge, Frank %A Tobin, Martin D %A Cho, Michael H %K Adult %K Case-Control Studies %K Cohort Studies %K Female %K Forced Expiratory Volume %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Phenotype %K Pulmonary Disease, Chronic Obstructive %K Risk Factors %K Vital Capacity %X

BACKGROUND: Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes.

METHODS: We constructed a polygenic risk score using a genome-wide association study of lung function (FEV and FEV/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV/FVC <0·7 and FEV <80% of predicted). Associations were tested using logistic regression models, adjusting for age, sex, height, smoking pack-years, and principal components of genetic ancestry. We assessed predictive performance of models by area under the curve. In a subset of studies, we also studied quantitative and qualitative CT imaging phenotypes that reflect parenchymal and airway pathology, and patterns of reduced lung growth.

FINDINGS: The polygenic risk score was associated with COPD in European (odds ratio [OR] per SD 1·81 [95% CI 1·74-1·88] and non-European (1·42 [1·34-1·51]) populations. Compared with the first decile, the tenth decile of the polygenic risk score was associated with COPD, with an OR of 7·99 (6·56-9·72) in European ancestry and 4·83 (3·45-6·77) in non-European ancestry cohorts. The polygenic risk score was superior to previously described genetic risk scores and, when combined with clinical risk factors (ie, age, sex, and smoking pack-years), showed improved prediction for COPD compared with a model comprising clinical risk factors alone (AUC 0·80 [0·79-0·81] vs 0·76 [0·75-0·76]). The polygenic risk score was associated with CT imaging phenotypes, including wall area percent, quantitative and qualitative measures of emphysema, local histogram emphysema patterns, and destructive emphysema subtypes. The polygenic risk score was associated with a reduced lung growth pattern.

INTERPRETATION: A risk score comprised of genetic variants can identify a small subset of individuals at markedly increased risk for moderate-to-severe COPD, emphysema subtypes associated with cigarette smoking, and patterns of reduced lung growth.

FUNDING: US National Institutes of Health, Wellcome Trust.

%B Lancet Respir Med %V 8 %P 696-708 %8 2020 07 %G eng %N 7 %R 10.1016/S2213-2600(20)30101-6 %0 Journal Article %J PLoS One %D 2020 %T Coagulation factor VIII, white matter hyperintensities and cognitive function: Results from the Cardiovascular Health Study. %A Rohmann, Jessica L %A Longstreth, W T %A Cushman, Mary %A Fitzpatrick, Annette L %A Heckbert, Susan R %A Rice, Kenneth %A Rosendaal, Frits R %A Sitlani, Colleen M %A Psaty, Bruce M %A Siegerink, Bob %K Aged %K Blood Coagulation %K Cognition %K Cross-Sectional Studies %K Factor VIII %K Female %K Humans %K Logistic Models %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Mental Status and Dementia Tests %K Up-Regulation %K White Matter %X

OBJECTIVE: To investigate the relationship between high FVIII clotting activity (FVIII:C), MRI-defined white matter hyperintensities (WMH) and cognitive function over time.

METHODS: Data from the population-based Cardiovascular Health Study (n = 5,888, aged ≥65) were used. FVIII:C was measured in blood samples taken at baseline. WMH burden was assessed on two cranial MRI scans taken roughly 5 years apart. Cognitive function was assessed annually using the Modified Mini-Mental State Examination (3MSE) and Digit Symbol Substitution Test (DSST). We used ordinal logistic regression models adjusted for demographic and cardiovascular factors in cross-sectional and longitudinal WMH analyses, and adjusted linear regression and linear mixed models in the analyses of cognitive function.

RESULTS: After adjustment for confounding, higher levels of FVIII:C were not strongly associated with the burden of WMH on the initial MRI scan (OR>p75 = 1.20, 95% CI 0.99-1.45; N = 2,735) nor with WMH burden worsening over time (OR>p75 = 1.18, 95% CI 0.87-1.59; N = 1,527). High FVIII:C showed no strong association with cognitive scores cross-sectionally (3MSE>p75 β = -0.06, 95%CI -0.45 to 0.32, N = 4,005; DSST>p75 β = -0.69, 95%CI -1.52 to 0.13, N = 3,954) or over time (3MSE>p75 β = -0.07,95% CI -0.58 to 0.44, N = 2,764; DSST>p75 β = -0.22, 95% CI -0.97 to 0.53, N = 2,306) after confounding adjustment.

INTERPRETATION: The results from this cohort study of older adult participants indicate no strong relationships between higher FVIII:C levels and WMH burden or cognitive function in cross-sectional and longitudinal analyses.

%B PLoS One %V 15 %P e0242062 %8 2020 %G eng %N 11 %R 10.1371/journal.pone.0242062 %0 Journal Article %J Nat Genet %D 2020 %T {Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals %A Surendran, P. %A Feofanova, E. V. %A Lahrouchi, N. %A Ntalla, I. %A Karthikeyan, S. %A Cook, J. %A Chen, L. %A Mifsud, B. %A Yao, C. %A Kraja, A. T. %A Cartwright, J. H. %A Hellwege, J. N. %A Giri, A. %A Tragante, V. %A Thorleifsson, G. %A Liu, D. J. %A Prins, B. P. %A Stewart, I. D. %A Cabrera, C. P. %A Eales, J. M. %A Akbarov, A. %A Auer, P. L. %A Bielak, L. F. %A Bis, J. C. %A Braithwaite, V. S. %A Brody, J. A. %A Daw, E. W. %A Warren, H. R. %A Drenos, F. %A Nielsen, S. F. %A Faul, J. D. %A Fauman, E. B. %A Fava, C. %A Ferreira, T. %A Foley, C. N. %A Franceschini, N. %A Gao, H. %A Giannakopoulou, O. %A Giulianini, F. %A Gudbjartsson, D. F. %A Guo, X. %A Harris, S. E. %A Havulinna, A. S. %A Helgadottir, A. %A Huffman, J. E. %A Hwang, S. J. %A Kanoni, S. %A Kontto, J. %A Larson, M. G. %A Li-Gao, R. %A Lindstr?m, J. %A Lotta, L. A. %A Lu, Y. %A Luan, J. %A Mahajan, A. %A Malerba, G. %A Masca, N. G. D. %A Mei, H. %A Menni, C. %A Mook-Kanamori, D. O. %A Mosen-Ansorena, D. %A M?ller-Nurasyid, M. %A Par?, G. %A Paul, D. S. %A Perola, M. %A Poveda, A. %A Rauramaa, R. %A Richard, M. %A Richardson, T. G. %A Sep?lveda, N. %A Sim, X. %A Smith, A. V. %A Smith, J. A. %A Staley, J. R. %A Stan?kov?, A. %A Sulem, P. %A Th?riault, S. %A Thorsteinsdottir, U. %A Trompet, S. %A Varga, T. V. %A Velez Edwards, D. R. %A Veronesi, G. %A Weiss, S. %A Willems, S. M. %A Yao, J. %A Young, R. %A Yu, B. %A Zhang, W. %A Zhao, J. H. %A Zhao, W. %A Zhao, W. %A Evangelou, E. %A Aeschbacher, S. %A Asllanaj, E. %A Blankenberg, S. %A Bonnycastle, L. L. %A Bork-Jensen, J. %A Brandslund, I. %A Braund, P. S. %A Burgess, S. %A Cho, K. %A Christensen, C. %A Connell, J. %A Mutsert, R. %A Dominiczak, A. F. %A D?rr, M. %A Eiriksdottir, G. %A Farmaki, A. E. %A Gaziano, J. M. %A Grarup, N. %A Grove, M. L. %A Hallmans, G. %A Hansen, T. %A Have, C. T. %A Heiss, G. %A J?rgensen, M. E. %A Jousilahti, P. %A Kajantie, E. %A Kamat, M. %A K?r?j?m?ki, A. %A Karpe, F. %A Koistinen, H. A. %A Kovesdy, C. P. %A Kuulasmaa, K. %A Laatikainen, T. %A Lannfelt, L. %A Lee, I. T. %A Lee, W. J. %A Linneberg, A. %A Martin, L. W. %A Moitry, M. %A Nadkarni, G. %A Neville, M. J. %A Palmer, C. N. A. %A Papanicolaou, G. J. %A Pedersen, O. %A Peters, J. %A Poulter, N. %A Rasheed, A. %A Rasmussen, K. L. %A Rayner, N. W. %A M?gi, R. %A Renstr?m, F. %A Rettig, R. %A Rossouw, J. %A Schreiner, P. J. %A Sever, P. S. %A Sigurdsson, E. L. %A Skaaby, T. %A Sun, Y. V. %A Sundstrom, J. %A Thorgeirsson, G. %A Esko, T. %A Trabetti, E. %A Tsao, P. S. %A Tuomi, T. %A Turner, S. T. %A Tzoulaki, I. %A Vaartjes, I. %A Vergnaud, A. C. %A Willer, C. J. %A Wilson, P. W. F. %A Witte, D. R. %A Yonova-Doing, E. %A Zhang, H. %A Aliya, N. %A Almgren, P. %A Amouyel, P. %A Asselbergs, F. W. %A Barnes, M. R. %A Blakemore, A. I. %A Boehnke, M. %A Bots, M. L. %A Bottinger, E. P. %A Buring, J. E. %A Chambers, J. C. %A Chen, Y. I. %A Chowdhury, R. %A Conen, D. %A Correa, A. %A Davey Smith, G. %A Boer, R. A. %A Deary, I. J. %A Dedoussis, G. %A Deloukas, P. %A Di Angelantonio, E. %A Elliott, P. %A Felix, S. B. %A Ferri?res, J. %A Ford, I. %A Fornage, M. %A Franks, P. W. %A Franks, S. %A Frossard, P. %A Gambaro, G. %A Gaunt, T. R. %A Groop, L. %A Gudnason, V. %A Harris, T. B. %A Hayward, C. %A Hennig, B. J. %A Herzig, K. H. %A Ingelsson, E. %A Tuomilehto, J. %A J?rvelin, M. R. %A Jukema, J. W. %A Kardia, S. L. R. %A Kee, F. %A Kooner, J. S. %A Kooperberg, C. %A Launer, L. J. %A Lind, L. %A Loos, R. J. F. %A Majumder, A. A. S. %A Laakso, M. %A McCarthy, M. I. %A Melander, O. %A Mohlke, K. L. %A Murray, A. D. %A Nordestgaard, B. G. %A Orho-Melander, M. %A Packard, C. J. %A Padmanabhan, S. %A Palmas, W. %A Polasek, O. %A Porteous, D. J. %A Prentice, A. M. %A Province, M. A. %A Relton, C. L. %A Rice, K. %A Ridker, P. M. %A Rolandsson, O. %A Rosendaal, F. R. %A Rotter, J. I. %A Rudan, I. %A Salomaa, V. %A Samani, N. J. %A Sattar, N. %A Sheu, W. H. %A Smith, B. H. %A Soranzo, N. %A Spector, T. D. %A Starr, J. M. %A Sebert, S. %A Taylor, K. D. %A Lakka, T. A. %A Timpson, N. J. %A Tobin, M. D. %A van der Harst, P. %A van der Meer, P. %A Ramachandran, V. S. %A Verweij, N. %A Virtamo, J. %A V?lker, U. %A Weir, D. R. %A Zeggini, E. %A Charchar, F. J. %A Wareham, N. J. %A Langenberg, C. %A Tomaszewski, M. %A Butterworth, A. S. %A Caulfield, M. J. %A Danesh, J. %A Edwards, T. L. %A Holm, H. %A Hung, A. M. %A Lindgren, C. M. %A Liu, C. %A Manning, A. K. %A Morris, A. P. %A Morrison, A. C. %A O'Donnell, C. J. %A Psaty, B. M. %A Saleheen, D. %A Stefansson, K. %A Boerwinkle, E. %A Chasman, D. I. %A Levy, D. %A Newton-Cheh, C. %A Munroe, P. B. %A Howson, J. M. M. %A de Boer, R. A. %A van der Harst, P. %A van der Meer, P. %A Verweij, N. %A Butterworth, A. S. %A Danesh, J. %A Langenberg, C. %A Deloukas, P. %A McCarthy, M. I. %A Franks, P. W. %A Rolandsson, O. %A Wareham, N. J. %A Prins, B. P. %A Zeggini, E. %A Hellwege, J. N. %A Giri, A. %A Edwards, D. R. V. %A Cho, K. %A Gaziano, J. M. %A Kovesdy, C. P. %A Sun, Y. V. %A Tsao, P. S. %A Wilson, P. W. F. %A Edwards, T. L. %A Hung, A. M. %A O'Donnell, C. J. %X Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to 1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10-8), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were 8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets. %B Nat Genet %V 52 %P 1314–1332 %8 12 %G eng %0 Journal Article %J Am J Epidemiol %D 2020 %T A Dyadic Growth Modeling Approach for Examining Associations Between Weight Gain and Lung Function Decline. %A Cornelius, Talea %A Schwartz, Joseph E %A Balte, Pallavi %A Bhatt, Surya P %A Cassano, Patricia A %A Currow, David %A Jacobs, David R %A Johnson, Miriam %A Kalhan, Ravi %A Kronmal, Richard %A Loehr, Laura %A O'Connor, George T %A Smith, Benjamin %A White, Wendy B %A Yende, Sachin %A Oelsner, Elizabeth C %K Adult %K Aged %K Body Mass Index %K Cohort Studies %K Humans %K Linear Models %K Lung %K Middle Aged %K Respiratory Function Tests %K Weight Gain %X

The relationship between body weight and lung function is complex. Using a dyadic multilevel linear modeling approach, treating body mass index (BMI; weight (kg)/height (m)2) and lung function as paired, within-person outcomes, we tested the hypothesis that persons with more rapid increase in BMI exhibit more rapid decline in lung function, as measured by forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and their ratio (FEV1:FVC). Models included random intercepts and slopes and adjusted for sociodemographic and smoking-related factors. A sample of 9,115 adults with paired measurements of BMI and lung function taken at ≥3 visits were selected from a pooled set of 5 US population-based cohort studies (1983-2018; mean age at baseline = 46 years; median follow-up, 19 years). At age 46 years, average annual rates of change in BMI, FEV1, FVC, and FEV1:FVC ratio were 0.22 kg/m2/year, -25.50 mL/year, -21.99 mL/year, and -0.24%/year, respectively. Persons with steeper BMI increases had faster declines in FEV1 (r = -0.16) and FVC (r = -0.26) and slower declines in FEV1:FVC ratio (r = 0.11) (all P values < 0.0001). Results were similar in subgroup analyses. Residual correlations were negative (P < 0.0001), suggesting additional interdependence between BMI and lung function. Results show that greater rates of weight gain are associated with greater rates of lung function loss.

%B Am J Epidemiol %V 189 %P 1173-1184 %8 2020 10 01 %G eng %N 10 %R 10.1093/aje/kwaa059 %0 Journal Article %J Nat Genet %D 2020 %T {Dynamic incorporation of multiple in silico functional annotations empowers rare variant association analysis of large whole-genome sequencing studies at scale %A Li, X. %A Li, Z. %A Zhou, H. %A Gaynor, S. M. %A Liu, Y. %A Chen, H. %A Sun, R. %A Dey, R. %A Arnett, D. K. %A Aslibekyan, S. %A Ballantyne, C. M. %A Bielak, L. F. %A Blangero, J. %A Boerwinkle, E. %A Bowden, D. W. %A Broome, J. G. %A Conomos, M. P. %A Correa, A. %A Cupples, L. A. %A Curran, J. E. %A Freedman, B. I. %A Guo, X. %A Hindy, G. %A Irvin, M. R. %A Kardia, S. L. R. %A Kathiresan, S. %A Khan, A. T. %A Kooperberg, C. L. %A Laurie, C. C. %A Liu, X. S. %A Mahaney, M. C. %A Manichaikul, A. W. %A Martin, L. W. %A Mathias, R. A. %A McGarvey, S. T. %A Mitchell, B. D. %A Montasser, M. E. %A Moore, J. E. %A Morrison, A. C. %A O'Connell, J. R. %A Palmer, N. D. %A Pampana, A. %A Peralta, J. M. %A Peyser, P. A. %A Psaty, B. M. %A Redline, S. %A Rice, K. M. %A Rich, S. S. %A Smith, J. A. %A Tiwari, H. K. %A Tsai, M. Y. %A Vasan, R. S. %A Wang, F. F. %A Weeks, D. E. %A Weng, Z. %A Wilson, J. G. %A Yanek, L. R. %A Neale, B. M. %A Sunyaev, S. R. %A Abecasis, G. R. %A Rotter, J. I. %A Willer, C. J. %A Peloso, G. M. %A Natarajan, P. %A Lin, X. %A Abe, N. %A Abecasis, G. R. %A Aguet, F. %A Albert, C. %A Almasy, L. %A Alonso, A. %A Ament, S. %A Anderson, P. %A Anugu, P. %A Applebaum-Bowden, D. %A Ardlie, K. %A Arking, D. %A Arnett, D. K. %A Ashley-Koch, A. %A Aslibekyan, S. %A Assimes, T. %A Auer, P. %A Avramopoulos, D. %A Barnard, J. %A Barnes, K. %A Barr, R. G. %A Barron-Casella, E. %A Barwick, L. %A Beaty, T. %A Beck, G. %A Becker, D. %A Becker, L. %A Beer, R. %A Beitelshees, A. %A Benjamin, E. %A Benos, T. %A Bezerra, M. %A Bielak, L. F. %A Bis, J. %A Blackwell, T. %A Blangero, J. %A Boerwinkle, E. %A Bowden, D. W. %A Bowler, R. %A Brody, J. %A Broeckel, U. %A Broome, J. G. %A Bunting, K. %A Burchard, E. %A Bustamante, C. %A Buth, E. %A Cade, B. %A Cardwell, J. %A Carey, V. %A Carty, C. %A Casaburi, R. %A Casella, J. %A Castaldi, P. %A Chaffin, M. %A Chang, C. %A Chang, Y. C. %A Chasman, D. %A Chavan, S. %A Chen, B. J. %A Chen, W. M. %A Chen, Y. I. %A Cho, M. %A Choi, S. H. %A Chuang, L. M. %A Chung, M. %A Chung, R. H. %A Clish, C. %A Comhair, S. %A Conomos, M. P. %A Cornell, E. %A Correa, A. %A Crandall, C. %A Crapo, J. %A Cupples, L. A. %A Curran, J. E. %A Curtis, J. %A Custer, B. %A Damcott, C. %A Darbar, D. %A Das, S. %A David, S. %A Davis, C. %A Daya, M. %A de Andrade, M. %A Fuentes, L. L. %A DeBaun, M. %A Deka, R. %A DeMeo, D. %A Devine, S. %A Duan, Q. %A Duggirala, R. %A Durda, J. P. %A Dutcher, S. %A Eaton, C. %A Ekunwe, L. %A El Boueiz, A. %A Ellinor, P. %A Emery, L. %A Erzurum, S. %A Farber, C. %A Fingerlin, T. %A Flickinger, M. %A Fornage, M. %A Franceschini, N. %A Frazar, C. %A Fu, M. %A Fullerton, S. M. %A Fulton, L. %A Gabriel, S. %A Gan, W. %A Gao, S. %A Gao, Y. %A Gass, M. %A Gelb, B. %A Geng, X. P. %A Geraci, M. %A Germer, S. %A Gerszten, R. %A Ghosh, A. %A Gibbs, R. %A Gignoux, C. %A Gladwin, M. %A Glahn, D. %A Gogarten, S. %A Gong, D. W. %A Goring, H. %A Graw, S. %A Grine, D. %A Gu, C. C. %A Guan, Y. %A Guo, X. %A Gupta, N. %A Haessler, J. %A Hall, M. %A Harris, D. %A Hawley, N. L. %A He, J. %A Heckbert, S. %A Hernandez, R. %A Herrington, D. %A Hersh, C. %A Hidalgo, B. %A Hixson, J. %A Hobbs, B. %A Hokanson, J. %A Hong, E. %A Hoth, K. %A Hsiung, C. A. %A Hung, Y. J. %A Huston, H. %A Hwu, C. M. %A Irvin, M. R. %A Jackson, R. %A Jain, D. %A Jaquish, C. %A Jhun, M. A. %A Johnsen, J. %A Johnson, A. %A Johnson, C. %A Johnston, R. %A Jones, K. %A Kang, H. M. %A Kaplan, R. %A Kardia, S. L. R. %A Kathiresan, S. %A Kelly, S. %A Kenny, E. %A Kessler, M. %A Khan, A. T. %A Kim, W. %A Kinney, G. %A Konkle, B. %A Kooperberg, C. L. %A Kramer, H. %A Lange, C. %A Lange, E. %A Lange, L. %A Laurie, C. C. %A Laurie, C. %A LeBoff, M. %A Lee, J. %A Lee, S. S. %A Lee, W. J. %A LeFaive, J. %A Levine, D. %A Levy, D. %A Lewis, J. %A Li, X. %A Li, Y. %A Lin, H. %A Lin, H. %A Lin, K. H. %A Lin, X. %A Liu, S. %A Liu, Y. %A Liu, Y. %A Loos, R. J. F. %A Lubitz, S. %A Lunetta, K. %A Luo, J. %A Mahaney, M. C. %A Make, B. %A Manichaikul, A. W. %A Manson, J. %A Margolin, L. %A Martin, L. W. %A Mathai, S. %A Mathias, R. A. %A May, S. %A McArdle, P. %A McDonald, M. L. %A McFarland, S. %A McGarvey, S. T. %A McGoldrick, D. %A McHugh, C. %A Mei, H. %A Mestroni, L. %A Meyers, D. A. %A Mikulla, J. %A Min, N. %A Minear, M. %A Minster, R. L. %A Mitchell, B. D. %A Moll, M. %A Montasser, M. E. %A Montgomery, C. %A Moscati, A. %A Musani, S. %A Mwasongwe, S. %A Mychaleckyj, J. C. %A Nadkarni, G. %A Naik, R. %A Naseri, T. %A Natarajan, P. %A Nekhai, S. %A Nelson, S. C. %A Neltner, B. %A Nickerson, D. %A North, K. %A O'Connell, J. 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A. %A Smith, J. %A Smith, N. %A Smith, T. %A Smoller, S. %A Snively, B. %A Snyder, M. %A Sofer, T. %A Sotoodehnia, N. %A Stilp, A. M. %A Storm, G. %A Streeten, E. %A Su, J. L. %A Sung, Y. J. %A Sylvia, J. %A Szpiro, A. %A Sztalryd, C. %A Taliun, D. %A Tang, H. %A Taub, M. %A Taylor, K. D. %A Taylor, M. %A Taylor, S. %A Telen, M. %A Thornton, T. A. %A Threlkeld, M. %A Tinker, L. %A Tirschwell, D. %A Tishkoff, S. %A Tiwari, H. K. %A Tong, C. %A Tracy, R. %A Tsai, M. Y. %A Vaidya, D. %A Van Den Berg, D. %A VandeHaar, P. %A Vrieze, S. %A Walker, T. %A Wallace, R. %A Walts, A. %A Wang, F. F. %A Wang, H. %A Watson, K. %A Weeks, D. E. %A Weir, B. %A Weiss, S. %A Weng, L. C. %A Wessel, J. %A Willer, C. J. %A Williams, K. %A Williams, L. K. %A Wilson, C. %A Wilson, J. G. %A Wong, Q. %A Wu, J. %A Xu, H. %A Yanek, L. R. %A Yang, I. %A Yang, R. %A Zaghloul, N. %A Zekavat, M. %A Zhang, Y. %A Zhao, S. X. %A Zhao, W. %A Zhi, D. %A Zhou, X. %A Zhu, X. %A Zody, M. %A Zoellner, S. %A Abdalla, M. %A Abecasis, G. R. %A Arnett, D. K. %A Aslibekyan, S. %A Assimes, T. %A Atkinson, E. %A Ballantyne, C. M. %A Beitelshees, A. %A Bielak, L. F. %A Bis, J. %A Bodea, C. %A Boerwinkle, E. %A Bowden, D. W. %A Brody, J. %A Cade, B. %A Carlson, J. %A Chang, I. S. %A Chen, Y. I. %A Chun, S. %A Chung, R. H. %A Conomos, M. P. %A Correa, A. %A Cupples, L. A. %A Damcott, C. %A de Vries, P. %A Do, R. %A Elliott, A. %A Fu, M. %A Ganna, A. %A Gong, D. W. %A Graham, S. %A Haas, M. %A Haring, B. %A He, J. %A Heckbert, S. %A Himes, B. %A Hixson, J. %A Irvin, M. R. %A Jain, D. %A Jarvik, G. %A Jhun, M. A. %A Jiang, J. %A Jun, G. %A Kalyani, R. %A Kardia, S. L. R. %A Kathiresan, S. %A Khera, A. %A Klarin, D. %A Kooperberg, C. L. %A Kral, B. %A Lange, L. %A Laurie, C. C. %A Laurie, C. %A Lemaitre, R. %A Li, Z. %A Li, X. %A Lin, X. %A Mahaney, M. C. %A Manichaikul, A. W. %A Martin, L. W. %A Mathias, R. A. %A Mathur, R. %A McGarvey, S. T. %A McHugh, C. %A McLenithan, J. %A Mikulla, J. %A Mitchell, B. D. %A Montasser, M. E. %A Moran, A. %A Morrison, A. C. %A Nakao, T. %A Natarajan, P. %A Nickerson, D. %A North, K. %A O'Connell, J. R. %A O'Donnell, C. %A Palmer, N. D. %A Pampana, A. %A Patel, A. %A Peloso, G. M. %A Perry, J. %A Peters, U. %A Peyser, P. A. %A Pirruccello, J. %A Pollin, T. %A Preuss, M. %A Psaty, B. M. %A Rao, D. C. %A Redline, S. %A Reed, R. %A Reiner, A. %A Rich, S. S. %A Rosenthal, S. %A Rotter, J. I. %A Schoenberg, J. %A Selvaraj, M. S. %A Sheu, W. H. %A Smith, J. A. %A Sofer, T. %A Stilp, A. M. %A Sunyaev, S. R. %A Surakka, I. %A Sztalryd, C. %A Tang, H. %A Taylor, K. D. %A Tsai, M. Y. %A Uddin, M. M. %A Urbut, S. %A Verbanck, M. %A Von Holle, A. %A Wang, H. %A Wang, F. F. %A Wiggins, K. %A Willer, C. J. %A Wilson, J. G. %A Wolford, B. %A Xu, H. %A Yanek, L. R. %A Zaghloul, N. %A Zekavat, M. %A Zhang, J. %X Large-scale whole-genome sequencing studies have enabled the analysis of rare variants (RVs) associated with complex phenotypes. Commonly used RV association tests have limited scope to leverage variant functions. We propose STAAR (variant-set test for association using annotation information), a scalable and powerful RV association test method that effectively incorporates both variant categories and multiple complementary annotations using a dynamic weighting scheme. For the latter, we introduce 'annotation principal components', multidimensional summaries of in silico variant annotations. STAAR accounts for population structure and relatedness and is scalable for analyzing very large cohort and biobank whole-genome sequencing studies of continuous and dichotomous traits. We applied STAAR to identify RVs associated with four lipid traits in 12,316 discovery and 17,822 replication samples from the Trans-Omics for Precision Medicine Program. We discovered and replicated new RV associations, including disruptive missense RVs of NPC1L1 and an intergenic region near APOC1P1 associated with low-density lipoprotein cholesterol. %B Nat Genet %V 52 %P 969–983 %8 Sep %G eng %0 Journal Article %J Hum Brain Mapp %D 2020 %T Estrogen, brain structure, and cognition in postmenopausal women. %A Boyle, Christina P %A Raji, Cyrus A %A Erickson, Kirk I %A Lopez, Oscar L %A Becker, James T %A Gach, H Michael %A Kuller, Lewis H %A Longstreth, William %A Carmichael, Owen T %A Riedel, Brandalyn C %A Thompson, Paul M %X

Declining estrogen levels before, during, and after menopause can affect memory and risk for Alzheimer's disease. Undesirable side effects of hormone variations emphasize a role for hormone therapy (HT) where possible benefits include a delay in the onset of dementia-yet findings are inconsistent. Effects of HT may be mediated by estrogen receptors found throughout the brain. Effects may also depend on lifestyle factors, timing of use, and genetic risk. We studied the impact of self-reported HT use on brain volume in 562 elderly women (71-94 years) with mixed cognitive status while adjusting for aforementioned factors. Covariate-adjusted voxelwise linear regression analyses using a model with 16 predictors showed HT use as positively associated with regional brain volumes, regardless of cognitive status. Examinations of other factors related to menopause, oophorectomy and hysterectomy status independently yielded positive effects on brain volume when added to our model. One interaction term, HTxBMI, out of several examined, revealed significant negative association with overall brain volume, suggesting a greater reduction in brain volume than BMI alone. Our main findings relating HT to regional brain volume were as hypothesized, but some exploratory analyses were not in line with existing hypotheses. Studies suggest lower levels of estrogen resulting from oophorectomy and hysterectomy affect brain volume negatively, and the addition of HT modifies the relation between BMI and brain volume positively. Effects of HT may depend on the age range assessed, motivating studies with a wider age range as well as a randomized design.

%B Hum Brain Mapp %8 2020 Sep 10 %G eng %R 10.1002/hbm.25200 %0 Journal Article %J J R Stat Soc Ser A Stat Soc %D 2020 %T Examining the causal mediating role of brain pathology on the relationship between diabetes and cognitive impairment: the Cardiovascular Health Study. %A Andrews, Ryan M %A Shpitser, Ilya %A Lopez, Oscar %A Longstreth, William T %A Chaves, Paulo H M %A Kuller, Lewis %A Carlson, Michelle C %X

The paper examines whether leads to incident mild cognitive impairment and dementia through brain hypoperfusion and white matter disease. We performed inverse odds ratio weighted causal mediation analyses to decompose the effect of diabetes on cognitive impairment into direct and indirect effects, and we found that approximately a third of the total effect of diabetes is mediated through vascular-related brain pathology. Our findings lend support for a common aetiological hypothesis regarding incident cognitive impairment, which is that diabetes increases the risk of clinical cognitive impairment in part by impacting the vasculature of the brain.

%B J R Stat Soc Ser A Stat Soc %V 183 %P 1705-1726 %8 2020 Oct %G eng %N 4 %R 10.1111/rssa.12570 %0 Journal Article %J PLoS Med %D 2020 %T {Fatty acids in the de novo lipogenesis pathway and incidence of type 2 diabetes: A pooled analysis of prospective cohort studies %A Imamura, F. %A Fretts, A. M. %A Marklund, M. %A Ardisson Korat, A. V. %A Yang, W. S. %A Lankinen, M. %A Qureshi, W. %A Helmer, C. %A Chen, T. A. %A Virtanen, J. K. %A Wong, K. %A Bassett, J. K. %A Murphy, R. %A Tintle, N. %A Yu, C. I. %A Brouwer, I. A. %A Chien, K. L. %A Chen, Y. Y. %A Wood, A. C. %A Del Gobbo, L. C. %A Djousse, L. %A Geleijnse, J. M. %A Giles, G. G. %A de Goede, J. %A Gudnason, V. %A Harris, W. S. %A Hodge, A. %A Hu, F. %A Koulman, A. %A Laakso, M. %A Lind, L. %A Lin, H. J. %A McKnight, B. %A Rajaobelina, K. %A Riserus, U. %A Robinson, J. G. %A Samieri, C. %A Senn, M. %A Siscovick, D. S. %A Soedamah-Muthu, S. S. %A Sotoodehnia, N. %A Sun, Q. %A Tsai, M. Y. %A Tuomainen, T. P. %A Uusitupa, M. %A Wagenknecht, L. E. %A Wareham, N. J. %A Wu, J. H. Y. %A Micha, R. %A Lemaitre, R. N. %A Mozaffarian, D. %A Forouhi, N. G. %X De novo lipogenesis (DNL) is the primary metabolic pathway synthesizing fatty acids from carbohydrates, protein, or alcohol. Our aim was to examine associations of in vivo levels of selected fatty acids (16:0, 16:1n7, 18:0, 18:1n9) in DNL with incidence of type 2 diabetes (T2D).\ Seventeen cohorts from 12 countries (7 from Europe, 7 from the United States, 1 from Australia, 1 from Taiwan; baseline years = 1970-1973 to 2006-2010) conducted harmonized individual-level analyses of associations of DNL-related fatty acids with incident T2D. In total, we evaluated 65,225 participants (mean ages = 52.3-75.5 years; % women = 20.4%-62.3% in 12 cohorts recruiting both sexes) and 15,383 incident cases of T2D over the 9-year follow-up on average. Cohort-specific association of each of 16:0, 16:1n7, 18:0, and 18:1n9 with incident T2D was estimated, adjusted for demographic factors, socioeconomic characteristics, alcohol, smoking, physical activity, dyslipidemia, hypertension, menopausal status, and adiposity. Cohort-specific associations were meta-analyzed with an inverse-variance-weighted approach. Each of the 4 fatty acids positively related to incident T2D. Relative risks (RRs) per cohort-specific range between midpoints of the top and bottom quintiles of fatty acid concentrations were 1.53 (1.41-1.66; p < 0.001) for 16:0, 1.40 (1.33-1.48; p < 0.001) for 16:1n-7, 1.14 (1.05-1.22; p = 0.001) for 18:0, and 1.16 (1.07-1.25; p < 0.001) for 18:1n9. Heterogeneity was seen across cohorts (I2 = 51.1%-73.1% for each fatty acid) but not explained by lipid fractions and global geographical regions. Further adjusted for triglycerides (and 16:0 when appropriate) to evaluate associations independent of overall DNL, the associations remained significant for 16:0, 16:1n7, and 18:0 but were attenuated for 18:1n9 (RR = 1.03, 95% confidence interval (CI) = 0.94-1.13). These findings had limitations in potential reverse causation and residual confounding by imprecisely measured or unmeasured factors.\ Concentrations of fatty acids in the DNL were positively associated with T2D incidence. Our findings support further work to investigate a possible role of DNL and individual fatty acids in the development of T2D. %B PLoS Med %V 17 %P e1003102 %8 06 %G eng %0 Journal Article %J Mol Psychiatry %D 2020 %T Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci. %A de Las Fuentes, Lisa %A Sung, Yun Ju %A Noordam, Raymond %A Winkler, Thomas %A Feitosa, Mary F %A Schwander, Karen %A Bentley, Amy R %A Brown, Michael R %A Guo, Xiuqing %A Manning, Alisa %A Chasman, Daniel I %A Aschard, Hugues %A Bartz, Traci M %A Bielak, Lawrence F %A Campbell, Archie %A Cheng, Ching-Yu %A Dorajoo, Rajkumar %A Hartwig, Fernando P %A Horimoto, A R V R %A Li, Changwei %A Li-Gao, Ruifang %A Liu, Yongmei %A Marten, Jonathan %A Musani, Solomon K %A Ntalla, Ioanna %A Rankinen, Tuomo %A Richard, Melissa %A Sim, Xueling %A Smith, Albert V %A Tajuddin, Salman M %A Tayo, Bamidele O %A Vojinovic, Dina %A Warren, Helen R %A Xuan, Deng %A Alver, Maris %A Boissel, Mathilde %A Chai, Jin-Fang %A Chen, Xu %A Christensen, Kaare %A Divers, Jasmin %A Evangelou, Evangelos %A Gao, Chuan %A Girotto, Giorgia %A Harris, Sarah E %A He, Meian %A Hsu, Fang-Chi %A Kuhnel, Brigitte %A Laguzzi, Federica %A Li, Xiaoyin %A Lyytikäinen, Leo-Pekka %A Nolte, Ilja M %A Poveda, Alaitz %A Rauramaa, Rainer %A Riaz, Muhammad %A Rueedi, Rico %A Shu, Xiao-Ou %A Snieder, Harold %A Sofer, Tamar %A Takeuchi, Fumihiko %A Verweij, Niek %A Ware, Erin B %A Weiss, Stefan %A Yanek, Lisa R %A Amin, Najaf %A Arking, Dan E %A Arnett, Donna K %A Bergmann, Sven %A Boerwinkle, Eric %A Brody, Jennifer A %A Broeckel, Ulrich %A Brumat, Marco %A Burke, Gregory %A Cabrera, Claudia P %A Canouil, Mickaël %A Chee, Miao Li %A Chen, Yii-Der Ida %A Cocca, Massimiliano %A Connell, John %A de Silva, H Janaka %A de Vries, Paul S %A Eiriksdottir, Gudny %A Faul, Jessica D %A Fisher, Virginia %A Forrester, Terrence %A Fox, Ervin F %A Friedlander, Yechiel %A Gao, He %A Gigante, Bruna %A Giulianini, Franco %A Gu, Chi Charles %A Gu, Dongfeng %A Harris, Tamara B %A He, Jiang %A Heikkinen, Sami %A Heng, Chew-Kiat %A Hunt, Steven %A Ikram, M Arfan %A Irvin, Marguerite R %A Kähönen, Mika %A Kavousi, Maryam %A Khor, Chiea Chuen %A Kilpeläinen, Tuomas O %A Koh, Woon-Puay %A Komulainen, Pirjo %A Kraja, Aldi T %A Krieger, J E %A Langefeld, Carl D %A Li, Yize %A Liang, Jingjing %A Liewald, David C M %A Liu, Ching-Ti %A Liu, Jianjun %A Lohman, Kurt K %A Mägi, Reedik %A McKenzie, Colin A %A Meitinger, Thomas %A Metspalu, Andres %A Milaneschi, Yuri %A Milani, Lili %A Mook-Kanamori, Dennis O %A Nalls, Mike A %A Nelson, Christopher P %A Norris, Jill M %A O'Connell, Jeff %A Ogunniyi, Adesola %A Padmanabhan, Sandosh %A Palmer, Nicholette D %A Pedersen, Nancy L %A Perls, Thomas %A Peters, Annette %A Petersmann, Astrid %A Peyser, Patricia A %A Polasek, Ozren %A Porteous, David J %A Raffel, Leslie J %A Rice, Treva K %A Rotter, Jerome I %A Rudan, Igor %A Rueda-Ochoa, Oscar-Leonel %A Sabanayagam, Charumathi %A Salako, Babatunde L %A Schreiner, Pamela J %A Shikany, James M %A Sidney, Stephen S %A Sims, Mario %A Sitlani, Colleen M %A Smith, Jennifer A %A Starr, John M %A Strauch, Konstantin %A Swertz, Morris A %A Teumer, Alexander %A Tham, Yih Chung %A Uitterlinden, André G %A Vaidya, Dhananjay %A van der Ende, M Yldau %A Waldenberger, Melanie %A Wang, Lihua %A Wang, Ya-Xing %A Wei, Wen-Bin %A Weir, David R %A Wen, Wanqing %A Yao, Jie %A Yu, Bing %A Yu, Caizheng %A Yuan, Jian-Min %A Zhao, Wei %A Zonderman, Alan B %A Becker, Diane M %A Bowden, Donald W %A Deary, Ian J %A Dörr, Marcus %A Esko, Tõnu %A Freedman, Barry I %A Froguel, Philippe %A Gasparini, Paolo %A Gieger, Christian %A Jonas, Jost Bruno %A Kammerer, Candace M %A Kato, Norihiro %A Lakka, Timo A %A Leander, Karin %A Lehtimäki, Terho %A Magnusson, Patrik K E %A Marques-Vidal, Pedro %A Penninx, Brenda W J H %A Samani, Nilesh J %A van der Harst, Pim %A Wagenknecht, Lynne E %A Wu, Tangchun %A Zheng, Wei %A Zhu, Xiaofeng %A Bouchard, Claude %A Cooper, Richard S %A Correa, Adolfo %A Evans, Michele K %A Gudnason, Vilmundur %A Hayward, Caroline %A Horta, Bernardo L %A Kelly, Tanika N %A Kritchevsky, Stephen B %A Levy, Daniel %A Palmas, Walter R %A Pereira, A C %A Province, Michael M %A Psaty, Bruce M %A Ridker, Paul M %A Rotimi, Charles N %A Tai, E Shyong %A van Dam, Rob M %A van Duijn, Cornelia M %A Wong, Tien Yin %A Rice, Kenneth %A Gauderman, W James %A Morrison, Alanna C %A North, Kari E %A Kardia, Sharon L R %A Caulfield, Mark J %A Elliott, Paul %A Munroe, Patricia B %A Franks, Paul W %A Rao, Dabeeru C %A Fornage, Myriam %X

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.

%B Mol Psychiatry %8 2020 May 05 %G eng %R 10.1038/s41380-020-0719-3 %0 Journal Article %J Alzheimers Dement (Amst) %D 2020 %T Genetic and regulatory architecture of Alzheimer's disease in the region. %A Kulminski, Alexander M %A Shu, Leonardo %A Loika, Yury %A He, Liang %A Nazarian, Alireza %A Arbeev, Konstantin %A Ukraintseva, Svetlana %A Yashin, Anatoliy %A Culminskaya, Irina %X

Introduction: Apolipoprotein E () ε2 and ε4 alleles encoded by rs7412 and rs429358 polymorphisms, respectively, are landmark contra and pro "risk" factors for Alzheimer's disease (AD).

Methods: We examined differences in linkage disequilibrium (LD) structures between (1) AD-affected and unaffected subjects and (2) older AD-unaffected and younger subjects in the 19q13.3 region harboring rs7412 and rs429358.

Results: AD is associated with sex-nonspecific heterogeneous patterns of decreased and increased LD of rs7412 and rs429358, respectively, with other polymorphisms from five genes in this region in AD-affected subjects. The LD patterns in older AD-unaffected subjects resembled those in younger individuals. Polarization of the ε4- and ε2 allele-related heterogeneous LD clusters differentiated cell types and implicated specific tissues in AD pathogenesis.

Discussion: Protection and predisposition to AD is characterized by an interplay of rs7412 and rs429358, with multiple polymorphisms in the 19q13.3 region in a tissue-specific manner, which is not driven by common evolutionary forces.

%B Alzheimers Dement (Amst) %V 12 %P e12008 %8 2020 %G eng %N 1 %R 10.1002/dad2.12008 %0 Journal Article %J Science %D 2020 %T The genetic architecture of the human cerebral cortex %A Grasby, Katrina L. %A Jahanshad, Neda %A Painter, Jodie N. %A Colodro-Conde, Lucía %A Bralten, Janita %A Hibar, Derrek P. %A Lind, Penelope A. %A Pizzagalli, Fabrizio %A Ching, Christopher R. K. %A McMahon, Mary Agnes B. %A Shatokhina, Natalia %A Zsembik, Leo C. P. %A Thomopoulos, Sophia I. %A Zhu, Alyssa H. %A Strike, Lachlan T. %A Agartz, Ingrid %A Alhusaini, Saud %A Almeida, Marcio A. A. %A Alnæs, Dag %A Amlien, Inge K. %A Andersson, Micael %A Ard, Tyler %A Armstrong, Nicola J. %A Ashley-Koch, Allison %A Atkins, Joshua R. %A Bernard, Manon %A Brouwer, Rachel M. %A Buimer, Elizabeth E. L. %A Bülow, Robin %A Bürger, Christian %A Cannon, Dara M. %A Chakravarty, Mallar %A Chen, Qiang %A Cheung, Joshua W. %A Couvy-Duchesne, Baptiste %A Dale, Anders M. %A Dalvie, Shareefa %A de Araujo, Tânia K. %A de Zubicaray, Greig I. %A de Zwarte, Sonja M. C. %A den Braber, Anouk %A Doan, Nhat Trung %A Dohm, Katharina %A Ehrlich, Stefan %A Engelbrecht, Hannah-Ruth %A Erk, Susanne %A Fan, Chun Chieh %A Fedko, Iryna O. %A Foley, Sonya F. %A Ford, Judith M. %A Fukunaga, Masaki %A Garrett, Melanie E. %A Ge, Tian %A Giddaluru, Sudheer %A Goldman, Aaron L. %A Green, Melissa J. %A Groenewold, Nynke A. %A Grotegerd, Dominik %A Gurholt, Tiril P. %A Gutman, Boris A. %A Hansell, Narelle K. %A Harris, Mathew A. %A Harrison, Marc B. %A Haswell, Courtney C. %A Hauser, Michael %A Herms, Stefan %A Heslenfeld, Dirk J. %A Ho, New Fei %A Hoehn, David %A Hoffmann, Per %A Holleran, Laurena %A Hoogman, Martine %A Hottenga, Jouke-Jan %A Ikeda, Masashi %A Janowitz, Deborah %A Jansen, Iris E. %A Jia, Tianye %A Jockwitz, Christiane %A Kanai, Ryota %A Karama, Sherif %A Kasperaviciute, Dalia %A Kaufmann, Tobias %A Kelly, Sinead %A Kikuchi, Masataka %A Klein, Marieke %A Knapp, Michael %A Knodt, Annchen R. %A Krämer, Bernd %A Lam, Max %A Lancaster, Thomas M. %A Lee, Phil H. %A Lett, Tristram A. %A Lewis, Lindsay B. %A Lopes-Cendes, Iscia %A Luciano, Michelle %A Macciardi, Fabio %A Marquand, Andre F. %A Mathias, Samuel R. %A Melzer, Tracy R. %A Milaneschi, Yuri %A Mirza-Schreiber, Nazanin %A Moreira, Jose C. V. %A Mühleisen, Thomas W. %A Müller-Myhsok, Bertram %A Najt, Pablo %A Nakahara, Soichiro %A Nho, Kwangsik %A Olde Loohuis, Loes M. %A Orfanos, Dimitri Papadopoulos %A Pearson, John F. %A Pitcher, Toni L. %A Pütz, Benno %A Quidé, Yann %A Ragothaman, Anjanibhargavi %A Rashid, Faisal M. %A Reay, William R. %A Redlich, Ronny %A Reinbold, Céline S. %A Repple, Jonathan %A Richard, Geneviève %A Riedel, Brandalyn C. %A Risacher, Shannon L. %A Rocha, Cristiane S. %A Mota, Nina Roth %A Salminen, Lauren %A Saremi, Arvin %A Saykin, Andrew J. %A Schlag, Fenja %A Schmaal, Lianne %A Schofield, Peter R. %A Secolin, Rodrigo %A Shapland, Chin Yang %A Shen, Li %A Shin, Jean %A Shumskaya, Elena %A Sønderby, Ida E. %A Sprooten, Emma %A Tansey, Katherine E. %A Teumer, Alexander %A Thalamuthu, Anbupalam %A Tordesillas-Gutierrez, Diana %A Turner, Jessica A. %A Uhlmann, Anne %A Vallerga, Costanza Ludovica %A van der Meer, Dennis %A van Donkelaar, Marjolein M. J. %A van Eijk, Liza %A van Erp, Theo G. M. %A van Haren, Neeltje E. M. %A van Rooij, Daan %A van Tol, Marie-Jose %A Veldink, Jan H. %A Verhoef, Ellen %A Walton, Esther %A Wang, Mingyuan %A Wang, Yunpeng %A Wardlaw, Joanna M. %A Wen, Wei %A Westlye, Lars T. %A Whelan, Christopher D. %A Witt, Stephanie H. %A Wittfeld, Katharina %A Wolf, Christiane %A Wolfers, Thomas %A Wu, Jing Qin %A Yasuda, Clarissa L. %A Zaremba, Dario %A Zhang, Zuo %A Zwiers, Marcel P. %A Artiges, Eric %A Assareh, Amelia A. %A Ayesa-Arriola, Rosa %A Belger, Aysenil %A Brandt, Christine L. %A Brown, Gregory G. %A Cichon, Sven %A Curran, Joanne E. %A Davies, Gareth E. %A Degenhardt, Franziska %A Dennis, Michelle F. %A Dietsche, Bruno %A Djurovic, Srdjan %A Doherty, Colin P. %A Espiritu, Ryan %A Garijo, Daniel %A Gil, Yolanda %A Gowland, Penny A. %A Green, Robert C. %A Häusler, Alexander N. %A Heindel, Walter %A Ho, Beng-Choon %A Hoffmann, Wolfgang U. %A Holsboer, Florian %A Homuth, Georg %A Hosten, Norbert %A Jack, Clifford R. %A Jang, MiHyun %A Jansen, Andreas %A Kimbrel, Nathan A. %A Kolskår, Knut %A Koops, Sanne %A Krug, Axel %A Lim, Kelvin O. %A Luykx, Jurjen J. %A Mathalon, Daniel H. %A Mather, Karen A. %A Mattay, Venkata S. %A Matthews, Sarah %A Mayoral Van Son, Jaqueline %A McEwen, Sarah C. %A Melle, Ingrid %A Morris, Derek W. %A Mueller, Bryon A. %A Nauck, Matthias %A Nordvik, Jan E. %A Nöthen, Markus M. %A O’Leary, Daniel S. %A Opel, Nils %A Martinot, Marie-Laure Paillère %A Pike, G. Bruce %A Preda, Adrian %A Quinlan, Erin B. %A Rasser, Paul E. %A Ratnakar, Varun %A Reppermund, Simone %A Steen, Vidar M. %A Tooney, Paul A. %A Torres, Fábio R. %A Veltman, Dick J. %A Voyvodic, James T. %A Whelan, Robert %A White, Tonya %A Yamamori, Hidenaga %A Adams, Hieab H. H. %A Bis, Joshua C. %A Debette, Stephanie %A DeCarli, Charles %A Fornage, Myriam %A Gudnason, Vilmundur %A Hofer, Edith %A Ikram, M. Arfan %A Launer, Lenore %A Longstreth, W. T. %A Lopez, Oscar L. %A Mazoyer, Bernard %A Mosley, Thomas H. %A Roshchupkin, Gennady V. %A Satizabal, Claudia L. %A Schmidt, Reinhold %A Seshadri, Sudha %A Yang, Qiong %A Alvim, Marina K. M. %A Ames, David %A Anderson, Tim J. %A Andreassen, Ole A. %A Arias-Vasquez, Alejandro %A Bastin, Mark E. %A Baune, Bernhard T. %A Beckham, Jean C. %A Blangero, John %A Boomsma, Dorret I. %A Brodaty, Henry %A Brunner, Han G. %A Buckner, Randy L. %A Buitelaar, Jan K. %A Bustillo, Juan R. %A Cahn, Wiepke %A Cairns, Murray J. %A Calhoun, Vince %A Carr, Vaughan J. %A Caseras, Xavier %A Caspers, Svenja %A Cavalleri, Gianpiero L. %A Cendes, Fernando %A Corvin, Aiden %A Crespo-Facorro, Benedicto %A Dalrymple-Alford, John C. %A Dannlowski, Udo %A de Geus, Eco J. C. %A Deary, Ian J. %A Delanty, Norman %A Depondt, Chantal %A Desrivières, Sylvane %A Donohoe, Gary %A Espeseth, Thomas %A Fernández, Guillén %A Fisher, Simon E. %A Flor, Herta %A Forstner, Andreas J. %A Francks, Clyde %A Franke, Barbara %A Glahn, David C. %A Gollub, Randy L. %A Grabe, Hans J. %A Gruber, Oliver %A Håberg, Asta K. %A Hariri, Ahmad R. %A Hartman, Catharina A. %A Hashimoto, Ryota %A Heinz, Andreas %A Henskens, Frans A. %A Hillegers, Manon H. J. %A Hoekstra, Pieter J. %A Holmes, Avram J. %A Hong, L. Elliot %A Hopkins, William D. %A Hulshoff Pol, Hilleke E. %A Jernigan, Terry L. %A Jönsson, Erik G. %A Kahn, René S. %A Kennedy, Martin A. %A Kircher, Tilo T. J. %A Kochunov, Peter %A Kwok, John B. J. %A Le Hellard, Stephanie %A Loughland, Carmel M. %A Martin, Nicholas G. %A Martinot, Jean-Luc %A McDonald, Colm %A McMahon, Katie L. %A Meyer-Lindenberg, Andreas %A Michie, Patricia T. %A Morey, Rajendra A. %A Mowry, Bryan %A Nyberg, Lars %A Oosterlaan, Jaap %A Ophoff, Roel A. %A Pantelis, Christos %A Paus, Tomáš %A Pausova, Zdenka %A Penninx, Brenda W. J. H. %A Polderman, Tinca J. C. %A Posthuma, Danielle %A Rietschel, Marcella %A Roffman, Joshua L. %A Rowland, Laura M. %A Sachdev, Perminder S. %A Sämann, Philipp G. %A Schall, Ulrich %A Schumann, Gunter %A Scott, Rodney J. %A Sim, Kang %A Sisodiya, Sanjay M. %A Smoller, Jordan W. %A Sommer, Iris E. %A St Pourcain, Beate %A Stein, Dan J. %A Toga, Arthur W. %A Trollor, Julian N. %A Van der Wee, Nic J. A. %A van ’t Ent, Dennis %A Völzke, Henry %A Walter, Henrik %A Weber, Bernd %A Weinberger, Daniel R. %A Wright, Margaret J. %A Zhou, Juan %A Stein, Jason L. %A Thompson, Paul M. %A Medland, Sarah E. %B Science %V 367 %P eaay6690 %8 Aug-03-2021 %G eng %U https://www.sciencemag.org/lookup/doi/10.1126/science.aay6690https://syndication.highwire.org/content/doi/10.1126/science.aay6690https://syndication.highwire.org/content/doi/10.1126/science.aay6690 %N 6484 %! Science %R 10.1126/science.aay6690 %0 Journal Article %J Nat Commun %D 2020 %T {Genetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults %A Hofer, E. %A Roshchupkin, G. V. %A Adams, H. H. H. %A Knol, M. J. %A Lin, H. %A Li, S. %A Zare, H. %A Ahmad, S. %A Armstrong, N. J. %A Satizabal, C. L. %A Bernard, M. %A Bis, J. C. %A Gillespie, N. A. %A Luciano, M. %A Mishra, A. %A Scholz, M. %A Teumer, A. %A Xia, R. %A Jian, X. %A Mosley, T. H. %A Saba, Y. %A Pirpamer, L. %A Seiler, S. %A Becker, J. T. %A Carmichael, O. %A Rotter, J. I. %A Psaty, B. M. %A Lopez, O. L. %A Amin, N. %A van der Lee, S. J. %A Yang, Q. %A Himali, J. J. %A Maillard, P. %A Beiser, A. S. %A DeCarli, C. %A Karama, S. %A Lewis, L. %A Harris, M. %A Bastin, M. E. %A Deary, I. J. %A Veronica Witte, A. %A Beyer, F. %A Loeffler, M. %A Mather, K. A. %A Schofield, P. R. %A Thalamuthu, A. %A Kwok, J. B. %A Wright, M. J. %A Ames, D. %A Trollor, J. %A Jiang, J. %A Brodaty, H. %A Wen, W. %A Vernooij, M. W. %A Hofman, A. %A Uitterlinden, A. G. %A Niessen, W. J. %A Wittfeld, K. %A B?low, R. %A V?lker, U. %A Pausova, Z. %A Bruce Pike, G. %A Maingault, S. %A Crivello, F. %A Tzourio, C. %A Amouyel, P. %A Mazoyer, B. %A Neale, M. C. %A Franz, C. E. %A Lyons, M. J. %A Panizzon, M. S. %A Andreassen, O. A. %A Dale, A. M. %A Logue, M. %A Grasby, K. L. %A Jahanshad, N. %A Painter, J. N. %A Colodro-Conde, L. %A Bralten, J. %A Hibar, D. P. %A Lind, P. A. %A Pizzagalli, F. %A Stein, J. L. %A Thompson, P. M. %A Medland, S. E. %A Sachdev, P. S. %A Kremen, W. S. %A Wardlaw, J. M. %A Villringer, A. %A van Duijn, C. M. %A Grabe, H. J. %A Longstreth, W. T. %A Fornage, M. %A Paus, T. %A Debette, S. %A Arfan Ikram, M. %A Schmidt, H. %A Schmidt, R. %A Seshadri, S. %A Grasby, K. L. %A Jahanshad, N. %A Painter, J. N. %A Colodro-Conde, L. %A Bralten, J. %A Hibar, D. P. %A Lind, P. A. %A Pizzagalli, F. %A Ching, C. R. K. %A McMahon, M. A. B. %A Shatokhina, N. %A Zsembik, L. C. P. %A Agartz, I. %A Alhusaini, S. %A Almeida, M. A. A. %A Aln?s, D. %A Amlien, I. K. %A Andersson, M. %A Ard, T. %A Armstrong, N. J. %A Ashley-Koch, A. %A Bernard, M. %A Brouwer, R. M. %A Buimer, E. E. L. %A B?low, R. %A B?rger, C. %A Cannon, D. M. %A Chakravarty, M. %A Chen, Q. %A Cheung, J. W. %A Couvy-Duchesne, B. %A Dale, A. M. %A Dalvie, S. %A de Araujo, T. K. %A de Zubicaray, G. I. %A de Zwarte, S. M. C. %A den Braber, A. %A Doan, N. T. %A Dohm, K. %A Ehrlich, S. %A Engelbrecht, H. R. %A Erk, S. %A Fan, C. C. %A Fedko, I. O. %A Foley, S. F. %A Ford, J. M. %A Fukunaga, M. %A Garrett, M. E. %A Ge, T. %A Giddaluru, S. %A Goldman, A. L. %A Groenewold, N. A. %A Grotegerd, D. %A Gurholt, T. P. %A Gutman, B. A. %A Hansell, N. K. %A Harris, M. A. %A Harrison, M. B. %A Haswell, C. C. %A Hauser, M. %A Herms, S. %A Heslenfeld, D. J. %A Ho, N. F. %A Hoehn, D. %A Hoffmann, P. %A Holleran, L. %A Hoogman, M. %A Hottenga, J. J. %A Ikeda, M. %A Janowitz, D. %A Jansen, I. E. %A Jia, T. %A Jockwitz, C. %A Kanai, R. %A Karama, S. %A Kasperaviciute, D. %A Kaufmann, T. %A Kelly, S. %A Kikuchi, M. %A Klein, M. %A Knapp, M. %A Knodt, A. R. %A Kr?mer, B. %A Lam, M. %A Lancaster, T. M. %A Lee, P. H. %A Lett, T. A. %A Lewis, L. B. %A Lopes-Cendes, I. %A Luciano, M. %A Macciardi, F. %A Marquand, A. F. %A Mathias, S. R. %A Melzer, T. R. %A Milaneschi, Y. %A Mirza-Schreiber, N. %A Moreira, J. C. V. %A M?hleisen, T. W. %A M?ller-Myhsok, B. %A Najt, P. %A Nakahara, S. %A Nho, K. %A Olde Loohuis, L. M. %A Orfanos, D. P. %A Pearson, J. F. %A Pitcher, T. L. %A P?tz, B. %A Ragothaman, A. %A Rashid, F. M. %A Redlich, R. %A Reinbold, C. S. %A Repple, J. %A Richard, G. %A Riedel, B. C. %A Risacher, S. L. %A Rocha, C. S. %A Mota, N. R. %A Salminen, L. %A Saremi, A. %A Saykin, A. J. %A Schlag, F. %A Schmaal, L. %A Schofield, P. R. %A Secolin, R. %A Shapland, C. Y. %A Shen, L. %A Shin, J. %A Shumskaya, E. %A S?nderby, I. E. %A Sprooten, E. %A Strike, L. T. %A Tansey, K. E. %A Teumer, A. %A Thalamuthu, A. %A Thomopoulos, S. I. %A Tordesillas-Guti?rrez, D. %A Turner, J. A. %A Uhlmann, A. %A Vallerga, C. L. %A van der Meer, D. %A van Donkelaar, M. M. J. %A van Eijk, L. %A van Erp, T. G. M. %A van Haren, N. E. M. %A van Rooij, D. %A van Tol, M. J. %A Veldink, J. H. %A Verhoef, E. %A Walton, E. %A Wang, M. %A Wang, Y. %A Wardlaw, J. M. %A Wen, W. %A Westlye, L. T. %A Whelan, C. D. %A Witt, S. H. %A Wittfeld, K. %A Wolf, C. %A Wolfers, T. %A Yasuda, C. L. %A Zaremba, D. %A Zhang, Z. %A Zhu, A. H. %A Zwiers, M. P. %A Artiges, E. %A Assareh, A. A. %A Ayesa-Arriola, R. %A Belger, A. %A Brandt, C. L. %A Brown, G. G. %A Cichon, S. %A Curran, J. E. %A Davies, G. E. %A Degenhardt, F. %A Dietsche, B. %A Djurovic, S. %A Doherty, C. P. %A Espiritu, R. %A Garijo, D. %A Gil, Y. %A Gowland, P. A. %A Green, R. C. %A H?usler, A. N. %A Heindel, W. %A Ho, B. C. %A Hoffmann, W. U. %A Holsboer, F. %A Homuth, G. %A Hosten, N. %A Jack, C. R. %A Jang, M. %A Jansen, A. %A Kolsk?r, K. %A Koops, S. %A Krug, A. %A Lim, K. O. %A Luykx, J. J. %A Mathalon, D. H. %A Mather, K. A. %A Mattay, V. S. %A Matthews, S. %A Son, J. M. V. %A McEwen, S. C. %A Melle, I. %A Morris, D. W. %A Mueller, B. A. %A Nauck, M. %A Nordvik, J. E. %A N?then, M. M. %A O'Leary, D. S. %A Opel, N. %A Martinot, M. -P. %A Pike, G. B. %A Preda, A. %A Quinlan, E. B. %A Ratnakar, V. %A Reppermund, S. %A Steen, V. M. %A Torres, F. R. %A Veltman, D. J. %A Voyvodic, J. T. %A Whelan, R. %A White, T. %A Yamamori, H. %A Alvim, M. K. M. %A Ames, D. %A Anderson, T. J. %A Andreassen, O. A. %A Arias-Vasquez, A. %A Bastin, M. E. %A Baune, B. T. %A Blangero, J. %A Boomsma, D. I. %A Brodaty, H. %A Brunner, H. G. %A Buckner, R. L. %A Buitelaar, J. K. %A Bustillo, J. R. %A Cahn, W. %A Calhoun, V. %A Caseras, X. %A Caspers, S. %A Cavalleri, G. L. %A Cendes, F. %A Corvin, A. %A Crespo-Facorro, B. %A Dalrymple-Alford, J. C. %A Dannlowski, U. %A de Geus, E. J. C. %A Deary, I. J. %A Delanty, N. %A Depondt, C. %A Desrivi?res, S. %A Donohoe, G. %A Espeseth, T. %A Fern?ndez, G. %A Fisher, S. E. %A Flor, H. %A Forstner, A. J. %A Francks, C. %A Franke, B. %A Glahn, D. C. %A Gollub, R. L. %A Grabe, H. J. %A Gruber, O. %A H?berg, A. K. %A Hariri, A. R. %A Hartman, C. A. %A Hashimoto, R. %A Heinz, A. %A Hillegers, M. H. J. %A Hoekstra, P. J. %A Holmes, A. J. %A Hong, L. E. %A Hopkins, W. D. %A Hulshoff Pol, H. E. %A Jernigan, T. L. %A J?nsson, E. G. %A Kahn, R. S. %A Kennedy, M. A. %A Kircher, T. T. J. %A Kochunov, P. %A Kwok, J. B. J. %A Hellard, S. L. %A Martin, N. G. %A Martinot, J. - %A McDonald, C. %A McMahon, K. L. %A Meyer-Lindenberg, A. %A Morey, R. A. %A Nyberg, L. %A Oosterlaan, J. %A Ophoff, R. A. %A Paus, T. %A Pausova, Z. %A Penninx, B. W. J. H. %A Polderman, T. J. C. %A Posthuma, D. %A Rietschel, M. %A Roffman, J. L. %A Rowland, L. M. %A Sachdev, P. S. %A S?mann, P. G. %A Schumann, G. %A Sim, K. %A Sisodiya, S. M. %A Smoller, J. W. %A Sommer, I. E. %A Pourcain, B. S. %A Stein, D. J. %A Toga, A. W. %A Trollor, J. N. %A Van der Wee, N. J. A. %A van 't Ent, D. %A V?lzke, H. %A Walter, H. %A Weber, B. %A Weinberger, D. R. %A Wright, M. J. %A Zhou, J. %A Stein, J. L. %A Thompson, P. M. %A Medland, S. E. %X Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging. %B Nat Commun %V 11 %P 4796 %8 09 %G eng %0 Journal Article %J Circ Genom Precis Med %D 2020 %T {Genetic Determinants of Electrocardiographic P-wave Duration and Relation to Atrial Fibrillation %A Weng, L. C. %A Hall, A. W. %A Choi, S. H. %A Jurgens, S. J. %A Haessler, J. %A Bihlmeyer, N. A. %A Grarup, N. %A Lin, H. %A Teumer, A. %A Li-Gao, R. %A Yao, J. %A Guo, X. %A Brody, J. A. %A M?ller-Nurasyid, M. %A Schramm, K. %A Verweij, N. %A van den Berg, M. E. %A van Setten, J. %A Isaacs, A. %A Ram?rez, J. %A Warren, H. R. %A Padmanabhan, S. %A Kors, J. A. %A de Boer, R. A. %A van der Meer, P. %A Sinner, M. F. %A Waldenberger, M. %A Psaty, B. M. %A Taylor, K. D. %A V?lker, U. %A Kanters, J. K. %A Li, M. %A Alonso, A. %A Perez, M. V. %A Vaartjes, I. %A Bots, M. L. %A Huang, P. L. %A Heckbert, S. R. %A Lin, H. J. %A Kornej, J. %A Munroe, P. B. %A van Duijn, C. M. %A Asselbergs, F. W. %A Stricker, B. H. %A van der Harst, P. %A K??b, S. %A Peters, A. %A Sotoodehnia, N. %A Rotter, J. I. %A Mook-Kanamori, D. O. %A D?rr, M. %A Felix, S. B. %A Linneberg, A. %A Hansen, T. %A Arking, D. E. %A Kooperberg, C. %A Benjamin, E. J. %A Lunetta, K. L. %A Ellinor, P. T. %A Lubitz, S. A. %X Background - The P-wave duration (PWD) is an electrocardiographic (ECG) measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF). We used exome chip data to examine the associations between common and rare variants with PWD. Methods - Fifteen studies comprising 64,440 individuals (56,943 European, 5,681 African, 1,186 Hispanic, 630 Asian), and 230,000 variants were used to examine associations with maximum PWD across the 12-lead ECG. Meta-analyses summarized association results for common variants; gene-based burden and SKAT tests examined low-frequency variant-PWD associations. Additionally, we examined the associations between PWD loci and AF using previous AF GWAS. Results - We identified 21 common and low-frequency genetic loci (14 novel) associated with maximum PWD, including several AF loci (TTN, CAND2, SCN10A, PITX2, CAV1, SYNPO2L, SOX5, TBX5, MYH6, RPL3L). The top variants at known sarcomere genes (TTN, MYH6) were associated with longer PWD and increased AF risk. However, top variants at other loci (e.g., PITX2 and SCN10A) were associated with longer PWD but lower AF risk. Conclusions - Our results highlight multiple novel genetic loci associated with PWD, and underscore the shared mechanisms of atrial conduction and AF. Prolonged PWD may be an endophenotype for several different genetic mechanisms of AF. %B Circ Genom Precis Med %8 Aug %G eng %0 Journal Article %J PLoS One %D 2020 %T Genetic loci associated with prevalent and incident myocardial infarction and coronary heart disease in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. %A Hahn, Julie %A Fu, Yi-Ping %A Brown, Michael R %A Bis, Joshua C %A de Vries, Paul S %A Feitosa, Mary F %A Yanek, Lisa R %A Weiss, Stefan %A Giulianini, Franco %A Smith, Albert Vernon %A Guo, Xiuqing %A Bartz, Traci M %A Becker, Diane M %A Becker, Lewis C %A Boerwinkle, Eric %A Brody, Jennifer A %A Chen, Yii-Der Ida %A Franco, Oscar H %A Grove, Megan %A Harris, Tamara B %A Hofman, Albert %A Hwang, Shih-Jen %A Kral, Brian G %A Launer, Lenore J %A Markus, Marcello R P %A Rice, Kenneth M %A Rich, Stephen S %A Ridker, Paul M %A Rivadeneira, Fernando %A Rotter, Jerome I %A Sotoodehnia, Nona %A Taylor, Kent D %A Uitterlinden, André G %A Völker, Uwe %A Völzke, Henry %A Yao, Jie %A Chasman, Daniel I %A Dörr, Marcus %A Gudnason, Vilmundur %A Mathias, Rasika A %A Post, Wendy %A Psaty, Bruce M %A Dehghan, Abbas %A O'Donnell, Christopher J %A Morrison, Alanna C %K Aging %K Coronary Artery Disease %K Cross-Sectional Studies %K Europe %K European Continental Ancestry Group %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Myocardial Infarction %K Polymorphism, Single Nucleotide %K Prospective Studies %X

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

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

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

%B PLoS One %V 15 %P e0230035 %8 2020 %G eng %N 11 %R 10.1371/journal.pone.0230035 %0 Journal Article %J Diabetes %D 2020 %T Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity. %A Yaghootkar, Hanieh %A Zhang, Yiying %A Spracklen, Cassandra N %A Karaderi, Tugce %A Huang, Lam Opal %A Bradfield, Jonathan %A Schurmann, Claudia %A Fine, Rebecca S %A Preuss, Michael H %A Kutalik, Zoltán %A Wittemans, Laura Bl %A Lu, Yingchang %A Metz, Sophia %A Willems, Sara M %A Li-Gao, Ruifang %A Grarup, Niels %A Wang, Shuai %A Molnos, Sophie %A Sandoval-Zárate, América A %A Nalls, Mike A %A Lange, Leslie A %A Haesser, Jeffrey %A Guo, Xiuqing %A Lyytikäinen, Leo-Pekka %A Feitosa, Mary F %A Sitlani, Colleen M %A Venturini, Cristina %A Mahajan, Anubha %A Kacprowski, Tim %A Wang, Carol A %A Chasman, Daniel I %A Amin, Najaf %A Broer, Linda %A Robertson, Neil %A Young, Kristin L %A Allison, Matthew %A Auer, Paul L %A Blüher, Matthias %A Borja, Judith B %A Bork-Jensen, Jette %A Carrasquilla, Germán D %A Christofidou, Paraskevi %A Demirkan, Ayse %A Doege, Claudia A %A Garcia, Melissa E %A Graff, Mariaelisa %A Guo, Kaiying %A Hakonarson, Hakon %A Hong, Jaeyoung %A Ida Chen, Yii-Der %A Jackson, Rebecca %A Jakupović, Hermina %A Jousilahti, Pekka %A Justice, Anne E %A Kähönen, Mika %A Kizer, Jorge R %A Kriebel, Jennifer %A LeDuc, Charles A %A Li, Jin %A Lind, Lars %A Luan, Jian'an %A Mackey, David %A Mangino, Massimo %A Männistö, Satu %A Martin Carli, Jayne F %A Medina-Gómez, Carolina %A Mook-Kanamori, Dennis O %A Morris, Andrew P %A de Mutsert, Renée %A Nauck, Matthias %A Nedeljkovic, Ivana %A Pennell, Craig E %A Pradhan, Arund D %A Psaty, Bruce M %A Raitakari, Olli T %A Scott, Robert A %A Skaaby, Tea %A Strauch, Konstantin %A Taylor, Kent D %A Teumer, Alexander %A Uitterlinden, André G %A Wu, Ying %A Yao, Jie %A Walker, Mark %A North, Kari E %A Kovacs, Peter %A Ikram, M Arfan %A van Duijn, Cornelia M %A Ridker, Paul M %A Lye, Stephen %A Homuth, Georg %A Ingelsson, Erik %A Spector, Tim D %A McKnight, Barbara %A Province, Michael A %A Lehtimäki, Terho %A Adair, Linda S %A Rotter, Jerome I %A Reiner, Alexander P %A Wilson, James G %A Harris, Tamara B %A Ripatti, Samuli %A Grallert, Harald %A Meigs, James B %A Salomaa, Veikko %A Hansen, Torben %A Willems van Dijk, Ko %A Wareham, Nicholas J %A Grant, Struan Fa %A Langenberg, Claudia %A Frayling, Timothy M %A Lindgren, Cecilia M %A Mohlke, Karen L %A Leibel, Rudolph L %A Loos, Ruth Jf %A Kilpeläinen, Tuomas O %X

Leptin influences food intake by informing the brain about the status of body fat stores. Rare mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in , and , and one intergenic variant near The missense variant Val94Met (rs17151919) in was common in individuals of African ancestry only and its association with lower leptin concentrations was specific to this ancestry (P=2x10, n=3,901). Using analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting leptin regulates early adiposity.

%B Diabetes %8 2020 Sep 11 %G eng %R 10.2337/db20-0070 %0 Journal Article %J Nat Commun %D 2020 %T {Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure %A Shah, S. %A Henry, A. %A Roselli, C. %A Lin, H. %A Sveinbj?rnsson, G. %A Fatemifar, G. %A Hedman, ?. K. %A Wilk, J. B. %A Morley, M. P. %A Chaffin, M. D. %A Helgadottir, A. %A Verweij, N. %A Dehghan, A. %A Almgren, P. %A Andersson, C. %A Aragam, K. G. %A ?rnl?v, J. %A Backman, J. D. %A Biggs, M. L. %A Bloom, H. L. %A Brandimarto, J. %A Brown, M. R. %A Buckbinder, L. %A Carey, D. J. %A Chasman, D. I. %A Chen, X. %A Chen, X. %A Chung, J. %A Chutkow, W. %A Cook, J. P. %A Delgado, G. E. %A Denaxas, S. %A Doney, A. S. %A D?rr, M. %A Dudley, S. C. %A Dunn, M. E. %A Engstr?m, G. %A Esko, T. %A Felix, S. B. %A Finan, C. %A Ford, I. %A Ghanbari, M. %A Ghasemi, S. %A Giedraitis, V. %A Giulianini, F. %A Gottdiener, J. S. %A Gross, S. %A Gu?bjartsson, D. F. %A Gutmann, R. %A Haggerty, C. M. %A van der Harst, P. %A Hyde, C. L. %A Ingelsson, E. %A Jukema, J. W. %A Kavousi, M. %A Khaw, K. T. %A Kleber, M. E. %A K?ber, L. %A Koekemoer, A. %A Langenberg, C. %A Lind, L. %A Lindgren, C. M. %A London, B. %A Lotta, L. A. %A Lovering, R. C. %A Luan, J. %A Magnusson, P. %A Mahajan, A. %A Margulies, K. B. %A M?rz, W. %A Melander, O. %A Mordi, I. R. %A Morgan, T. %A Morris, A. D. %A Morris, A. P. %A Morrison, A. C. %A Nagle, M. W. %A Nelson, C. P. %A Niessner, A. %A Niiranen, T. %A O'Donoghue, M. L. %A Owens, A. T. %A Palmer, C. N. A. %A Parry, H. M. %A Perola, M. %A Portilla-Fernandez, E. %A Psaty, B. M. %A Rice, K. M. %A Ridker, P. M. %A Romaine, S. P. R. %A Rotter, J. I. %A Salo, P. %A Salomaa, V. %A van Setten, J. %A Shalaby, A. A. %A Smelser, D. T. %A Smith, N. L. %A Stender, S. %A Stott, D. J. %A Svensson, P. %A Tammesoo, M. L. %A Taylor, K. D. %A Teder-Laving, M. %A Teumer, A. %A Thorgeirsson, G. %A Thorsteinsdottir, U. %A Torp-Pedersen, C. %A Trompet, S. %A Tyl, B. %A Uitterlinden, A. G. %A Veluchamy, A. %A V?lker, U. %A Voors, A. A. %A Wang, X. %A Wareham, N. J. %A Waterworth, D. %A Weeke, P. E. %A Weiss, R. %A Wiggins, K. L. %A Xing, H. %A Yerges-Armstrong, L. M. %A Yu, B. %A Zannad, F. %A Zhao, J. H. %A Hemingway, H. %A Samani, N. J. %A McMurray, J. J. V. %A Yang, J. %A Visscher, P. M. %A Newton-Cheh, C. %A Malarstig, A. %A Holm, H. %A Lubitz, S. A. %A Sattar, N. %A Holmes, M. V. %A Cappola, T. P. %A Asselbergs, F. W. %A Hingorani, A. D. %A Kuchenbaecker, K. %A Ellinor, P. T. %A Lang, C. C. %A Stefansson, K. %A Smith, J. G. %A Vasan, R. S. %A Swerdlow, D. I. %A Lumbers, R. T. %A Abecasis, G. %A Backman, J. %A Bai, X. %A Balasubramanian, S. %A Banerjee, N. %A Baras, A. %A Barnard, L. %A Beechert, C. %A Blumenfeld, A. %A Cantor, M. %A Chai, Y. %A Chung, J. %A Coppola, G. %A Damask, A. %A Dewey, F. %A Economides, A. %A Eom, G. %A Forsythe, C. %A Fuller, E. D. %A Gu, Z. %A Gurski, L. %A Guzzardo, P. M. %A Habegger, L. %A Hahn, Y. %A Hawes, A. %A van Hout, C. %A Jones, M. B. %A Khalid, S. %A Lattari, M. %A Li, A. %A Lin, N. %A Liu, D. %A Lopez, A. %A Manoochehri, K. %A Marchini, J. %A Marcketta, A. %A Maxwell, E. K. %A McCarthy, S. %A Mitnaul, L. J. %A O'Dushlaine, C. %A Overton, J. D. %A Padilla, M. S. %A Paulding, C. %A Penn, J. %A Pradhan, M. %A Reid, J. G. %A Schleicher, T. D. %A Schurmann, C. %A Shuldiner, A. %A Staples, J. C. %A Sun, D. %A Toledo, K. %A Ulloa, R. H. %A Widom, L. %A Wolf, S. E. %A Yadav, A. %A Ye, B. %X Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies. %B Nat Commun %V 11 %P 163 %8 01 %G eng %0 Journal Article %J Stroke %D 2020 %T {Genome-Wide Association Study Meta-Analysis of Stroke in 22 000 Individuals of African Descent Identifies Novel Associations With Stroke %A Keene, K. L. %A Hyacinth, H. I. %A Bis, J. C. %A Kittner, S. J. %A Mitchell, B. D. %A Cheng, Y. C. %A Pare, G. %A Chong, M. %A O'Donnell, M. %A Meschia, J. F. %A Chen, W. M. %A Sale, M. M. %A Rich, S. S. %A Nalls, M. A. %A Zonderman, A. B. %A Evans, M. K. %A Wilson, J. G. %A Correa, A. %A Markus, H. S. %A Traylor, M. %A Lewis, C. M. %A Carty, C. L. %A Reiner, A. %A Haessler, J. %A Langefeld, C. D. %A Gottesman, R. %A Mosley, T. H. %A Woo, D. %A Yaffe, K. %A Liu, Y. %A Longstreth, W. T. %A Psaty, B. M. %A Kooperberg, C. %A Lange, L. A. %A Sacco, R. %A Rundek, T. %A Lee, J. M. %A Cruchaga, C. %A Furie, K. L. %A Arnett, D. K. %A Benavente, O. R. %A Grewal, R. P. %A Peddareddygari, L. R. %A Dichgans, M. %A Malik, R. %A Worrall, B. B. %A Fornage, M. %X Stroke is a complex disease with multiple genetic and environmental risk factors. Blacks endure a nearly 2-fold greater risk of stroke and are 2× to 3× more likely to die from stroke than European Americans.\ The COMPASS (Consortium of Minority Population Genome-Wide Association Studies of Stroke) has conducted a genome-wide association meta-analysis of stroke in >22 000 individuals of African ancestry (3734 cases, 18 317 controls) from 13 cohorts.\ In meta-analyses, we identified one single nucleotide polymorphism (rs55931441) near the HNF1A gene that reached genome-wide significance (P=4.62×10-8) and an additional 29 variants with suggestive evidence of association (P<1×10-6), representing 24 unique loci. For validation, a look-up analysis for a 100 kb region flanking the COMPASS single nucleotide polymorphism was performed in SiGN (Stroke Genetics Network) Europeans, SiGN Hispanics, and METASTROKE (Europeans). Using a stringent Bonferroni correction P value of 2.08×10-3 (0.05/24 unique loci), we were able to validate associations at the HNF1A locus in both SiGN (P=8.18×10-4) and METASTROKE (P=1.72×10-3) European populations. Overall, 16 of 24 loci showed evidence for validation across multiple populations. Previous studies have reported associations between variants in the HNF1A gene and lipids, C-reactive protein, and risk of coronary artery disease and stroke. Suggestive associations with variants in the SFXN4 and TMEM108 genes represent potential novel ischemic stroke loci.\ These findings represent the most thorough investigation of genetic determinants of stroke in individuals of African descent, to date. %B Stroke %V 51 %P 2454–2463 %8 Aug %G eng %0 Journal Article %J Sci Rep %D 2020 %T {An individual participant data analysis of prospective cohort studies on the association between subclinical thyroid dysfunction and depressive symptoms %A Wildisen, L. %A Del Giovane, C. %A Moutzouri, E. %A Beglinger, S. %A Syrogiannouli, L. %A Collet, T. H. %A Cappola, A. R. %A ?svold, B. O. %A Bakker, S. J. L. %A Yeap, B. B. %A Almeida, O. P. %A Ceresini, G. %A Dullaart, R. P. F. %A Ferrucci, L. %A Grabe, H. %A Jukema, J. W. %A Nauck, M. %A Trompet, S. %A V?lzke, H. %A Westendorp, R. %A Gussekloo, J. %A Kl?ppel, S. %A Aujesky, D. %A Bauer, D. %A Peeters, R. %A Feller, M. %A Rodondi, N. %X {In subclinical hypothyroidism, the presence of depressive symptoms is often a reason for starting levothyroxine treatment. However, data are conflicting on the association between subclinical thyroid dysfunction and depressive symptoms. We aimed to examine the association between subclinical thyroid dysfunction and depressive symptoms in all prospective cohorts with relevant data available. We performed a systematic review of the literature from Medline, Embase, Cumulative Index to Nursing and Allied Health Literature, and the Cochrane Library from inception to 10th May 2019. We included prospective cohorts with data on thyroid status at baseline and depressive symptoms during follow-up. The primary outcome was depressive symptoms measured at first available follow-up, expressed on the Beck's Depression Inventory (BDI) scale (range 0-63, higher values indicate more depressive symptoms, minimal clinically important difference: 5 points). We performed a two-stage individual participant data (IPD) analysis comparing participants with subclinical hypo- or hyperthyroidism versus euthyroidism, adjusting for depressive symptoms at baseline, age, sex, education, and income (PROSPERO CRD42018091627). Six cohorts met the inclusion criteria, with IPD on 23,038 participants. Their mean age was 60 years, 65% were female, 21,025 were euthyroid, 1342 had subclinical hypothyroidism and 671 subclinical hyperthyroidism. At first available follow-up [mean 8.2 (± 4.3) years], BDI scores did not differ between participants with subclinical hypothyroidism (mean difference = 0.29, 95% confidence interval = - 0.17 to 0.76 %B Sci Rep %V 10 %P 19111 %8 11 %G eng %0 Journal Article %J Nature %D 2020 %T Inherited causes of clonal haematopoiesis in 97,691 whole genomes. %A Bick, Alexander G %A Weinstock, Joshua S %A Nandakumar, Satish K %A Fulco, Charles P %A Bao, Erik L %A Zekavat, Seyedeh M %A Szeto, Mindy D %A Liao, Xiaotian %A Leventhal, Matthew J %A Nasser, Joseph %A Chang, Kyle %A Laurie, Cecelia %A Burugula, Bala Bharathi %A Gibson, Christopher J %A Lin, Amy E %A Taub, Margaret A %A Aguet, Francois %A Ardlie, Kristin %A Mitchell, Braxton D %A Barnes, Kathleen C %A Moscati, Arden %A Fornage, Myriam %A Redline, Susan %A Psaty, Bruce M %A Silverman, Edwin K %A Weiss, Scott T %A Palmer, Nicholette D %A Vasan, Ramachandran S %A Burchard, Esteban G %A Kardia, Sharon L R %A He, Jiang %A Kaplan, Robert C %A Smith, Nicholas L %A Arnett, Donna K %A Schwartz, David A %A Correa, Adolfo %A de Andrade, Mariza %A Guo, Xiuqing %A Konkle, Barbara A %A Custer, Brian %A Peralta, Juan M %A Gui, Hongsheng %A Meyers, Deborah A %A McGarvey, Stephen T %A Chen, Ida Yii-Der %A Shoemaker, M Benjamin %A Peyser, Patricia A %A Broome, Jai G %A Gogarten, Stephanie M %A Wang, Fei Fei %A Wong, Quenna %A Montasser, May E %A Daya, Michelle %A Kenny, Eimear E %A North, Kari E %A Launer, Lenore J %A Cade, Brian E %A Bis, Joshua C %A Cho, Michael H %A Lasky-Su, Jessica %A Bowden, Donald W %A Cupples, L Adrienne %A Mak, Angel C Y %A Becker, Lewis C %A Smith, Jennifer A %A Kelly, Tanika N %A Aslibekyan, Stella %A Heckbert, Susan R %A Tiwari, Hemant K %A Yang, Ivana V %A Heit, John A %A Lubitz, Steven A %A Johnsen, Jill M %A Curran, Joanne E %A Wenzel, Sally E %A Weeks, Daniel E %A Rao, Dabeeru C %A Darbar, Dawood %A Moon, Jee-Young %A Tracy, Russell P %A Buth, Erin J %A Rafaels, Nicholas %A Loos, Ruth J F %A Durda, Peter %A Liu, Yongmei %A Hou, Lifang %A Lee, Jiwon %A Kachroo, Priyadarshini %A Freedman, Barry I %A Levy, Daniel %A Bielak, Lawrence F %A Hixson, James E %A Floyd, James S %A Whitsel, Eric A %A Ellinor, Patrick T %A Irvin, Marguerite R %A Fingerlin, Tasha E %A Raffield, Laura M %A Armasu, Sebastian M %A Wheeler, Marsha M %A Sabino, Ester C %A Blangero, John %A Williams, L Keoki %A Levy, Bruce D %A Sheu, Wayne Huey-Herng %A Roden, Dan M %A Boerwinkle, Eric %A Manson, JoAnn E %A Mathias, Rasika A %A Desai, Pinkal %A Taylor, Kent D %A Johnson, Andrew D %A Auer, Paul L %A Kooperberg, Charles %A Laurie, Cathy C %A Blackwell, Thomas W %A Smith, Albert V %A Zhao, Hongyu %A Lange, Ethan %A Lange, Leslie %A Rich, Stephen S %A Rotter, Jerome I %A Wilson, James G %A Scheet, Paul %A Kitzman, Jacob O %A Lander, Eric S %A Engreitz, Jesse M %A Ebert, Benjamin L %A Reiner, Alexander P %A Jaiswal, Siddhartha %A Abecasis, Goncalo %A Sankaran, Vijay G %A Kathiresan, Sekar %A Natarajan, Pradeep %X

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer and coronary heart disease-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP). Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.

%B Nature %V 586 %P 763-768 %8 2020 10 %G eng %N 7831 %R 10.1038/s41586-020-2819-2 %0 Journal Article %J J Clin Endocrinol Metab %D 2020 %T Intact and C-Terminal FGF23 Assays-Do Kidney Function, Inflammation, and Low Iron Influence Relationships With Outcomes? %A Sharma, Shilpa %A Katz, Ronit %A Bullen, Alexander L %A Chaves, Paulo H M %A de Leeuw, Peter W %A Kroon, Abraham A %A Houben, Alfons J H M %A Shlipak, Michael G %A Ix, Joachim H %X

CONTEXT: Higher fibroblast growth factor-23 (FGF23) concentrations are associated with heart failure and mortality in diverse populations, but the strengths of associations differ markedly depending up on which assay is used.

OBJECTIVE: We sought to evaluate whether iron deficiency, inflammation, or kidney function account for differences in the strengths of associations between these 2 FGF23 assays with clinical outcomes.

DESIGN: Case cohort study from the Cardiovascular Health Study.

SETTING: A total of 844 community-dwelling individuals aged 65 years or older with and without chronic kidney disease were followed for 10 years.

OUTCOMES: Outcomes included death, incident heart failure (HF), and incident myocardial infarction (MI). Exposure was baseline intact and C-terminal FGF23. Using modified Cox models, adjusting sequentially we tested whether observed associations of each assay with outcomes were attenuated by iron status, inflammation, kidney function, or their combinations.

RESULTS: FGF23 measured by either assay was associated with mortality in unadjusted analysis (intact FGF23 hazard ratio [HR] per 2-fold higher 1.45; 95% CI, 1.25-1.68; C-terminal FGF23 HR 1.38; 95% CI, 1.26-1.50). Adjustment for kidney function completely attenuated associations of intact FGF23 with mortality (HR 1.00; 95% CI, 0.85-1.17), but had much less influence on the association of C-terminal FGF23, for which results remained significant after adjustment (HR 1.15; 95% CI, 1.04-1.28). Attenuation was much less with adjustment for iron status or inflammation. Results were similar for the HF end point. Neither C-terminal or intact FGF23 was associated with MI risk.

CONCLUSIONS: The relationship of FGF23 with clinical end points is markedly different depending on the type of FGF23 assay used. The associations of biologically active FGF23 with clinical end points may be confounded by kidney disease, and thus much weaker than previously thought.

%B J Clin Endocrinol Metab %V 105 %8 2020 Dec 01 %G eng %N 12 %R 10.1210/clinem/dgaa665 %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2020 %T Level and change in N-terminal pro B-type Natriuretic Peptide and kidney function and survival to age 90. %A Häberle, Astrid D %A Biggs, Mary L %A Cushman, Mary %A Psaty, Bruce M %A Newman, Anne B %A Shlipak, Michael G %A Gottdiener, John %A Wu, Chenkai %A Gardin, Julius M %A Bansal, Nisha %A Odden, Michelle C %X

BACKGROUND: Many traditional cardiovascular risk factors do not predict survival to very old age. Studies have shown associations of estimated glomerular filtration rate (eGFR) and N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) with cardiovascular disease and mortality in older populations. This study aimed to evaluate the associations of the level and change in eGFR and NT-pro-BNP with longevity to age 90 years.

METHODS: The population included participants (n=3,645) in the Cardiovascular Health Study, aged between 67-75 at baseline. The main exposures were eGFR, calculated with the Berlin Initiative Study equation (BIS2), and NT-pro-BNP, and the main outcome was survival to age 90. Mixed models were used to estimate level and change of the main exposures.

RESULTS: There was an association between baseline level and change of both eGFR and NT-pro-BNP and survival to 90, and this association persisted after adjustment for covariates. Each 10 ml/min per 1.73 m2 higher eGFR level was associated with an adjusted odds ratio (OR) of 1.23 (95% CI: 1.13, 1.34) of survival to 90, and a 0.5 ml/min/ 1.73 m2 slower decline in eGFR was associated with an OR of 1.51 (95% CI: 1.31, 1.74). A 2-fold higher level of NT-pro-BNP level had an adjusted OR of 0.67 (95% CI: 0.61, 0.73), and a 1.05-fold increase per year in NT-pro-BNP had an OR of 0.53 (95% CI: 0.43, 0.65) for survival to age 90.

CONCLUSION: eGFR and NT-pro-BNP appear to be important risk factors for longevity to age 90.

%B J Gerontol A Biol Sci Med Sci %8 2020 May 17 %G eng %R 10.1093/gerona/glaa124 %0 Journal Article %J Clin Neurol Neurosurg %D 2020 %T Long-term cognitive decline and mortality after carotid endarterectomy. %A Thirumala, Parthasarathy D %A Reddy, Rajiv P %A Lopez, Oscar L %A Chang, Yue-Fang %A Becker, James T %A Kuller, Lewis H %X

OBJECTIVES: To date no studies have evaluated long term cognitive decline after carotid endarterectomy (CEA). We evaluated whether participants who had CEA were at increased risk of cognitive decline over participants who didn't undergo CEA.

PATIENTS AND METHODS: The patients in the study were participants in the Cardiovascular Health Study (CHS), a study of 5201 men and women over the age of 65 who were recruited from four communities (Pittsburgh, Pennsylvania; Sacramento, California; Winston-Salem, North Carolina; Hagerstown, Maryland) in 1988-89. The outcomes measured were 1) Decline in 3MSE and digit symbol substitution test (DSST) scores after CEA compared to before CEA. 2) All-cause mortality in CHS cohort among participants who did and did not have CEA.

RESULTS: CEA patients had significantly greater annual decrease in the DSST scores -2.43 (SD 4.21) compared to those who did not have a CEA -1.1 (SD 2.57) (p < 0.001) but this was not seen in the 3MSE scores. CEA patients had increased the risk of decline in DSST (OR 2.41, 95 % CI 1.49, 3.88) and 3MSE (OR 2.17, 95 % CI 1.35, 3.48) scores after adjusting for age, gender, race and educational status. CEA was associated with all-cause mortality in the long term with a HR of 2.72 (95 % CI 2.22, 3.34) after adjusting for covariates. Participants with lower baseline 3MSE scores HR 1.39 (1.27, 1.51), lower DSST scores <34 HR 1.69(1.54, 1.85) were more likely deceased.

CONCLUSIONS: CEA patients are at increased risk of lower scores on 3MSE and DSST testing in the long term. Mortality in the CHS cohort was higher in participants who underwent CEA. Further, lower 3MSE and DSST scores increased the risk of mortality.

%B Clin Neurol Neurosurg %V 194 %P 105823 %8 2020 Jul %G eng %R 10.1016/j.clineuro.2020.105823 %0 Journal Article %J Lancet Respir Med %D 2020 %T Lung function decline in former smokers and low-intensity current smokers: a secondary data analysis of the NHLBI Pooled Cohorts Study. %A Oelsner, Elizabeth C %A Balte, Pallavi P %A Bhatt, Surya P %A Cassano, Patricia A %A Couper, David %A Folsom, Aaron R %A Freedman, Neal D %A Jacobs, David R %A Kalhan, Ravi %A Mathew, Amanda R %A Kronmal, Richard A %A Loehr, Laura R %A London, Stephanie J %A Newman, Anne B %A O'Connor, George T %A Schwartz, Joseph E %A Smith, Lewis J %A White, Wendy B %A Yende, Sachin %K Adult %K Aged %K Case-Control Studies %K Ex-Smokers %K Female %K Follow-Up Studies %K Humans %K Lung %K Male %K Middle Aged %K National Heart, Lung, and Blood Institute (U.S.) %K Non-Smokers %K Respiratory Physiological Phenomena %K Smokers %K Smoking %K Spirometry %K United States %K Young Adult %X

BACKGROUND: Former smokers now outnumber current smokers in many developed countries, and current smokers are smoking fewer cigarettes per day. Some data suggest that lung function decline normalises with smoking cessation; however, mechanistic studies suggest that lung function decline could continue. We hypothesised that former smokers and low-intensity current smokers have accelerated lung function decline compared with never-smokers, including among those without prevalent lung disease.

METHODS: We used data on six US population-based cohorts included in the NHLBI Pooled Cohort Study. We restricted the sample to participants with valid spirometry at two or more exams. Two cohorts recruited younger adults (≥17 years), two recruited middle-aged and older adults (≥45 years), and two recruited only elderly adults (≥65 years) with examinations done between 1983 and 2014. FEV decline in sustained former smokers and current smokers was compared to that of never-smokers by use of mixed models adjusted for sociodemographic and anthropometric factors. Differential FEV decline was also evaluated according to duration of smoking cessation and cumulative (number of pack-years) and current (number of cigarettes per day) cigarette consumption.

FINDINGS: 25 352 participants (ages 17-93 years) completed 70 228 valid spirometry exams. Over a median follow-up of 7 years (IQR 3-20), FEV decline at the median age (57 years) was 31·01 mL per year (95% CI 30·66-31·37) in sustained never-smokers, 34·97 mL per year (34·36-35·57) in former smokers, and 39·92 mL per year (38·92-40·92) in current smokers. With adjustment, former smokers showed an accelerated FEV decline of 1·82 mL per year (95% CI 1·24-2·40) compared to never-smokers, which was approximately 20% of the effect estimate for current smokers (9·21 mL per year; 95% CI 8·35-10·08). Compared to never-smokers, accelerated FEV decline was observed in former smokers for decades after smoking cessation and in current smokers with low cumulative cigarette consumption (<10 pack-years). With respect to current cigarette consumption, the effect estimate for FEV decline in current smokers consuming less than five cigarettes per day (7·65 mL per year; 95% CI 6·21-9·09) was 68% of that in current smokers consuming 30 or more cigarettes per day (11·24 mL per year; 9·86-12·62), and around five times greater than in former smokers (1·57 mL per year; 1·00-2·14). Among participants without prevalent lung disease, associations were attenuated but were consistent with the main results.

INTERPRETATION: Former smokers and low-intensity current smokers have accelerated lung function decline compared with never-smokers. These results suggest that all levels of smoking exposure are likely to be associated with lasting and progressive lung damage.

FUNDING: National Institutes of Health, National Heart Lung and Blood Institute, and US Environmental Protection Agency.

%B Lancet Respir Med %V 8 %P 34-44 %8 2020 01 %G eng %N 1 %R 10.1016/S2213-2600(19)30276-0 %0 Journal Article %J Eur J Epidemiol %D 2020 %T Mendelian randomization analysis does not support causal associations of birth weight with hypertension risk and blood pressure in adulthood. %A Zheng, Yan %A Huang, Tao %A Wang, Tiange %A Mei, Zhendong %A Sun, Zhonghan %A Zhang, Tao %A Ellervik, Christina %A Chai, Jin-Fang %A Sim, Xueling %A van Dam, Rob M %A Tai, E-Shyong %A Koh, Woon-Puay %A Dorajoo, Rajkumar %A Saw, Seang-Mei %A Sabanayagam, Charumathi %A Wong, Tien Yin %A Gupta, Preeti %A Rossing, Peter %A Ahluwalia, Tarunveer S %A Vinding, Rebecca K %A Bisgaard, Hans %A Bønnelykke, Klaus %A Wang, Yujie %A Graff, Mariaelisa %A Voortman, Trudy %A van Rooij, Frank J A %A Hofman, Albert %A van Heemst, Diana %A Noordam, Raymond %A Estampador, Angela C %A Varga, Tibor V %A Enzenbach, Cornelia %A Scholz, Markus %A Thiery, Joachim %A Burkhardt, Ralph %A Orho-Melander, Marju %A Schulz, Christina-Alexandra %A Ericson, Ulrika %A Sonestedt, Emily %A Kubo, Michiaki %A Akiyama, Masato %A Zhou, Ang %A Kilpeläinen, Tuomas O %A Hansen, Torben %A Kleber, Marcus E %A Delgado, Graciela %A McCarthy, Mark %A Lemaitre, Rozenn N %A Felix, Janine F %A Jaddoe, Vincent W V %A Wu, Ying %A Mohlke, Karen L %A Lehtimäki, Terho %A Wang, Carol A %A Pennell, Craig E %A Schunkert, Heribert %A Kessler, Thorsten %A Zeng, Lingyao %A Willenborg, Christina %A Peters, Annette %A Lieb, Wolfgang %A Grote, Veit %A Rzehak, Peter %A Koletzko, Berthold %A Erdmann, Jeanette %A Munz, Matthias %A Wu, Tangchun %A He, Meian %A Yu, Caizheng %A Lecoeur, Cécile %A Froguel, Philippe %A Corella, Dolores %A Moreno, Luis A %A Lai, Chao-Qiang %A Pitkänen, Niina %A Boreham, Colin A %A Ridker, Paul M %A Rosendaal, Frits R %A de Mutsert, Renée %A Power, Chris %A Paternoster, Lavinia %A Sørensen, Thorkild I A %A Tjønneland, Anne %A Overvad, Kim %A Djoussé, Luc %A Rivadeneira, Fernando %A Lee, Nanette R %A Raitakari, Olli T %A Kähönen, Mika %A Viikari, Jorma %A Langhendries, Jean-Paul %A Escribano, Joaquin %A Verduci, Elvira %A Dedoussis, George %A König, Inke %A Balkau, Beverley %A Coltell, Oscar %A Dallongeville, Jean %A Meirhaeghe, Aline %A Amouyel, Philippe %A Gottrand, Frédéric %A Pahkala, Katja %A Niinikoski, Harri %A Hyppönen, Elina %A März, Winfried %A Mackey, David A %A Gruszfeld, Dariusz %A Tucker, Katherine L %A Fumeron, Frédéric %A Estruch, Ramon %A Ordovas, Jose M %A Arnett, Donna K %A Mook-Kanamori, Dennis O %A Mozaffarian, Dariush %A Psaty, Bruce M %A North, Kari E %A Chasman, Daniel I %A Qi, Lu %X

Epidemiology studies suggested that low birthweight was associated with a higher risk of hypertension in later life. However, little is known about the causality of such associations. In our study, we evaluated the causal association of low birthweight with adulthood hypertension following a standard analytic protocol using the study-level data of 183,433 participants from 60 studies (CHARGE-BIG consortium), as well as that with blood pressure using publicly available summary-level genome-wide association data from EGG consortium of 153,781 participants, ICBP consortium and UK Biobank cohort together of 757,601 participants. We used seven SNPs as the instrumental variable in the study-level analysis and 47 SNPs in the summary-level analysis. In the study-level analyses, decreased birthweight was associated with a higher risk of hypertension in adults (the odds ratio per 1 standard deviation (SD) lower birthweight, 1.22; 95% CI 1.16 to 1.28), while no association was found between genetically instrumented birthweight and hypertension risk (instrumental odds ratio for causal effect per 1 SD lower birthweight, 0.97; 95% CI 0.68 to 1.41). Such results were consistent with that from the summary-level analyses, where the genetically determined low birthweight was not associated with blood pressure measurements either. One SD lower genetically determined birthweight was not associated with systolic blood pressure (β = - 0.76, 95% CI - 2.45 to 1.08 mmHg), 0.06 mmHg lower diastolic blood pressure (β = - 0.06, 95% CI - 0.93 to 0.87 mmHg), or pulse pressure (β = - 0.65, 95% CI - 1.38 to 0.69 mmHg, all p > 0.05). Our findings suggest that the inverse association of birthweight with hypertension risk from observational studies was not supported by large Mendelian randomization analyses.

%B Eur J Epidemiol %V 35 %P 685-697 %8 2020 Jul %G eng %N 7 %R 10.1007/s10654-020-00638-z %0 Journal Article %J Kidney Int %D 2020 %T Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline. %A Gorski, Mathias %A Jung, Bettina %A Li, Yong %A Matias-Garcia, Pamela R %A Wuttke, Matthias %A Coassin, Stefan %A Thio, Chris H L %A Kleber, Marcus E %A Winkler, Thomas W %A Wanner, Veronika %A Chai, Jin-Fang %A Chu, Audrey Y %A Cocca, Massimiliano %A Feitosa, Mary F %A Ghasemi, Sahar %A Hoppmann, Anselm %A Horn, Katrin %A Li, Man %A Nutile, Teresa %A Scholz, Markus %A Sieber, Karsten B %A Teumer, Alexander %A Tin, Adrienne %A Wang, Judy %A Tayo, Bamidele O %A Ahluwalia, Tarunveer S %A Almgren, Peter %A Bakker, Stephan J L %A Banas, Bernhard %A Bansal, Nisha %A Biggs, Mary L %A Boerwinkle, Eric %A Bottinger, Erwin P %A Brenner, Hermann %A Carroll, Robert J %A Chalmers, John %A Chee, Miao-Li %A Chee, Miao-Ling %A Cheng, Ching-Yu %A Coresh, Josef %A de Borst, Martin H %A Degenhardt, Frauke %A Eckardt, Kai-Uwe %A Endlich, Karlhans %A Franke, Andre %A Freitag-Wolf, Sandra %A Gampawar, Piyush %A Gansevoort, Ron T %A Ghanbari, Mohsen %A Gieger, Christian %A Hamet, Pavel %A Ho, Kevin %A Hofer, Edith %A Holleczek, Bernd %A Xian Foo, Valencia Hui %A Hutri-Kähönen, Nina %A Hwang, Shih-Jen %A Ikram, M Arfan %A Josyula, Navya Shilpa %A Kähönen, Mika %A Khor, Chiea-Chuen %A Koenig, Wolfgang %A Kramer, Holly %A Krämer, Bernhard K %A Kuhnel, Brigitte %A Lange, Leslie A %A Lehtimäki, Terho %A Lieb, Wolfgang %A Loos, Ruth J F %A Lukas, Mary Ann %A Lyytikäinen, Leo-Pekka %A Meisinger, Christa %A Meitinger, Thomas %A Melander, Olle %A Milaneschi, Yuri %A Mishra, Pashupati P %A Mononen, Nina %A Mychaleckyj, Josyf C %A Nadkarni, Girish N %A Nauck, Matthias %A Nikus, Kjell %A Ning, Boting %A Nolte, Ilja M %A O'Donoghue, Michelle L %A Orho-Melander, Marju %A Pendergrass, Sarah A %A Penninx, Brenda W J H %A Preuss, Michael H %A Psaty, Bruce M %A Raffield, Laura M %A Raitakari, Olli T %A Rettig, Rainer %A Rheinberger, Myriam %A Rice, Kenneth M %A Rosenkranz, Alexander R %A Rossing, Peter %A Rotter, Jerome I %A Sabanayagam, Charumathi %A Schmidt, Helena %A Schmidt, Reinhold %A Schöttker, Ben %A Schulz, Christina-Alexandra %A Sedaghat, Sanaz %A Shaffer, Christian M %A Strauch, Konstantin %A Szymczak, Silke %A Taylor, Kent D %A Tremblay, Johanne %A Chaker, Layal %A van der Harst, Pim %A van der Most, Peter J %A Verweij, Niek %A Völker, Uwe %A Waldenberger, Melanie %A Wallentin, Lars %A Waterworth, Dawn M %A White, Harvey D %A Wilson, James G %A Wong, Tien-Yin %A Woodward, Mark %A Yang, Qiong %A Yasuda, Masayuki %A Yerges-Armstrong, Laura M %A Zhang, Yan %A Snieder, Harold %A Wanner, Christoph %A Böger, Carsten A %A Köttgen, Anna %A Kronenberg, Florian %A Pattaro, Cristian %A Heid, Iris M %X

Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m at follow-up among those with eGFRcrea 60 mL/min/1.73m or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.

%B Kidney Int %8 2020 Oct 30 %G eng %R 10.1016/j.kint.2020.09.030 %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2020 %T Metabolites Associated with Walking Ability Among the Oldest Old from the CHS All Stars Study. %A Marron, Megan M %A Wendell, Stacy G %A Boudreau, Robert M %A Clish, Clary B %A Santanasto, Adam J %A Tseng, George C %A Zmuda, Joseph M %A Newman, Anne B %K Aged %K Aged, 80 and over %K Case-Control Studies %K Female %K Geriatric Assessment %K Humans %K Male %K Metabolomics %K Risk Factors %K Walking %K Walking Speed %X

BACKGROUND: Low walking ability is highly prevalent with advancing age and predicts major health outcomes. Metabolomics may help to better characterize differences in walking ability among older adults, providing insight into potentially altered molecular processes underlying age-related decline in functioning. We sought to identify metabolites and metabolic pathways associated with high versus low walking ability among 120 participants ages 79-95 from the CHS All Stars study.

METHODS: Using a nested case-control design, 60 randomly selected participants with low walking ability were matched one-to-one on age, gender, race, and fasting time with 60 participants with high walking ability. High versus low walking ability was defined as being in the best versus worst tertiles for both gait speed (≥0.9 vs <0.7 m/s) and the Walking Ability Index (7-9 vs 0-1). Using liquid chromatography-mass spectrometry, 569 metabolites were identified in overnight-fasting plasma.

RESULTS: Ninety-six metabolites were associated with walking ability, where 24% were triacylglycerols. Triacylglycerols that were higher among those with high walking ability consisted mostly of polyunsaturated fatty acids, whereas triacylglycerols that were lower among those with high walking ability consisted mostly of saturated or monounsaturated fatty acids. Body composition partly explained associations between some metabolites and walking ability. Proline and arginine metabolism was a top pathway associated with walking ability.

CONCLUSION: These results may partly reflect pathways of modifiable risk factors, including excess dietary lipids and lack of physical activity, contributing to obesity and further alterations in metabolic pathways that lead to age-related decline in walking ability in this older adult cohort.

%B J Gerontol A Biol Sci Med Sci %V 75 %P 2371-2378 %8 2020 11 13 %G eng %N 12 %R 10.1093/gerona/glaa030 %0 Journal Article %J BMC Med %D 2020 %T {Mitochondrial DNA copy number and incident atrial fibrillation %A Zhao, D. %A Bartz, T. M. %A Sotoodehnia, N. %A Post, W. S. %A Heckbert, S. R. %A Alonso, A. %A Longchamps, R. J. %A Castellani, C. A. %A Hong, Y. S. %A Rotter, J. I. %A Lin, H. J. %A O'Rourke, B. %A Pankratz, N. %A Lane, J. A. %A Yang, S. Y. %A Guallar, E. %A Arking, D. E. %X Mechanistic studies suggest that mitochondria DNA (mtDNA) dysfunction may be associated with increased risk of atrial fibrillation (AF). The association between mtDNA copy number (mtDNA-CN) and incident AF in the general population, however, remains unknown.\ We conducted prospective analyses of 19,709 participants from the Atherosclerosis Risk in Communities Study (ARIC), the Multi-Ethnic Study of Atherosclerosis (MESA), and the Cardiovascular Health Study (CHS). mtDNA-CN from the peripheral blood was calculated from probe intensities on the Affymetrix Genome-Wide Human single nucleotide polymorphisms (SNP) Array 6.0 in ARIC and MESA and from multiplexed real-time quantitative polymerase chain reaction (qPCR) in CHS. Incident AF cases were identified through electrocardiograms, review of hospital discharge codes, Medicare claims, and death certificates.\ The median follow-up time was 21.4 years in ARIC, 12.9 years in MESA, and 11.0 years in CHS, during which 4021 participants developed incident atrial fibrillation (1761 in ARIC, 790 in MESA, and 1470 in CHS). In fully adjusted models, participants with the lowest quintile of mitochondria DNA copy number had an overall 13% increased risk (95% CI 1 to 27%) of incident atrial fibrillation compared to those with the highest quintile. Dose-response spline analysis also showed an inverse association between mitochondria DNA copy number and hazard for atrial fibrillation for all three cohorts. These associations were consistent across subgroups.\ Mitochondria DNA copy number was inversely associated with the risk of AF independent of traditional cardiovascular risk factors. These findings implicate mitochondria DNA copy number as a novel risk factor for atrial fibrillation. Further research is warranted to understand the underlying mechanisms and to evaluate the role of mitochondria DNA copy number in the management of atrial fibrillation risk. %B BMC Med %V 18 %P 246 %8 Sep %G eng %0 Journal Article %J Genome Med %D 2020 %T Mitochondrial DNA copy number can influence mortality and cardiovascular disease via methylation of nuclear DNA CpGs. %A Castellani, Christina A %A Longchamps, Ryan J %A Sumpter, Jason A %A Newcomb, Charles E %A Lane, John A %A Grove, Megan L %A Bressler, Jan %A Brody, Jennifer A %A Floyd, James S %A Bartz, Traci M %A Taylor, Kent D %A Wang, Penglong %A Tin, Adrienne %A Coresh, Josef %A Pankow, James S %A Fornage, Myriam %A Guallar, Eliseo %A O'Rourke, Brian %A Pankratz, Nathan %A Liu, Chunyu %A Levy, Daniel %A Sotoodehnia, Nona %A Boerwinkle, Eric %A Arking, Dan E %X

BACKGROUND: Mitochondrial DNA copy number (mtDNA-CN) has been associated with a variety of aging-related diseases, including all-cause mortality. However, the mechanism by which mtDNA-CN influences disease is not currently understood. One such mechanism may be through regulation of nuclear gene expression via the modification of nuclear DNA (nDNA) methylation.

METHODS: To investigate this hypothesis, we assessed the relationship between mtDNA-CN and nDNA methylation in 2507 African American (AA) and European American (EA) participants from the Atherosclerosis Risk in Communities (ARIC) study. To validate our findings, we assayed an additional 2528 participants from the Cardiovascular Health Study (CHS) (N = 533) and Framingham Heart Study (FHS) (N = 1995). We further assessed the effect of experimental modification of mtDNA-CN through knockout of TFAM, a regulator of mtDNA replication, via CRISPR-Cas9.

RESULTS: Thirty-four independent CpGs were associated with mtDNA-CN at genome-wide significance (P < 5 × 10). Meta-analysis across all cohorts identified six mtDNA-CN-associated CpGs at genome-wide significance (P < 5 × 10). Additionally, over half of these CpGs were associated with phenotypes known to be associated with mtDNA-CN, including coronary heart disease, cardiovascular disease, and mortality. Experimental modification of mtDNA-CN demonstrated that modulation of mtDNA-CN results in changes in nDNA methylation and gene expression of specific CpGs and nearby transcripts. Strikingly, the "neuroactive ligand receptor interaction" KEGG pathway was found to be highly overrepresented in the ARIC cohort (P = 5.24 × 10), as well as the TFAM knockout methylation (P = 4.41 × 10) and expression (P = 4.30 × 10) studies.

CONCLUSIONS: These results demonstrate that changes in mtDNA-CN influence nDNA methylation at specific loci and result in differential expression of specific genes that may impact human health and disease via altered cell signaling.

%B Genome Med %V 12 %P 84 %8 2020 Sep 28 %G eng %N 1 %R 10.1186/s13073-020-00778-7 %0 Journal Article %J Nat Commun %D 2020 %T Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction. %A Ntalla, Ioanna %A Weng, Lu-Chen %A Cartwright, James H %A Hall, Amelia Weber %A Sveinbjornsson, Gardar %A Tucker, Nathan R %A Choi, Seung Hoan %A Chaffin, Mark D %A Roselli, Carolina %A Barnes, Michael R %A Mifsud, Borbala %A Warren, Helen R %A Hayward, Caroline %A Marten, Jonathan %A Cranley, James J %A Concas, Maria Pina %A Gasparini, Paolo %A Boutin, Thibaud %A Kolcic, Ivana %A Polasek, Ozren %A Rudan, Igor %A Araujo, Nathalia M %A Lima-Costa, Maria Fernanda %A Ribeiro, Antonio Luiz P %A Souza, Renan P %A Tarazona-Santos, Eduardo %A Giedraitis, Vilmantas %A Ingelsson, Erik %A Mahajan, Anubha %A Morris, Andrew P %A del Greco M, Fabiola %A Foco, Luisa %A Gögele, Martin %A Hicks, Andrew A %A Cook, James P %A Lind, Lars %A Lindgren, Cecilia M %A Sundström, Johan %A Nelson, Christopher P %A Riaz, Muhammad B %A Samani, Nilesh J %A Sinagra, Gianfranco %A Ulivi, Sheila %A Kähönen, Mika %A Mishra, Pashupati P %A Mononen, Nina %A Nikus, Kjell %A Caulfield, Mark J %A Dominiczak, Anna %A Padmanabhan, Sandosh %A Montasser, May E %A O'Connell, Jeff R %A Ryan, Kathleen %A Shuldiner, Alan R %A Aeschbacher, Stefanie %A Conen, David %A Risch, Lorenz %A Thériault, Sébastien %A Hutri-Kähönen, Nina %A Lehtimäki, Terho %A Lyytikäinen, Leo-Pekka %A Raitakari, Olli T %A Barnes, Catriona L K %A Campbell, Harry %A Joshi, Peter K %A Wilson, James F %A Isaacs, Aaron %A Kors, Jan A %A van Duijn, Cornelia M %A Huang, Paul L %A Gudnason, Vilmundur %A Harris, Tamara B %A Launer, Lenore J %A Smith, Albert V %A Bottinger, Erwin P %A Loos, Ruth J F %A Nadkarni, Girish N %A Preuss, Michael H %A Correa, Adolfo %A Mei, Hao %A Wilson, James %A Meitinger, Thomas %A Müller-Nurasyid, Martina %A Peters, Annette %A Waldenberger, Melanie %A Mangino, Massimo %A Spector, Timothy D %A Rienstra, Michiel %A van de Vegte, Yordi J %A van der Harst, Pim %A Verweij, Niek %A Kääb, Stefan %A Schramm, Katharina %A Sinner, Moritz F %A Strauch, Konstantin %A Cutler, Michael J %A Fatkin, Diane %A London, Barry %A Olesen, Morten %A Roden, Dan M %A Benjamin Shoemaker, M %A Gustav Smith, J %A Biggs, Mary L %A Bis, Joshua C %A Brody, Jennifer A %A Psaty, Bruce M %A Rice, Kenneth %A Sotoodehnia, Nona %A De Grandi, Alessandro %A Fuchsberger, Christian %A Pattaro, Cristian %A Pramstaller, Peter P %A Ford, Ian %A Wouter Jukema, J %A Macfarlane, Peter W %A Trompet, Stella %A Dörr, Marcus %A Felix, Stephan B %A Völker, Uwe %A Weiss, Stefan %A Havulinna, Aki S %A Jula, Antti %A Sääksjärvi, Katri %A Salomaa, Veikko %A Guo, Xiuqing %A Heckbert, Susan R %A Lin, Henry J %A Rotter, Jerome I %A Taylor, Kent D %A Yao, Jie %A de Mutsert, Renée %A Maan, Arie C %A Mook-Kanamori, Dennis O %A Noordam, Raymond %A Cucca, Francesco %A Ding, Jun %A Lakatta, Edward G %A Qian, Yong %A Tarasov, Kirill V %A Levy, Daniel %A Lin, Honghuang %A Newton-Cheh, Christopher H %A Lunetta, Kathryn L %A Murray, Alison D %A Porteous, David J %A Smith, Blair H %A Stricker, Bruno H %A Uitterlinden, Andre %A van den Berg, Marten E %A Haessler, Jeffrey %A Jackson, Rebecca D %A Kooperberg, Charles %A Peters, Ulrike %A Reiner, Alexander P %A Whitsel, Eric A %A Alonso, Alvaro %A Arking, Dan E %A Boerwinkle, Eric %A Ehret, Georg B %A Soliman, Elsayed Z %A Avery, Christy L %A Gogarten, Stephanie M %A Kerr, Kathleen F %A Laurie, Cathy C %A Seyerle, Amanda A %A Stilp, Adrienne %A Assa, Solmaz %A Abdullah Said, M %A Yldau van der Ende, M %A Lambiase, Pier D %A Orini, Michele %A Ramirez, Julia %A Van Duijvenboden, Stefan %A Arnar, David O %A Gudbjartsson, Daniel F %A Holm, Hilma %A Sulem, Patrick %A Thorleifsson, Gudmar %A Thorolfsdottir, Rosa B %A Thorsteinsdottir, Unnur %A Benjamin, Emelia J %A Tinker, Andrew %A Stefansson, Kari %A Ellinor, Patrick T %A Jamshidi, Yalda %A Lubitz, Steven A %A Munroe, Patricia B %X

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.

%B Nat Commun %V 11 %P 2542 %8 2020 May 21 %G eng %N 1 %R 10.1038/s41467-020-15706-x %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2020 %T Patterns of Cardiovascular Risk Factors in Old Age and Survival and Health Status at 90. %A Odden, Michelle C %A Rawlings, Andreea M %A Arnold, Alice M %A Cushman, Mary %A Biggs, Mary L %A Psaty, Bruce M %A Newman, Anne B %X

BACKGROUND: The population age 90 years and older is the fastest growing segment of the U.S. population. Only recently is it possible to study the factors that portend survival to this age.

METHODS: Among participants of the Cardiovascular Health Study, we studied the association of repeated measures of cardiovascular risk factors measured over 15-23 years of follow-up and not only survival to 90 years of age, but also healthy aging outcomes among the population who reached age 90. We included participants aged 67-75 years at baseline (n = 3,613/5,888) to control for birth cohort effects, and followed participants until death or age 90 (median follow-up = 14.7 years).

RESULTS: Higher systolic blood pressure was associated with a lower likelihood of survival to age 90, although this association was attenuated at older ages (p-value for interaction <.001) and crossed the null for measurements taken in participants' 80's. Higher levels of high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and body mass index (BMI) were associated with greater longevity. Among the survivors to age 90, those with worse cardiovascular profile (high blood pressure, LDL cholesterol, glucose, and BMI; low HDL cholesterol) had lower likelihood of remaining free of cardiovascular disease, cognitive impairment, and disability.

CONCLUSION: In summary, we observed paradoxical associations between some cardiovascular risk factors and survival to old age; whereas, among those who survive to very old age, these risk factors were associated with higher risk of adverse health outcomes.

%B J Gerontol A Biol Sci Med Sci %8 2020 Apr 08 %G eng %R 10.1093/gerona/glaa043 %0 Journal Article %J JAMA Netw Open %D 2020 %T Performance of the Pooled Cohort Equations to Estimate Atherosclerotic Cardiovascular Disease Risk by Body Mass Index. %A Khera, Rohan %A Pandey, Ambarish %A Ayers, Colby R %A Carnethon, Mercedes R %A Greenland, Philip %A Ndumele, Chiadi E %A Nambi, Vijay %A Seliger, Stephen L %A Chaves, Paulo H M %A Safford, Monika M %A Cushman, Mary %A Xanthakis, Vanessa %A Vasan, Ramachandran S %A Mentz, Robert J %A Correa, Adolfo %A Lloyd-Jones, Donald M %A Berry, Jarett D %A de Lemos, James A %A Neeland, Ian J %K Adult %K Aged %K Body Mass Index %K Cardiovascular Diseases %K Cohort Studies %K Correlation of Data %K Female %K Humans %K Longitudinal Studies %K Male %K Middle Aged %K Proportional Hazards Models %K Prospective Studies %K Risk Assessment %K Risk Factors %X

Importance: Obesity is a global health challenge and a risk factor for atherosclerotic cardiovascular disease (ASVCD). Performance of the pooled cohort equations (PCE) for ASCVD risk by body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) is unknown.

Objective: To assess performance of the PCE across clinical BMI categories.

Design, Setting, and Participants: This cohort study used pooled individual-level data from 8 community-based, prospective, longitudinal cohort studies with 10-year ASCVD event follow-up from 1996 to 2016. We included all adults ages 40 to 79 years without baseline ASCVD or statin use, resulting in a sample size of 37 311 participants. Data were analyzed from August 2017 to July 2020.

Exposures: Participant BMI category: underweight (<18.5), normal weight (18.5 to <25), overweight (25 to <30), mild obesity (30 to <35), and moderate to severe obesity (≥35).

Main Outcomes and Measures: Discrimination (Harrell C statistic) and calibration (Nam-D'Agostino χ2 goodness-of-fit test) of the PCE across BMI categories. Improvement in discrimination and net reclassification with addition of BMI, waist circumference, and high-sensitivity C-reactive protein (hsCRP) to the PCE.

Results: Among 37 311 participants (mean [SD] age, 58.6 [11.8] years; 21 897 [58.7%] women), 380 604 person-years of follow-up were conducted. Mean (SD) baseline BMI was 29.0 (6.2), and 360 individuals (1.0%) were in the underweight category, 9937 individuals (26.6%) were in the normal weight category, 13 601 individuals (36.4%) were in the overweight category, 7783 individuals (20.9%) were in the mild obesity category, and 5630 individuals (15.1%) were in the moderate to severe obesity category. Median (interquartile range [IQR]) 10-year estimated ASCVD risk was 7.1% (2.5%-15.4%), and 3709 individuals (9.9%) developed ASCVD over a median (IQR) 10.8 [8.5-12.6] years. The PCE overestimated ASCVD risk in the overall cohort (estimated/observed [E/O] risk ratio, 1.22; 95% CI, 1.18-1.26) and across all BMI categories except the underweight category. Calibration was better near the clinical decision threshold in all BMI groups but worse among individuals with moderate or severe obesity (E/O risk ratio, 1.36; 95% CI, 1.25-1.47) and among those with the highest estimated ASCVD risk ≥20%. The PCE C statistic overall was 0.760 (95% CI, 0.753-0.767), with lower discrimination in the moderate or severe obesity group (C statistic, 0.742; 95% CI, 0.721-0.763) compared with the normal-range BMI group (C statistic, 0.785; 95% CI, 0.772-0.798). Waist circumference (hazard ratio, 1.07 per 1-SD increase; 95% CI, 1.03-1.11) and hsCRP (hazard ratio, 1.07 per 1-SD increase; 95% CI, 1.05-1.09), but not BMI, were associated with increased ASCVD risk when added to the PCE. However, these factors did not improve model performance (C statistic, 0.760; 95% CI, 0.753-0.767) with or without added metrics.

Conclusions and Relevance: These findings suggest that the PCE had acceptable model discrimination and were well calibrated at clinical decision thresholds but overestimated risk of ASCVD for individuals in overweight and obese categories, particularly individuals with high estimated risk. Incorporation of the usual clinical measures of obesity did not improve risk estimation of the PCE. Future research is needed to determine whether incorporation of alternative high-risk obesity markers (eg, weight trajectory or measures of visceral or ectopic fat) into the PCE may improve risk prediction.

%B JAMA Netw Open %V 3 %P e2023242 %8 2020 10 01 %G eng %N 10 %R 10.1001/jamanetworkopen.2020.23242 %0 Journal Article %J Cell %D 2020 %T The Polygenic and Monogenic Basis of Blood Traits and Diseases. %A Vuckovic, Dragana %A Bao, Erik L %A Akbari, Parsa %A Lareau, Caleb A %A Mousas, Abdou %A Jiang, Tao %A Chen, Ming-Huei %A Raffield, Laura M %A Tardaguila, Manuel %A Huffman, Jennifer E %A Ritchie, Scott C %A Megy, Karyn %A Ponstingl, Hannes %A Penkett, Christopher J %A Albers, Patrick K %A Wigdor, Emilie M %A Sakaue, Saori %A Moscati, Arden %A Manansala, Regina %A Lo, Ken Sin %A Qian, Huijun %A Akiyama, Masato %A Bartz, Traci M %A Ben-Shlomo, Yoav %A Beswick, Andrew %A Bork-Jensen, Jette %A Bottinger, Erwin P %A Brody, Jennifer A %A van Rooij, Frank J A %A Chitrala, Kumaraswamy N %A Wilson, Peter W F %A Choquet, Helene %A Danesh, John %A Di Angelantonio, Emanuele %A Dimou, Niki %A Ding, Jingzhong %A Elliott, Paul %A Esko, Tõnu %A Evans, Michele K %A Felix, Stephan B %A Floyd, James S %A Broer, Linda %A Grarup, Niels %A Guo, Michael H %A Guo, Qi %A Greinacher, Andreas %A Haessler, Jeff %A Hansen, Torben %A Howson, Joanna M M %A Huang, Wei %A Jorgenson, Eric %A Kacprowski, Tim %A Kähönen, Mika %A Kamatani, Yoichiro %A Kanai, Masahiro %A Karthikeyan, Savita %A Koskeridis, Fotios %A Lange, Leslie A %A Lehtimäki, Terho %A Linneberg, Allan %A Liu, Yongmei %A Lyytikäinen, Leo-Pekka %A Manichaikul, Ani %A Matsuda, Koichi %A Mohlke, Karen L %A Mononen, Nina %A Murakami, Yoshinori %A Nadkarni, Girish N %A Nikus, Kjell %A Pankratz, Nathan %A Pedersen, Oluf %A Preuss, Michael %A Psaty, Bruce M %A Raitakari, Olli T %A Rich, Stephen S %A Rodriguez, Benjamin A T %A Rosen, Jonathan D %A Rotter, Jerome I %A Schubert, Petra %A Spracklen, Cassandra N %A Surendran, Praveen %A Tang, Hua %A Tardif, Jean-Claude %A Ghanbari, Mohsen %A Völker, Uwe %A Völzke, Henry %A Watkins, Nicholas A %A Weiss, Stefan %A Cai, Na %A Kundu, Kousik %A Watt, Stephen B %A Walter, Klaudia %A Zonderman, Alan B %A Cho, Kelly %A Li, Yun %A Loos, Ruth J F %A Knight, Julian C %A Georges, Michel %A Stegle, Oliver %A Evangelou, Evangelos %A Okada, Yukinori %A Roberts, David J %A Inouye, Michael %A Johnson, Andrew D %A Auer, Paul L %A Astle, William J %A Reiner, Alexander P %A Butterworth, Adam S %A Ouwehand, Willem H %A Lettre, Guillaume %A Sankaran, Vijay G %A Soranzo, Nicole %X

Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation.

%B Cell %V 182 %P 1214-1231.e11 %8 2020 Sep 03 %G eng %N 5 %R 10.1016/j.cell.2020.08.008 %0 Journal Article %J Diab Vasc Dis Res %D 2020 %T Pre-diabetes, diabetes and predictors of incident angina among older women and men in the Cardiovascular Health Study. %A Mathenge, Njambi %A Fan, Wenjun %A Wong, Nathan D %A Hirsch, Calvin %A Delaney, Chris Joseph %A Amsterdam, Ezra A %A Koch, Bruce %A Calara, Rico %A Gardin, Julius M %K Age Factors %K Aged %K Angina Pectoris %K Diabetes Mellitus %K Female %K Humans %K Incidence %K Male %K Prediabetic State %K Prognosis %K Prospective Studies %K Risk Assessment %K Risk Factors %K Sex Factors %K Time Factors %K United States %X

Diabetes mellitus and angina pectoris are important conditions in older persons. The utility of pre-diabetes mellitus, diabetes mellitus and other risk factors as predictors of incident angina pectoris among older adults has not been characterized. We examined incident angina pectoris rates by sex and diabetes mellitus status in 4511 adults aged ⩾65 years without coronary heart disease at baseline from the Cardiovascular Health Study. Cox regression examined predictors of incident angina pectoris, including pre-diabetes mellitus or diabetes mellitus adjusted for sociodemographic characteristics and other risk factors, over 12.2 ± 6.9 years of follow-up. Overall, 39.1% of participants had pre-diabetes mellitus, 14.0% had diabetes mellitus and 532 (11.8%) had incident angina pectoris. Incident angina pectoris rates per 1000 person-years in those with neither condition, pre-diabetes mellitus, and diabetes mellitus were 7.9, 9.0 and 12.3 in women and 10.3, 11.2 and 14.5 in men, respectively. Pre-diabetes mellitus and diabetes mellitus were not independently associated with incident AP; however, key predictors of AP were male sex, low-density lipoprotein-cholesterol, triglycerides, systolic blood pressure, antihypertensive medication and difficulty performing at least one instrumental activity of daily living (all  < 0.05 to  < 0.01). In our cohort of older adult participants, while the incidence of AP is greater in those with diabetes mellitus, neither diabetes mellitus nor pre-diabetes mellitus independently predicted incident angina pectoris.

%B Diab Vasc Dis Res %V 17 %P 1479164119888476 %8 2020 Jan-Feb %G eng %N 1 %R 10.1177/1479164119888476 %0 Journal Article %J J Am Geriatr Soc %D 2020 %T Putative Cut-Points in Sarcopenia Components and Incident Adverse Health Outcomes: An SDOC Analysis. %A Cawthon, Peggy M %A Manini, Todd %A Patel, Sheena M %A Newman, Anne %A Travison, Thomas %A Kiel, Douglas P %A Santanasto, Adam J %A Ensrud, Kristine E %A Xue, Qian-Li %A Shardell, Michelle %A Duchowny, Kate %A Erlandson, Kristine M %A Pencina, Karol M %A Fielding, Roger A %A Magaziner, Jay %A Kwok, Timothy %A Karlsson, Magnus %A Ohlsson, Claes %A Mellström, Dan %A Hirani, Vasant %A Ribom, Eva %A Correa-de-Araujo, Rosaly %A Bhasin, Shalender %X

OBJECTIVES: Analyses performed by the Sarcopenia Definitions and Outcomes Consortium (SDOC) identified cut-points in several metrics of grip strength for consideration in a definition of sarcopenia. We describe the associations between the SDOC-identified metrics of low grip strength (absolute or standardized to body size/composition); low dual-energy x-ray absorptiometry (DXA) lean mass as previously defined in the literature (appendicular lean mass [ALM]/ht ); and slowness (walking speed <.8 m/s) with subsequent adverse outcomes (falls, hip fractures, mobility limitation, and mortality).

DESIGN: Individual-level, sex-stratified pooled analysis. We calculated odds ratios (ORs) or hazard ratios (HRs) for incident falls, mobility limitation, hip fractures, and mortality. Follow-up time ranged from 1 year for falls to 8.8 ± 2.3 years for mortality.

SETTING: Eight prospective observational cohort studies.

PARTICIPANTS: A total of 13,421 community-dwelling men and 4,828 community-dwelling women. MEASUREMENTS Grip strength by hand dynamometry, gait speed, and lean mass by DXA.

RESULTS: Low grip strength (absolute or standardized to body size/composition) was associated with incident outcomes, usually independently of slowness, in both men and women. ORs and HRs generally ranged from 1.2 to 3.0 for those below vs above the cut-point. DXA lean mass was not consistently associated with these outcomes. When considered together, those who had both muscle weakness by absolute grip strength (<35.5 kg in men and <20 kg in women) and slowness were consistently more likely to have a fall, hip fracture, mobility limitation, or die than those without either slowness or muscle weakness.

CONCLUSION: Older men and women with both muscle weakness and slowness have a higher likelihood of adverse health outcomes. These results support the inclusion of grip strength and walking speed as components in a summary definition of sarcopenia. J Am Geriatr Soc 68:1429-1437, 2020.

%B J Am Geriatr Soc %V 68 %P 1429-1437 %8 2020 Jul %G eng %N 7 %R 10.1111/jgs.16517 %0 Journal Article %J Am J Cardiol %D 2020 %T Relation of Biomarkers of Cardiac Injury, Stress, and Fibrosis With Cardiac Mechanics in Patients ≥ 65 Years of Age. %A Gottdiener, John S %A Seliger, Stephen %A DeFilippi, Christopher %A Christenson, Robert %A Baldridge, Abigail S %A Kizer, Jorge R %A Psaty, Bruce M %A Shah, Sanjiv J %X

High sensitivity cardiac troponin T (hscTnT), soluble ST2 (sST2), N-terminal B-type natriuretic peptide (NT-proBNP), and galectin-3 are biomarkers of cardiac injury, stress, myocardial stretch, and fibrosis. Elevated levels are associated with poor outcomes. However, their association with cardiac mechanics in older persons is unknown. Associations between these biomarkers and cardiac mechanics derived from speckle tracking echocardiography, including left ventricular longitudinal strain (LVLS), early diastolic strain, and left atrial reservoir strain (LARS) were evaluated using standardized beta coefficients () in a cross sectional analysis with cardiac biomarkers in older patients without cardiovascular disease, low ejection fraction, or wall motion abnormalities. Biomarker associations with strain were attenuated by demographics and risk factors. In adjusted models, LVLS was associated with continuous measures of hscTnT (β-0.06, p = 0.020), sST2 (β -0.05, p = 0.024) and NT-proBNP (β -0.06, p = 0.007). "High" levels (i.e., greater than prognostic cutpoint) of hscTnT (>13 ng/ml), sST2 (>35 ng/ml), and NT-proBNP (>190 pg/ml) were also associated with worse LVLS. In risk factor adjusted models, LARS was associated with hscTnT (β -0.08, p = 0.003) and NT-proBNP (β-0.18, p <0.0001). High hscTnT (>13 ng/ml) and high NT-proBNP (>190 pg/ml) were also both associated with worse LARS. Gal-3 was not associated with any strain measure. In conclusion, in persons ≥ 65 years of age, without cardiovascular disease, low ejection fraction, or wall motion abnormalities, hscTnT, sST2, and NT-proBNP are associated with worse LVLS. HscTnT and NT-proBNP are associated with worse LARS. In conclusion, these subclinical increases in blood biomarkers, and their associations with subtle diastolic and systolic dysfunction, may represent pre-clinical heart failure.

%B Am J Cardiol %8 2020 Sep 16 %G eng %R 10.1016/j.amjcard.2020.09.013 %0 Journal Article %J Circ Genom Precis Med %D 2020 %T Role of Rare and Low-Frequency Variants in Gene-Alcohol Interactions on Plasma Lipid Levels. %A Wang, Zhe %A Chen, Han %A Bartz, Traci M %A Bielak, Lawrence F %A Chasman, Daniel I %A Feitosa, Mary F %A Franceschini, Nora %A Guo, Xiuqing %A Lim, Elise %A Noordam, Raymond %A Richard, Melissa A %A Wang, Heming %A Cade, Brian %A Cupples, L Adrienne %A de Vries, Paul S %A Giulanini, Franco %A Lee, Jiwon %A Lemaitre, Rozenn N %A Martin, Lisa W %A Reiner, Alex P %A Rich, Stephen S %A Schreiner, Pamela J %A Sidney, Stephen %A Sitlani, Colleen M %A Smith, Jennifer A %A Willems van Dijk, Ko %A Yao, Jie %A Zhao, Wei %A Fornage, Myriam %A Kardia, Sharon L R %A Kooperberg, Charles %A Liu, Ching-Ti %A Mook-Kanamori, Dennis O %A Province, Michael A %A Psaty, Bruce M %A Redline, Susan %A Ridker, Paul M %A Rotter, Jerome I %A Boerwinkle, Eric %A Morrison, Alanna C %X

BACKGROUND: Alcohol intake influences plasma lipid levels, and such effects may be moderated by genetic variants. We aimed to characterize the role of aggregated rare and low-frequency protein-coding variants in gene by alcohol consumption interactions associated with fasting plasma lipid levels.

METHODS: In the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, fasting plasma triglycerides and high- and low-density lipoprotein cholesterol were measured in 34 153 individuals with European ancestry from 5 discovery studies and 32 277 individuals from 6 replication studies. Rare and low-frequency functional protein-coding variants (minor allele frequency, ≤5%) measured by an exome array were aggregated by genes and evaluated by a gene-environment interaction test and a joint test of genetic main and gene-environment interaction effects. Two dichotomous self-reported alcohol consumption variables, current drinker, defined as any recurrent drinking behavior, and regular drinker, defined as the subset of current drinkers who consume at least 2 drinks per week, were considered.

RESULTS: We discovered and replicated 21 gene-lipid associations at 13 known lipid loci through the joint test. Eight loci (, , , , , , , and ) remained significant after conditioning on the common index single-nucleotide polymorphism identified by previous genome-wide association studies, suggesting an independent role for rare and low-frequency variants at these loci. One significant gene-alcohol interaction on triglycerides in a novel locus was significantly discovered (=6.65×10 for the interaction test) and replicated at nominal significance level (=0.013) in .

CONCLUSIONS: In conclusion, this study applied new gene-based statistical approaches and suggested that rare and low-frequency genetic variants interacted with alcohol consumption on lipid levels.

%B Circ Genom Precis Med %V 13 %P e002772 %8 2020 Aug %G eng %N 4 %R 10.1161/CIRCGEN.119.002772 %0 Journal Article %J J Am Coll Cardiol %D 2020 %T Sex-Specific Associations of Cardiovascular Risk Factors and Biomarkers With Incident Heart Failure. %A Suthahar, Navin %A Lau, Emily S %A Blaha, Michael J %A Paniagua, Samantha M %A Larson, Martin G %A Psaty, Bruce M %A Benjamin, Emelia J %A Allison, Matthew A %A Bartz, Traci M %A Januzzi, James L %A Levy, Daniel %A Meems, Laura M G %A Bakker, Stephan J L %A Lima, João A C %A Cushman, Mary %A Lee, Douglas S %A Wang, Thomas J %A deFilippi, Christopher R %A Herrington, David M %A Nayor, Matthew %A Vasan, Ramachandran S %A Gardin, Julius M %A Kizer, Jorge R %A Bertoni, Alain G %A Allen, Norrina B %A Gansevoort, Ron T %A Shah, Sanjiv J %A Gottdiener, John S %A Ho, Jennifer E %A de Boer, Rudolf A %X

BACKGROUND: Whether cardiovascular (CV) disease risk factors and biomarkers associate differentially with heart failure (HF) risk in men and women is unclear.

OBJECTIVES: The purpose of this study was to evaluate sex-specific associations of CV risk factors and biomarkers with incident HF.

METHODS: The analysis was performed using data from 4 community-based cohorts with 12.5 years of follow-up. Participants (recruited between 1989 and 2002) were free of HF at baseline. Biomarker measurements included natriuretic peptides, cardiac troponins, plasminogen activator inhibitor-1, D-dimer, fibrinogen, C-reactive protein, sST2, galectin-3, cystatin-C, and urinary albumin-to-creatinine ratio.

RESULTS: Among 22,756 participants (mean age 60 ± 13 years, 53% women), HF occurred in 2,095 participants (47% women). Age, smoking, type 2 diabetes mellitus, hypertension, body mass index, atrial fibrillation, myocardial infarction, left ventricular hypertrophy, and left bundle branch block were strongly associated with HF in both sexes (p < 0.001), and the combined clinical model had good discrimination in men (C-statistic = 0.80) and in women (C-statistic = 0.83). The majority of biomarkers were strongly and similarly associated with HF in both sexes. The clinical model improved modestly after adding natriuretic peptides in men (ΔC-statistic = 0.006; likelihood ratio chi-square = 146; p < 0.001), and after adding cardiac troponins in women (ΔC-statistic = 0.003; likelihood ratio chi-square = 73; p < 0.001).

CONCLUSIONS: CV risk factors are strongly and similarly associated with incident HF in both sexes, highlighting the similar importance of risk factor control in reducing HF risk in the community. There are subtle sex-related differences in the predictive value of individual biomarkers, but the overall improvement in HF risk estimation when included in a clinical HF risk prediction model is limited in both sexes.

%B J Am Coll Cardiol %V 76 %P 1455-1465 %8 2020 Sep 22 %G eng %N 12 %R 10.1016/j.jacc.2020.07.044 %0 Journal Article %J Kidney Int %D 2020 %T A systematic review and participant-level meta-analysis found little association of retinal microvascular caliber and reduced kidney function. %A Lye, Weng Kit %A Paterson, Euan %A Patterson, Christopher C %A Maxwell, Alexander P %A Binte Mohammed Abdul, Riswana Banu %A Tai, E Shyong %A Cheng, Ching Yu %A Kayama, Takamasa %A Yamashita, Hidetoshi %A Sarnak, Mark %A Shlipak, Michael %A Matsushita, Kunihiro %A Mutlu, Unal %A Ikram, Mohammad A %A Klaver, Caroline %A Kifley, Annette %A Mitchell, Paul %A Myers, Chelsea %A Klein, Barbara E %A Klein, Ronald %A Wong, Tien Y %A Sabanayagam, Charumathi %A McKay, Gareth J %X

Previously, variation in retinal vascular caliber has been reported in association with chronic kidney disease (CKD) but findings remain inconsistent. To help clarify this we conducted individual participant data meta-analysis and aggregate data meta-analysis on summary estimates to evaluate cross-sectional associations between retinal vascular caliber and CKD. A systematic review was performed using Medline and EMBASE for articles published until October 2018. The aggregate analysis used a two-stage approach combining summary estimates from eleven studies (44,803 patients) while the individual participant analysis used a one-stage approach combining raw data from nine studies (33,222 patients). CKD stages 3-5 was defined as an estimated glomerular filtration rate under 60 mL/min/1.73m. Retinal arteriolar and venular caliber (central retinal arteriolar and venular equivalent) were assessed from retinal photographs using computer-assisted methods. Logistic regression estimated relative risk of CKD stages 3-5 associated with a 20 μm decrease (approximately one standard deviation) in central retinal arteriolar and venular equivalent. Prevalence of CKD stages 3-5 was 11.2 % of 33,222 and 11.3 % of 44,803 patients in the individual participant and aggregate data analysis, respectively. No significant associations were detected in adjusted analyses between central retinal arteriolar and venular equivalent and CKD stages 3-5 in the aggregate analysis for central retinal arteriolar relative risk (0.98, 95% confidence interval 0.94-1.03); venular equivalent (0.99, 0.95- 1.04) or individual participant central retinal arteriolar (0.99, 0.95-1.04) or venular equivalent (1.01, 0.97-1.05). Thus, meta-analysis provided little evidence to suggest that cross sectional direct measurements of retinal vascular caliber was associated with CKD stages 3-5 in the general population. Hence, meta-analyses of longitudinal studies evaluating the association between retinal parameters and CKD stages 3-5 may be warranted.

%B Kidney Int %8 2020 Aug 15 %G eng %R 10.1016/j.kint.2020.06.033 %0 Journal Article %J Cell %D 2020 %T Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations. %A Chen, Ming-Huei %A Raffield, Laura M %A Mousas, Abdou %A Sakaue, Saori %A Huffman, Jennifer E %A Moscati, Arden %A Trivedi, Bhavi %A Jiang, Tao %A Akbari, Parsa %A Vuckovic, Dragana %A Bao, Erik L %A Zhong, Xue %A Manansala, Regina %A Laplante, Véronique %A Chen, Minhui %A Lo, Ken Sin %A Qian, Huijun %A Lareau, Caleb A %A Beaudoin, Mélissa %A Hunt, Karen A %A Akiyama, Masato %A Bartz, Traci M %A Ben-Shlomo, Yoav %A Beswick, Andrew %A Bork-Jensen, Jette %A Bottinger, Erwin P %A Brody, Jennifer A %A van Rooij, Frank J A %A Chitrala, Kumaraswamynaidu %A Cho, Kelly %A Choquet, Helene %A Correa, Adolfo %A Danesh, John %A Di Angelantonio, Emanuele %A Dimou, Niki %A Ding, Jingzhong %A Elliott, Paul %A Esko, Tõnu %A Evans, Michele K %A Floyd, James S %A Broer, Linda %A Grarup, Niels %A Guo, Michael H %A Greinacher, Andreas %A Haessler, Jeff %A Hansen, Torben %A Howson, Joanna M M %A Huang, Qin Qin %A Huang, Wei %A Jorgenson, Eric %A Kacprowski, Tim %A Kähönen, Mika %A Kamatani, Yoichiro %A Kanai, Masahiro %A Karthikeyan, Savita %A Koskeridis, Fotis %A Lange, Leslie A %A Lehtimäki, Terho %A Lerch, Markus M %A Linneberg, Allan %A Liu, Yongmei %A Lyytikäinen, Leo-Pekka %A Manichaikul, Ani %A Martin, Hilary C %A Matsuda, Koichi %A Mohlke, Karen L %A Mononen, Nina %A Murakami, Yoshinori %A Nadkarni, Girish N %A Nauck, Matthias %A Nikus, Kjell %A Ouwehand, Willem H %A Pankratz, Nathan %A Pedersen, Oluf %A Preuss, Michael %A Psaty, Bruce M %A Raitakari, Olli T %A Roberts, David J %A Rich, Stephen S %A Rodriguez, Benjamin A T %A Rosen, Jonathan D %A Rotter, Jerome I %A Schubert, Petra %A Spracklen, Cassandra N %A Surendran, Praveen %A Tang, Hua %A Tardif, Jean-Claude %A Trembath, Richard C %A Ghanbari, Mohsen %A Völker, Uwe %A Völzke, Henry %A Watkins, Nicholas A %A Zonderman, Alan B %A Wilson, Peter W F %A Li, Yun %A Butterworth, Adam S %A Gauchat, Jean-François %A Chiang, Charleston W K %A Li, Bingshan %A Loos, Ruth J F %A Astle, William J %A Evangelou, Evangelos %A van Heel, David A %A Sankaran, Vijay G %A Okada, Yukinori %A Soranzo, Nicole %A Johnson, Andrew D %A Reiner, Alexander P %A Auer, Paul L %A Lettre, Guillaume %X

Most loci identified by GWASs have been found in populations of European ancestry (EUR). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EUR individuals, we identified 5,552 trait-variant associations at p < 5 × 10, including 71 novel associations not found in EUR populations. We also identified 28 additional novel variants in ancestry-specific, non-EUR meta-analyses, including an IL7 missense variant in South Asians associated with lymphocyte count in vivo and IL-7 secretion levels in vitro. Fine-mapping prioritized variants annotated as functional and generated 95% credible sets that were 30% smaller when using the trans-ethnic as opposed to the EUR-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations and compared genetic architecture and the effect of natural selection on these blood phenotypes between populations. Altogether, our results for hematological traits highlight the value of a more global representation of populations in genetic studies.

%B Cell %V 182 %P 1198-1213.e14 %8 2020 Sep 03 %G eng %N 5 %R 10.1016/j.cell.2020.06.045 %0 Journal Article %J Neurology %D 2020 %T Twenty-seven-year time trends in dementia incidence in Europe and the United States: The Alzheimer Cohorts Consortium %A Wolters, Frank J %A Chibnik, L B %A Waziry, Reem %A Anderson, Roy %B Neurology %V 95 %8 08/2020 %G eng %N 5 %9 journal %& e519 %0 Journal Article %J Circ Genom Precis Med %D 2020 %T Whole Blood DNA Methylation Signatures of Diet Are Associated With Cardiovascular Disease Risk Factors and All-Cause Mortality. %A Ma, Jiantao %A Rebholz, Casey M %A Braun, Kim V E %A Reynolds, Lindsay M %A Aslibekyan, Stella %A Xia, Rui %A Biligowda, Niranjan G %A Huan, Tianxiao %A Liu, Chunyu %A Mendelson, Michael M %A Joehanes, Roby %A Hu, Emily A %A Vitolins, Mara Z %A Wood, Alexis C %A Lohman, Kurt %A Ochoa-Rosales, Carolina %A van Meurs, Joyce %A Uitterlinden, Andre %A Liu, Yongmei %A Elhadad, Mohamed A %A Heier, Margit %A Waldenberger, Melanie %A Peters, Annette %A Colicino, Elena %A Whitsel, Eric A %A Baldassari, Antoine %A Gharib, Sina A %A Sotoodehnia, Nona %A Brody, Jennifer A %A Sitlani, Colleen M %A Tanaka, Toshiko %A Hill, W David %A Corley, Janie %A Deary, Ian J %A Zhang, Yan %A Schöttker, Ben %A Brenner, Hermann %A Walker, Maura E %A Ye, Shumao %A Nguyen, Steve %A Pankow, Jim %A Demerath, Ellen W %A Zheng, Yinan %A Hou, Lifang %A Liang, Liming %A Lichtenstein, Alice H %A Hu, Frank B %A Fornage, Myriam %A Voortman, Trudy %A Levy, Daniel %X

BACKGROUND: DNA methylation patterns associated with habitual diet have not been well studied.

METHODS: Diet quality was characterized using a Mediterranean-style diet score and the Alternative Healthy Eating Index score. We conducted ethnicity-specific and trans-ethnic epigenome-wide association analyses for diet quality and leukocyte-derived DNA methylation at over 400 000 CpGs (cytosine-guanine dinucleotides) in 5 population-based cohorts including 6662 European ancestry, 2702 African ancestry, and 360 Hispanic ancestry participants. For diet-associated CpGs identified in epigenome-wide analyses, we conducted Mendelian randomization (MR) analysis to examine their relations to cardiovascular disease risk factors and examined their longitudinal associations with all-cause mortality.

RESULTS: We identified 30 CpGs associated with either Mediterranean-style diet score or Alternative Healthy Eating Index, or both, in European ancestry participants. Among these CpGs, 12 CpGs were significantly associated with all-cause mortality (Bonferroni corrected <1.6×10). Hypermethylation of cg18181703 () was associated with higher scores of both Mediterranean-style diet score and Alternative Healthy Eating Index and lower risk for all-cause mortality (=5.7×10). Ten additional diet-associated CpGs were nominally associated with all-cause mortality (<0.05). MR analysis revealed 8 putatively causal associations for 6 CpGs with 4 cardiovascular disease risk factors (body mass index, triglycerides, high-density lipoprotein cholesterol concentrations, and type 2 diabetes mellitus; Bonferroni corrected MR <4.5×10). For example, hypermethylation of cg11250194 () was associated with lower triglyceride concentrations (MR, =1.5×10).and hypermethylation of cg02079413 (; ) was associated with body mass index (corrected MR, =1×10).

CONCLUSIONS: Habitual diet quality was associated with differential peripheral leukocyte DNA methylation levels of 30 CpGs, most of which were also associated with multiple health outcomes, in European ancestry individuals. These findings demonstrate that integrative genomic analysis of dietary information may reveal molecular targets for disease prevention and treatment.

%B Circ Genom Precis Med %V 13 %P e002766 %8 2020 Aug %G eng %N 4 %R 10.1161/CIRCGEN.119.002766 %0 Journal Article %J Nat Commun %D 2020 %T Whole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants. %A Zhao, Xutong %A Qiao, Dandi %A Yang, Chaojie %A Kasela, Silva %A Kim, Wonji %A Ma, Yanlin %A Shrine, Nick %A Batini, Chiara %A Sofer, Tamar %A Taliun, Sarah A Gagliano %A Sakornsakolpat, Phuwanat %A Balte, Pallavi P %A Prokopenko, Dmitry %A Yu, Bing %A Lange, Leslie A %A Dupuis, Josée %A Cade, Brian E %A Lee, Jiwon %A Gharib, Sina A %A Daya, Michelle %A Laurie, Cecelia A %A Ruczinski, Ingo %A Cupples, L Adrienne %A Loehr, Laura R %A Bartz, Traci M %A Morrison, Alanna C %A Psaty, Bruce M %A Vasan, Ramachandran S %A Wilson, James G %A Taylor, Kent D %A Durda, Peter %A Johnson, W Craig %A Cornell, Elaine %A Guo, Xiuqing %A Liu, Yongmei %A Tracy, Russell P %A Ardlie, Kristin G %A Aguet, Francois %A VanDenBerg, David J %A Papanicolaou, George J %A Rotter, Jerome I %A Barnes, Kathleen C %A Jain, Deepti %A Nickerson, Deborah A %A Muzny, Donna M %A Metcalf, Ginger A %A Doddapaneni, Harshavardhan %A Dugan-Perez, Shannon %A Gupta, Namrata %A Gabriel, Stacey %A Rich, Stephen S %A O'Connor, George T %A Redline, Susan %A Reed, Robert M %A Laurie, Cathy C %A Daviglus, Martha L %A Preudhomme, Liana K %A Burkart, Kristin M %A Kaplan, Robert C %A Wain, Louise V %A Tobin, Martin D %A London, Stephanie J %A Lappalainen, Tuuli %A Oelsner, Elizabeth C %A Abecasis, Goncalo R %A Silverman, Edwin K %A Barr, R Graham %A Cho, Michael H %A Manichaikul, Ani %K Adult %K African Americans %K Aged %K Aged, 80 and over %K Alpha-Ketoglutarate-Dependent Dioxygenase FTO %K Calcium-Binding Proteins %K Feasibility Studies %K Female %K Follow-Up Studies %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Intracellular Signaling Peptides and Proteins %K Lung %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Protein Inhibitors of Activated STAT %K Pulmonary Disease, Chronic Obstructive %K Respiratory Physiological Phenomena %K Small Ubiquitin-Related Modifier Proteins %K Whole Genome Sequencing %X

Chronic obstructive pulmonary disease (COPD), diagnosed by reduced lung function, is a leading cause of morbidity and mortality. We performed whole genome sequence (WGS) analysis of lung function and COPD in a multi-ethnic sample of 11,497 participants from population- and family-based studies, and 8499 individuals from COPD-enriched studies in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. We identify at genome-wide significance 10 known GWAS loci and 22 distinct, previously unreported loci, including two common variant signals from stratified analysis of African Americans. Four novel common variants within the regions of PIAS1, RGN (two variants) and FTO show evidence of replication in the UK Biobank (European ancestry n ~ 320,000), while colocalization analyses leveraging multi-omic data from GTEx and TOPMed identify potential molecular mechanisms underlying four of the 22 novel loci. Our study demonstrates the value of performing WGS analyses and multi-omic follow-up in cohorts of diverse ancestry.

%B Nat Commun %V 11 %P 5182 %8 2020 10 14 %G eng %N 1 %R 10.1038/s41467-020-18334-7 %0 Journal Article %J Blood %D 2021 %T {Association between ABO haplotypes and the risk of venous thrombosis: impact on disease risk estimation %A Goumidi, L. %A Thibord, F. %A Wiggins, K. L. %A Li-Gao, R. %A Brown, M. R. %A van Hylckama Vlieg, A. %A Souto, J. C. %A Soria, J. M. %A Ibrahim-Kosta, M. %A Saut, N. %A Daian, D. %A Olaso, R. %A Amouyel, P. %A Debette, S. %A Boland, A. %A Bailly, P. %A Morrison, A. C. %A Mook-Kanamori, D. O. %A Deleuze, J. F. %A Johnson, A. %A de Vries, P. S. %A Sabater-Lleal, M. %A Chiaroni, J. %A Smith, N. L. %A Rosendaal, F. R. %A Chasman, D. I. %A Trégouët, D. A. %A Morange, P. E. %X 10.1182/blood.2020008997Genetic risk score (GRS) analysis is a popular approach to derive individual risk prediction models for complex diseases. In venous thrombosis (VT), such type of analysis shall integrate information at the ABO blood group locus, which is one of the major susceptibility loci. However, there is no consensus about which single nucleotide polymorphisms (SNPs) must be investigated when properly assessing association between ABO locus and VT risk. Using comprehensive haplotype analyses of ABO blood group tagging SNPs in 5425 cases and 8445 controls from 6 studies, we demonstrate that using only rs8176719 (tagging O1) to correctly assess the impact of ABO locus on VT risk is suboptimal, because 5% of rs8176719-delG carriers do not have an increased risk of developing VT. Instead, we recommend the use of 4 SNPs, rs2519093 (tagging A1), rs1053878 (A2), rs8176743 (B), and rs41302905 (O2), when assessing the impact of ABO locus on VT risk to avoid any risk misestimation. Compared with the O1 haplotype, the A2 haplotype is associated with a modest increase in VT risk (odds ratio, ∼1.2), the A1 and B haplotypes are associated with an ∼1.8-fold increased risk, whereas the O2 haplotype tends to be slightly protective (odds ratio, ∼0.80). In addition, although the A1 and B blood groups are associated with increased von Willebrand factor and factor VIII plasma levels, only the A1 blood group is associated with ICAM levels, but in an opposite direction, leaving additional avenues to be explored to fully understand the spectrum of biological effects mediated by ABO locus on cardiovascular traits. %B Blood %V 137 %P 2394–2402 %8 Apr %G eng %0 Journal Article %J JAMA Neurol %D 2021 %T Association Between Intracerebral Hemorrhage and Subsequent Arterial Ischemic Events in Participants From 4 Population-Based Cohort Studies. %A Murthy, Santosh B %A Zhang, Cenai %A Diaz, Ivan %A Levitan, Emily B %A Koton, Silvia %A Bartz, Traci M %A DeRosa, Janet T %A Strobino, Kevin %A Colantonio, Lisandro D %A Iadecola, Costantino %A Safford, Monika M %A Howard, Virginia J %A Longstreth, W T %A Gottesman, Rebecca F %A Sacco, Ralph L %A Elkind, Mitchell S V %A Howard, George %A Kamel, Hooman %X

Importance: Intracerebral hemorrhage and arterial ischemic disease share risk factors, to our knowledge, but the association between the 2 conditions remains unknown.

Objective: To evaluate whether intracerebral hemorrhage was associated with an increased risk of incident ischemic stroke and myocardial infarction.

Design, Setting, and Participants: An analysis was conducted of pooled longitudinal participant-level data from 4 population-based cohort studies in the United States: the Atherosclerosis Risk in Communities (ARIC) study, the Cardiovascular Health Study (CHS), the Northern Manhattan Study (NOMAS), and the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. Patients were enrolled from 1987 to 2007, and the last available follow-up was December 31, 2018. Data were analyzed from September 1, 2019, to March 31, 2020.

Exposure: Intracerebral hemorrhage, as assessed by an adjudication committee based on predefined clinical and radiologic criteria.

Main Outcomes and Measures: The primary outcome was an arterial ischemic event, defined as a composite of ischemic stroke or myocardial infarction, centrally adjudicated within each study. Secondary outcomes were ischemic stroke and myocardial infarction. Participants with prevalent intracerebral hemorrhage, ischemic stroke, or myocardial infarction at their baseline study visit were excluded. Cox proportional hazards regression was used to examine the association between intracerebral hemorrhage and subsequent arterial ischemic events after adjustment for baseline age, sex, race/ethnicity, vascular comorbidities, and antithrombotic medications.

Results: Of 55 131 participants, 47 866 (27 639 women [57.7%]; mean [SD] age, 62.2 [10.2] years) were eligible for analysis. During a median follow-up of 12.7 years (interquartile range, 7.7-19.5 years), there were 318 intracerebral hemorrhages and 7648 arterial ischemic events. The incidence of an arterial ischemic event was 3.6 events per 100 person-years (95% CI, 2.7-5.0 events per 100 person-years) after intracerebral hemorrhage vs 1.1 events per 100 person-years (95% CI, 1.1-1.2 events per 100 person-years) among those without intracerebral hemorrhage. In adjusted models, intracerebral hemorrhage was associated with arterial ischemic events (hazard ratio [HR], 2.3; 95% CI, 1.7-3.1), ischemic stroke (HR, 3.1; 95% CI, 2.1-4.5), and myocardial infarction (HR, 1.9; 95% CI, 1.2-2.9). In sensitivity analyses, intracerebral hemorrhage was associated with arterial ischemic events when updating covariates in a time-varying manner (HR, 2.2; 95% CI, 1.6-3.0); when using incidence density matching (odds ratio, 2.3; 95% CI, 1.3-4.2); when including participants with prevalent intracerebral hemorrhage, ischemic stroke, or myocardial infarction (HR, 2.2; 95% CI, 1.6-2.9); and when using death as a competing risk (subdistribution HR, 1.6; 95% CI, 1.1-2.1).

Conclusions and Relevance: This study found that intracerebral hemorrhage was associated with an increased risk of ischemic stroke and myocardial infarction. These findings suggest that intracerebral hemorrhage may be a novel risk marker for arterial ischemic events.

%B JAMA Neurol %V 78 %P 809-816 %8 2021 Jul 01 %G eng %N 7 %R 10.1001/jamaneurol.2021.0925 %0 Journal Article %J JAMA %D 2021 %T Association Between Preserved Ratio Impaired Spirometry and Clinical Outcomes in US Adults. %A Wan, Emily S %A Balte, Pallavi %A Schwartz, Joseph E %A Bhatt, Surya P %A Cassano, Patricia A %A Couper, David %A Daviglus, Martha L %A Dransfield, Mark T %A Gharib, Sina A %A Jacobs, David R %A Kalhan, Ravi %A London, Stephanie J %A Navas-Acien, Ana %A O'Connor, George T %A Sanders, Jason L %A Smith, Benjamin M %A White, Wendy %A Yende, Sachin %A Oelsner, Elizabeth C %K Adult %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Female %K Forced Expiratory Volume %K Humans %K Lung %K Lung Diseases %K Male %K Middle Aged %K Prevalence %K Retrospective Studies %K Spirometry %K United States %K Vital Capacity %X

Importance: Chronic lung diseases are a leading cause of morbidity and mortality. Unlike chronic obstructive pulmonary disease, clinical outcomes associated with proportional reductions in expiratory lung volumes without obstruction, otherwise known as preserved ratio impaired spirometry (PRISm), are poorly understood.

Objective: To examine the prevalence, correlates, and clinical outcomes associated with PRISm in US adults.

Design, Setting, and Participants: The National Heart, Lung, and Blood Institute (NHLBI) Pooled Cohorts Study was a retrospective study with harmonized pooled data from 9 US general population-based cohorts (enrollment, 65 251 participants aged 18 to 102 years of whom 53 701 participants had valid baseline lung function) conducted from 1971-2011 (final follow-up, December 2018).

Exposures: Participants were categorized into mutually exclusive groups by baseline lung function. PRISm was defined as the ratio of forced expiratory volume in the first second to forced vital capacity (FEV1:FVC) greater than or equal to 0.70 and FEV1 less than 80% predicted; obstructive spirometry FEV1:FVC ratio of less than 0.70; and normal spirometry FEV1:FVC ratio greater than or equal to 0.7 and FEV1 greater than or equal to 80% predicted.

Main Outcomes and Measures: Main outcomes were all-cause mortality, respiratory-related mortality, coronary heart disease (CHD)-related mortality, respiratory-related events (hospitalizations and mortality), and CHD-related events (hospitalizations and mortality) classified by adjudication or validated administrative criteria. Absolute risks were adjusted for age and smoking status. Poisson and Cox proportional hazards models comparing PRISm vs normal spirometry were adjusted for age, sex, race and ethnicity, education, body mass index, smoking status, cohort, and comorbidities.

Results: Among all participants (mean [SD] age, 53.2 [15.8] years, 56.4% women, 48.5% never-smokers), 4582 (8.5%) had PRISm. The presence of PRISm relative to normal spirometry was significantly associated with obesity (prevalence, 48.3% vs 31.4%; prevalence ratio [PR], 1.68 [95% CI, 1.55-1.82]), underweight (prevalence, 1.4% vs 1.0%; PR, 2.20 [95% CI, 1.72-2.82]), female sex (prevalence, 60.3% vs 59.0%; PR, 1.07 [95% CI, 1.01-1.13]), and current smoking (prevalence, 25.2% vs 17.5%; PR, 1.33 [95% CI, 1.22-1.45]). PRISm, compared with normal spirometry, was significantly associated with greater all-cause mortality (29.6/1000 person-years vs 18.0/1000 person-years; difference, 11.6/1000 person-years [95% CI, 10.0-13.1]; adjusted hazard ratio [HR], 1.50 [95% CI, 1.42-1.59]), respiratory-related mortality (2.1/1000 person-years vs 1.0/1000 person-years; difference, 1.1/1000 person-years [95% CI, 0.7-1.6]; adjusted HR, 1.95 [95% CI, 1.54-2.48]), CHD-related mortality (5.4/1000 person-years vs 2.6/1000 person-years; difference, 2.7/1000 person-years [95% CI, 2.1-3.4]; adjusted HR, 1.55 [95% CI, 1.36-1.77]), respiratory-related events (12.2/1000 person-years vs 6.0/1000 person-years; difference, 6.2/1000 person-years [95% CI, 4.9-7.5]; adjusted HR, 1.90 [95% CI, 1.69-2.14]), and CHD-related events (11.7/1000 person-years vs 7.0/1000 person-years; difference, 4.7/1000 person-years [95% CI, 3.7-5.8]; adjusted HR, 1.30 [95% CI, 1.18-1.42]).

Conclusions and Relevance: In a large, population-based sample of US adults, baseline PRISm, compared with normal spirometry, was associated with a small but statistically significant increased risk for mortality and adverse cardiovascular and respiratory outcomes. Further research is needed to explore whether this association is causal.

%B JAMA %V 326 %P 2287-2298 %8 2021 12 14 %G eng %N 22 %R 10.1001/jama.2021.20939 %0 Journal Article %J Transl Psychiatry %D 2021 %T Association of low-frequency and rare coding variants with information processing speed. %A Bressler, Jan %A Davies, Gail %A Smith, Albert V %A Saba, Yasaman %A Bis, Joshua C %A Jian, Xueqiu %A Hayward, Caroline %A Yanek, Lisa %A Smith, Jennifer A %A Mirza, Saira S %A Wang, Ruiqi %A Adams, Hieab H H %A Becker, Diane %A Boerwinkle, Eric %A Campbell, Archie %A Cox, Simon R %A Eiriksdottir, Gudny %A Fawns-Ritchie, Chloe %A Gottesman, Rebecca F %A Grove, Megan L %A Guo, Xiuqing %A Hofer, Edith %A Kardia, Sharon L R %A Knol, Maria J %A Koini, Marisa %A Lopez, Oscar L %A Marioni, Riccardo E %A Nyquist, Paul %A Pattie, Alison %A Polasek, Ozren %A Porteous, David J %A Rudan, Igor %A Satizabal, Claudia L %A Schmidt, Helena %A Schmidt, Reinhold %A Sidney, Stephen %A Simino, Jeannette %A Smith, Blair H %A Turner, Stephen T %A van der Lee, Sven J %A Ware, Erin B %A Whitmer, Rachel A %A Yaffe, Kristine %A Yang, Qiong %A Zhao, Wei %A Gudnason, Vilmundur %A Launer, Lenore J %A Fitzpatrick, Annette L %A Psaty, Bruce M %A Fornage, Myriam %A Arfan Ikram, M %A van Duijn, Cornelia M %A Seshadri, Sudha %A Mosley, Thomas H %A Deary, Ian J %K Adult %K Aging %K Cognition %K Genome-Wide Association Study %K Geroscience %K Humans %K Polymorphism, Single Nucleotide %K Ubiquitin-Protein Ligases %X

Measures of information processing speed vary between individuals and decline with age. Studies of aging twins suggest heritability may be as high as 67%. The Illumina HumanExome Bead Chip genotyping array was used to examine the association of rare coding variants with performance on the Digit-Symbol Substitution Test (DSST) in community-dwelling adults participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. DSST scores were available for 30,576 individuals of European ancestry from nine cohorts and for 5758 individuals of African ancestry from four cohorts who were older than 45 years and free of dementia and clinical stroke. Linear regression models adjusted for age and gender were used for analysis of single genetic variants, and the T5, T1, and T01 burden tests that aggregate the number of rare alleles by gene were also applied. Secondary analyses included further adjustment for education. Meta-analyses to combine cohort-specific results were carried out separately for each ancestry group. Variants in RNF19A reached the threshold for statistical significance (p = 2.01 × 10) using the T01 test in individuals of European descent. RNF19A belongs to the class of E3 ubiquitin ligases that confer substrate specificity when proteins are ubiquitinated and targeted for degradation through the 26S proteasome. Variants in SLC22A7 and OR51A7 were suggestively associated with DSST scores after adjustment for education for African-American participants and in the European cohorts, respectively. Further functional characterization of its substrates will be required to confirm the role of RNF19A in cognitive function.

%B Transl Psychiatry %V 11 %P 613 %8 2021 12 04 %G eng %N 1 %R 10.1038/s41398-021-01736-6 %0 Journal Article %J J Card Fail %D 2021 %T Association of Midlife Cardiovascular Risk Factors With the Risk of Heart Failure Subtypes Later in Life. %A Cohen, Laura P %A Vittinghoff, Eric %A Pletcher, Mark J %A Allen, Norrina B %A Shah, Sanjiv J %A Wilkins, John T %A Chang, Patricia P %A Ndumele, Chiadi E %A Newman, Anne B %A Ives, Diane %A Maurer, Mathew S %A Oelsner, Elizabeth C %A Moran, Andrew E %A Zhang, Yiyi %X

BACKGROUND: Independent associations between cardiovascular risk factor exposures during midlife and later life development of heart failure (HF) with preserved ejection fraction (HFpEF) versus reduced EF (HFrEF) have not been previously studied.

METHODS: We pooled data from 4 US cohort studies (Atherosclerosis Risk in Communities, Cardiovascular Health, Health , Aging and Body Composition, and Multi-Ethnic Study of Atherosclerosis) and imputed annual risk factor trajectories for body mass index, systolic and diastolic blood pressure, low-density lipoprotein and high-density lipoprotein cholesterol, and glucose starting from age 40 years. Time-weighted average exposures to each risk factor during midlife and later life were calculated and analyzed for associations with the development of HFpEF or HFrEF.

RESULTS: A total of 23,861 participants were included (mean age at first in-person visit, 61.8 ±1 0.2 years; 56.6% female). During a median follow-up of 12 years, there were 3666 incident HF events, of which 51% had EF measured, including 934 with HFpEF and 739 with HFrEF. A high midlife systolic blood pressure and low midlife high-density lipoprotein cholesterol were associated with HFrEF, and a high midlife body mass index, systolic blood pressure, pulse pressure, and glucose were associated with HFpEF. After adjusting for later life exposures, only midlife pulse pressure remained independently associated with HFpEF.

CONCLUSIONS: Midlife exposure to cardiovascular risk factors are differentially associated with HFrEF and HFpEF later in life. Having a higher pulse pressure during midlife is associated with a greater risk for HFpEF but not HFrEF, independent of later life exposures.

%B J Card Fail %V 27 %P 435-444 %8 2021 Apr %G eng %N 4 %R 10.1016/j.cardfail.2020.11.008 %0 Journal Article %J Cell Genom %D 2021 %T Association of mitochondrial DNA copy number with cardiometabolic diseases. %A Liu, Xue %A Longchamps, Ryan J %A Wiggins, Kerri L %A Raffield, Laura M %A Bielak, Lawrence F %A Zhao, Wei %A Pitsillides, Achilleas %A Blackwell, Thomas W %A Yao, Jie %A Guo, Xiuqing %A Kurniansyah, Nuzulul %A Thyagarajan, Bharat %A Pankratz, Nathan %A Rich, Stephen S %A Taylor, Kent D %A Peyser, Patricia A %A Heckbert, Susan R %A Seshadri, Sudha %A Cupples, L Adrienne %A Boerwinkle, Eric %A Grove, Megan L %A Larson, Nicholas B %A Smith, Jennifer A %A Vasan, Ramachandran S %A Sofer, Tamar %A Fitzpatrick, Annette L %A Fornage, Myriam %A Ding, Jun %A Correa, Adolfo %A Abecasis, Goncalo %A Psaty, Bruce M %A Wilson, James G %A Levy, Daniel %A Rotter, Jerome I %A Bis, Joshua C %A Satizabal, Claudia L %A Arking, Dan E %A Liu, Chunyu %X

Mitochondrial DNA (mtDNA) is present in multiple copies in human cells. We evaluated cross-sectional associations of whole blood mtDNA copy number (CN) with several cardiometabolic disease traits in 408,361 participants of multiple ancestries in TOPMed and UK Biobank. Age showed a threshold association with mtDNA CN: among younger participants (<65 years of age), each additional 10 years of age was associated with 0.03 standard deviation (s.d.) higher level of mtDNA CN ( = 0.0014) versus a 0.14 s.d. lower level of mtDNA CN ( = 1.82 × 10) among older participants (≥65 years). At lower mtDNA CN levels, we found age-independent associations with increased odds of obesity ( = 5.6 × 10), hypertension ( = 2.8 × 10), diabetes ( = 3.6 × 10), and hyperlipidemia ( = 6.3 × 10). The observed decline in mtDNA CN after 65 years of age may be a key to understanding age-related diseases.

%B Cell Genom %V 1 %8 2021 Oct 13 %G eng %N 1 %R 10.1016/j.xgen.2021.100006 %0 Journal Article %J Osteoporos Int %D 2021 %T Associations of hemoglobin and change in hemoglobin with risk of incident hip fracture in older men and women: the cardiovascular health study. %A Valderrábano, R J %A Bůžková, P %A Chang, P-Y %A Zakai, N A %A Fink, H A %A Robbins, J A %A Wu, J Y %A Lee, J S %X

In a multi-site longitudinal cohort study, decreasing hemoglobin was associated with increased hip fracture risk in men. Anemia was associated with hip fracture in men and in African American women. Decreasing hemoglobin may be a marker of progressing bone fragility, making its serial measurement useful for fracture risk stratification.

INTRODUCTION: Hematopoiesis and bone health are interdependent. Anemia has been associated with risk of fracture in humans. To further elucidate this relationship, we hypothesized that decreasing hemoglobin could indicate defective hematopoiesis and would also predict fracture risk.

METHODS: We performed a prospective analysis from study baseline (1992) of the Cardiovascular Health Study, a multi-site longitudinal cohort study. A total of 4670 men and women, ages >65 years, who were able to consent and not institutionalized or wheelchair bound, had hemoglobin (Hb) measured in 1992. For 4006 subjects, Hb change from 1989 to 1992 was annualized and divided into sex-specific quartiles. Incident hip fractures were verified against Medicare claims data during a median follow-up of 11.8 years.

RESULTS: Nested Cox proportional-hazard models estimated association of hip fracture with anemia (men Hb <13 g/dL, women Hb <12 g/dL) and separately, greatest Hb decrease (versus others). Anemia was associated with increased hip fracture risk in all men (HR 1.59; 95% CI 1.01-2.50) and African American women (HR 3.21; 95% CI 1.07-9.63). In men, an annualized Hb loss of >0.36 g/dL/year was associated with a higher risk of hip fracture (HR 1.67; 95% CI 1.10-2.54), which was lessened by anemia at the start of fracture follow-up (HR 1.53; 95% CI 0.99-2.39).

CONCLUSIONS: Decreasing Hb may be an early marker for subsequent hip fracture risk in men, which may be less informative once an anemia threshold is crossed. Only African American women with anemia had increased hip fracture risk, suggesting a race difference in this relationship.

%B Osteoporos Int %8 2021 Feb 12 %G eng %R 10.1007/s00198-021-05873-y %0 Journal Article %J HGG Adv %D 2021 %T BinomiRare: A robust test for association of a rare genetic variant with a binary outcome for mixed models and any case-control proportion. %A Sofer, Tamar %A Lee, Jiwon %A Kurniansyah, Nuzulul %A Jain, Deepti %A Laurie, Cecelia A %A Gogarten, Stephanie M %A Conomos, Matthew P %A Heavner, Ben %A Hu, Yao %A Kooperberg, Charles %A Haessler, Jeffrey %A Vasan, Ramachandran S %A Cupples, L Adrienne %A Coombes, Brandon J %A Seyerle, Amanda %A Gharib, Sina A %A Chen, Han %A O'Connell, Jeffrey R %A Zhang, Man %A Gottlieb, Daniel J %A Psaty, Bruce M %A Longstreth, W T %A Rotter, Jerome I %A Taylor, Kent D %A Rich, Stephen S %A Guo, Xiuqing %A Boerwinkle, Eric %A Morrison, Alanna C %A Pankow, James S %A Johnson, Andrew D %A Pankratz, Nathan %A Reiner, Alex P %A Redline, Susan %A Smith, Nicholas L %A Rice, Kenneth M %A Schifano, Elizabeth D %X

Whole-genome sequencing (WGS) and whole-exome sequencing studies have become increasingly available and are being used to identify rare genetic variants associated with health and disease outcomes. Investigators routinely use mixed models to account for genetic relatedness or other clustering variables (e.g., family or household) when testing genetic associations. However, no existing tests of the association of a rare variant with a binary outcome in the presence of correlated data control the type 1 error where there are (1) few individuals harboring the rare allele, (2) a small proportion of cases relative to controls, and (3) covariates to adjust for. Here, we address all three issues in developing a framework for testing rare variant association with a binary trait in individuals harboring at least one risk allele. In this framework, we estimate outcome probabilities under the null hypothesis and then use them, within the individuals with at least one risk allele, to test variant associations. We extend the BinomiRare test, which was previously proposed for independent observations, and develop the Conway-Maxwell-Poisson (CMP) test and study their properties in simulations. We show that the BinomiRare test always controls the type 1 error, while the CMP test sometimes does not. We then use the BinomiRare test to test the association of rare genetic variants in target genes with small-vessel disease (SVD) stroke, short sleep, and venous thromboembolism (VTE), in whole-genome sequence data from the Trans-Omics for Precision Medicine (TOPMed) program.

%B HGG Adv %V 2 %8 2021 Jul 08 %G eng %N 3 %R 10.1016/j.xhgg.2021.100040 %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 Arch Osteoporos %D 2021 %T Cardiovascular autonomic nervous system function and hip fracture risk: the Cardiovascular Health Study. %A Stein, Phyllis K %A Bůzková, Petra %A Fink, Howard A %A Robbins, John A %A Mukamal, Kenneth J %A Cauley, Jane A %A Carbone, Laura %A Elam, Rachel %A McMillan, David W %A Valderrabano, Rodrigo %A Barzilay, Joshua I %K Aged %K Autonomic Nervous System %K Female %K Heart Rate %K Hip Fractures %K Humans %K Osteoporosis %K Proportional Hazards Models %X

Among 1299 older adults with 24-h Holter monitoring data at baseline, followed for approximately 15 years, 190 incident hip fractures occurred. Increased heart rate variability was independently associated with reduced risk of hip fracture among female participants.

PURPOSE: Autonomic nervous system function modulates bone remodeling in rodent osteoporosis models. We tested whether cardiovascular autonomic function is associated with hip fracture risk in humans.

METHODS: Participants were 1299 subjects from the Cardiovascular Health Study (mean age 72.8 years). Eight heart rate variability (HRV) measures (time and frequency domains, detrended fluctuation analysis variables, and heart rate turbulence) were derived from 24-h Holter monitor scans in sinus rhythm. Median follow-up for incident hip fracture was 14.7 years [IQR 9.1, 20.2]. Cox proportional hazards models were used to calculate hazard ratios (95% confidence intervals, CI).

RESULTS: There were 144 hip fractures among 714 women (1.31 [1.06, 1.61] per 100-person years) and 46 among 585 men (0.62 [0.43, 0.90] per 100 person-years). From among HRV variables examined, a one standard deviation (SD) higher variation between normal heart beats over 24 h (the SD of NN intervals [SDNN]) was associated with a multivariable-adjusted lower hip fracture risk (HR [Formula: see text] 0.80; 95% CI 0.65-0.99; p = 0.04) in women. The adjusted association between very low frequency power, and hip fracture was borderline statistically significant in women (HR [Formula: see text] 0.82; 95% CI, 0.66-1.00; p = 0.06). When the 8 HRV variables were considered conjointly and adjusted for each other's association with hip fracture risk, a 1 SD higher SDNN value was significantly associated with reduced hip fracture risk in women (HR 0.74; 95% CI, 0.50-0.99; p = 0.05). No HRV variables were associated with hip fracture in men.

CONCLUSIONS: In older women, increased heart rate variation is associated with hip fracture risk.

%B Arch Osteoporos %V 16 %P 163 %8 2021 10 31 %G eng %N 1 %R 10.1007/s11657-021-01028-y %0 Journal Article %J Ann Epidemiol %D 2021 %T Cardiovascular damage phenotypes and all-cause and CVD mortality in older adults. %A Miller, Lindsay M %A Wu, Chenkai %A Hirsch, Calvin H %A Lopez, Oscar L %A Cushman, Mary %A Odden, Michelle C %X

PURPOSE: The association between CVD risk factors and mortality is well established, however, current tools for addressing subgroups have focused on the overall burden of disease. The identification of risky combinations of characteristics may lead to a better understanding of physiologic pathways that underlie morbidity and mortality in older adults.

METHODS: Participants included 5067 older adults from the Cardiovascular Health Study, followed for up to 6 years. Using latent class analysis (LCA), we created CV damage phenotypes based on probabilities of abnormal brain infarctions, major echocardiogram abnormalities, N-terminal probrain natriuretic peptide, troponin T, interleukin-6, c reactive-protein, galectin-3, cystatin C. We assigned class descriptions based on the probability of having an abnormality among risk factors, such that a healthy phenotype would have low probabilities in all risk factors. Participants were assigned to phenotypes based on the maximum probability of membership. We used Cox-proportional hazards regression to evaluate the association between the categorical CV damage phenotype and all-cause and CVD-mortality.

RESULTS: The analysis yielded 5 CV damage phenotypes consistent with the following descriptions: healthy (59%), cardio-renal (11%), cardiac (15%), multisystem morbidity (6%), and inflammatory (9%). All four phenotypes were statistically associated with a greater risk of all-cause mortality when compared with the healthy phenotype. The multisystem morbidity phenotype had the greatest risk of all-cause death (HR: 4.02; 95% CI: 3.44, 4.70), and CVD-mortality (HR: 4.90, 95% CI: 3.95, 6.06).

CONCLUSIONS: Five CV damage phenotypes emerged from CVD risk factor measures. CV damage across multiple systems confers a greater mortality risk compared to damage in any single domain.

%B Ann Epidemiol %V 63 %P 35-40 %8 2021 Jul 30 %G eng %R 10.1016/j.annepidem.2021.07.012 %0 Journal Article %J Nat Commun %D 2021 %T Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices. %A Natarajan, Pradeep %A Pampana, Akhil %A Graham, Sarah E %A Ruotsalainen, Sanni E %A Perry, James A %A de Vries, Paul S %A Broome, Jai G %A Pirruccello, James P %A Honigberg, Michael C %A Aragam, Krishna %A Wolford, Brooke %A Brody, Jennifer A %A Antonacci-Fulton, Lucinda %A Arden, Moscati %A Aslibekyan, Stella %A Assimes, Themistocles L %A Ballantyne, Christie M %A Bielak, Lawrence F %A Bis, Joshua C %A Cade, Brian E %A Do, Ron %A Doddapaneni, Harsha %A Emery, Leslie S %A Hung, Yi-Jen %A Irvin, Marguerite R %A Khan, Alyna T %A Lange, Leslie %A Lee, Jiwon %A Lemaitre, Rozenn N %A Martin, Lisa W %A Metcalf, Ginger %A Montasser, May E %A Moon, Jee-Young %A Muzny, Donna %A O'Connell, Jeffrey R %A Palmer, Nicholette D %A Peralta, Juan M %A Peyser, Patricia A %A Stilp, Adrienne M %A Tsai, Michael %A Wang, Fei Fei %A Weeks, Daniel E %A Yanek, Lisa R %A Wilson, James G %A Abecasis, Goncalo %A Arnett, Donna K %A Becker, Lewis C %A Blangero, John %A Boerwinkle, Eric %A Bowden, Donald W %A Chang, Yi-Cheng %A Chen, Yii-der I %A Choi, Won Jung %A Correa, Adolfo %A Curran, Joanne E %A Daly, Mark J %A Dutcher, Susan K %A Ellinor, Patrick T %A Fornage, Myriam %A Freedman, Barry I %A Gabriel, Stacey %A Germer, Soren %A Gibbs, Richard A %A He, Jiang %A Hveem, Kristian %A Jarvik, Gail P %A Kaplan, Robert C %A Kardia, Sharon L R %A Kenny, Eimear %A Kim, Ryan W %A Kooperberg, Charles %A Laurie, Cathy C %A Lee, Seonwook %A Lloyd-Jones, Don M %A Loos, Ruth J F %A Lubitz, Steven A %A Mathias, Rasika A %A Martinez, Karine A Viaud %A McGarvey, Stephen T %A Mitchell, Braxton D %A Nickerson, Deborah A %A North, Kari E %A Palotie, Aarno %A Park, Cheol Joo %A Psaty, Bruce M %A Rao, D C %A Redline, Susan %A Reiner, Alexander P %A Seo, Daekwan %A Seo, Jeong-Sun %A Smith, Albert V %A Tracy, Russell P %A Vasan, Ramachandran S %A Kathiresan, Sekar %A Cupples, L Adrienne %A Rotter, Jerome I %A Morrison, Alanna C %A Rich, Stephen S %A Ripatti, Samuli %A Willer, Cristen %A Peloso, Gina M %X

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.

%B Nat Commun %V 12 %P 2182 %8 2021 04 12 %G eng %N 1 %R 10.1038/s41467-021-22339-1 %0 Journal Article %J Epilepsia %D 2021 %T Cognitive decline in older adults with epilepsy: The Cardiovascular Health Study. %A Choi, Hyunmi %A Thacker, Evan L %A Longstreth, William T %A Elkind, Mitchell S V %A Boehme, Amelia K %X

OBJECTIVE: Cognitive decline is a major concern for older adults with epilepsy. Whether and how much faster older adults with epilepsy experience cognitive decline beyond expected age-related cognitive change remain unclear. We sought to estimate and compare rates of cognitive decline in older adults with and without epilepsy.

METHODS: The Cardiovascular Health Study is a population-based longitudinal cohort study of 5888 US adults aged 65+. Cognitive function was assessed annually with Modified Mini-Mental State Exam (3MS) and Digit Symbol Substitution Test (DSST). We used linear mixed models to estimate average rates of decline in 3MS and DSST scores by epilepsy status (prevalent, incident, or no epilepsy), adjusted for risk factors associated with cognitive decline.

RESULTS: The rate of decline in 3MS was significantly faster in prevalent epilepsy (P < .001) and after incident epilepsy (P = .002) compared with no epilepsy. Prevalent epilepsy and apolipoprotein E gene (APOE) ε4 (ApoE4) had a synergistic interaction, whereby prevalent epilepsy and ApoE4 together were associated with 1.51 points faster annual decline in 3MS than would be expected if prevalent epilepsy and ApoE4 did not interact (P < .001). Older adults with prevalent epilepsy had a significantly lower initial DSST score and faster rate of decline compared to those with no epilepsy (P < .001).

SIGNIFICANCE: Faster decline in global cognitive ability seen in this study validates concerns of patients. ApoE4 allele status was an effect modifier of the relationship between cognitive decline and prevalent epilepsy. Further research is warranted to explore biological mechanisms and possible interventions to mitigate cognitive decline.

%B Epilepsia %V 62 %P 85-97 %8 2021 Jan %G eng %N 1 %R 10.1111/epi.16748 %0 Journal Article %J Heart %D 2021 %T Cumulative burden of clinically significant aortic stenosis in community-dwelling older adults. %A Owens, David S %A Bartz, Traci M %A Bůzková, Petra %A Massera, Daniele %A Biggs, Mary L %A Carlson, Selma D %A Psaty, Bruce M %A Sotoodehnia, Nona %A Gottdiener, John S %A Kizer, Jorge R %X

OBJECTIVES: Current estimates of aortic stenosis (AS) frequency have mostly relied on cross-sectional echocardiographic or longitudinal administrative data, making understanding of AS burden incomplete. We performed case adjudications to evaluate the frequency of AS and assess differences by age, sex and race in an older cohort with long-term follow-up.

METHODS: We developed case-capture methods using study echocardiograms, procedure and diagnosis codes, heart failure events and deaths for targeted review of medical records in the Cardiovascular Health Study to identify moderate or severe AS and related procedures or hospitalisations. The primary outcome was clinically significant AS (severe AS or procedure). Assessment of incident AS burden was based on subdistribution survival methods, while associations with age, sex and race relied on cause-specific survival methods.

RESULTS: The cohort comprised 5795 participants (age 73±6, 42.2% male, 14.3% Black). Cumulative frequency of clinically significant AS at maximal 25-year follow-up was 3.69% (probable/definite) to 4.67% (possible/probable/definite), while the corresponding 20-year cumulative incidence was 2.88% to 3.71%. Of incident cases, about 85% had a hospitalisation for severe AS, but roughly half did not undergo valve intervention. The adjusted incidence of clinically significant AS was higher in men (HR 1.62 [95% CI 1.21 to 2.17]) and increased with age (HR 1.08 [95% CI 1.04 to 1.11]), but was lower in Blacks (HR 0.43 [95% CI 0.23 to 0.81]).

CONCLUSIONS: In this community-based study, we identified a higher burden of clinically significant AS than reported previously, with differences by age, sex and race. These findings have important implications for public health resource planning, although the lower burden in Blacks merits further study.

%B Heart %8 2021 Jun 02 %G eng %R 10.1136/heartjnl-2021-319025 %0 Journal Article %J Nat Commun %D 2021 %T Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes. %A Goodrich, Julia K %A Singer-Berk, Moriel %A Son, Rachel %A Sveden, Abigail %A Wood, Jordan %A England, Eleina %A Cole, Joanne B %A Weisburd, Ben %A Watts, Nick %A Caulkins, Lizz %A Dornbos, Peter %A Koesterer, Ryan %A Zappala, Zachary %A Zhang, Haichen %A Maloney, Kristin A %A Dahl, Andy %A Aguilar-Salinas, Carlos A %A Atzmon, Gil %A Barajas-Olmos, Francisco %A Barzilai, Nir %A Blangero, John %A Boerwinkle, Eric %A Bonnycastle, Lori L %A Bottinger, Erwin %A Bowden, Donald W %A Centeno-Cruz, Federico %A Chambers, John C %A Chami, Nathalie %A Chan, Edmund %A Chan, Juliana %A Cheng, Ching-Yu %A Cho, Yoon Shin %A Contreras-Cubas, Cecilia %A Córdova, Emilio %A Correa, Adolfo %A DeFronzo, Ralph A %A Duggirala, Ravindranath %A Dupuis, Josée %A Garay-Sevilla, Ma Eugenia %A García-Ortiz, Humberto %A Gieger, Christian %A Glaser, Benjamin %A González-Villalpando, Clicerio %A Gonzalez, Ma Elena %A Grarup, Niels %A Groop, Leif %A Gross, Myron %A Haiman, Christopher %A Han, Sohee %A Hanis, Craig L %A Hansen, Torben %A Heard-Costa, Nancy L %A Henderson, Brian E %A Hernandez, Juan Manuel Malacara %A Hwang, Mi Yeong %A Islas-Andrade, Sergio %A Jørgensen, Marit E %A Kang, Hyun Min %A Kim, Bong-Jo %A Kim, Young Jin %A Koistinen, Heikki A %A Kooner, Jaspal Singh %A Kuusisto, Johanna %A Kwak, Soo-Heon %A Laakso, Markku %A Lange, Leslie %A Lee, Jong-Young %A Lee, Juyoung %A Lehman, Donna M %A Linneberg, Allan %A Liu, Jianjun %A Loos, Ruth J F %A Lyssenko, Valeriya %A Ma, Ronald C W %A Martínez-Hernández, Angélica %A Meigs, James B %A Meitinger, Thomas %A Mendoza-Caamal, Elvia %A Mohlke, Karen L %A Morris, Andrew D %A Morrison, Alanna C %A Ng, Maggie C Y %A Nilsson, Peter M %A O'Donnell, Christopher J %A Orozco, Lorena %A Palmer, Colin N A %A Park, Kyong Soo %A Post, Wendy S %A Pedersen, Oluf %A Preuss, Michael %A Psaty, Bruce M %A Reiner, Alexander P %A Revilla-Monsalve, Cristina %A Rich, Stephen S %A Rotter, Jerome I %A Saleheen, Danish %A Schurmann, Claudia %A Sim, Xueling %A Sladek, Rob %A Small, Kerrin S %A So, Wing Yee %A Spector, Timothy D %A Strauch, Konstantin %A Strom, Tim M %A Tai, E Shyong %A Tam, Claudia H T %A Teo, Yik Ying %A Thameem, Farook %A Tomlinson, Brian %A Tracy, Russell P %A Tuomi, Tiinamaija %A Tuomilehto, Jaakko %A Tusié-Luna, Teresa %A van Dam, Rob M %A Vasan, Ramachandran S %A Wilson, James G %A Witte, Daniel R %A Wong, Tien-Yin %A Burtt, Noel P %A Zaitlen, Noah %A McCarthy, Mark I %A Boehnke, Michael %A Pollin, Toni I %A Flannick, Jason %A Mercader, Josep M %A O'Donnell-Luria, Anne %A Baxter, Samantha %A Florez, Jose C %A MacArthur, Daniel G %A Udler, Miriam S %K Adult %K Biological Variation, Population %K Biomarkers %K Diabetes Mellitus, Type 2 %K Dyslipidemias %K Exome %K Genetic Predisposition to Disease %K Genotype %K Humans %K Multifactorial Inheritance %K Penetrance %K Risk Assessment %X

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias.

%B Nat Commun %V 12 %P 3505 %8 2021 06 09 %G eng %N 1 %R 10.1038/s41467-021-23556-4 %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 Clin Nutr %D 2021 %T Egg consumption, overall diet quality, and risk of type 2 diabetes and coronary heart disease: A pooling project of US prospective cohorts. %A Djoussé, Luc %A Zhou, Guohai %A McClelland, Robyn L %A Ma, Nanxun %A Zhou, Xia %A Kabagambe, Edmond K %A Talegawkar, Sameera A %A Judd, Suzanne E %A Biggs, Mary L %A Fitzpatrick, Annette L %A Clark, Cheryl R %A Gagnon, David R %A Steffen, Lyn M %A Gaziano, J Michael %A Lee, I-Min %A Buring, Julie E %A Manson, JoAnn E %K Adult %K Aged %K Cohort Studies %K Coronary Disease %K Diabetes Mellitus, Type 2 %K Diet %K Eggs %K Humans %K Middle Aged %K Prospective Studies %K Risk Factors %K United States %X

BACKGROUND AND AIMS: Data on the relation of egg consumption with risk of type 2 diabetes (T2D) and coronary heart disease (CHD) are limited and inconsistent. Few studies have controlled for overall dietary patterns in egg-T2D or egg-CHD analyses, and it is unclear whether any observed elevated risks of T2D and CHD with frequent egg consumption is real or due to confounding by dietary habits. We tested the hypothesis that frequent egg consumption is associated with a higher risk of T2D and CHD risk after adjustment for overall dietary patterns among adults.

DESIGN: We used prospective cohort design to complete time-to-event analyses.

METHODS: We pooled de novo, harmonized, individual-level analyses from nine US cohorts (n = 103,811). Cox regression was used to estimate hazard ratios separately in each cohort adjusting for age, ethnicity, body mass index (BMI), exercise, smoking, alcohol intake, and dietary patterns. We pooled cohort-specific results using an inverse-variance weighted method to estimate summary relative risks.

RESULTS: Median age ranged from 25 to 72 years. Median egg consumption was 1 egg per week in most of the cohorts. While egg consumption up to one per week was not associated with T2D risk, consumption of ≥2 eggs per week was associated with elevated risk [27% elevated risk of T2D comparing 7+ eggs/week with none (95% CI: 16%-37%)]. There was little evidence for heterogeneity across cohorts and we observed similar conclusions when stratified by BMI. Overall, egg consumption was not associated with the risk of CHD. However, in a sensitivity analysis, there was a 30% higher risk of CHD (95% CI: 3%-56%) restricted to older adults consuming 5-6 eggs/week.

CONCLUSIONS: Our data showed an elevated risk of T2D with egg consumption of ≥2 eggs per week but not with <2 eggs/week. While there was no overall association of egg consumption with CHD risk, the elevated CHD observed with consumption of 5-6 eggs/week in older cohorts merits further investigation.

%B Clin Nutr %V 40 %P 2475-2482 %8 2021 05 %G eng %N 5 %R 10.1016/j.clnu.2021.03.003 %0 Journal Article %J Nat Commun %D 2021 %T {Epigenome-wide association meta-analysis of DNA methylation with coffee and tea consumption %A Karabegović, I. %A Portilla-Fernandez, E. %A Li, Y. %A Ma, J. %A Maas, S. C. E. %A Sun, D. %A Hu, E. A. %A Kühnel, B. %A Zhang, Y. %A Ambatipudi, S. %A Fiorito, G. %A Huang, J. %A Castillo-Fernandez, J. E. %A Wiggins, K. L. %A de Klein, N. %A Grioni, S. %A Swenson, B. R. %A Polidoro, S. %A Treur, J. L. %A Cuenin, C. %A Tsai, P. C. %A Costeira, R. %A Chajes, V. %A Braun, K. %A Verweij, N. %A Kretschmer, A. %A Franke, L. %A van Meurs, J. B. J. %A Uitterlinden, A. G. %A de Knegt, R. J. %A Ikram, M. A. %A Dehghan, A. %A Peters, A. %A Schöttker, B. %A Gharib, S. A. %A Sotoodehnia, N. %A Bell, J. T. %A Elliott, P. %A Vineis, P. %A Relton, C. %A Herceg, Z. %A Brenner, H. %A Waldenberger, M. %A Rebholz, C. M. %A Voortman, T. %A Pan, Q. %A Fornage, M. %A Levy, D. %A Kayser, M. %A Ghanbari, M. %X 10.1038/s41467-021-22752-6Coffee and tea are extensively consumed beverages worldwide which have received considerable attention regarding health. Intake of these beverages is consistently linked to, among others, reduced risk of diabetes and liver diseases; however, the mechanisms of action remain elusive. Epigenetics is suggested as a mechanism mediating the effects of dietary and lifestyle factors on disease onset. Here we report the results from epigenome-wide association studies (EWAS) on coffee and tea consumption in 15,789 participants of European and African-American ancestries from 15 cohorts. EWAS meta-analysis of coffee consumption reveals 11 CpGs surpassing the epigenome-wide significance threshold (P-value <1.1×10-7), which annotated to the AHRR, F2RL3, FLJ43663, HDAC4, GFI1 and PHGDH genes. Among them, cg14476101 is significantly associated with expression of the PHGDH and risk of fatty liver disease. Knockdown of PHGDH expression in liver cells shows a correlation with expression levels of genes associated with circulating lipids, suggesting a role of PHGDH in hepatic-lipid metabolism. EWAS meta-analysis on tea consumption reveals no significant association, only two CpGs annotated to CACNA1A and PRDM16 genes show suggestive association (P-value <5.0×10-6). These findings indicate that coffee-associated changes in DNA methylation levels may explain the mechanism of action of coffee consumption in conferring risk of diseases. %B Nat Commun %V 12 %P 2830 %8 05 %G eng %0 Journal Article %J Nat Commun %D 2021 %T Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus. %A Tin, Adrienne %A Schlosser, Pascal %A Matias-Garcia, Pamela R %A Thio, Chris H L %A Joehanes, Roby %A Liu, Hongbo %A Yu, Zhi %A Weihs, Antoine %A Hoppmann, Anselm %A Grundner-Culemann, Franziska %A Min, Josine L %A Kuhns, Victoria L Halperin %A Adeyemo, Adebowale A %A Agyemang, Charles %A Arnlöv, Johan %A Aziz, Nasir A %A Baccarelli, Andrea %A Bochud, Murielle %A Brenner, Hermann %A Bressler, Jan %A Breteler, Monique M B %A Carmeli, Cristian %A Chaker, Layal %A Coresh, Josef %A Corre, Tanguy %A Correa, Adolfo %A Cox, Simon R %A Delgado, Graciela E %A Eckardt, Kai-Uwe %A Ekici, Arif B %A Endlich, Karlhans %A Floyd, James S %A Fraszczyk, Eliza %A Gao, Xu %A Gào, Xīn %A Gelber, Allan C %A Ghanbari, Mohsen %A Ghasemi, Sahar %A Gieger, Christian %A Greenland, Philip %A Grove, Megan L %A Harris, Sarah E %A Hemani, Gibran %A Henneman, Peter %A Herder, Christian %A Horvath, Steve %A Hou, Lifang %A Hurme, Mikko A %A Hwang, Shih-Jen %A Kardia, Sharon L R %A Kasela, Silva %A Kleber, Marcus E %A Koenig, Wolfgang %A Kooner, Jaspal S %A Kronenberg, Florian %A Kuhnel, Brigitte %A Ladd-Acosta, Christine %A Lehtimäki, Terho %A Lind, Lars %A Liu, Dan %A Lloyd-Jones, Donald M %A Lorkowski, Stefan %A Lu, Ake T %A Marioni, Riccardo E %A März, Winfried %A McCartney, Daniel L %A Meeks, Karlijn A C %A Milani, Lili %A Mishra, Pashupati P %A Nauck, Matthias %A Nowak, Christoph %A Peters, Annette %A Prokisch, Holger %A Psaty, Bruce M %A Raitakari, Olli T %A Ratliff, Scott M %A Reiner, Alex P %A Schöttker, Ben %A Schwartz, Joel %A Sedaghat, Sanaz %A Smith, Jennifer A %A Sotoodehnia, Nona %A Stocker, Hannah R %A Stringhini, Silvia %A Sundström, Johan %A Swenson, Brenton R %A van Meurs, Joyce B J %A van Vliet-Ostaptchouk, Jana V %A Venema, Andrea %A Völker, Uwe %A Winkelmann, Juliane %A Wolffenbuttel, Bruce H R %A Zhao, Wei %A Zheng, Yinan %A Loh, Marie %A Snieder, Harold %A Waldenberger, Melanie %A Levy, Daniel %A Akilesh, Shreeram %A Woodward, Owen M %A Susztak, Katalin %A Teumer, Alexander %A Köttgen, Anna %K Amino Acid Transport System y+ %K Cohort Studies %K CpG Islands %K DNA Methylation %K Epigenome %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Glucose Transport Proteins, Facilitative %K Gout %K Humans %K Male %K Uric Acid %X

Elevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p < 1.1E-7) CpGs explain 11.6% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.

%B Nat Commun %V 12 %P 7173 %8 2021 12 09 %G eng %N 1 %R 10.1038/s41467-021-27198-4 %0 Journal Article %J J Am Heart Assoc %D 2021 %T Estimating Systolic Blood Pressure Intervention Trial Participant Posttrial Survival Using Pooled Epidemiologic Cohort Data. %A Bellows, Brandon K %A Zhang, Yiyi %A Zhang, Zugui %A Lloyd-Jones, Donald M %A Bress, Adam P %A King, Jordan B %A Kolm, Paul %A Cushman, William C %A Johnson, Karen C %A Tamariz, Leonardo %A Oelsner, Elizabeth C %A Shea, Steven %A Newman, Anne B %A Ives, Diane G %A Couper, David %A Moran, Andrew E %A Weintraub, William S %X

Background Intensive systolic blood pressure treatment (<120 mm Hg) in SPRINT (Systolic Blood Pressure Intervention Trial) improved survival compared with standard treatment (<140 mm Hg) over a median follow-up of 3.3 years. We projected life expectancy after observed follow-up in SPRINT using SPRINT-eligible participants in the NHLBI-PCS (National Heart, Lung, and Blood Institute Pooled Cohorts Study). Methods and Results We used propensity scores to weight SPRINT-eligible NHLBI-PCS participants to resemble SPRINT participants. In SPRINT participants, we estimated in-trial survival (<4 years) using a time-based flexible parametric survival model. In SPRINT-eligible NHLBI-PCS participants, we estimated posttrial survival (≥4 years) using an age-based flexible parametric survival model and applied the formula to SPRINT participants to predict posttrial survival. We projected overall life expectancy for each SPRINT participant and compared it to parametric regression (eg, Gompertz) projections based on SPRINT data alone. We included 8584 SPRINT and 10 593 SPRINT-eligible NHLBI-PCS participants. After propensity weighting, mean (SD) age was 67.9 (9.4) and 68.2 (8.8) years, and 35.5% and 37.6% were women in SPRINT and NHLBI-PCS, respectively. Using the NHLBI-PCS-based method, projected mean life expectancy from randomization was 21.0 (7.4) years with intensive and 19.1 (7.2) years with standard treatment. Using the Gompertz regression, life expectancy was 11.2 (2.3) years with intensive and 10.5 (2.2) years with standard treatment. Conclusions Combining SPRINT and NHLBI-PCS observed data likely offers a more realistic estimate of life expectancy than parametrically extrapolating SPRINT data alone. These results offer insight into the potential long-term effectiveness of intensive SBP goals.

%B J Am Heart Assoc %V 10 %P e020361 %8 2021 May 18 %G eng %N 10 %R 10.1161/JAHA.120.020361 %0 Journal Article %J J Thromb Haemost %D 2021 %T FGL1 as a modulator of plasma D-dimer levels: Exome-wide marker analysis of plasma tPA, PAI-1, and D-dimer. %A Thibord, Florian %A Song, Ci %A Pattee, Jack %A Rodriguez, Benjamin A T %A Chen, Ming-Huei %A O'Donnell, Christopher J %A Kleber, Marcus E %A Delgado, Graciela E %A Guo, Xiuqing %A Yao, Jie %A Taylor, Kent D %A Ozel, Ayse Bilge %A Brody, Jennifer A %A McKnight, Barbara %A Gyorgy, Beata %A Simonsick, Eleanor %A Leonard, Hampton L %A Carrasquilla, Germán D %A Guindo-Martinez, Marta %A Silveira, Angela %A Temprano-Sagrera, Gerard %A Yanek, Lisa R %A Becker, Diane M %A Mathias, Rasika A %A Becker, Lewis C %A Raffield, Laura M %A Kilpeläinen, Tuomas O %A Grarup, Niels %A Pedersen, Oluf %A Hansen, Torben %A Linneberg, Allan %A Hamsten, Anders %A Watkins, Hugh %A Sabater-Lleal, Maria %A Nalls, Mike A %A Trégouët, David-Alexandre %A Morange, Pierre-Emmanuel %A Psaty, Bruce M %A Tracy, Russel P %A Smith, Nicholas L %A Desch, Karl C %A Cushman, Mary %A Rotter, Jerome I %A de Vries, Paul S %A Pankratz, Nathan D %A Folsom, Aaron R %A Morrison, Alanna C %A März, Winfried %A Tang, Weihong %A Johnson, Andrew D %X

BACKGROUND: Use of targeted exome-arrays with common, rare variants and functionally enriched variation has led to discovery of new genes contributing to population variation in risk factors. Plasminogen activator-inhibitor 1 (PAI-1), tissue plasminogen activator (tPA), and the plasma product D-dimer are important components of the fibrinolytic system. There have been few large-scale genome-wide or exome-wide studies of PAI-1, tPA, and D-dimer.

OBJECTIVES: We sought to discover new genetic loci contributing to variation in these traits using an exome-array approach.

METHODS: Cohort-level analyses and fixed effects meta-analyses of PAI-1 (n = 15 603), tPA (n = 6876,) and D-dimer (n = 19 306) from 12 cohorts of European ancestry with diverse study design were conducted, including single-variant analyses and gene-based burden testing.

RESULTS: Five variants located in NME7, FGL1, and the fibrinogen locus, all associated with D-dimer levels, achieved genome-wide significance (P < 5 × 10 ). Replication was sought for these 5 variants, as well as 45 well-imputed variants with P < 1 × 10 in the discovery using an independent cohort. Replication was observed for three out of the five significant associations, including a novel and uncommon (0.013 allele frequency) coding variant p.Trp256Leu in FGL1 (fibrinogen-like-1) with increased plasma D-dimer levels. Additionally, a candidate-gene approach revealed a suggestive association for a coding variant (rs143202684-C) in SERPINB2, and suggestive associations with consistent effect in the replication analysis include an intronic variant (rs11057830-A) in SCARB1 associated with increased D-dimer levels.

CONCLUSION: This work provides new evidence for a role of FGL1 in hemostasis.

%B J Thromb Haemost %8 2021 Apr 20 %G eng %R 10.1111/jth.15345 %0 Journal Article %J Nature %D 2021 %T Genetic insights into biological mechanisms governing human ovarian ageing. %A Ruth, Katherine S %A Day, Felix R %A Hussain, Jazib %A Martínez-Marchal, Ana %A Aiken, Catherine E %A Azad, Ajuna %A Thompson, Deborah J %A Knoblochova, Lucie %A Abe, Hironori %A Tarry-Adkins, Jane L %A Gonzalez, Javier Martin %A Fontanillas, Pierre %A Claringbould, Annique %A Bakker, Olivier B %A Sulem, Patrick %A Walters, Robin G %A Terao, Chikashi %A Turon, Sandra %A Horikoshi, Momoko %A Lin, Kuang %A Onland-Moret, N Charlotte %A Sankar, Aditya %A Hertz, Emil Peter Thrane %A Timshel, Pascal N %A Shukla, Vallari %A Borup, Rehannah %A Olsen, Kristina W %A Aguilera, Paula %A Ferrer-Roda, Mònica %A Huang, Yan %A Stankovic, Stasa %A Timmers, Paul R H J %A Ahearn, Thomas U %A Alizadeh, Behrooz Z %A Naderi, Elnaz %A Andrulis, Irene L %A Arnold, Alice M %A Aronson, Kristan J %A Augustinsson, Annelie %A Bandinelli, Stefania %A Barbieri, Caterina M %A Beaumont, Robin N %A Becher, Heiko %A Beckmann, Matthias W %A Benonisdottir, Stefania %A Bergmann, Sven %A Bochud, Murielle %A Boerwinkle, Eric %A Bojesen, Stig E %A Bolla, Manjeet K %A Boomsma, Dorret I %A Bowker, Nicholas %A Brody, Jennifer A %A Broer, Linda %A Buring, Julie E %A Campbell, Archie %A Campbell, Harry %A Castelao, Jose E %A Catamo, Eulalia %A Chanock, Stephen J %A Chenevix-Trench, Georgia %A Ciullo, Marina %A Corre, Tanguy %A Couch, Fergus J %A Cox, Angela %A Crisponi, Laura %A Cross, Simon S %A Cucca, Francesco %A Czene, Kamila %A Smith, George Davey %A de Geus, Eco J C N %A de Mutsert, Renée %A De Vivo, Immaculata %A Demerath, Ellen W %A Dennis, Joe %A Dunning, Alison M %A Dwek, Miriam %A Eriksson, Mikael %A Esko, Tõnu %A Fasching, Peter A %A Faul, Jessica D %A Ferrucci, Luigi %A Franceschini, Nora %A Frayling, Timothy M %A Gago-Dominguez, Manuela %A Mezzavilla, Massimo %A García-Closas, Montserrat %A Gieger, Christian %A Giles, Graham G %A Grallert, Harald %A Gudbjartsson, Daniel F %A Gudnason, Vilmundur %A Guénel, Pascal %A Haiman, Christopher A %A Håkansson, Niclas %A Hall, Per %A Hayward, Caroline %A He, Chunyan %A He, Wei %A Heiss, Gerardo %A Høffding, Miya K %A Hopper, John L %A Hottenga, Jouke J %A Hu, Frank %A Hunter, David %A Ikram, Mohammad A %A Jackson, Rebecca D %A Joaquim, Micaella D R %A John, Esther M %A Joshi, Peter K %A Karasik, David %A Kardia, Sharon L R %A Kartsonaki, Christiana %A Karlsson, Robert %A Kitahara, Cari M %A Kolcic, Ivana %A Kooperberg, Charles %A Kraft, Peter %A Kurian, Allison W %A Kutalik, Zoltán %A La Bianca, Martina %A Lachance, Genevieve %A Langenberg, Claudia %A Launer, Lenore J %A Laven, Joop S E %A Lawlor, Deborah A %A Le Marchand, Loïc %A Li, Jingmei %A Lindblom, Annika %A Lindström, Sara %A Lindstrom, Tricia %A Linet, Martha %A Liu, Yongmei %A Liu, Simin %A Luan, Jian'an %A Mägi, Reedik %A Magnusson, Patrik K E %A Mangino, Massimo %A Mannermaa, Arto %A Marco, Brumat %A Marten, Jonathan %A Martin, Nicholas G %A Mbarek, Hamdi %A McKnight, Barbara %A Medland, Sarah E %A Meisinger, Christa %A Meitinger, Thomas %A Menni, Cristina %A Metspalu, Andres %A Milani, Lili %A Milne, Roger L %A Montgomery, Grant W %A Mook-Kanamori, Dennis O %A Mulas, Antonella %A Mulligan, Anna M %A Murray, Alison %A Nalls, Mike A %A Newman, Anne %A Noordam, Raymond %A Nutile, Teresa %A Nyholt, Dale R %A Olshan, Andrew F %A Olsson, Håkan %A Painter, Jodie N %A Patel, Alpa V %A Pedersen, Nancy L %A Perjakova, Natalia %A Peters, Annette %A Peters, Ulrike %A Pharoah, Paul D P %A Polasek, Ozren %A Porcu, Eleonora %A Psaty, Bruce M %A Rahman, Iffat %A Rennert, Gad %A Rennert, Hedy S %A Ridker, Paul M %A Ring, Susan M %A Robino, Antonietta %A Rose, Lynda M %A Rosendaal, Frits R %A Rossouw, Jacques %A Rudan, Igor %A Rueedi, Rico %A Ruggiero, Daniela %A Sala, Cinzia F %A Saloustros, Emmanouil %A Sandler, Dale P %A Sanna, Serena %A Sawyer, Elinor J %A Sarnowski, Chloe %A Schlessinger, David %A Schmidt, Marjanka K %A Schoemaker, Minouk J %A Schraut, Katharina E %A Scott, Christopher %A Shekari, Saleh %A Shrikhande, Amruta %A Smith, Albert V %A Smith, Blair H %A Smith, Jennifer A %A Sorice, Rossella %A Southey, Melissa C %A Spector, Tim D %A Spinelli, John J %A Stampfer, Meir %A Stöckl, Doris %A van Meurs, Joyce B J %A Strauch, Konstantin %A Styrkarsdottir, Unnur %A Swerdlow, Anthony J %A Tanaka, Toshiko %A Teras, Lauren R %A Teumer, Alexander %A Þorsteinsdottir, Unnur %A Timpson, Nicholas J %A Toniolo, Daniela %A Traglia, Michela %A Troester, Melissa A %A Truong, Thérèse %A Tyrrell, Jessica %A Uitterlinden, André G %A Ulivi, Sheila %A Vachon, Celine M %A Vitart, Veronique %A Völker, Uwe %A Vollenweider, Peter %A Völzke, Henry %A Wang, Qin %A Wareham, Nicholas J %A Weinberg, Clarice R %A Weir, David R %A Wilcox, Amber N %A van Dijk, Ko Willems %A Willemsen, Gonneke %A Wilson, James F %A Wolffenbuttel, Bruce H R %A Wolk, Alicja %A Wood, Andrew R %A Zhao, Wei %A Zygmunt, Marek %A Chen, Zhengming %A Li, Liming %A Franke, Lude %A Burgess, Stephen %A Deelen, Patrick %A Pers, Tune H %A Grøndahl, Marie Louise %A Andersen, Claus Yding %A Pujol, Anna %A Lopez-Contreras, Andres J %A Daniel, Jeremy A %A Stefansson, Kari %A Chang-Claude, Jenny %A van der Schouw, Yvonne T %A Lunetta, Kathryn L %A Chasman, Daniel I %A Easton, Douglas F %A Visser, Jenny A %A Ozanne, Susan E %A Namekawa, Satoshi H %A Solc, Petr %A Murabito, Joanne M %A Ong, Ken K %A Hoffmann, Eva R %A Murray, Anna %A Roig, Ignasi %A Perry, John R B %X

Reproductive longevity is essential for fertility and influences healthy ageing in women, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.

%B Nature %V 596 %P 393-397 %8 2021 Aug %G eng %N 7872 %R 10.1038/s41586-021-03779-7 %0 Journal Article %J Hum Mol Genet %D 2021 %T {Genome-Wide Association Study of Circulating Interleukin 6 Levels Identifies Novel Loci %A Ahluwalia, T. S. %A Prins, B. P. %A Abdollahi, M. %A Armstrong, N. J. %A Aslibekyan, S. %A Bain, L. %A Jefferis, B. %A Baumert, J. %A Beekman, M. %A Ben-Shlomo, Y. %A Bis, J. C. %A Mitchell, B. D. %A de Geus, E. %A Delgado, G. E. %A Marek, D. %A Eriksson, J. %A Kajantie, E. %A Kanoni, S. %A Kemp, J. P. %A Lu, C. %A Marioni, R. E. %A McLachlan, S. %A Milaneschi, Y. %A Nolte, I. M. %A Petrelis, A. M. %A Porcu, E. %A Sabater-Lleal, M. %A Naderi, E. %A Seppälä, I. %A Shah, T. %A Singhal, G. %A Standl, M. %A Teumer, A. %A Thalamuthu, A. %A Thiering, E. %A Trompet, S. %A Ballantyne, C. M. %A Benjamin, E. J. %A Casas, J. P. %A Toben, C. %A Dedoussis, G. %A Deelen, J. %A Durda, P. %A Engmann, J. %A Feitosa, M. F. %A Grallert, H. %A Hammarstedt, A. %A Harris, S. E. %A Homuth, G. %A Hottenga, J. J. %A Jalkanen, S. %A Jamshidi, Y. %A Jawahar, M. C. %A Jess, T. %A Kivimaki, M. %A Kleber, M. E. %A Lahti, J. %A Liu, Y. %A Marques-Vidal, P. %A Mellström, D. %A Mooijaart, S. P. %A Müller-Nurasyid, M. %A Penninx, B. %A Revez, J. A. %A Rossing, P. %A Räikkönen, K. %A Sattar, N. %A Scharnagl, H. %A Sennblad, B. %A Silveira, A. %A Pourcain, B. S. %A Timpson, N. J. %A Trollor, J. %A van Dongen, J. %A van Heemst, D. %A Visvikis-Siest, S. %A Vollenweider, P. %A Völker, U. %A Waldenberger, M. %A Willemsen, G. %A Zabaneh, D. %A Morris, R. W. %A Arnett, D. K. %A Baune, B. T. %A Boomsma, D. I. %A Chang, Y. C. %A Deary, I. J. %A Deloukas, P. %A Eriksson, J. G. %A Evans, D. M. %A Ferreira, M. A. %A Gaunt, T. %A Gudnason, V. %A Hamsten, A. %A Heinrich, J. %A Hingorani, A. %A Humphries, S. E. %A Jukema, J. W. %A Koeing, W. %A Kumari, M. %A Kutalik, Z. %A Lawlor, D. A. %A Lehtimäki, T. %A März, W. %A Mather, K. %A Naitza, S. %A Nauck, M. %A Ohlsson, C. %A Price, J. F. %A Raitakari, O. %A Rice, K. %A Sachdev, P. S. %A Slagboom, E. %A Sørensen, T. I. A. %A Spector, T. %A Stacey, D. %A Stathopoulou, M. G. %A Tanaka, T. %A Wannamethee, S. G. %A Whincup, P. %A Rotter, J. I. %A Dehghan, A. %A Boerwinkle, E. %A Psaty, B. M. %A Snieder, H. %A Alizadeh, B. Z. %X Interleukin-6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery, and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed-effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on Chromosome (Chr) 2q14, (pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology. %B Hum Mol Genet %8 Jan %G eng %0 Journal Article %J Nat Commun %D 2021 %T {Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women %A Jones, G. %A Trajanoska, K. %A Santanasto, A. J. %A Stringa, N. %A Kuo, C. L. %A Atkins, J. L. %A Lewis, J. R. %A Duong, T. %A Hong, S. %A Biggs, M. L. %A Luan, J. %A Sarnowski, C. %A Lunetta, K. L. %A Tanaka, T. %A Wojczynski, M. K. %A Cvejkus, R. %A Nethander, M. %A Ghasemi, S. %A Yang, J. %A Zillikens, M. C. %A Walter, S. %A Sicinski, K. %A Kague, E. %A Ackert-Bicknell, C. L. %A Arking, D. E. %A Windham, B. G. %A Boerwinkle, E. %A Grove, M. L. %A Graff, M. %A Spira, D. %A Demuth, I. %A Van der Velde, N. %A de Groot, L. C. P. G. M. %A Psaty, B. M. %A Odden, M. C. %A Fohner, A. E. %A Langenberg, C. %A Wareham, N. J. %A Bandinelli, S. %A van Schoor, N. M. %A Huisman, M. %A Tan, Q. %A Zmuda, J. %A Mellström, D. %A Karlsson, M. %A Bennett, D. A. %A Buchman, A. S. %A De Jager, P. L. %A Uitterlinden, A. G. %A Völker, U. %A Kocher, T. %A Teumer, A. %A Rodriguéz-Mañas, L. %A García, F. J. %A Carnicero, J. A. %A Herd, P. %A Bertram, L. %A Ohlsson, C. %A Murabito, J. M. %A Melzer, D. %A Kuchel, G. A. %A Ferrucci, L. %A Karasik, D. %A Rivadeneira, F. %A Kiel, D. P. %A Pilling, L. C. %X Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10-17), arthritis (GDF5 p = 4 × 10-13), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing. %B Nat Commun %V 12 %P 654 %8 01 %G eng %0 Journal Article %J ESC Heart Fail %D 2021 %T {The genomics of heart failure: design and rationale of the HERMES consortium %A Lumbers, R. T. %A Shah, S. %A Lin, H. %A Czuba, T. %A Henry, A. %A Swerdlow, D. I. %A Malarstig, A. %A Andersson, C. %A Verweij, N. %A Holmes, M. V. %A Ärnlöv, J. %A Svensson, P. %A Hemingway, H. %A Sallah, N. %A Almgren, P. %A Aragam, K. G. %A Asselin, G. %A Backman, J. D. %A Biggs, M. L. %A Bloom, H. L. %A Boersma, E. %A Brandimarto, J. %A Brown, M. R. %A Brunner-La Rocca, H. P. %A Carey, D. J. %A Chaffin, M. D. %A Chasman, D. I. %A Chazara, O. %A Chen, X. %A Chen, X. %A Chung, J. H. %A Chutkow, W. %A Cleland, J. G. F. %A Cook, J. P. %A de Denus, S. %A Dehghan, A. %A Delgado, G. E. %A Denaxas, S. %A Doney, A. S. %A Dörr, M. %A Dudley, S. C. %A Engström, G. %A Esko, T. %A Fatemifar, G. %A Felix, S. B. %A Finan, C. %A Ford, I. %A Fougerousse, F. %A Fouodjio, R. %A Ghanbari, M. %A Ghasemi, S. %A Giedraitis, V. %A Giulianini, F. %A Gottdiener, J. S. %A Gross, S. %A Guðbjartsson, D. F. %A Gui, H. %A Gutmann, R. %A Haggerty, C. M. %A van der Harst, P. %A Hedman, Å. K. %A Helgadottir, A. %A Hillege, H. %A Hyde, C. L. %A Jacob, J. %A Jukema, J. W. %A Kamanu, F. %A Kardys, I. %A Kavousi, M. %A Khaw, K. T. %A Kleber, M. E. %A Køber, L. %A Koekemoer, A. %A Kraus, B. %A Kuchenbaecker, K. %A Langenberg, C. %A Lind, L. %A Lindgren, C. M. %A London, B. %A Lotta, L. A. %A Lovering, R. C. %A Luan, J. %A Magnusson, P. %A Mahajan, A. %A Mann, D. %A Margulies, K. B. %A Marston, N. A. %A März, W. %A McMurray, J. J. V. %A Melander, O. %A Melloni, G. %A Mordi, I. R. %A Morley, M. P. %A Morris, A. D. %A Morris, A. P. %A Morrison, A. C. %A Nagle, M. W. %A Nelson, C. P. %A Newton-Cheh, C. %A Niessner, A. %A Niiranen, T. %A Nowak, C. %A O'Donoghue, M. L. %A Owens, A. T. %A Palmer, C. N. A. %A Pare, G. %A Perola, M. %A Perreault, L. L. %A Portilla-Fernandez, E. %A Psaty, B. M. %A Rice, K. M. %A Ridker, P. M. %A Romaine, S. P. R. %A Roselli, C. %A Rotter, J. I. %A Ruff, C. T. %A Sabatine, M. S. %A Salo, P. %A Salomaa, V. %A van Setten, J. %A Shalaby, A. A. %A Smelser, D. T. %A Smith, N. L. %A Stefansson, K. %A Stender, S. %A Stott, D. J. %A Sveinbjornsson, G. %A Tammesoo, M. L. %A Tardif, J. C. %A Taylor, K. D. %A Teder-Laving, M. %A Teumer, A. %A Thorgeirsson, G. %A Thorsteinsdottir, U. %A Torp-Pedersen, C. %A Trompet, S. %A Tuckwell, D. %A Tyl, B. %A Uitterlinden, A. G. %A Vaura, F. %A Veluchamy, A. %A Visscher, P. M. %A Völker, U. %A Voors, A. A. %A Wang, X. %A Wareham, N. J. %A Weeke, P. E. %A Weiss, R. %A White, H. D. %A Wiggins, K. L. %A Xing, H. %A Yang, J. %A Yang, Y. %A Yerges-Armstrong, L. M. %A Yu, B. %A Zannad, F. %A Zhao, F. %A Wilk, J. B. %A Holm, H. %A Sattar, N. %A Lubitz, S. A. %A Lanfear, D. E. %A Shah, S. %A Dunn, M. E. %A Wells, Q. S. %A Asselbergs, F. W. %A Hingorani, A. D. %A Dubé, M. P. %A Samani, N. J. %A Lang, C. C. %A Cappola, T. P. %A Ellinor, P. T. %A Vasan, R. S. %A Smith, J. G. %X The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure.\ under an additive genetic model.\ HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction. %B ESC Heart Fail %8 Sep %G eng %0 Journal Article %J J Thromb Haemost %D 2021 %T Hemostatic factor levels and cognitive decline in older adults: The Cardiovascular Health Study. %A Harrington, Laura B %A Ehlert, Alexa N %A Thacker, Evan L %A Jenny, Nancy S %A Lopez, Oscar %A Cushman, Mary %A Fitzpatrick, Annette %A Mukamal, Kenneth J %A Jensen, Majken K %X

BACKGROUND: Hemostasis is a key factor in cerebrovascular disease, but the association of hemostatic factors with cognitive decline is unclear.

OBJECTIVE: To prospectively evaluate associations of 20 hemostatic factor levels with changes in cognition during ≥8 years of follow-up in the Cardiovascular Health Study (CHS) of older adults.

METHODS: We included participants of an existing CHS cross-sectional substudy (n = 400) with hemostatic factors measured in 1989-1990. Between 1989-1990 and 1998-1999, cognitive function was measured using the Modified Mini-Mental State Examination (3MSE) and Digit Symbol Substitution Tests. Mixed-effects linear regression models estimated change in cognitive function over time, adjusting for sociodemographic and clinical factors and APOE genotype, using Bonferroni adjustment. We also derived principal components to account for the interrelationship among factors.

RESULTS: Of 20 factors evaluated individually, only higher levels of plasmin-α -antiplasmin complex (PAP), tissue factor pathway inhibitor (TFPI), and lower factor X (FXc) levels were associated with faster cognitive decline, estimated by annual change in 3MSE points (1 standard deviation PAP β = -0.65, 95% confidence interval [CI]: -1.08 to -0.21; TFPI β = -0.55, 95% CI: -0.90 to -0.19; FXc β = 0.52, 95% CI: 0.21-0.84). One of four principal components, loading positively on D-dimer, prothrombin fragment 1.2 (F1.2), and PAP was significantly associated with change in 3MSE.

CONCLUSIONS: Levels of PAP, TPFI, and FXc and a combination of factors driven by PAP, D-dimer, and F1.2 were associated with cognitive decline. Whether these findings can be used to improve dementia prevention or prediction requires further study.

%B J Thromb Haemost %8 2021 Mar 16 %G eng %R 10.1111/jth.15300 %0 Journal Article %J PLoS One %D 2021 %T Identification of novel and rare variants associated with handgrip strength using whole genome sequence data from the NHLBI Trans-Omics in Precision Medicine (TOPMed) Program. %A Sarnowski, Chloe %A Chen, Han %A Biggs, Mary L %A Wassertheil-Smoller, Sylvia %A Bressler, Jan %A Irvin, Marguerite R %A Ryan, Kathleen A %A Karasik, David %A Arnett, Donna K %A Cupples, L Adrienne %A Fardo, David W %A Gogarten, Stephanie M %A Heavner, Benjamin D %A Jain, Deepti %A Kang, Hyun Min %A Kooperberg, Charles %A Mainous, Arch G %A Mitchell, Braxton D %A Morrison, Alanna C %A O'Connell, Jeffrey R %A Psaty, Bruce M %A Rice, Kenneth %A Smith, Albert V %A Vasan, Ramachandran S %A Windham, B Gwen %A Kiel, Douglas P %A Murabito, Joanne M %A Lunetta, Kathryn L %X

Handgrip strength is a widely used measure of muscle strength and a predictor of a range of morbidities including cardiovascular diseases and all-cause mortality. Previous genome-wide association studies of handgrip strength have focused on common variants primarily in persons of European descent. We aimed to identify rare and ancestry-specific genetic variants associated with handgrip strength by conducting whole-genome sequence association analyses using 13,552 participants from six studies representing diverse population groups from the Trans-Omics in Precision Medicine (TOPMed) Program. By leveraging multiple handgrip strength measures performed in study participants over time, we increased our effective sample size by 7-12%. Single-variant analyses identified ten handgrip strength loci among African-Americans: four rare variants, five low-frequency variants, and one common variant. One significant and four suggestive genes were identified associated with handgrip strength when aggregating rare and functional variants; all associations were ancestry-specific. We additionally leveraged the different ancestries available in the UK Biobank to further explore the ancestry-specific association signals from the single-variant association analyses. In conclusion, our study identified 11 new loci associated with handgrip strength with rare and/or ancestry-specific genetic variations, highlighting the added value of whole-genome sequencing in diverse samples. Several of the associations identified using single-variant or aggregate analyses lie in genes with a function relevant to the brain or muscle or were reported to be associated with muscle or age-related traits. Further studies in samples with sequence data and diverse ancestries are needed to confirm these findings.

%B PLoS One %V 16 %P e0253611 %8 2021 %G eng %N 7 %R 10.1371/journal.pone.0253611 %0 Journal Article %J Nat Commun %D 2021 %T Identification of putative causal loci in whole-genome sequencing data via knockoff statistics. %A He, Zihuai %A Liu, Linxi %A Wang, Chen %A Le Guen, Yann %A Lee, Justin %A Gogarten, Stephanie %A Lu, Fred %A Montgomery, Stephen %A Tang, Hua %A Silverman, Edwin K %A Cho, Michael H %A Greicius, Michael %A Ionita-Laza, Iuliana %K Algorithms %K Causality %K Computer Simulation %K Data Interpretation, Statistical %K Datasets as Topic %K Genetic Loci %K Genetic Predisposition to Disease %K Genome, Human %K Genome-Wide Association Study %K Humans %K Linkage Disequilibrium %K Markov Chains %K Models, Genetic %K Polymorphism, Single Nucleotide %K Reproducibility of Results %K Whole Genome Sequencing %X

The analysis of whole-genome sequencing studies is challenging due to the large number of rare variants in noncoding regions and the lack of natural units for testing. We propose a statistical method to detect and localize rare and common risk variants in whole-genome sequencing studies based on a recently developed knockoff framework. It can (1) prioritize causal variants over associations due to linkage disequilibrium thereby improving interpretability; (2) help distinguish the signal due to rare variants from shadow effects of significant common variants nearby; (3) integrate multiple knockoffs for improved power, stability, and reproducibility; and (4) flexibly incorporate state-of-the-art and future association tests to achieve the benefits proposed here. In applications to whole-genome sequencing data from the Alzheimer's Disease Sequencing Project (ADSP) and COPDGene samples from NHLBI Trans-Omics for Precision Medicine (TOPMed) Program we show that our method compared with conventional association tests can lead to substantially more discoveries.

%B Nat Commun %V 12 %P 3152 %8 2021 05 25 %G eng %N 1 %R 10.1038/s41467-021-22889-4 %0 Journal Article %J Nat Commun %D 2021 %T Meta-analyses identify DNA methylation associated with kidney function and damage. %A Schlosser, Pascal %A Tin, Adrienne %A Matias-Garcia, Pamela R %A Thio, Chris H L %A Joehanes, Roby %A Liu, Hongbo %A Weihs, Antoine %A Yu, Zhi %A Hoppmann, Anselm %A Grundner-Culemann, Franziska %A Min, Josine L %A Adeyemo, Adebowale A %A Agyemang, Charles %A Arnlöv, Johan %A Aziz, Nasir A %A Baccarelli, Andrea %A Bochud, Murielle %A Brenner, Hermann %A Breteler, Monique M B %A Carmeli, Cristian %A Chaker, Layal %A Chambers, John C %A Cole, Shelley A %A Coresh, Josef %A Corre, Tanguy %A Correa, Adolfo %A Cox, Simon R %A de Klein, Niek %A Delgado, Graciela E %A Domingo-Relloso, Arce %A Eckardt, Kai-Uwe %A Ekici, Arif B %A Endlich, Karlhans %A Evans, Kathryn L %A Floyd, James S %A Fornage, Myriam %A Franke, Lude %A Fraszczyk, Eliza %A Gao, Xu %A Gào, Xīn %A Ghanbari, Mohsen %A Ghasemi, Sahar %A Gieger, Christian %A Greenland, Philip %A Grove, Megan L %A Harris, Sarah E %A Hemani, Gibran %A Henneman, Peter %A Herder, Christian %A Horvath, Steve %A Hou, Lifang %A Hurme, Mikko A %A Hwang, Shih-Jen %A Jarvelin, Marjo-Riitta %A Kardia, Sharon L R %A Kasela, Silva %A Kleber, Marcus E %A Koenig, Wolfgang %A Kooner, Jaspal S %A Kramer, Holly %A Kronenberg, Florian %A Kuhnel, Brigitte %A Lehtimäki, Terho %A Lind, Lars %A Liu, Dan %A Liu, Yongmei %A Lloyd-Jones, Donald M %A Lohman, Kurt %A Lorkowski, Stefan %A Lu, Ake T %A Marioni, Riccardo E %A März, Winfried %A McCartney, Daniel L %A Meeks, Karlijn A C %A Milani, Lili %A Mishra, Pashupati P %A Nauck, Matthias %A Navas-Acien, Ana %A Nowak, Christoph %A Peters, Annette %A Prokisch, Holger %A Psaty, Bruce M %A Raitakari, Olli T %A Ratliff, Scott M %A Reiner, Alex P %A Rosas, Sylvia E %A Schöttker, Ben %A Schwartz, Joel %A Sedaghat, Sanaz %A Smith, Jennifer A %A Sotoodehnia, Nona %A Stocker, Hannah R %A Stringhini, Silvia %A Sundström, Johan %A Swenson, Brenton R %A Tellez-Plaza, Maria %A van Meurs, Joyce B J %A van Vliet-Ostaptchouk, Jana V %A Venema, Andrea %A Verweij, Niek %A Walker, Rosie M %A Wielscher, Matthias %A Winkelmann, Juliane %A Wolffenbuttel, Bruce H R %A Zhao, Wei %A Zheng, Yinan %A Loh, Marie %A Snieder, Harold %A Levy, Daniel %A Waldenberger, Melanie %A Susztak, Katalin %A Köttgen, Anna %A Teumer, Alexander %K Adult %K Aged %K CpG Islands %K DNA Methylation %K Female %K Glomerular Filtration Rate %K Humans %K Interferon Regulatory Factors %K Kidney %K Kidney Function Tests %K LIM Domain Proteins %K Male %K Membrane Proteins %K Middle Aged %K Renal Insufficiency, Chronic %K Transcription Factors %X

Chronic kidney disease is a major public health burden. Elevated urinary albumin-to-creatinine ratio is a measure of kidney damage, and used to diagnose and stage chronic kidney disease. To extend the knowledge on regulatory mechanisms related to kidney function and disease, we conducted a blood-based epigenome-wide association study for estimated glomerular filtration rate (n = 33,605) and urinary albumin-to-creatinine ratio (n = 15,068) and detected 69 and seven CpG sites where DNA methylation was associated with the respective trait. The majority of these findings showed directionally consistent associations with the respective clinical outcomes chronic kidney disease and moderately increased albuminuria. Associations of DNA methylation with kidney function, such as CpGs at JAZF1, PELI1 and CHD2 were validated in kidney tissue. Methylation at PHRF1, LDB2, CSRNP1 and IRF5 indicated causal effects on kidney function. Enrichment analyses revealed pathways related to hemostasis and blood cell migration for estimated glomerular filtration rate, and immune cell activation and response for urinary albumin-to-creatinineratio-associated CpGs.

%B Nat Commun %V 12 %P 7174 %8 2021 12 09 %G eng %N 1 %R 10.1038/s41467-021-27234-3 %0 Journal Article %J HGG Adv %D 2021 %T Multi-Ancestry Genome-wide Association Study Accounting for Gene-Psychosocial Factor Interactions Identifies Novel Loci for Blood Pressure Traits. %A Sun, Daokun %A Richard, Melissa %A Musani, Solomon K %A Sung, Yun Ju %A Winkler, Thomas W %A Schwander, Karen %A Chai, Jin Fang %A Guo, Xiuqing %A Kilpeläinen, Tuomas O %A Vojinovic, Dina %A Aschard, Hugues %A Bartz, Traci M %A Bielak, Lawrence F %A Brown, Michael R %A Chitrala, Kumaraswamy %A Hartwig, Fernando P %A Horimoto, Andrea R V R %A Liu, Yongmei %A Manning, Alisa K %A Noordam, Raymond %A Smith, Albert V %A Harris, Sarah E %A Kuhnel, Brigitte %A Lyytikäinen, Leo-Pekka %A Nolte, Ilja M %A Rauramaa, Rainer %A van der Most, Peter J %A Wang, Rujia %A Ware, Erin B %A Weiss, Stefan %A Wen, Wanqing %A Yanek, Lisa R %A Arking, Dan E %A Arnett, Donna K %A Barac, Ana %A Boerwinkle, Eric %A Broeckel, Ulrich %A Chakravarti, Aravinda %A Chen, Yii-Der Ida %A Cupples, L Adrienne %A Davigulus, Martha L %A de Las Fuentes, Lisa %A de Mutsert, Renée %A de Vries, Paul S %A Delaney, Joseph A C %A Roux, Ana V Diez %A Dörr, Marcus %A Faul, Jessica D %A Fretts, Amanda M %A Gallo, Linda C %A Grabe, Hans Jörgen %A Gu, C Charles %A Harris, Tamara B %A Hartman, Catharina C A %A Heikkinen, Sami %A Ikram, M Arfan %A Isasi, Carmen %A Johnson, W Craig %A Jonas, Jost Bruno %A Kaplan, Robert C %A Komulainen, Pirjo %A Krieger, Jose E %A Levy, Daniel %A Liu, Jianjun %A Lohman, Kurt %A Luik, Annemarie I %A Martin, Lisa W %A Meitinger, Thomas %A Milaneschi, Yuri %A O'Connell, Jeff R %A Palmas, Walter R %A Peters, Annette %A Peyser, Patricia A %A Pulkki-Råback, Laura %A Raffel, Leslie J %A Reiner, Alex P %A Rice, Kenneth %A Robinson, Jennifer G %A Rosendaal, Frits R %A Schmidt, Carsten Oliver %A Schreiner, Pamela J %A Schwettmann, Lars %A Shikany, James M %A Shu, Xiao-Ou %A Sidney, Stephen %A Sims, Mario %A Smith, Jennifer A %A Sotoodehnia, Nona %A Strauch, Konstantin %A Tai, E Shyong %A Taylor, Kent %A Uitterlinden, André G %A van Duijn, Cornelia M %A Waldenberger, Melanie %A Wee, Hwee-Lin %A Wei, Wen-Bin %A Wilson, Gregory %A Xuan, Deng %A Yao, Jie %A Zeng, Donglin %A Zhao, Wei %A Zhu, Xiaofeng %A Zonderman, Alan B %A Becker, Diane M %A Deary, Ian J %A Gieger, Christian %A Lakka, Timo A %A Lehtimäki, Terho %A North, Kari E %A Oldehinkel, Albertine J %A Penninx, Brenda W J H %A Snieder, Harold %A Wang, Ya-Xing %A Weir, David R %A Zheng, Wei %A Evans, Michele K %A Gauderman, W James %A Gudnason, Vilmundur %A Horta, Bernardo L %A Liu, Ching-Ti %A Mook-Kanamori, Dennis O %A Morrison, Alanna C %A Pereira, Alexandre C %A Psaty, Bruce M %A Amin, Najaf %A Fox, Ervin R %A Kooperberg, Charles %A Sim, Xueling %A Bierut, Laura %A Rotter, Jerome I %A Kardia, Sharon L R %A Franceschini, Nora %A Rao, Dabeeru C %A Fornage, Myriam %X

Psychological and social factors are known to influence blood pressure (BP) and risk of hypertension and associated cardiovascular diseases. To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptoms, anxiety symptoms, and social support. Analyses were performed using a two-stage design in a sample of up to 128,894 adults from 5 ancestry groups. In the combined meta-analyses of Stages 1 and 2, we identified 59 loci (p value <5e-8), including nine novel BP loci. The novel associations were observed mostly with pulse pressure, with fewer observed with mean arterial pressure. Five novel loci were identified in African ancestry, and all but one showed patterns of interaction with at least one psychosocial factor. Functional annotation of the novel loci supports a major role for genes implicated in the immune response (), synaptic function and neurotransmission (), as well as genes previously implicated in neuropsychiatric or stress-related disorders (). These findings underscore the importance of considering psychological and social factors in gene discovery for BP, especially in non-European populations.

%B HGG Adv %V 2 %8 2021 Jan 14 %G eng %N 1 %R 10.1016/j.xhgg.2020.100013 %0 Journal Article %J Mol Psychiatry %D 2021 %T Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure. %A Wang, Heming %A Noordam, Raymond %A Cade, Brian E %A Schwander, Karen %A Winkler, Thomas W %A Lee, Jiwon %A Sung, Yun Ju %A Bentley, Amy R %A Manning, Alisa K %A Aschard, Hugues %A Kilpeläinen, Tuomas O %A Ilkov, Marjan %A Brown, Michael R %A Horimoto, Andrea R %A Richard, Melissa %A Bartz, Traci M %A Vojinovic, Dina %A Lim, Elise %A Nierenberg, Jovia L %A Liu, Yongmei %A Chitrala, Kumaraswamynaidu %A Rankinen, Tuomo %A Musani, Solomon K %A Franceschini, Nora %A Rauramaa, Rainer %A Alver, Maris %A Zee, Phyllis C %A Harris, Sarah E %A van der Most, Peter J %A Nolte, Ilja M %A Munroe, Patricia B %A Palmer, Nicholette D %A Kuhnel, Brigitte %A Weiss, Stefan %A Wen, Wanqing %A Hall, Kelly A %A Lyytikäinen, Leo-Pekka %A O'Connell, Jeff %A Eiriksdottir, Gudny %A Launer, Lenore J %A de Vries, Paul S %A Arking, Dan E %A Chen, Han %A Boerwinkle, Eric %A Krieger, Jose E %A Schreiner, Pamela J %A Sidney, Stephen %A Shikany, James M %A Rice, Kenneth %A Chen, Yii-Der Ida %A Gharib, Sina A %A Bis, Joshua C %A Luik, Annemarie I %A Ikram, M Arfan %A Uitterlinden, André G %A Amin, Najaf %A Xu, Hanfei %A Levy, Daniel %A He, Jiang %A Lohman, Kurt K %A Zonderman, Alan B %A Rice, Treva K %A Sims, Mario %A Wilson, Gregory %A Sofer, Tamar %A Rich, Stephen S %A Palmas, Walter %A Yao, Jie %A Guo, Xiuqing %A Rotter, Jerome I %A Biermasz, Nienke R %A Mook-Kanamori, Dennis O %A Martin, Lisa W %A Barac, Ana %A Wallace, Robert B %A Gottlieb, Daniel J %A Komulainen, Pirjo %A Heikkinen, Sami %A Mägi, Reedik %A Milani, Lili %A Metspalu, Andres %A Starr, John M %A Milaneschi, Yuri %A Waken, R J %A Gao, Chuan %A Waldenberger, Melanie %A Peters, Annette %A Strauch, Konstantin %A Meitinger, Thomas %A Roenneberg, Till %A Völker, Uwe %A Dörr, Marcus %A Shu, Xiao-Ou %A Mukherjee, Sutapa %A Hillman, David R %A Kähönen, Mika %A Wagenknecht, Lynne E %A Gieger, Christian %A Grabe, Hans J %A Zheng, Wei %A Palmer, Lyle J %A Lehtimäki, Terho %A Gudnason, Vilmundur %A Morrison, Alanna C %A Pereira, Alexandre C %A Fornage, Myriam %A Psaty, Bruce M %A van Duijn, Cornelia M %A Liu, Ching-Ti %A Kelly, Tanika N %A Evans, Michele K %A Bouchard, Claude %A Fox, Ervin R %A Kooperberg, Charles %A Zhu, Xiaofeng %A Lakka, Timo A %A Esko, Tõnu %A North, Kari E %A Deary, Ian J %A Snieder, Harold %A Penninx, Brenda W J H %A Gauderman, W James %A Rao, Dabeeru C %A Redline, Susan %A van Heemst, Diana %X

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 P < 5 × 10), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (P < 5 × 10). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (P = 2 × 10). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (P < 10). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.

%B Mol Psychiatry %8 2021 Apr 15 %G eng %R 10.1038/s41380-021-01087-0 %0 Journal Article %J Nat Commun %D 2021 %T {A multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids %A Jhun, M. A. %A Mendelson, M. %A Wilson, R. %A Gondalia, R. %A Joehanes, R. %A Salfati, E. %A Zhao, X. %A Braun, K. V. E. %A Do, A. N. %A Hedman, Å. K. %A Zhang, T. %A Carnero-Montoro, E. %A Shen, J. %A Bartz, T. M. %A Brody, J. A. %A Montasser, M. E. %A O'Connell, J. R. %A Yao, C. %A Xia, R. %A Boerwinkle, E. %A Grove, M. %A Guan, W. %A Liliane, P. %A Singmann, P. %A Müller-Nurasyid, M. %A Meitinger, T. %A Gieger, C. %A Peters, A. %A Zhao, W. %A Ware, E. B. %A Smith, J. A. %A Dhana, K. %A van Meurs, J. %A Uitterlinden, A. %A Ikram, M. A. %A Ghanbari, M. %A Zhi, D. %A Gustafsson, S. %A Lind, L. %A Li, S. %A Sun, D. %A Spector, T. D. %A Chen, Y. I. %A Damcott, C. %A Shuldiner, A. R. %A Absher, D. M. %A Horvath, S. %A Tsao, P. S. %A Kardia, S. %A Psaty, B. M. %A Sotoodehnia, N. %A Bell, J. T. %A Ingelsson, E. %A Chen, W. %A Dehghan, A. %A Arnett, D. K. %A Waldenberger, M. %A Hou, L. %A Whitsel, E. A. %A Baccarelli, A. %A Levy, D. %A Fornage, M. %A Irvin, M. R. %A Assimes, T. L. %X 10.1038/s41467-021-23899-yHere we examine the association between DNA methylation in circulating leukocytes and blood lipids in a multi-ethnic sample of 16,265 subjects. We identify 148, 35, and 4 novel associations among Europeans, African Americans, and Hispanics, respectively, and an additional 186 novel associations through a trans-ethnic meta-analysis. We observe a high concordance in the direction of effects across racial/ethnic groups, a high correlation of effect sizes between high-density lipoprotein and triglycerides, a modest overlap of associations with epigenome-wide association studies of other cardio-metabolic traits, and a largely non-overlap with lipid loci identified to date through genome-wide association studies. Thirty CpGs reached significance in at least 2 racial/ethnic groups including 7 that showed association with the expression of an annotated gene. CpGs annotated to CPT1A showed evidence of being influenced by triglycerides levels. DNA methylation levels of circulating leukocytes show robust and consistent association with blood lipid levels across multiple racial/ethnic groups. %B Nat Commun %V 12 %P 3987 %8 06 %G eng %0 Journal Article %J Circ Genom Precis Med %D 2021 %T Multiethnic Genome-Wide Association Study of Subclinical Atherosclerosis in Individuals With Type 2 Diabetes. %A Lu, Yingchang %A Dimitrov, Latchezar %A Chen, Shyh-Huei %A Bielak, Lawrence F %A Bis, Joshua C %A Feitosa, Mary F %A Lu, Lingyi %A Kavousi, Maryam %A Raffield, Laura M %A Smith, Albert V %A Wang, Lihua %A Weiss, Stefan %A Yao, Jie %A Zhu, Jiaxi %A Gudmundsson, Elias F %A Gudmundsdottir, Valborg %A Bos, Daniel %A Ghanbari, Mohsen %A Ikram, M Arfan %A Hwang, Shih-Jen %A Taylor, Kent D %A Budoff, Matthew J %A Gislason, Gauti K %A O'Donnell, Christopher J %A An, Ping %A Franceschini, Nora %A Freedman, Barry I %A Fu, Yi-Ping %A Guo, Xiuqing %A Heiss, Gerardo %A Kardia, Sharon L R %A Wilson, James G %A Langefeld, Carl D %A Schminke, Ulf %A Uitterlinden, André G %A Lange, Leslie A %A Peyser, Patricia A %A Gudnason, Vilmundur G %A Psaty, Bruce M %A Rotter, Jerome I %A Bowden, Donald W %A Ng, Maggie C Y %X

BACKGROUND: Coronary artery calcification (CAC) and carotid artery intima-media thickness (cIMT) are measures of subclinical atherosclerosis in asymptomatic individuals and strong risk factors for cardiovascular disease. Type 2 diabetes (T2D) is an independent cardiovascular disease risk factor that accelerates atherosclerosis.

METHODS: We performed meta-analyses of genome-wide association studies in up to 2500 T2D individuals of European ancestry (EA) and 1590 T2D individuals of African ancestry with or without exclusion of prevalent cardiovascular disease, for CAC measured by cardiac computed tomography, and 3608 individuals of EA and 838 individuals of African ancestry with T2D for cIMT measured by ultrasonography within the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium.

RESULTS: We replicated 2 loci (rs9369640 and rs9349379 near and rs10757278 near ) for CAC and one locus for cIMT (rs7412 and rs445925 near ) that were previously reported in the general EA populations. We identified one novel CAC locus (rs8000449 near at 13q13.3) at =2.0×10 in EA. No additional loci were identified with the meta-analyses of EA and African ancestry. The expression quantitative trait loci analysis with nearby expressed genes derived from arterial wall and metabolic tissues from the Genotype-Tissue Expression project pinpoints , encoding a matricellular protein involved in bone formation and bone matrix organization, as the potential candidate gene at this locus. In addition, we found significant associations (<3.1×10) for 3 previously reported coronary artery disease loci for these subclinical atherosclerotic phenotypes (rs2891168 near and rs11170820 near for CAC, and rs7412 near for cIMT).

CONCLUSIONS: Our results provide potential biological mechanisms that could link CAC and cIMT to increased cardiovascular disease risk in individuals with T2D.

%B Circ Genom Precis Med %V 14 %P e003258 %8 2021 Aug %G eng %N 4 %R 10.1161/CIRCGEN.120.003258 %0 Journal Article %J Blood Cancer Discov %D 2021 %T is mutated in clonal hematopoiesis and myelodysplastic syndromes and impacts RNA splicing. %A Beauchamp, Ellen M %A Leventhal, Matthew %A Bernard, Elsa %A Hoppe, Emma R %A Todisco, Gabriele %A Creignou, Maria %A Gallì, Anna %A Castellano, Cecilia A %A McConkey, Marie %A Tarun, Akansha %A Wong, Waihay %A Schenone, Monica %A Stanclift, Caroline %A Tanenbaum, Benjamin %A Malolepsza, Edyta %A Nilsson, Björn %A Bick, Alexander G %A Weinstock, Joshua S %A Miller, Mendy %A Niroula, Abhishek %A Dunford, Andrew %A Taylor-Weiner, Amaro %A Wood, Timothy %A Barbera, Alex %A Anand, Shankara %A Psaty, Bruce M %A Desai, Pinkal %A Cho, Michael H %A Johnson, Andrew D %A Loos, Ruth %A MacArthur, Daniel G %A Lek, Monkol %A Neuberg, Donna S %A Lage, Kasper %A Carr, Steven A %A Hellstrom-Lindberg, Eva %A Malcovati, Luca %A Papaemmanuil, Elli %A Stewart, Chip %A Getz, Gad %A Bradley, Robert K %A Jaiswal, Siddhartha %A Ebert, Benjamin L %X

Clonal hematopoiesis results from somatic mutations in cancer driver genes in hematopoietic stem cells. We sought to identify novel drivers of clonal expansion using an unbiased analysis of sequencing data from 84,683 persons and identified common mutations in the 5-methylcytosine reader, , as well as in , , and . We also identified these mutations at low frequency in myelodysplastic syndrome patients. edited mouse hematopoietic stem and progenitor cells exhibited a competitive advantage and increased genome-wide intron retention. mutations potentially link DNA methylation and RNA splicing, the two most commonly mutated pathways in clonal hematopoiesis and MDS.

%B Blood Cancer Discov %V 2 %P 500-517 %8 2021 Sep %G eng %N 5 %R 10.1158/2643-3230.BCD-20-0224 %0 Journal Article %J Diabetes Care %D 2021 %T n-3 Fatty Acid Biomarkers and Incident Type 2 Diabetes: An Individual Participant-Level Pooling Project of 20 Prospective Cohort Studies %A Qian, F. %A Ardisson Korat, A. V. %A Imamura, F. %A Marklund, M. %A Tintle, N. %A Virtanen, J. K. %A Zhou, X. %A Bassett, J. K. %A Lai, H. %A Hirakawa, Y. %A Chien, K. L. %A Wood, A. C. %A Lankinen, M. %A Murphy, R. A. %A Samieri, C. %A Pertiwi, K. %A de Mello, V. D. %A Guan, W. %A Forouhi, N. G. %A Wareham, N. %A Hu, I. C. F. B. %A Riserus, U. %A Lind, L. %A Harris, W. S. %A Shadyab, A. H. %A Robinson, J. G. %A Steffen, L. M. %A Hodge, A. %A Giles, G. G. %A Ninomiya, T. %A Uusitupa, M. %A Tuomilehto, J. %A m, J. %A Laakso, M. %A Siscovick, D. S. %A Helmer, C. %A Geleijnse, J. M. %A Wu, J. H. Y. %A Fretts, A. %A Lemaitre, R. N. %A Micha, R. %A Mozaffarian, D. %A Sun, Q. %X -linolenic acid (ALA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) with T2D risk through an individual participant-level pooled analysis.\ For our analysis we incorporated data from a global consortium of 20 prospective studies from 14 countries. We included 65,147 participants who had blood measurements of ALA, EPA, DPA, or DHA and were free of diabetes at baseline. De novo harmonized analyses were performed in each cohort following a prespecified protocol, and cohort-specific associations were pooled using inverse variance-weighted meta-analysis.\ 0.001). ALA was not associated with T2D (HR 0.97 [95% CI 0.92, 1.02]) per interquintile range. Associations were robust across prespecified subgroups as well as in sensitivity analyses.\ Higher circulating biomarkers of seafood-derived n-3 fatty acids, including EPA, DPA, DHA, and their sum, were associated with lower risk of T2D in a global consortium of prospective studies. The biomarker of plant-derived ALA was not significantly associated with T2D risk. %B Diabetes Care %V 44 %P 1133–1142 %8 May %G eng %0 Journal Article %J Alzheimers Dement %D 2021 %T Ophthalmic conditions associated with dementia risk: The Cardiovascular Health Study. %A Hwang, Phillip H %A Longstreth, Will T %A Thielke, Stephen M %A Francis, Courtney E %A Carone, Marco %A Kuller, Lewis H %A Fitzpatrick, Annette L %X

INTRODUCTION: Ophthalmic conditions and dementia appear to overlap and may share common pathways, but research has not differentiated dementia subtypes.

METHODS: Diagnoses of cataracts, age-related macular degeneration (AMD), diabetic retinopathy (DR), and glaucoma were based on medical histories and International Classification of Diseases, Ninth Revision (ICD-9) codes for 3375 participants from the Cardiovascular Health Study. Dementia, including Alzheimer's disease (AD) and vascular dementia (VaD), was classified using standardized research criteria.

RESULTS: Cataracts were associated with AD (hazard ratio [HR] = 1.34; 95% confidence interval [CI] = 1.01-1.80) and VaD/mixed dementia (HR = 1.41; 95% CI = 1.02-1.95). AMD was associated with AD only (HR = 1.87; 95% CI = 1.13-3.09), whereas DR was associated with VaD/mixed dementia only (HR = 2.63; 95% CI = 1.10-6.27).

DISCUSSION: Differential associations between specific ophthalmic conditions and dementia subtypes may elucidate pathophysiologic pathways. Lack of association between glaucoma and dementia was most surprising from these analyses.

%B Alzheimers Dement %8 2021 Mar 31 %G eng %R 10.1002/alz.12313 %0 Journal Article %J JAMA Cardiol %D 2021 %T Performance of the American Heart Association/American College of Cardiology Pooled Cohort Equations to Estimate Atherosclerotic Cardiovascular Disease Risk by Self-reported Physical Activity Levels. %A Pandey, Ambarish %A Mehta, Anurag %A Paluch, Amanda %A Ning, Hongyan %A Carnethon, Mercedes R %A Allen, Norrina B %A Michos, Erin D %A Berry, Jarett D %A Lloyd-Jones, Donald M %A Wilkins, John T %X

Importance: The American Heart Association/American College of Cardiology pooled cohort equations (PCEs) are used for predicting 10-year atherosclerotic cardiovascular disease (ASCVD) risk. Pooled cohort equation risk prediction capabilities across self-reported leisure-time physical activity (LTPA) levels and the change in model performance with addition of LTPA to the PCE are unclear.

Objective: To evaluate PCE risk prediction performance across self-reported LTPA levels and the change in model performance by adding LTPA to the existing PCE model.

Design, Setting, and Participants: Individual-level pooling of data from 3 longitudinal cohort studies-Atherosclerosis Risk in Communities, Multi-Ethnic Study of Atherosclerosis, and Cardiovascular Health Study-was performed. A total of 18 824 participants were stratified into 4 groups based on self-reported LTPA levels: inactive (0 metabolic equivalent of task [MET]-min/wk), less than guideline-recommended (<500 MET-min/wk), guideline-recommended (500-1000 MET-min/week), and greater than guideline-recommended (>1000 MET-min/wk). Pooled cohort equation risk discrimination was studied using the C statistic and reclassification capabilities were studied using the Greenwood Nam-D'Agostino χ2 goodness-of-fit test. Change in risk discrimination and reclassification on adding LTPA to PCEs was evaluated using change in C statistic, integrated discrimination index, and categorical net reclassification index.

Main Outcomes and Measures: Adjudicated ASCVD events during 10-year follow-up.

Results: Among 18 824 participants studied, 10 302 were women (54.7%); mean (SD) age was 57.6 (8.2) years. A total of 5868 participants (31.2%) were inactive, 3849 (20.4%) had less than guideline-recommended LTPA, 3372 (17.9%) had guideline-recommended LTPA, and 5735 (30.5%) had greater than guideline-recommended LTPA level. Higher LTPA levels were associated with a lower risk of ASCVD after adjustment for risk factors (hazard ratio [HR] per 1-SD higher LTPA, 0.91; 95% CI, 0.86-0.96). Across LTPA groups, PCE risk discrimination (C statistic, 0.76-0.78) and risk calibration (all χ2 P > .10) was similar. Addition of LTPA to the PCE model resulted in no significant change in the C statistic (0.0005; 95% CI, -0.0004 to 0.0015; P = .28) and categorical net reclassification index (-0.003; 95% CI, -0.010 to 0.010; P = .95), but a minimal improvement in the integrated discrimination index (0.0008; 95% CI, 0.0002-0.0013; P = .005) was observed. Similar results were noted when cohort-specific coefficients were used for creating the baseline model.

Conclusions and Relevance: Higher self-reported LTPA levels appear to be associated with lower ASCVD risk and increasing LTPA promotes cardiovascular wellness. These findings suggest the American Heart Association/American College of Cardiology PCEs are accurate at estimating the probability of 10-year ASCVD risk regardless of LTPA level. The addition of self-reported LTPA to PCEs does not appear to be associated with improvement in risk prediction model performance.

%B JAMA Cardiol %V 6 %P 690-696 %8 2021 Jun 01 %G eng %N 6 %R 10.1001/jamacardio.2021.0948 %0 Journal Article %J Front Pharmacol %D 2021 %T The Pharmacogenetics of Statin Therapy on Clinical Events: No Evidence that Genetic Variation Affects Statin Response on Myocardial Infarction. %A Trompet, Stella %A Postmus, Iris %A Warren, Helen R %A Noordam, Raymond %A Smit, Roelof A J %A Theusch, Elizabeth %A Li, Xiaohui %A Arsenault, Benoit %A Chasman, Daniel I %A Hitman, Graham A %A Munroe, Patricia B %A Rotter, Jerome I %A Psaty, Bruce M %A Caulfield, Mark J %A Krauss, Ron M %A Cupples, Adrienne L %A Jukema, Wouter J %X

The pharmacogenetic effect on cardiovascular disease reduction in response to statin treatment has only been assessed in small studies. In a pharmacogenetic genome wide association study (GWAS) analysis within the Genomic Investigation of Statin Therapy (GIST) consortium, we investigated whether genetic variation was associated with the response of statins on cardiovascular disease risk reduction. The investigated endpoint was incident myocardial infarction (MI) defined as coronary heart disease death and definite and suspect non-fatal MI. For imputed single nucleotide polymorphisms (SNPs), regression analysis was performed on expected allelic dosage and meta-analysed with a fixed-effects model, inverse variance weighted meta-analysis. All SNPs with -values <5.0 × 10 in stage 1 GWAS meta-analysis were selected for further investigation in stage-2. As a secondary analysis, we extracted SNPs from the Stage-1 GWAS meta-analysis results based on predefined hypotheses to possibly modifying the effect of statin therapy on MI. In stage-1 meta-analysis (eight studies, = 10,769, 4,212 cases), we observed no genome-wide significant results ( < 5.0 × 10). A total of 144 genetic variants were followed-up in the second stage (three studies, = 1,525, 180 cases). In the combined meta-analysis, no genome-wide significant hits were identified. Moreover, none of the look-ups of SNPs known to be associated with either CHD or with statin response to cholesterol levels reached Bonferroni level of significance within our stage-1 meta-analysis. This GWAS analysis did not provide evidence that genetic variation affects statin response on cardiovascular risk reduction. It does not appear likely that genetic testing for predicting effects of statins on clinical events will become a useful tool in clinical practice.

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J. %A Correa, A. %A Boerwinkle, E. %A Arking, D. E. %A Rotter, J. I. %A Rich, S. S. %A Whitsel, E. A. %A Perez, M. %A Kooperberg, C. %A Fornwalt, B. K. %A Lunetta, K. L. %A Ellinor, P. T. %A Lubitz, S. A. %X Alterations in electrocardiographic (ECG) intervals are well-known markers for arrhythmia and sudden cardiac death (SCD) risk. While the genetics of arrhythmia syndromes have been studied, relations between electrocardiographic intervals and rare genetic variation at a population level are poorly understood.\ Using a discovery sample of 29 000 individuals with whole-genome sequencing from Trans-Omics in Precision Medicine and replication in nearly 100 000 with whole-exome sequencing from the UK Biobank and MyCode, we examined associations between low-frequency and rare coding variants with 5 routinely measured electrocardiographic traits (RR, P-wave, PR, and QRS intervals and corrected QT interval).\ ), a marker of SCD risk. Incomplete penetrance of such deleterious variation was common as over 70% of carriers had normal electrocardiographic intervals.\ Our findings indicate that large-scale high-depth sequence data and electrocardiographic analysis identifies monogenic arrhythmia susceptibility genes and rare variants with large effects. Known pathogenic variation in conventional arrhythmia and SCD genes exhibited incomplete penetrance and accounted for only a small fraction of marked electrocardiographic interval prolongation. %B Circ Genom Precis Med %V 14 %P e003300 %8 Aug %G eng %0 Journal Article %J Nature %D 2021 %T Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program. %A Taliun, Daniel %A Harris, Daniel N %A Kessler, Michael D %A Carlson, Jedidiah %A Szpiech, Zachary A %A Torres, Raul %A Taliun, Sarah A Gagliano %A Corvelo, André %A Gogarten, Stephanie M %A Kang, Hyun Min %A Pitsillides, Achilleas N %A LeFaive, Jonathon %A Lee, Seung-Been %A Tian, Xiaowen %A Browning, Brian L %A Das, Sayantan %A Emde, Anne-Katrin %A Clarke, Wayne E %A Loesch, Douglas P %A Shetty, Amol C %A Blackwell, Thomas W %A Smith, Albert V %A Wong, Quenna %A Liu, Xiaoming %A Conomos, Matthew P %A Bobo, Dean M %A Aguet, Francois %A Albert, Christine %A Alonso, Alvaro %A Ardlie, Kristin G %A Arking, Dan E %A Aslibekyan, Stella %A Auer, Paul L %A Barnard, John %A Barr, R Graham %A Barwick, Lucas %A Becker, Lewis C %A Beer, Rebecca L %A Benjamin, Emelia J %A Bielak, Lawrence F %A Blangero, John %A Boehnke, Michael %A Bowden, Donald W %A Brody, Jennifer A %A Burchard, Esteban G %A Cade, Brian E %A Casella, James F %A Chalazan, Brandon %A Chasman, Daniel I %A Chen, Yii-Der Ida %A Cho, Michael H %A Choi, Seung Hoan %A Chung, Mina K %A Clish, Clary B %A Correa, Adolfo %A Curran, Joanne E %A Custer, Brian %A Darbar, Dawood %A Daya, Michelle %A de Andrade, Mariza %A DeMeo, Dawn L %A Dutcher, Susan K %A Ellinor, Patrick T %A Emery, Leslie S %A Eng, Celeste %A Fatkin, Diane %A Fingerlin, Tasha %A Forer, Lukas %A Fornage, Myriam %A Franceschini, Nora %A Fuchsberger, Christian %A Fullerton, Stephanie M %A Germer, Soren %A Gladwin, Mark T %A Gottlieb, Daniel J %A Guo, Xiuqing %A Hall, Michael E %A He, Jiang %A Heard-Costa, Nancy L %A Heckbert, Susan R %A Irvin, Marguerite R %A Johnsen, Jill M %A Johnson, Andrew D %A Kaplan, Robert %A Kardia, Sharon L R %A Kelly, Tanika %A Kelly, Shannon %A Kenny, Eimear E %A Kiel, Douglas P %A Klemmer, Robert %A Konkle, Barbara A %A Kooperberg, Charles %A Köttgen, Anna %A Lange, Leslie A %A Lasky-Su, Jessica %A Levy, Daniel %A Lin, Xihong %A Lin, Keng-Han %A Liu, Chunyu %A Loos, Ruth J F %A Garman, Lori %A Gerszten, Robert %A Lubitz, Steven A %A Lunetta, Kathryn L %A Mak, Angel C Y %A Manichaikul, Ani %A Manning, Alisa K %A Mathias, Rasika A %A McManus, David D %A McGarvey, Stephen T %A Meigs, James B %A Meyers, Deborah A %A Mikulla, Julie L %A Minear, Mollie A %A Mitchell, Braxton D %A Mohanty, Sanghamitra %A Montasser, May E %A Montgomery, Courtney %A Morrison, Alanna C %A Murabito, Joanne M %A Natale, Andrea %A Natarajan, Pradeep %A Nelson, Sarah C %A North, Kari E %A O'Connell, Jeffrey R %A Palmer, Nicholette D %A Pankratz, Nathan %A Peloso, Gina M %A Peyser, Patricia A %A Pleiness, Jacob %A Post, Wendy S %A Psaty, Bruce M %A Rao, D C %A Redline, Susan %A Reiner, Alexander P %A Roden, Dan %A Rotter, Jerome I %A Ruczinski, Ingo %A Sarnowski, Chloe %A Schoenherr, Sebastian %A Schwartz, David A %A Seo, Jeong-Sun %A Seshadri, Sudha %A Sheehan, Vivien A %A Sheu, Wayne H %A Shoemaker, M Benjamin %A Smith, Nicholas L %A Smith, Jennifer A %A Sotoodehnia, Nona %A Stilp, Adrienne M %A Tang, Weihong %A Taylor, Kent D %A Telen, Marilyn %A Thornton, Timothy A %A Tracy, Russell P %A Van Den Berg, David J %A Vasan, Ramachandran S %A Viaud-Martinez, Karine A %A Vrieze, Scott %A Weeks, Daniel E %A Weir, Bruce S %A Weiss, Scott T %A Weng, Lu-Chen %A Willer, Cristen J %A Zhang, Yingze %A Zhao, Xutong %A Arnett, Donna K %A Ashley-Koch, Allison E %A Barnes, Kathleen C %A Boerwinkle, Eric %A Gabriel, Stacey %A Gibbs, Richard %A Rice, Kenneth M %A Rich, Stephen S %A Silverman, Edwin K %A Qasba, Pankaj %A Gan, Weiniu %A Papanicolaou, George J %A Nickerson, Deborah A %A Browning, Sharon R %A Zody, Michael C %A Zöllner, Sebastian %A Wilson, James G %A Cupples, L Adrienne %A Laurie, Cathy C %A Jaquish, Cashell E %A Hernandez, Ryan D %A O'Connor, Timothy D %A Abecasis, Goncalo R %X

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes). In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.

%B Nature %V 590 %P 290-299 %8 2021 02 %G eng %N 7845 %R 10.1038/s41586-021-03205-y %0 Journal Article %J Osteoporos Int %D 2021 %T Serum non-esterified fatty acid levels and hip fracture risk: The Cardiovascular Health Study. %A Barzilay, J I %A Bůžková, P %A Djoussé, L %A Ix, J %A Kizer, J %A Cauley, J %A Matthan, N %A Lichtenstein, A H %A Mukamal, K J %X

Among elderly participants from the Cardiovascular Health Study, we found that non-esterified trans fatty acid levels had a significant prospective association with hip fracture risk. Other non-esterified fatty acid classes were not associated with hip fracture risk.

INTRODUCTION: Serum non-esterified fatty acids (NEFAs) are bioactive metabolic intermediates that can be taken up by bone tissue. Their associations with hip fracture risk have not been previously examined.

METHODS: Thirty-five individual NEFAs in five classes (saturated [SFA], mono-un-saturated [MUFA], poly-unsaturated n-6 and n-3 [PUFA], and trans-FA) were measured in Cardiovascular Health Study participants (n = 2139, mean age 77.8 years) without known diabetes. The multivariable associations of NEFA levels with hip fracture risk were evaluated in Cox hazards models.

RESULTS: We documented 303 incident hip fractures during 11.1 years of follow-up. Among the five NEFA classes, total trans FA levels were positively associated with higher hip fracture risk (HR 1.17 [95% CI, 1.04, 1.31; p = 0.01] per one standard deviation higher level). The SFA lignoceric acid (24:0) was positively associated with higher risk (HR 1.09 [1.04, 1.1]; p < 0.001), while behenic (22:0) and docosatetraenoic (22:4 n6) acids were associated with lower risk (HR 0.76 [0.61, 0.94]; p = 0.01; 0.84 [0.70, 1.00]; p = 0.05, respectively).

CONCLUSION: Total plasma trans NEFA levels are related to hip fracture risk, suggesting an unrecognized benefit of their systematic removal from food. Novel associations of individual NEFAs with hip fracture risk require confirmation in other cohort studies.

%B Osteoporos Int %8 2021 Mar 02 %G eng %R 10.1007/s00198-021-05897-4 %0 Journal Article %J Nat Commun %D 2021 %T {Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability %A Lagou, V. %A M?gi, R. %A Hottenga, J. J. %A Grallert, H. %A Perry, J. R. B. %A Bouatia-Naji, N. %A Marullo, L. %A Rybin, D. %A Jansen, R. %A Min, J. L. %A Dimas, A. S. %A Ulrich, A. %A Zudina, L. %A G?din, J. R. %A Jiang, L. %A Faggian, A. %A Bonnefond, A. %A Fadista, J. %A Stathopoulou, M. G. %A Isaacs, A. %A Willems, S. M. %A Navarro, P. %A Tanaka, T. %A Jackson, A. U. %A Montasser, M. E. %A O'Connell, J. R. %A Bielak, L. F. %A Webster, R. J. %A Saxena, R. %A Stafford, J. M. %A Pourcain, B. S. %A Timpson, N. J. %A Salo, P. %A Shin, S. Y. %A Amin, N. %A Smith, A. V. %A Li, G. %A Verweij, N. %A Goel, A. %A Ford, I. %A Johnson, P. C. D. %A Johnson, T. %A Kapur, K. %A Thorleifsson, G. %A Strawbridge, R. J. %A Rasmussen-Torvik, L. J. %A Esko, T. %A Mihailov, E. %A Fall, T. %A Fraser, R. M. %A Mahajan, A. %A Kanoni, S. %A Giedraitis, V. %A Kleber, M. E. %A Silbernagel, G. %A Meyer, J. %A M?ller-Nurasyid, M. %A Ganna, A. %A Sarin, A. P. %A Yengo, L. %A Shungin, D. %A Luan, J. %A Horikoshi, M. %A An, P. %A Sanna, S. %A Boettcher, Y. %A Rayner, N. W. %A Nolte, I. M. %A Zemunik, T. %A Iperen, E. V. %A Kovacs, P. %A Hastie, N. D. %A Wild, S. H. %A McLachlan, S. %A Campbell, S. %A Polasek, O. %A Carlson, O. %A Egan, J. %A Kiess, W. %A Willemsen, G. %A Kuusisto, J. %A Laakso, M. %A Dimitriou, M. %A Hicks, A. A. %A Rauramaa, R. %A Bandinelli, S. %A Thorand, B. %A Liu, Y. %A Miljkovic, I. %A Lind, L. %A Doney, A. %A Perola, M. %A Hingorani, A. %A Kivimaki, M. %A Kumari, M. %A Bennett, A. J. %A Groves, C. J. %A Herder, C. %A Koistinen, H. A. %A Kinnunen, L. %A Faire, U. %A Bakker, S. J. L. %A Uusitupa, M. %A Palmer, C. N. A. %A Jukema, J. W. %A Sattar, N. %A Pouta, A. %A Snieder, H. %A Boerwinkle, E. %A Pankow, J. S. %A Magnusson, P. K. %A Krus, U. %A Scapoli, C. %A de Geus, E. J. C. N. %A Bl?her, M. %A Wolffenbuttel, B. H. R. %A Province, M. A. %A Abecasis, G. R. %A Meigs, J. B. %A Hovingh, G. K. %A Lindstr?m, J. %A Wilson, J. F. %A Wright, A. F. %A Dedoussis, G. V. %A Bornstein, S. R. %A Schwarz, P. E. H. %A T?njes, A. %A Winkelmann, B. R. %A Boehm, B. O. %A M?rz, W. %A Metspalu, A. %A Price, J. F. %A Deloukas, P. %A K?rner, A. %A Lakka, T. A. %A Keinanen-Kiukaanniemi, S. M. %A Saaristo, T. E. %A Bergman, R. N. %A Tuomilehto, J. %A Wareham, N. J. %A Langenberg, C. %A M?nnist?, S. %A Franks, P. W. %A Hayward, C. %A Vitart, V. %A Kaprio, J. %A Visvikis-Siest, S. %A Balkau, B. %A Altshuler, D. %A Rudan, I. %A Stumvoll, M. %A Campbell, H. %A van Duijn, C. M. %A Gieger, C. %A Illig, T. %A Ferrucci, L. %A Pedersen, N. L. %A Pramstaller, P. P. %A Boehnke, M. %A Frayling, T. M. %A Shuldiner, A. R. %A Peyser, P. A. %A Kardia, S. L. R. %A Palmer, L. J. %A Penninx, B. W. %A Meneton, P. %A Harris, T. B. %A Navis, G. %A Harst, P. V. %A Smith, G. D. %A Forouhi, N. G. %A Loos, R. J. F. %A Salomaa, V. %A Soranzo, N. %A Boomsma, D. I. %A Groop, L. %A Tuomi, T. %A Hofman, A. %A Munroe, P. B. %A Gudnason, V. %A Siscovick, D. S. %A Watkins, H. %A Lecoeur, C. %A Vollenweider, P. %A Franco-Cereceda, A. %A Eriksson, P. %A Jarvelin, M. R. %A Stefansson, K. %A Hamsten, A. %A Nicholson, G. %A Karpe, F. %A Dermitzakis, E. T. %A Lindgren, C. M. %A McCarthy, M. I. %A Froguel, P. %A Kaakinen, M. A. %A Lyssenko, V. %A Watanabe, R. M. %A Ingelsson, E. %A Florez, J. C. %A Dupuis, J. %A Barroso, I. %A Morris, A. P. %A Prokopenko, I. %X Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes. %B Nat Commun %V 12 %P 24 %8 01 %G eng %0 Journal Article %J Nat Commun %D 2021 %T {Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability %A Lagou, V. %A Mägi, R. %A Hottenga, J. J. %A Grallert, H. %A Perry, J. R. B. %A Bouatia-Naji, N. %A Marullo, L. %A Rybin, D. %A Jansen, R. %A Min, J. L. %A Dimas, A. S. %A Ulrich, A. %A Zudina, L. %A Gådin, J. R. %A Jiang, L. %A Faggian, A. %A Bonnefond, A. %A Fadista, J. %A Stathopoulou, M. G. %A Isaacs, A. %A Willems, S. M. %A Navarro, P. %A Tanaka, T. %A Jackson, A. U. %A Montasser, M. E. %A O'Connell, J. R. %A Bielak, L. F. %A Webster, R. J. %A Saxena, R. %A Stafford, J. M. %A Pourcain, B. S. %A Timpson, N. J. %A Salo, P. %A Shin, S. Y. %A Amin, N. %A Smith, A. V. %A Li, G. %A Verweij, N. %A Goel, A. %A Ford, I. %A Johnson, P. C. D. %A Johnson, T. %A Kapur, K. %A Thorleifsson, G. %A Strawbridge, R. J. %A Rasmussen-Torvik, L. J. %A Esko, T. %A Mihailov, E. %A Fall, T. %A Fraser, R. M. %A Mahajan, A. %A Kanoni, S. %A Giedraitis, V. %A Kleber, M. E. %A Silbernagel, G. %A Meyer, J. %A Müller-Nurasyid, M. %A Ganna, A. %A Sarin, A. P. %A Yengo, L. %A Shungin, D. %A Luan, J. %A Horikoshi, M. %A An, P. %A Sanna, S. %A Boettcher, Y. %A Rayner, N. W. %A Nolte, I. M. %A Zemunik, T. %A Iperen, E. V. %A Kovacs, P. %A Hastie, N. D. %A Wild, S. H. %A McLachlan, S. %A Campbell, S. %A Polasek, O. %A Carlson, O. %A Egan, J. %A Kiess, W. %A Willemsen, G. %A Kuusisto, J. %A Laakso, M. %A Dimitriou, M. %A Hicks, A. A. %A Rauramaa, R. %A Bandinelli, S. %A Thorand, B. %A Liu, Y. %A Miljkovic, I. %A Lind, L. %A Doney, A. %A Perola, M. %A Hingorani, A. %A Kivimaki, M. %A Kumari, M. %A Bennett, A. J. %A Groves, C. J. %A Herder, C. %A Koistinen, H. A. %A Kinnunen, L. %A Faire, U. %A Bakker, S. J. L. %A Uusitupa, M. %A Palmer, C. N. A. %A Jukema, J. W. %A Sattar, N. %A Pouta, A. %A Snieder, H. %A Boerwinkle, E. %A Pankow, J. S. %A Magnusson, P. K. %A Krus, U. %A Scapoli, C. %A de Geus, E. J. C. N. %A Blüher, M. %A Wolffenbuttel, B. H. R. %A Province, M. A. %A Abecasis, G. R. %A Meigs, J. B. %A Hovingh, G. K. %A Lindström, J. %A Wilson, J. F. %A Wright, A. F. %A Dedoussis, G. V. %A Bornstein, S. R. %A Schwarz, P. E. H. %A Tonjes, A. %A Winkelmann, B. R. %A Boehm, B. O. %A März, W. %A Metspalu, A. %A Price, J. F. %A Deloukas, P. %A Körner, A. %A Lakka, T. A. %A Keinanen-Kiukaanniemi, S. M. %A Saaristo, T. E. %A Bergman, R. N. %A Tuomilehto, J. %A Wareham, N. J. %A Langenberg, C. %A Männistö, S. %A Franks, P. W. %A Hayward, C. %A Vitart, V. %A Kaprio, J. %A Visvikis-Siest, S. %A Balkau, B. %A Altshuler, D. %A Rudan, I. %A Stumvoll, M. %A Campbell, H. %A van Duijn, C. M. %A Gieger, C. %A Illig, T. %A Ferrucci, L. %A Pedersen, N. L. %A Pramstaller, P. P. %A Boehnke, M. %A Frayling, T. M. %A Shuldiner, A. R. %A Peyser, P. A. %A Kardia, S. L. R. %A Palmer, L. J. %A Penninx, B. W. %A Meneton, P. %A Harris, T. B. %A Navis, G. %A Harst, P. V. %A Smith, G. D. %A Forouhi, N. G. %A Loos, R. J. F. %A Salomaa, V. %A Soranzo, N. %A Boomsma, D. I. %A Groop, L. %A Tuomi, T. %A Hofman, A. %A Munroe, P. B. %A Gudnason, V. %A Siscovick, D. S. %A Watkins, H. %A Lecoeur, C. %A Vollenweider, P. %A Franco-Cereceda, A. %A Eriksson, P. %A Jarvelin, M. R. %A Stefansson, K. %A Hamsten, A. %A Nicholson, G. %A Karpe, F. %A Dermitzakis, E. T. %A Lindgren, C. M. %A McCarthy, M. I. %A Froguel, P. %A Kaakinen, M. A. %A Lyssenko, V. %A Watanabe, R. M. %A Ingelsson, E. %A Florez, J. C. %A Dupuis, J. %A Barroso, I. %A Morris, A. P. %A Prokopenko, I. %X Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes. %B Nat Commun %V 12 %P 24 %8 01 %G eng %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2021 %T Statins and cognitive decline in the Cardiovascular Health Study: A comparison of different analytical approaches. %A Zeki Al Hazzouri, Adina %A Jawadekar, Neal %A Grasset, Leslie %A Kaiser, Paulina %A Kezios, Katrina %A Calonico, Sebastian %A Glymour, M Maria %A Hirsch, Calvin %A Arnold, Alice M %A Varadhan, Ravi %A Opoodden, Michelle C %X

BACKGROUND: Despite their well-established benefits for the prevention of cardiovascular disease, robust evidence on the effects of statins on cognition is largely inconclusive. We apply various study designs and analytical approaches to mimic randomized controlled trial (RCT) effects from observational data.

METHODS: We used observational data from 5,580 participants enrolled in the Cardiovascular Health Study from 1989/90 to 1999/2000. We conceptualized the cohort as an overlapping sequence of non-randomized trials. We compared multiple selection (eligible population, prevalent users, new-users) and analytic approaches (multivariable adjustment, inverse probability treatment weights, propensity score matching) to evaluate the association between statin use and 5-year change in global cognitive function, assessed using the Modified Mini-Mental State (3MS) examination.

RESULTS: When comparing prevalent users to non-users (N=2,772), statin use was associated with slower cognitive decline over 5 years (adjusted annual change in 3MSE = 0.34 points/year; 95% CI:0.05;0.63). Compared to prevalent user design, estimates from new user designs (e.g. comparing eligible statin initiators to non-initiators) were attenuated showing either null or negative association, though not significant. For example, in a propensity score-matched sample of statin-eligible individuals (N=454), annual 3MS change comparing statin initiators to non-initiators was -0.21 points/year (95% CI:-0.81;0.39).

CONCLUSIONS: The association of statin use and cognitive decline is attenuated towards the null when using rigorous analytical approaches that more closely mimic RCTs. Point estimates, even within the same study, may vary depending on the analytical methods used. Further studies that leverage natural or quasi experiments around statin use are needed to replicate our findings.

%B J Gerontol A Biol Sci Med Sci %8 2021 Jul 31 %G eng %R 10.1093/gerona/glab220 %0 Journal Article %J Circ Genom Precis Med %D 2021 %T Sugar-Sweetened Beverage Consumption May Modify Associations Between Genetic Variants in the CHREBP (Carbohydrate Responsive Element Binding Protein) Locus and HDL-C (High-Density Lipoprotein Cholesterol) and Triglyceride Concentrations. %A Haslam, Danielle E %A Peloso, Gina M %A Guirette, Melanie %A Imamura, Fumiaki %A Bartz, Traci M %A Pitsillides, Achilleas N %A Wang, Carol A %A Li-Gao, Ruifang %A Westra, Jason M %A Pitkänen, Niina %A Young, Kristin L %A Graff, Mariaelisa %A Wood, Alexis C %A Braun, Kim V E %A Luan, Jian'an %A Kähönen, Mika %A Kiefte-de Jong, Jessica C %A Ghanbari, Mohsen %A Tintle, Nathan %A Lemaitre, Rozenn N %A Mook-Kanamori, Dennis O %A North, Kari %A Helminen, Mika %A Mossavar-Rahmani, Yasmin %A Snetselaar, Linda %A Martin, Lisa W %A Viikari, Jorma S %A Oddy, Wendy H %A Pennell, Craig E %A Rosendall, Frits R %A Ikram, M Arfan %A Uitterlinden, André G %A Psaty, Bruce M %A Mozaffarian, Dariush %A Rotter, Jerome I %A Taylor, Kent D %A Lehtimäki, Terho %A Raitakari, Olli T %A Livingston, Kara A %A Voortman, Trudy %A Forouhi, Nita G %A Wareham, Nick J %A de Mutsert, Renée %A Rich, Steven S %A Manson, JoAnn E %A Mora, Samia %A Ridker, Paul M %A Merino, Jordi %A Meigs, James B %A Dashti, Hassan S %A Chasman, Daniel I %A Lichtenstein, Alice H %A Smith, Caren E %A Dupuis, Josée %A Herman, Mark A %A McKeown, Nicola M %X

BACKGROUND: ChREBP (carbohydrate responsive element binding protein) is a transcription factor that responds to sugar consumption. Sugar-sweetened beverage (SSB) consumption and genetic variants in the locus have separately been linked to HDL-C (high-density lipoprotein cholesterol) and triglyceride concentrations. We hypothesized that SSB consumption would modify the association between genetic variants in the locus and dyslipidemia.

METHODS: Data from 11 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (N=63 599) and the UK Biobank (N=59 220) were used to quantify associations of SSB consumption, genetic variants, and their interaction on HDL-C and triglyceride concentrations using linear regression models. A total of 1606 single nucleotide polymorphisms within or near were considered. SSB consumption was estimated from validated questionnaires, and participants were grouped by their estimated intake.

RESULTS: In a meta-analysis, rs71556729 was significantly associated with higher HDL-C concentrations only among the highest SSB consumers (β, 2.12 [95% CI, 1.16-3.07] mg/dL per allele; <0.0001), but not significantly among the lowest SSB consumers (=0.81; <0.0001). Similar results were observed for 2 additional variants (rs35709627 and rs71556736). For triglyceride, rs55673514 was positively associated with triglyceride concentrations only among the highest SSB consumers (β, 0.06 [95% CI, 0.02-0.09] ln-mg/dL per allele, =0.001) but not the lowest SSB consumers (=0.84; =0.0005).

CONCLUSIONS: Our results identified genetic variants in the locus that may protect against SSB-associated reductions in HDL-C and other variants that may exacerbate SSB-associated increases in triglyceride concentrations. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00005133, NCT00005121, NCT00005487, and NCT00000479.

%B Circ Genom Precis Med %V 14 %P e003288 %8 2021 Aug %G eng %N 4 %R 10.1161/CIRCGEN.120.003288 %0 Journal Article %J J Am Coll Cardiol %D 2021 %T Supplemental Association of Clonal Hematopoiesis With Incident Heart Failure. %A Yu, Bing %A Roberts, Mary B %A Raffield, Laura M %A Zekavat, Seyedeh Maryam %A Nguyen, Ngoc Quynh H %A Biggs, Mary L %A Brown, Michael R %A Griffin, Gabriel %A Desai, Pinkal %A Correa, Adolfo %A Morrison, Alanna C %A Shah, Amil M %A Niroula, Abhishek %A Uddin, Md Mesbah %A Honigberg, Michael C %A Ebert, Benjamin L %A Psaty, Bruce M %A Whitsel, Eric A %A Manson, JoAnn E %A Kooperberg, Charles %A Bick, Alexander G %A Ballantyne, Christie M %A Reiner, Alex P %A Natarajan, Pradeep %A Eaton, Charles B %K Aged %K Clonal Hematopoiesis %K Correlation of Data %K Demography %K DNA-Binding Proteins %K Female %K Heart Failure %K Humans %K Janus Kinase 2 %K Male %K Middle Aged %K Mutation %K Proportional Hazards Models %K Proto-Oncogene Proteins %K Repressor Proteins %K Risk Factors %K Stroke Volume %K Ventricular Dysfunction, Left %K Whole Exome Sequencing %X

BACKGROUND: Age-related clonal hematopoiesis of indeterminate potential (CHIP), defined as clonally expanded leukemogenic sequence variations (particularly in DNMT3A, TET2, ASXL1, and JAK2) in asymptomatic individuals, is associated with cardiovascular events, including recurrent heart failure (HF).

OBJECTIVES: This study sought to evaluate whether CHIP is associated with incident HF.

METHODS: CHIP status was obtained from whole exome or genome sequencing of blood DNA in participants without prevalent HF or hematological malignancy from 5 cohorts. Cox proportional hazards models were performed within each cohort, adjusting for demographic and clinical risk factors, followed by fixed-effect meta-analyses. Large CHIP clones (defined as variant allele frequency >10%), HF with or without baseline coronary heart disease, and left ventricular ejection fraction were evaluated in secondary analyses.

RESULTS: Of 56,597 individuals (59% women, mean age 58 years at baseline), 3,406 (6%) had CHIP, and 4,694 developed HF (8.3%) over up to 20 years of follow-up. CHIP was prospectively associated with a 25% increased risk of HF in meta-analysis (hazard ratio: 1.25; 95% confidence interval: 1.13-1.38) with consistent associations across cohorts. ASXL1, TET2, and JAK2 sequence variations were each associated with an increased risk of HF, whereas DNMT3A sequence variations were not associated with HF. Secondary analyses suggested large CHIP was associated with a greater risk of HF (hazard ratio: 1.29; 95% confidence interval: 1.15-1.44), and the associations for CHIP on HF with and without prior coronary heart disease were homogenous. ASXL1 sequence variations were associated with reduced left ventricular ejection fraction.

CONCLUSIONS: CHIP, particularly sequence variations in ASXL1, TET2, and JAK2, represents a new risk factor for HF.

%B J Am Coll Cardiol %V 78 %P 42-52 %8 2021 07 06 %G eng %N 1 %R 10.1016/j.jacc.2021.04.085 %0 Journal Article %J Am J Epidemiol %D 2021 %T A System for Phenotype Harmonization in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. %A Stilp, Adrienne M %A Emery, Leslie S %A Broome, Jai G %A Buth, Erin J %A Khan, Alyna T %A Laurie, Cecelia A %A Wang, Fei Fei %A Wong, Quenna %A Chen, Dongquan %A D'Augustine, Catherine M %A Heard-Costa, Nancy L %A Hohensee, Chancellor R %A Johnson, William Craig %A Juarez, Lucia D %A Liu, Jingmin %A Mutalik, Karen M %A Raffield, Laura M %A Wiggins, Kerri L %A de Vries, Paul S %A Kelly, Tanika N %A Kooperberg, Charles %A Natarajan, Pradeep %A Peloso, Gina M %A Peyser, Patricia A %A Reiner, Alex P %A Arnett, Donna K %A Aslibekyan, Stella %A Barnes, Kathleen C %A Bielak, Lawrence F %A Bis, Joshua C %A Cade, Brian E %A Chen, Ming-Huei %A Correa, Adolfo %A Cupples, L Adrienne %A de Andrade, Mariza %A Ellinor, Patrick T %A Fornage, Myriam %A Franceschini, Nora %A Gan, Weiniu %A Ganesh, Santhi K %A Graffelman, Jan %A Grove, Megan L %A Guo, Xiuqing %A Hawley, Nicola L %A Hsu, Wan-Ling %A Jackson, Rebecca D %A Jaquish, Cashell E %A Johnson, Andrew D %A Kardia, Sharon L R %A Kelly, Shannon %A Lee, Jiwon %A Mathias, Rasika A %A McGarvey, Stephen T %A Mitchell, Braxton D %A Montasser, May E %A Morrison, Alanna C %A North, Kari E %A Nouraie, Seyed Mehdi %A Oelsner, Elizabeth C %A Pankratz, Nathan %A Rich, Stephen S %A Rotter, Jerome I %A Smith, Jennifer A %A Taylor, Kent D %A Vasan, Ramachandran S %A Weeks, Daniel E %A Weiss, Scott T %A Wilson, Carla G %A Yanek, Lisa R %A Psaty, Bruce M %A Heckbert, Susan R %A Laurie, Cathy C %X

Genotype-phenotype association studies often combine phenotype data from multiple studies to increase power. Harmonization of the data usually requires substantial effort due to heterogeneity in phenotype definitions, study design, data collection procedures, and data set organization. Here we describe a centralized system for phenotype harmonization that includes input from phenotype domain and study experts, quality control, documentation, reproducible results, and data sharing mechanisms. This system was developed for the National Heart, Lung and Blood Institute's Trans-Omics for Precision Medicine program, which is generating genomic and other omics data for >80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants from up to 17 studies per phenotype (participants recruited 1948-2012). We discuss challenges in this undertaking and how they were addressed. The harmonized phenotype data and associated documentation have been submitted to National Institutes of Health data repositories for controlled-access by the scientific community. We also provide materials to facilitate future harmonization efforts by the community, which include (1) the code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify or extend these harmonizations to additional studies; and (2) results of labeling thousands of phenotype variables with controlled vocabulary terms.

%B Am J Epidemiol %8 2021 Apr 16 %G eng %R 10.1093/aje/kwab115 %0 Journal Article %J Nat Genet %D 2021 %T {The trans-ancestral genomic architecture of glycemic traits %A Chen, J. %A Spracklen, C. N. %A Marenne, G. %A Varshney, A. %A Corbin, L. J. %A Luan, J. %A Willems, S. M. %A Wu, Y. %A Zhang, X. %A Horikoshi, M. %A Boutin, T. S. %A Mägi, R. %A Waage, J. %A Li-Gao, R. %A Chan, K. H. K. %A Yao, J. %A Anasanti, M. D. %A Chu, A. Y. %A Claringbould, A. %A Heikkinen, J. %A Hong, J. %A Hottenga, J. J. %A Huo, S. %A Kaakinen, M. A. %A Louie, T. %A März, W. %A Moreno-Macias, H. %A Ndungu, A. %A Nelson, S. C. %A Nolte, I. M. %A North, K. E. %A Raulerson, C. K. %A Ray, D. %A Rohde, R. %A Rybin, D. %A Schurmann, C. %A Sim, X. %A Southam, L. %A Stewart, I. D. %A Wang, C. A. %A Wang, Y. %A Wu, P. %A Zhang, W. %A Ahluwalia, T. S. %A Appel, E. V. R. %A Bielak, L. F. %A Brody, J. A. %A Burtt, N. P. %A Cabrera, C. P. %A Cade, B. E. %A Chai, J. F. %A Chai, X. %A Chang, L. C. %A Chen, C. H. %A Chen, B. H. %A Chitrala, K. N. %A Chiu, Y. F. %A de Haan, H. G. %A Delgado, G. E. %A Demirkan, A. %A Duan, Q. %A Engmann, J. %A Fatumo, S. A. %A Gayán, J. %A Giulianini, F. %A Gong, J. H. %A Gustafsson, S. %A Hai, Y. %A Hartwig, F. P. %A He, J. %A Heianza, Y. %A Huang, T. %A Huerta-Chagoya, A. %A Hwang, M. Y. %A Jensen, R. A. %A Kawaguchi, T. %A Kentistou, K. A. %A Kim, Y. J. %A Kleber, M. E. %A Kooner, I. K. %A Lai, S. %A Lange, L. A. %A Langefeld, C. D. %A Lauzon, M. %A Li, M. %A Ligthart, S. %A Liu, J. %A Loh, M. %A Long, J. %A Lyssenko, V. %A Mangino, M. %A Marzi, C. %A Montasser, M. E. %A Nag, A. %A Nakatochi, M. %A Noce, D. %A Noordam, R. %A Pistis, G. %A Preuss, M. %A Raffield, L. %A Rasmussen-Torvik, L. J. %A Rich, S. S. %A Robertson, N. R. %A Rueedi, R. %A Ryan, K. %A Sanna, S. %A Saxena, R. %A Schraut, K. E. %A Sennblad, B. %A Setoh, K. %A Smith, A. V. %A Sparsø, T. %A Strawbridge, R. J. %A Takeuchi, F. %A Tan, J. %A Trompet, S. %A van den Akker, E. %A van der Most, P. J. %A Verweij, N. %A Vogel, M. %A Wang, H. %A Wang, C. %A Wang, N. %A Warren, H. R. %A Wen, W. %A Wilsgaard, T. %A Wong, A. %A Wood, A. R. %A Xie, T. %A Zafarmand, M. H. %A Zhao, J. H. %A Zhao, W. %A Amin, N. %A Arzumanyan, Z. %A Astrup, A. %A Bakker, S. J. L. %A Baldassarre, D. %A Beekman, M. %A Bergman, R. N. %A Bertoni, A. %A Blüher, M. %A Bonnycastle, L. L. %A Bornstein, S. R. %A Bowden, D. W. %A Cai, Q. %A Campbell, A. %A Campbell, H. %A Chang, Y. C. %A de Geus, E. J. C. %A Dehghan, A. %A Du, S. %A Eiriksdottir, G. %A Farmaki, A. E. %A Frånberg, M. %A Fuchsberger, C. %A Gao, Y. %A Gjesing, A. P. %A Goel, A. %A Han, S. %A Hartman, C. A. %A Herder, C. %A Hicks, A. A. %A Hsieh, C. H. %A Hsueh, W. A. %A Ichihara, S. %A Igase, M. %A Ikram, M. A. %A Johnson, W. C. %A Jørgensen, M. E. %A Joshi, P. K. %A Kalyani, R. R. %A Kandeel, F. R. %A Katsuya, T. %A Khor, C. C. %A Kiess, W. %A Kolcic, I. %A Kuulasmaa, T. %A Kuusisto, J. %A Läll, K. %A Lam, K. %A Lawlor, D. A. %A Lee, N. R. %A Lemaitre, R. N. %A Li, H. %A Lin, S. Y. %A Lindström, J. %A Linneberg, A. %A Liu, J. %A Lorenzo, C. %A Matsubara, T. %A Matsuda, F. %A Mingrone, G. %A Mooijaart, S. %A Moon, S. %A Nabika, T. %A Nadkarni, G. N. %A Nadler, J. L. %A Nelis, M. %A Neville, M. J. %A Norris, J. M. %A Ohyagi, Y. %A Peters, A. %A Peyser, P. A. %A Polasek, O. %A Qi, Q. %A Raven, D. %A Reilly, D. F. %A Reiner, A. %A Rivideneira, F. %A Roll, K. %A Rudan, I. %A Sabanayagam, C. %A Sandow, K. %A Sattar, N. %A Schürmann, A. %A Shi, J. %A Stringham, H. M. %A Taylor, K. D. %A Teslovich, T. M. %A Thuesen, B. %A Timmers, P. R. H. J. %A Tremoli, E. %A Tsai, M. Y. %A Uitterlinden, A. %A van Dam, R. M. %A van Heemst, D. %A van Hylckama Vlieg, A. %A Van Vliet-Ostaptchouk, J. V. %A Vangipurapu, J. %A Vestergaard, H. %A Wang, T. %A Willems van Dijk, K. %A Zemunik, T. %A Abecasis, G. R. %A Adair, L. S. %A Aguilar-Salinas, C. A. %A Alarcón-Riquelme, M. E. %A An, P. %A Aviles-Santa, L. %A Becker, D. M. %A Beilin, L. J. %A Bergmann, S. %A Bisgaard, H. %A Black, C. %A Boehnke, M. %A Boerwinkle, E. %A Böhm, B. O. %A Bønnelykke, K. %A Boomsma, D. I. %A Bottinger, E. P. %A Buchanan, T. A. %A Canouil, M. %A Caulfield, M. J. %A Chambers, J. C. %A Chasman, D. I. %A Chen, Y. I. %A Cheng, C. Y. %A Collins, F. S. %A Correa, A. %A Cucca, F. %A de Silva, H. J. %A Dedoussis, G. %A Elmståhl, S. %A Evans, M. K. %A Ferrannini, E. %A Ferrucci, L. %A Florez, J. C. %A Franks, P. W. %A Frayling, T. M. %A Froguel, P. %A Gigante, B. %A Goodarzi, M. O. %A Gordon-Larsen, P. %A Grallert, H. %A Grarup, N. %A Grimsgaard, S. %A Groop, L. %A Gudnason, V. %A Guo, X. %A Hamsten, A. %A Hansen, T. %A Hayward, C. %A Heckbert, S. R. %A Horta, B. L. %A Huang, W. %A Ingelsson, E. %A James, P. S. %A Jarvelin, M. R. %A Jonas, J. B. %A Jukema, J. W. %A Kaleebu, P. %A Kaplan, R. %A Kardia, S. L. R. %A Kato, N. %A Keinanen-Kiukaanniemi, S. M. %A Kim, B. J. %A Kivimaki, M. %A Koistinen, H. A. %A Kooner, J. S. %A Körner, A. %A Kovacs, P. %A Kuh, D. %A Kumari, M. %A Kutalik, Z. %A Laakso, M. %A Lakka, T. A. %A Launer, L. J. %A Leander, K. %A Li, H. %A Lin, X. %A Lind, L. %A Lindgren, C. %A Liu, S. %A Loos, R. J. F. %A Magnusson, P. K. E. %A Mahajan, A. %A Metspalu, A. %A Mook-Kanamori, D. O. %A Mori, T. A. %A Munroe, P. B. %A Njølstad, I. %A O'Connell, J. R. %A Oldehinkel, A. J. %A Ong, K. K. %A Padmanabhan, S. %A Palmer, C. N. A. %A Palmer, N. D. %A Pedersen, O. %A Pennell, C. E. %A Porteous, D. J. %A Pramstaller, P. P. %A Province, M. A. %A Psaty, B. M. %A Qi, L. %A Raffel, L. J. %A Rauramaa, R. %A Redline, S. %A Ridker, P. M. %A Rosendaal, F. R. %A Saaristo, T. E. %A Sandhu, M. %A Saramies, J. %A Schneiderman, N. %A Schwarz, P. %A Scott, L. J. %A Selvin, E. %A Sever, P. %A Shu, X. O. %A Slagboom, P. E. %A Small, K. S. %A Smith, B. H. %A Snieder, H. %A Sofer, T. %A Sørensen, T. I. A. %A Spector, T. D. %A Stanton, A. %A Steves, C. J. %A Stumvoll, M. %A Sun, L. %A Tabara, Y. %A Tai, E. S. %A Timpson, N. J. %A Tonjes, A. %A Tuomilehto, J. %A Tusie, T. %A Uusitupa, M. %A van der Harst, P. %A van Duijn, C. %A Vitart, V. %A Vollenweider, P. %A Vrijkotte, T. G. M. %A Wagenknecht, L. E. %A Walker, M. %A Wang, Y. X. %A Wareham, N. J. %A Watanabe, R. M. %A Watkins, H. %A Wei, W. B. %A Wickremasinghe, A. R. %A Willemsen, G. %A Wilson, J. F. %A Wong, T. Y. %A Wu, J. Y. %A Xiang, A. H. %A Yanek, L. R. %A Yengo, L. %A Yokota, M. %A Zeggini, E. %A Zheng, W. %A Zonderman, A. B. %A Rotter, J. I. %A Gloyn, A. L. %A McCarthy, M. I. %A Dupuis, J. %A Meigs, J. B. %A Scott, R. A. %A Prokopenko, I. %A Leong, A. %A Liu, C. T. %A Parker, S. C. J. %A Mohlke, K. L. %A Langenberg, C. %A Wheeler, E. %A Morris, A. P. %A Barroso, I. %A de Haan, H. G. %A van den Akker, E. %A van der Most, P. J. %A de Geus, E. J. C. %A van Dam, R. M. %A van Heemst, D. %A van Hylckama Vlieg, A. %A van Willems van Dijk, K. %A de Silva, H. J. %A van der Harst, P. %A van Duijn, C. %X 10.1038/s41588-021-00852-9Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10-8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution. %B Nat Genet %V 53 %P 840–860 %8 06 %G eng %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2021 %T What Cut-Point in Gait Speed Best Discriminates Community-Dwelling Older Adults With Mobility Complaints From Those Without? A Pooled Analysis From the Sarcopenia Definitions and Outcomes Consortium. %A Cawthon, Peggy M %A Patel, Sheena M %A Kritchevsky, Stephen B %A Newman, Anne B %A Santanasto, Adam %A Kiel, Douglas P %A Travison, Thomas G %A Lane, Nancy %A Cummings, Steven R %A Orwoll, Eric S %A Duchowny, Kate A %A Kwok, Timothy %A Hirani, Vasant %A Schousboe, John %A Karlsson, Magnus K %A Mellström, Dan %A Ohlsson, Claes %A Ljunggren, Osten %A Xue, Qian-Li %A Shardell, Michelle %A Jordan, Joanne M %A Pencina, Karol M %A Fielding, Roger A %A Magaziner, Jay %A Correa-de-Araujo, Rosaly %A Bhasin, Shalender %A Manini, Todd M %K Aged %K Female %K Gait %K Humans %K Independent Living %K Male %K Mobility Limitation %K Sarcopenia %K Walking %K Walking Speed %X

BACKGROUND: Cut-points to define slow walking speed have largely been derived from expert opinion.

METHODS: Study participants (13 589 men and 5043 women aged ≥65years) had walking speed (m/s) measured over 4-6 m (mean ± SD: 1.20 ± 0.27 m/s in men and 0.94 ± 0.24 m/s in women.) Mobility limitation was defined as any self-reported difficulty with walking approximately 1/4 mile (prevalence: 12.6% men, 26.4% women). Sex-stratified classification and regression tree (CART) models with 10-fold cross-validation identified walking speed cut-points that optimally discriminated those who reported mobility limitation from those who did not.

RESULTS: Among 5043 women, CART analysis identified 2 cut-points, classifying 4144 (82.2%) with walking speed ≥0.75 m/s, which we labeled as "fast"; 478 (9.5%) as "intermediate" (walking speed ≥0.62 m/s but <0.75 m/s); and 421 (8.3%) as "slow" (walking speed <0.62 m/s). Among 13 589 men, CART analysis identified 3 cut-points, classifying 10 001 (73.6%) with walking speed ≥1.00 m/s ("very fast"); 2901 (21.3%) as "fast" (walking speed ≥0.74 m/s but <1.00 m/s); 497 (3.7%) as "intermediate" (walking speed ≥0.57 m/s but <0.74 m/s); and 190 (1.4%) as "slow" (walking speed <0.57 m/s). Prevalence of self-reported mobility limitation was lowest in the "fast" or "very fast" (11% for men and 19% for women) and highest in the "slow" (60.5% in men and 71.0% in women). Rounding the 2 slower cut-points to 0.60 m/s and 0.75 m/s reclassified very few participants.

CONCLUSIONS: Cut-points in walking speed of approximately 0.60 m/s and 0.75 m/s discriminate those with self-reported mobility limitation from those without.

%B J Gerontol A Biol Sci Med Sci %V 76 %P e321-e327 %8 2021 09 13 %G eng %N 10 %R 10.1093/gerona/glab183 %0 Journal Article %J EBioMedicine %D 2021 %T Whole genome sequence analyses of eGFR in 23,732 people representing multiple ancestries in the NHLBI trans-omics for precision medicine (TOPMed) consortium. %A Lin, Bridget M %A Grinde, Kelsey E %A Brody, Jennifer A %A Breeze, Charles E %A Raffield, Laura M %A Mychaleckyj, Josyf C %A Thornton, Timothy A %A Perry, James A %A Baier, Leslie J %A de Las Fuentes, Lisa %A Guo, Xiuqing %A Heavner, Benjamin D %A Hanson, Robert L %A Hung, Yi-Jen %A Qian, Huijun %A Hsiung, Chao A %A Hwang, Shih-Jen %A Irvin, Margaret R %A Jain, Deepti %A Kelly, Tanika N %A Kobes, Sayuko %A Lange, Leslie %A Lash, James P %A Li, Yun %A Liu, Xiaoming %A Mi, Xuenan %A Musani, Solomon K %A Papanicolaou, George J %A Parsa, Afshin %A Reiner, Alex P %A Salimi, Shabnam %A Sheu, Wayne H-H %A Shuldiner, Alan R %A Taylor, Kent D %A Smith, Albert V %A Smith, Jennifer A %A Tin, Adrienne %A Vaidya, Dhananjay %A Wallace, Robert B %A Yamamoto, Kenichi %A Sakaue, Saori %A Matsuda, Koichi %A Kamatani, Yoichiro %A Momozawa, Yukihide %A Yanek, Lisa R %A Young, Betsi A %A Zhao, Wei %A Okada, Yukinori %A Abecasis, Gonzalo %A Psaty, Bruce M %A Arnett, Donna K %A Boerwinkle, Eric %A Cai, Jianwen %A Yii-Der Chen, Ida %A Correa, Adolfo %A Cupples, L Adrienne %A He, Jiang %A Kardia, Sharon Lr %A Kooperberg, Charles %A Mathias, Rasika A %A Mitchell, Braxton D %A Nickerson, Deborah A %A Turner, Steve T %A Vasan, Ramachandran S %A Rotter, Jerome I %A Levy, Daniel %A Kramer, Holly J %A Köttgen, Anna %A Rich, Stephen S %A Lin, Dan-Yu %A Browning, Sharon R %A Franceschini, Nora %X

BACKGROUND: Genetic factors that influence kidney traits have been understudied for low frequency and ancestry-specific variants.

METHODS: We combined whole genome sequencing (WGS) data from 23,732 participants from 10 NHLBI Trans-Omics for Precision Medicine (TOPMed) Program multi-ethnic studies to identify novel loci for estimated glomerular filtration rate (eGFR). Participants included European, African, East Asian, and Hispanic ancestries. We applied linear mixed models using a genetic relationship matrix estimated from the WGS data and adjusted for age, sex, study, and ethnicity.

FINDINGS: When testing single variants, we identified three novel loci driven by low frequency variants more commonly observed in non-European ancestry (PRKAA2, rs180996919, minor allele frequency [MAF] 0.04%, P = 6.1 × 10; METTL8, rs116951054, MAF 0.09%, P = 4.5 × 10; and MATK, rs539182790, MAF 0.05%, P = 3.4 × 10). We also replicated two known loci for common variants (rs2461702, MAF=0.49, P = 1.2 × 10, nearest gene GATM, and rs71147340, MAF=0.34, P = 3.3 × 10, CDK12). Testing aggregated variants within a gene identified the MAF gene. A statistical approach based on local ancestry helped to identify replication samples for ancestry-specific variants.

INTERPRETATION: This study highlights challenges in studying variants influencing kidney traits that are low frequency in populations and more common in non-European ancestry.

%B EBioMedicine %V 63 %P 103157 %8 2021 Jan %G eng %R 10.1016/j.ebiom.2020.103157 %0 Journal Article %J Hum Mol Genet %D 2021 %T Whole genome sequence analysis of platelet traits in the NHLBI trans-omics for precision medicine initiative. %A Little, Amarise %A Hu, Yao %A Sun, Quan %A Jain, Deepti %A Broome, Jai %A Chen, Ming-Huei %A Thibord, Florian %A McHugh, Caitlin %A Surendran, Praveen %A Blackwell, Thomas W %A Brody, Jennifer A %A Bhan, Arunoday %A Chami, Nathalie %A Vries, Paul S %A Ekunwe, Lynette %A Heard-Costa, Nancy %A Hobbs, Brian D %A Manichaikul, Ani %A Moon, Jee-Young %A Preuss, Michael H %A Ryan, Kathleen %A Wang, Zhe %A Wheeler, Marsha %A Yanek, Lisa R %A Abecasis, Goncalo R %A Almasy, Laura %A Beaty, Terri H %A Becker, Lewis C %A Blangero, John %A Boerwinkle, Eric %A Butterworth, Adam S %A Choquet, Helene %A Correa, Adolfo %A Curran, Joanne E %A Faraday, Nauder %A Fornage, Myriam %A Glahn, David C %A Hou, Lifang %A Jorgenson, Eric %A Kooperberg, Charles %A Lewis, Joshua P %A Lloyd-Jones, Donald M %A Loos, Ruth J F %A Min, Nancy %A Mitchell, Braxton D %A Morrison, Alanna C %A Nickerson, Debbie %A North, Kari E %A O'Connell, Jeffrey R %A Pankratz, Nathan %A Psaty, Bruce M %A Vasan, Ramachandran S %A Rich, Stephen S %A Rotter, Jerome I %A Smith, Albert V %A Smith, Nicholas L %A Tang, Hua %A Tracy, Russell P %A Conomos, Matthew P %A Laurie, Cecelia A %A Mathias, Rasika A %A Li, Yun %A Auer, Paul L %A Thornton, Timothy %A Reiner, Alexander P %A Johnson, Andrew D %A Raffield, Laura M %X

Platelets play a key role in thrombosis and hemostasis. Platelet count (PLT) and mean platelet volume (MPV) are highly heritable quantitative traits, with hundreds of genetic signals previously identified, mostly in European ancestry populations. We here utilize whole genome sequencing from NHLBI's Trans-Omics for Precision Medicine Initiative (TOPMed) in a large multi-ethnic sample to further explore common and rare variation contributing to PLT (n = 61 200) and MPV (n = 23 485). We identified and replicated secondary signals at MPL (rs532784633) and PECAM1 (rs73345162), both more common in African ancestry populations. We also observed rare variation in Mendelian platelet related disorder genes influencing variation in platelet traits in TOPMed cohorts (not enriched for blood disorders). For example, association of GP9 with lower PLT and higher MPV was partly driven by a pathogenic Bernard-Soulier syndrome variant (rs5030764, p.Asn61Ser), and the signals at TUBB1 and CD36 were partly driven by loss of function variants not annotated as pathogenic in ClinVar (rs199948010 and rs571975065). However, residual signal remained for these gene-based signals after adjusting for lead variants, suggesting that additional variants in Mendelian genes with impacts in general population cohorts remain to be identified. Gene-based signals were also identified at several GWAS identified loci for genes not annotated for Mendelian platelet disorders (PTPRH, TET2, CHEK2), with somatic variation driving the result at TET2. These results highlight the value of whole genome sequencing in populations of diverse genetic ancestry to identify novel regulatory and coding signals, even for well-studied traits like platelet traits.

%B Hum Mol Genet %8 2021 Sep 06 %G eng %R 10.1093/hmg/ddab252 %0 Journal Article %J Genome Med %D 2021 %T Whole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program. %A Cade, Brian E %A Lee, Jiwon %A Sofer, Tamar %A Wang, Heming %A Zhang, Man %A Chen, Han %A Gharib, Sina A %A Gottlieb, Daniel J %A Guo, Xiuqing %A Lane, Jacqueline M %A Liang, Jingjing %A Lin, Xihong %A Mei, Hao %A Patel, Sanjay R %A Purcell, Shaun M %A Saxena, Richa %A Shah, Neomi A %A Evans, Daniel S %A Hanis, Craig L %A Hillman, David R %A Mukherjee, Sutapa %A Palmer, Lyle J %A Stone, Katie L %A Tranah, Gregory J %A Abecasis, Goncalo R %A Boerwinkle, Eric A %A Correa, Adolfo %A Cupples, L Adrienne %A Kaplan, Robert C %A Nickerson, Deborah A %A North, Kari E %A Psaty, Bruce M %A Rotter, Jerome I %A Rich, Stephen S %A Tracy, Russell P %A Vasan, Ramachandran S %A Wilson, James G %A Zhu, Xiaofeng %A Redline, Susan %X

BACKGROUND: Sleep-disordered breathing is a common disorder associated with significant morbidity. The genetic architecture of sleep-disordered breathing remains poorly understood. Through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, we performed the first whole-genome sequence analysis of sleep-disordered breathing.

METHODS: The study sample was comprised of 7988 individuals of diverse ancestry. Common-variant and pathway analyses included an additional 13,257 individuals. We examined five complementary traits describing different aspects of sleep-disordered breathing: the apnea-hypopnea index, average oxyhemoglobin desaturation per event, average and minimum oxyhemoglobin saturation across the sleep episode, and the percentage of sleep with oxyhemoglobin saturation < 90%. We adjusted for age, sex, BMI, study, and family structure using MMSKAT and EMMAX mixed linear model approaches. Additional bioinformatics analyses were performed with MetaXcan, GIGSEA, and ReMap.

RESULTS: We identified a multi-ethnic set-based rare-variant association (p = 3.48 × 10) on chromosome X with ARMCX3. Additional rare-variant associations include ARMCX3-AS1, MRPS33, and C16orf90. Novel common-variant loci were identified in the NRG1 and SLC45A2 regions, and previously associated loci in the IL18RAP and ATP2B4 regions were associated with novel phenotypes. Transcription factor binding site enrichment identified associations with genes implicated with respiratory and craniofacial traits. Additional analyses identified significantly associated pathways.

CONCLUSIONS: We have identified the first gene-based rare-variant associations with objectively measured sleep-disordered breathing traits. Our results increase the understanding of the genetic architecture of sleep-disordered breathing and highlight associations in genes that modulate lung development, inflammation, respiratory rhythmogenesis, and HIF1A-mediated hypoxic response.

%B Genome Med %V 13 %P 136 %8 2021 08 26 %G eng %N 1 %R 10.1186/s13073-021-00917-8 %0 Journal Article %J Am J Hum Genet %D 2021 %T Whole-genome sequencing association analysis of quantitative red blood cell phenotypes: The NHLBI TOPMed program. %A Hu, Yao %A Stilp, Adrienne M %A McHugh, Caitlin P %A Rao, Shuquan %A Jain, Deepti %A Zheng, Xiuwen %A Lane, John %A Méric de Bellefon, Sébastian %A Raffield, Laura M %A Chen, Ming-Huei %A Yanek, Lisa R %A Wheeler, Marsha %A Yao, Yao %A Ren, Chunyan %A Broome, Jai %A Moon, Jee-Young %A de Vries, Paul S %A Hobbs, Brian D %A Sun, Quan %A Surendran, Praveen %A Brody, Jennifer A %A Blackwell, Thomas W %A Choquet, Helene %A Ryan, Kathleen %A Duggirala, Ravindranath %A Heard-Costa, Nancy %A Wang, Zhe %A Chami, Nathalie %A Preuss, Michael H %A Min, Nancy %A Ekunwe, Lynette %A Lange, Leslie A %A Cushman, Mary %A Faraday, Nauder %A Curran, Joanne E %A Almasy, Laura %A Kundu, Kousik %A Smith, Albert V %A Gabriel, Stacey %A Rotter, Jerome I %A Fornage, Myriam %A Lloyd-Jones, Donald M %A Vasan, Ramachandran S %A Smith, Nicholas L %A North, Kari E %A Boerwinkle, Eric %A Becker, Lewis C %A Lewis, Joshua P %A Abecasis, Goncalo R %A Hou, Lifang %A O'Connell, Jeffrey R %A Morrison, Alanna C %A Beaty, Terri H %A Kaplan, Robert %A Correa, Adolfo %A Blangero, John %A Jorgenson, Eric %A Psaty, Bruce M %A Kooperberg, Charles %A Walton, Russell T %A Kleinstiver, Benjamin P %A Tang, Hua %A Loos, Ruth J F %A Soranzo, Nicole %A Butterworth, Adam S %A Nickerson, Debbie %A Rich, Stephen S %A Mitchell, Braxton D %A Johnson, Andrew D %A Auer, Paul L %A Li, Yun %A Mathias, Rasika A %A Lettre, Guillaume %A Pankratz, Nathan %A Laurie, Cathy C %A Laurie, Cecelia A %A Bauer, Daniel E %A Conomos, Matthew P %A Reiner, Alexander P %K Adult %K Aged %K Chromosomes, Human, Pair 16 %K Datasets as Topic %K Erythrocytes %K Female %K Gene Editing %K Genetic Variation %K Genome-Wide Association Study %K HEK293 Cells %K Humans %K Male %K Middle Aged %K National Heart, Lung, and Blood Institute (U.S.) %K Phenotype %K Quality Control %K Reproducibility of Results %K United States %X

Whole-genome sequencing (WGS), a powerful tool for detecting novel coding and non-coding disease-causing variants, has largely been applied to clinical diagnosis of inherited disorders. Here we leveraged WGS data in up to 62,653 ethnically diverse participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and assessed statistical association of variants with seven red blood cell (RBC) quantitative traits. We discovered 14 single variant-RBC trait associations at 12 genomic loci, which have not been reported previously. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, and G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these discovered variants are rare/low frequency, and several are observed disproportionately among non-European Ancestry (African, Hispanic/Latino, or East Asian) populations. We identified a 3 bp indel p.Lys2169del (g.88717175_88717177TCT[4]) (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis (MIM: 194380), associated with higher mean corpuscular hemoglobin concentration (MCHC). In stepwise conditional analysis and in gene-based rare variant aggregated association analysis, we identified several of the variants in HBB, HBA1, TMPRSS6, and G6PD that represent the carrier state for known coding, promoter, or splice site loss-of-function variants that cause inherited RBC disorders. Finally, we applied base and nuclease editing to demonstrate that the sentinel variant rs112097551 (nearest gene RPN1) acts through a cis-regulatory element that exerts long-range control of the gene RUVBL1 which is essential for hematopoiesis. Together, these results demonstrate the utility of WGS in ethnically diverse population-based samples and gene editing for expanding knowledge of the genetic architecture of quantitative hematologic traits and suggest a continuum between complex trait and Mendelian red cell disorders.

%B Am J Hum Genet %V 108 %P 874-893 %8 2021 05 06 %G eng %N 5 %R 10.1016/j.ajhg.2021.04.003 %0 Journal Article %J Am J Hum Genet %D 2021 %T Whole-genome sequencing in diverse subjects identifies genetic correlates of leukocyte traits: The NHLBI TOPMed program. %A Mikhaylova, Anna V %A McHugh, Caitlin P %A Polfus, Linda M %A Raffield, Laura M %A Boorgula, Meher Preethi %A Blackwell, Thomas W %A Brody, Jennifer A %A Broome, Jai %A Chami, Nathalie %A Chen, Ming-Huei %A Conomos, Matthew P %A Cox, Corey %A Curran, Joanne E %A Daya, Michelle %A Ekunwe, Lynette %A Glahn, David C %A Heard-Costa, Nancy %A Highland, Heather M %A Hobbs, Brian D %A Ilboudo, Yann %A Jain, Deepti %A Lange, Leslie A %A Miller-Fleming, Tyne W %A Min, Nancy %A Moon, Jee-Young %A Preuss, Michael H %A Rosen, Jonathon %A Ryan, Kathleen %A Smith, Albert V %A Sun, Quan %A Surendran, Praveen %A de Vries, Paul S %A Walter, Klaudia %A Wang, Zhe %A Wheeler, Marsha %A Yanek, Lisa R %A Zhong, Xue %A Abecasis, Goncalo R %A Almasy, Laura %A Barnes, Kathleen C %A Beaty, Terri H %A Becker, Lewis C %A Blangero, John %A Boerwinkle, Eric %A Butterworth, Adam S %A Chavan, Sameer %A Cho, Michael H %A Choquet, Helene %A Correa, Adolfo %A Cox, Nancy %A DeMeo, Dawn L %A Faraday, Nauder %A Fornage, Myriam %A Gerszten, Robert E %A Hou, Lifang %A Johnson, Andrew D %A Jorgenson, Eric %A Kaplan, Robert %A Kooperberg, Charles %A Kundu, Kousik %A Laurie, Cecelia A %A Lettre, Guillaume %A Lewis, Joshua P %A Li, Bingshan %A Li, Yun %A Lloyd-Jones, Donald M %A Loos, Ruth J F %A Manichaikul, Ani %A Meyers, Deborah A %A Mitchell, Braxton D %A Morrison, Alanna C %A Ngo, Debby %A Nickerson, Deborah A %A Nongmaithem, Suraj %A North, Kari E %A O'Connell, Jeffrey R %A Ortega, Victor E %A Pankratz, Nathan %A Perry, James A %A Psaty, Bruce M %A Rich, Stephen S %A Soranzo, Nicole %A Rotter, Jerome I %A Silverman, Edwin K %A Smith, Nicholas L %A Tang, Hua %A Tracy, Russell P %A Thornton, Timothy A %A Vasan, Ramachandran S %A Zein, Joe %A Mathias, Rasika A %A Reiner, Alexander P %A Auer, Paul L %K Asthma %K Biomarkers %K Dermatitis, Atopic %K Genetic Predisposition to Disease %K Genome, Human %K Genome-Wide Association Study %K Humans %K Leukocytes %K National Heart, Lung, and Blood Institute (U.S.) %K Phenotype %K Polymorphism, Single Nucleotide %K Prognosis %K Proteome %K Pulmonary Disease, Chronic Obstructive %K Quantitative Trait Loci %K United Kingdom %K United States %K Whole Genome Sequencing %X

Many common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts generated from 109,563,748 variants in the autosomes and the X chromosome in the Trans-Omics for Precision Medicine (TOPMed) program, which included data from 61,802 individuals of diverse ancestry. We discovered and replicated 7 leukocyte trait associations, including (1) the association between a chromosome X, pseudo-autosomal region (PAR), noncoding variant located between cytokine receptor genes (CSF2RA and CLRF2) and lower eosinophil count; and (2) associations between single variants found predominantly among African Americans at the S1PR3 (9q22.1) and HBB (11p15.4) loci and monocyte and lymphocyte counts, respectively. We further provide evidence indicating that the newly discovered eosinophil-lowering chromosome X PAR variant might be associated with reduced susceptibility to common allergic diseases such as atopic dermatitis and asthma. Additionally, we found a burden of very rare FLT3 (13q12.2) variants associated with monocyte counts. Together, these results emphasize the utility of whole-genome sequencing in diverse samples in identifying associations missed by European-ancestry-driven GWASs.

%B Am J Hum Genet %V 108 %P 1836-1851 %8 2021 10 07 %G eng %N 10 %R 10.1016/j.ajhg.2021.08.007 %0 Journal Article %J Nat Genet %D 2022 %T Assessing the contribution of rare variants to complex trait heritability from whole-genome sequence data. %A Wainschtein, Pierrick %A Jain, Deepti %A Zheng, Zhili %A Cupples, L Adrienne %A Shadyab, Aladdin H %A McKnight, Barbara %A Shoemaker, Benjamin M %A Mitchell, Braxton D %A Psaty, Bruce M %A Kooperberg, Charles %A Liu, Ching-Ti %A Albert, Christine M %A Roden, Dan %A Chasman, Daniel I %A Darbar, Dawood %A Lloyd-Jones, Donald M %A Arnett, Donna K %A Regan, Elizabeth A %A Boerwinkle, Eric %A Rotter, Jerome I %A O'Connell, Jeffrey R %A Yanek, Lisa R %A de Andrade, Mariza %A Allison, Matthew A %A McDonald, Merry-Lynn N %A Chung, Mina K %A Fornage, Myriam %A Chami, Nathalie %A Smith, Nicholas L %A Ellinor, Patrick T %A Vasan, Ramachandran S %A Mathias, Rasika A %A Loos, Ruth J F %A Rich, Stephen S %A Lubitz, Steven A %A Heckbert, Susan R %A Redline, Susan %A Guo, Xiuqing %A Chen, Y -D Ida %A Laurie, Cecelia A %A Hernandez, Ryan D %A McGarvey, Stephen T %A Goddard, Michael E %A Laurie, Cathy C %A North, Kari E %A Lange, Leslie A %A Weir, Bruce S %A Yengo, Loic %A Yang, Jian %A Visscher, Peter M %X

Analyses of data from genome-wide association studies on unrelated individuals have shown that, for human traits and diseases, approximately one-third to two-thirds of heritability is captured by common SNPs. However, it is not known whether the remaining heritability is due to the imperfect tagging of causal variants by common SNPs, in particular whether the causal variants are rare, or whether it is overestimated due to bias in inference from pedigree data. Here we estimated heritability for height and body mass index (BMI) from whole-genome sequence data on 25,465 unrelated individuals of European ancestry. The estimated heritability was 0.68 (standard error 0.10) for height and 0.30 (standard error 0.10) for body mass index. Low minor allele frequency variants in low linkage disequilibrium (LD) with neighboring variants were enriched for heritability, to a greater extent for protein-altering variants, consistent with negative selection. Our results imply that rare variants, in particular those in regions of low linkage disequilibrium, are a major source of the still missing heritability of complex traits and disease.

%B Nat Genet %V 54 %P 263-273 %8 2022 Mar %G eng %N 3 %R 10.1038/s41588-021-00997-7 %0 Journal Article %J Am J Med %D 2022 %T The Association of Lipids and Lipoproteins with Hip Fracture Risk the Cardiovascular Health Study. %A Barzilay, Joshua I %A Bůzková, Petra %A Kuller, Lewis H %A Cauley, Jane A %A Fink, Howard A %A Sheets, Kerry %A Robbins, John A %A Carbone, Laura D %A Elam, Rachel E %A Mukamal, Kenneth J %X

BACKGROUND: It is uncertain if lipids or lipoproteins are associated with osteoporotic fractures. In this study, incident hip fracture risk according to conventional lipid levels and lipoprotein levels and sizes was examined.

METHODS: We followed 5832 participants aged ≥65 years from the Cardiovascular Health Study for hip fracture for a mean of 13.5 (SD 5.7) years. Standard enzymatic methods were used to determine lipid levels (HDL-c, LDL-c, triglycerides). Nuclear magnetic resonance spectroscopy was used to measure lipoprotein fractions (VLDL-P, LDL-P, HDL-P) in a subset of 1849 participants.

RESULTS: We documented 755 incident hip fractures among women (1.19 fractures per 100 participant years [95% CI, 1.04, 1.35]) and 197 among men (0.67 fractures per 100 participant years [95% CI, 0.41, 1.10]) over an average follow-up. HDL-c and LDL-c levels had statistically significant non-linear U-shaped relationships with hip fracture risk (HDL-c, p=0.009; LDL-c, p=0.02). Triglyceride levels were not significantly associated with hip fracture risk. In fully adjusted conjoint models, higher VLDL-P concentration [HR per 1-standard (SD) increment 1.47 (1.13, 1.91)] and size [HR per 1-SD increment 1.24 [1.05, 1.46]) and higher HDL-P size (HR per 1-SD increment 1.81 [1.25, 2.62]) were all associated with higher hip fracture risk.

CONCLUSIONS: Lipids and lipoproteins are associated with hip fracture risk in older adults. The associations are complex. Mechanistic studies are needed to understand these findings.

%B Am J Med %8 2022 Jun 06 %G eng %R 10.1016/j.amjmed.2022.05.024 %0 Journal Article %J Genome Res %D 2022 %T {An association test of the spatial distribution of rare missense variants within protein structures identifies Alzheimer's disease-related patterns %A Jin, B. %A Capra, J. A. %A Benchek, P. %A Wheeler, N. %A Naj, A. C. %A Hamilton-Nelson, K. L. %A Farrell, J. J. %A Leung, Y. Y. %A Kunkle, B. %A Vadarajan, B. %A Schellenberg, G. D. %A Mayeux, R. %A Wang, L. S. %A Farrer, L. A. %A Pericak-Vance, M. A. %A Martin, E. R. %A Haines, J. L. %A Crawford, D. C. %A Bush, W. S. %X is a novel AD risk gene that has a cluster of variants primarily shared by case subjects around the Sec6 domain. This cluster is also validated in an independent replication data set and a validation data set with a larger sample size. %B Genome Res %V 32 %P 778–790 %8 04 %G eng %0 Journal Article %J J Am Heart Assoc %D 2022 %T Circulating Soluble CD163, Associations With Cardiovascular Outcomes and Mortality, and Identification of Genetic Variants in Older Individuals: The Cardiovascular Health Study. %A Durda, Peter %A Raffield, Laura M %A Lange, Ethan M %A Olson, Nels C %A Jenny, Nancy Swords %A Cushman, Mary %A Deichgraeber, Pia %A Grarup, Niels %A Jonsson, Anna %A Hansen, Torben %A Mychaleckyj, Josyf C %A Psaty, Bruce M %A Reiner, Alex P %A Tracy, Russell P %A Lange, Leslie A %K Aged %K Antigens, CD %K Antigens, Differentiation, Myelomonocytic %K Asialoglycoprotein Receptor %K Biomarkers %K Cardiovascular Diseases %K Female %K Genome-Wide Association Study %K Heart Failure %K Humans %K Longitudinal Studies %K Male %X

Background Monocytes/macrophages participate in cardiovascular disease. CD163 (cluster of differentiation 163) is a monocyte/macrophage receptor, and the shed sCD163 (soluble CD163) reflects monocyte/macrophage activation. We examined the association of sCD163 with incident cardiovascular disease events and performed a genome-wide association study to identify sCD163-associated variants. Methods and Results We measured plasma sCD163 in 5214 adults (aged ≥65 years, 58.7% women, 16.2% Black) of the CHS (Cardiovascular Health Study). We used Cox regression models (associations of sCD163 with incident events and mortality); median follow-up was 26 years. Genome-wide association study analyses were stratified on race. Adjusted for age, sex, and race and ethnicity, sCD163 levels were associated with all-cause mortality (hazard ratio [HR], 1.08 [95% CI, 1.04-1.12] per SD increase), cardiovascular disease mortality (HR, 1.15 [95% CI, 1.09-1.21]), incident coronary heart disease (HR, 1.10 [95% CI, 1.04-1.16]), and incident heart failure (HR, 1.18 [95% CI, 1.12-1.25]). When further adjusted (eg, cardiovascular disease risk factors), only incident coronary heart disease lost significance. In European American individuals, genome-wide association studies identified 38 variants on chromosome 2 near (top result rs62165726, =3.3×10),19 variants near chromosome 17 gene (rs55714927, =1.5×10), and 18 variants near chromosome 11 gene . These regions replicated in the European ancestry ADDITION-PRO cohort, a longitudinal cohort study nested in the Danish arm of the Anglo-Danish-Dutch study of Intensive Treatment Intensive Treatment In peOple with screeNdetcted Diabetes in Primary Care. In Black individuals, we identified 9 variants on chromosome 6 (rs3129781 =7.1×10) in the region, and 3 variants (rs115391969 =4.3×10) near the chromosome 16 gene Conclusions Monocyte function, as measured by sCD163, may be predictive of overall and cardiovascular-specific mortality and incident heart failure.

%B J Am Heart Assoc %V 11 %P e024374 %8 2022 Nov %G eng %N 21 %R 10.1161/JAHA.121.024374 %0 Journal Article %J Stroke %D 2022 %T Clonal Hematopoiesis Is Associated With Higher Risk of Stroke. %A Bhattacharya, Romit %A Zekavat, Seyedeh M %A Haessler, Jeffrey %A Fornage, Myriam %A Raffield, Laura %A Uddin, Md Mesbah %A Bick, Alexander G %A Niroula, Abhishek %A Yu, Bing %A Gibson, Christopher %A Griffin, Gabriel %A Morrison, Alanna C %A Psaty, Bruce M %A Longstreth, William T %A Bis, Joshua C %A Rich, Stephen S %A Rotter, Jerome I %A Tracy, Russell P %A Correa, Adolfo %A Seshadri, Sudha %A Johnson, Andrew %A Collins, Jason M %A Hayden, Kathleen M %A Madsen, Tracy E %A Ballantyne, Christie M %A Jaiswal, Siddhartha %A Ebert, Benjamin L %A Kooperberg, Charles %A Manson, JoAnn E %A Whitsel, Eric A %A Natarajan, Pradeep %A Reiner, Alexander P %X

BACKGROUND AND PURPOSE: Clonal hematopoiesis of indeterminate potential (CHIP) is a novel age-related risk factor for cardiovascular disease-related morbidity and mortality. The association of CHIP with risk of incident ischemic stroke was reported previously in an exploratory analysis including a small number of incident stroke cases without replication and lack of stroke subphenotyping. The purpose of this study was to discover whether CHIP is a risk factor for ischemic or hemorrhagic stroke.

METHODS: We utilized plasma genome sequence data of blood DNA to identify CHIP in 78 752 individuals from 8 prospective cohorts and biobanks. We then assessed the association of CHIP and commonly mutated individual CHIP driver genes (, , and ) with any stroke, ischemic stroke, and hemorrhagic stroke.

RESULTS: CHIP was associated with an increased risk of total stroke (hazard ratio, 1.14 [95% CI, 1.03-1.27]; =0.01) after adjustment for age, sex, and race. We observed associations with CHIP with risk of hemorrhagic stroke (hazard ratio, 1.24 [95% CI, 1.01-1.51]; =0.04) and with small vessel ischemic stroke subtypes. In gene-specific association results, showed the strongest association with total stroke and ischemic stroke, whereas and were each associated with increased risk of hemorrhagic stroke.

CONCLUSIONS: CHIP is associated with an increased risk of stroke, particularly with hemorrhagic and small vessel ischemic stroke. Future studies clarifying the relationship between CHIP and subtypes of stroke are needed.

%B Stroke %V 53 %P 788-797 %8 2022 Mar %G eng %N 3 %R 10.1161/STROKEAHA.121.037388 %0 Journal Article %J Nat Commun %D 2022 %T {Clonal hematopoiesis of indeterminate potential, DNA methylation, and risk for coronary artery disease %A Uddin, M. D. M. %A Nguyen, N. Q. H. %A Yu, B. %A Brody, J. A. %A Pampana, A. %A Nakao, T. %A Fornage, M. %A Bressler, J. %A Sotoodehnia, N. %A Weinstock, J. S. %A Honigberg, M. C. %A Nachun, D. %A Bhattacharya, R. %A Griffin, G. K. %A Chander, V. %A Gibbs, R. A. %A Rotter, J. I. %A Liu, C. %A Baccarelli, A. A. %A Chasman, D. I. %A Whitsel, E. A. %A Kiel, D. P. %A Murabito, J. M. %A Boerwinkle, E. %A Ebert, B. L. %A Jaiswal, S. %A Floyd, J. S. %A Bick, A. G. %A Ballantyne, C. M. %A Psaty, B. M. %A Natarajan, P. %A Conneely, K. N. %X Age-related changes to the genome-wide DNA methylation (DNAm) pattern observed in blood are well-documented. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by the age-related acquisition and expansion of leukemogenic mutations in hematopoietic stem cells (HSCs), is associated with blood cancer and coronary artery disease (CAD). Epigenetic regulators DNMT3A and TET2 are the two most frequently mutated CHIP genes. Here, we present results from an epigenome-wide association study for CHIP in 582 Cardiovascular Health Study (CHS) participants, with replication in 2655 Atherosclerosis Risk in Communities (ARIC) Study participants. We show that DNMT3A and TET2 CHIP have distinct and directionally opposing genome-wide DNAm association patterns consistent with their regulatory roles, albeit both promoting self-renewal of HSCs. Mendelian randomization analyses indicate that a subset of DNAm alterations associated with these two leading CHIP genes may promote the risk for CAD. %B Nat Commun %V 13 %P 5350 %8 Sep %G eng %0 Journal Article %J Cell Rep Med %D 2022 %T Correlations between complex human phenotypes vary by genetic background, gender, and environment. %A Elgart, Michael %A Goodman, Matthew O %A Isasi, Carmen %A Chen, Han %A Morrison, Alanna C %A de Vries, Paul S %A Xu, Huichun %A Manichaikul, Ani W %A Guo, Xiuqing %A Franceschini, Nora %A Psaty, Bruce M %A Rich, Stephen S %A Rotter, Jerome I %A Lloyd-Jones, Donald M %A Fornage, Myriam %A Correa, Adolfo %A Heard-Costa, Nancy L %A Vasan, Ramachandran S %A Hernandez, Ryan %A Kaplan, Robert C %A Redline, Susan %A Sofer, Tamar %K Female %K Genetic Background %K Humans %K Male %K Phenotype %X

We develop a closed-form Haseman-Elston estimator for genetic and environmental correlation coefficients between complex phenotypes, which we term HEc, that is as precise as GCTA yet ∼20× faster. We estimate genetic and environmental correlations between over 7,000 phenotype pairs in subgroups from the Trans-Omics in Precision Medicine (TOPMed) program. We demonstrate substantial differences in both heritabilities and genetic correlations for multiple phenotypes and phenotype pairs between individuals of self-reported Black, Hispanic/Latino, and White backgrounds. We similarly observe differences in many of the genetic and environmental correlations between genders. To estimate the contribution of genetics to the observed phenotypic correlation, we introduce "fractional genetic correlation" as the fraction of phenotypic correlation explained by genetics. Finally, we quantify the enrichment of correlations between phenotypic domains, each of which is comprised of multiple phenotypes. Altogether, we demonstrate that the observed correlations between complex human phenotypes depend on the genetic background of the individuals, their gender, and their environment.

%B Cell Rep Med %V 3 %P 100844 %8 2022 Dec 20 %G eng %N 12 %R 10.1016/j.xcrm.2022.100844 %0 Journal Article %J Circulation %D 2022 %T Cross-Ancestry Investigation of Venous Thromboembolism Genomic Predictors. %A Thibord, Florian %A Klarin, Derek %A Brody, Jennifer A %A Chen, Ming-Huei %A Levin, Michael G %A Chasman, Daniel I %A Goode, Ellen L %A Hveem, Kristian %A Teder-Laving, Maris %A Martinez-Perez, Angel %A Aïssi, Dylan %A Daian-Bacq, Delphine %A Ito, Kaoru %A Natarajan, Pradeep %A Lutsey, Pamela L %A Nadkarni, Girish N %A de Vries, Paul S %A Cuellar-Partida, Gabriel %A Wolford, Brooke N %A Pattee, Jack W %A Kooperberg, Charles %A Braekkan, Sigrid K %A Li-Gao, Ruifang %A Saut, Noémie %A Sept, Corriene %A Germain, Marine %A Judy, Renae L %A Wiggins, Kerri L %A Ko, Darae %A O'Donnell, Christopher J %A Taylor, Kent D %A Giulianini, Franco %A de Andrade, Mariza %A Nøst, Therese H %A Boland, Anne %A Empana, Jean-Philippe %A Koyama, Satoshi %A Gilliland, Thomas %A Do, Ron %A Huffman, Jennifer E %A Wang, Xin %A Zhou, Wei %A Manuel Soria, Jose %A Carlos Souto, Juan %A Pankratz, Nathan %A Haessler, Jeffery %A Hindberg, Kristian %A Rosendaal, Frits R %A Turman, Constance %A Olaso, Robert %A Kember, Rachel L %A Bartz, Traci M %A Lynch, Julie A %A Heckbert, Susan R %A Armasu, Sebastian M %A Brumpton, Ben %A Smadja, David M %A Jouven, Xavier %A Komuro, Issei %A Clapham, Katharine R %A Loos, Ruth J F %A Willer, Cristen J %A Sabater-Lleal, Maria %A Pankow, James S %A Reiner, Alexander P %A Morelli, Vania M %A Ridker, Paul M %A Vlieg, Astrid van Hylckama %A Deleuze, Jean-Francois %A Kraft, Peter %A Rader, Daniel J %A Min Lee, Kyung %A Psaty, Bruce M %A Heidi Skogholt, Anne %A Emmerich, Joseph %A Suchon, Pierre %A Rich, Stephen S %A Vy, Ha My T %A Tang, Weihong %A Jackson, Rebecca D %A Hansen, John-Bjarne %A Morange, Pierre-Emmanuel %A Kabrhel, Christopher %A Trégouët, David-Alexandre %A Damrauer, Scott M %A Johnson, Andrew D %A Smith, Nicholas L %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genomics %K Humans %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Thrombosis %K Venous Thromboembolism %X

BACKGROUND: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources.

METHODS: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations.

RESULTS: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis.

CONCLUSIONS: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.

%B Circulation %V 146 %P 1225-1242 %8 2022 Oct 18 %G eng %N 16 %R 10.1161/CIRCULATIONAHA.122.059675 %0 Journal Article %J Circulation %D 2022 %T Diabetes Status Modifies the Association Between Different Measures of Obesity and Heart Failure Risk Among Older Adults: A Pooled Analysis of Community-Based NHLBI Cohorts. %A Patel, Kershaw V %A Segar, Matthew W %A Lavie, Carl J %A Kondamudi, Nitin %A Neeland, Ian J %A Almandoz, Jaime P %A Martin, Corby K %A Carbone, Salvatore %A Butler, Javed %A Powell-Wiley, Tiffany M %A Pandey, Ambarish %K Aged %K Cohort Studies %K Diabetes Mellitus %K Female %K Heart Failure %K Humans %K Male %K National Heart, Lung, and Blood Institute (U.S.) %K Obesity %K Risk Factors %K United States %X

BACKGROUND: Obesity and diabetes are associated with a higher risk of heart failure (HF). The interrelationships between different measures of adiposity-overall obesity, central obesity, fat mass (FM)-and diabetes status for HF risk are not well-established.

METHODS: Participant-level data from the ARIC study (Atherosclerosis Risk in Communities; visit 5) and the CHS (Cardiovascular Health Study; visit 1) cohorts were obtained from the National Heart, Lung, and Blood Institute Biologic Specimen and Data Repository Information Coordinating Center, harmonized, and pooled for the present analysis, excluding individuals with prevalent HF. FM was estimated in all participants using established anthropometric prediction equations additionally validated using the bioelectrical impedance-based FM in the ARIC subgroup. Incident HF events on follow-up were captured across both cohorts using similar adjudication methods. Multivariable-adjusted Fine-Gray models were created to evaluate the associations of body mass index (BMI), waist circumference (WC), and FM with risk of HF in the overall cohort as well as among those with versus without diabetes at baseline. The population attributable risk of overall obesity (BMI≥30 kg/m), abdominal obesity (WC>88 and 102 cm in women and men, respectively), and high FM (above sex-specific median) for incident HF was evaluated among participants with and without diabetes.

RESULTS: The study included 10 387 participants (52.9% ARIC; 25.1% diabetes; median age, 74 years). The correlation between predicted and bioelectrical impedance-based FM was high (=0.90; n=5038). During a 5-year follow-up, 447 participants developed HF (4.3%). Higher levels of each adiposity measure were significantly associated with higher HF risk (hazard ratio [95% CI] per 1 SD higher BMI=1.15 [1.05, 1.27], WC=1.22 [1.10, 1.36]; FM=1.13 [1.02, 1.25]). A significant interaction was noted between diabetes status and measures of BMI ( interaction=0.04) and WC ( interaction=0.004) for the risk of HF. In stratified analysis, higher measures of each adiposity parameter were significantly associated with higher HF risk in individuals with diabetes (hazard ratio [95% CI] per 1 SD higher BMI=1.29 [1.14-1.47]; WC=1.48 [1.29-1.70]; FM=1.25 [1.09-1.43]) but not those without diabetes, including participants with prediabetes and euglycemia. The population attributable risk percentage of overall obesity, abdominal obesity, and high FM for incident HF was higher among participants with diabetes (12.8%, 29.9%, and 13.7%, respectively) versus those without diabetes (≤1% for each).

CONCLUSIONS: Higher BMI, WC, and FM are strongly associated with greater risk of HF among older adults, particularly among those with prevalent diabetes.

%B Circulation %V 145 %P 268-278 %8 2022 01 25 %G eng %N 4 %R 10.1161/CIRCULATIONAHA.121.055830 %0 Journal Article %J Commun Biol %D 2022 %T Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals. %A Winkler, Thomas W %A Rasheed, Humaira %A Teumer, Alexander %A Gorski, Mathias %A Rowan, Bryce X %A Stanzick, Kira J %A Thomas, Laurent F %A Tin, Adrienne %A Hoppmann, Anselm %A Chu, Audrey Y %A Tayo, Bamidele %A Thio, Chris H L %A Cusi, Daniele %A Chai, Jin-Fang %A Sieber, Karsten B %A Horn, Katrin %A Li, Man %A Scholz, Markus %A Cocca, Massimiliano %A Wuttke, Matthias %A van der Most, Peter J %A Yang, Qiong %A Ghasemi, Sahar %A Nutile, Teresa %A Li, Yong %A Pontali, Giulia %A Günther, Felix %A Dehghan, Abbas %A Correa, Adolfo %A Parsa, Afshin %A Feresin, Agnese %A de Vries, Aiko P J %A Zonderman, Alan B %A Smith, Albert V %A Oldehinkel, Albertine J %A De Grandi, Alessandro %A Rosenkranz, Alexander R %A Franke, Andre %A Teren, Andrej %A Metspalu, Andres %A Hicks, Andrew A %A Morris, Andrew P %A Tönjes, Anke %A Morgan, Anna %A Podgornaia, Anna I %A Peters, Annette %A Körner, Antje %A Mahajan, Anubha %A Campbell, Archie %A Freedman, Barry I %A Spedicati, Beatrice %A Ponte, Belen %A Schöttker, Ben %A Brumpton, Ben %A Banas, Bernhard %A Krämer, Bernhard K %A Jung, Bettina %A Åsvold, Bjørn Olav %A Smith, Blair H %A Ning, Boting %A Penninx, Brenda W J H %A Vanderwerff, Brett R %A Psaty, Bruce M %A Kammerer, Candace M %A Langefeld, Carl D %A Hayward, Caroline %A Spracklen, Cassandra N %A Robinson-Cohen, Cassianne %A Hartman, Catharina A %A Lindgren, Cecilia M %A Wang, Chaolong %A Sabanayagam, Charumathi %A Heng, Chew-Kiat %A Lanzani, Chiara %A Khor, Chiea-Chuen %A Cheng, Ching-Yu %A Fuchsberger, Christian %A Gieger, Christian %A Shaffer, Christian M %A Schulz, Christina-Alexandra %A Willer, Cristen J %A Chasman, Daniel I %A Gudbjartsson, Daniel F %A Ruggiero, Daniela %A Toniolo, Daniela %A Czamara, Darina %A Porteous, David J %A Waterworth, Dawn M %A Mascalzoni, Deborah %A Mook-Kanamori, Dennis O %A Reilly, Dermot F %A Daw, E Warwick %A Hofer, Edith %A Boerwinkle, Eric %A Salvi, Erika %A Bottinger, Erwin P %A Tai, E-Shyong %A Catamo, Eulalia %A Rizzi, Federica %A Guo, Feng %A Rivadeneira, Fernando %A Guilianini, Franco %A Sveinbjornsson, Gardar %A Ehret, Georg %A Waeber, Gérard %A Biino, Ginevra %A Girotto, Giorgia %A Pistis, Giorgio %A Nadkarni, Girish N %A Delgado, Graciela E %A Montgomery, Grant W %A Snieder, Harold %A Campbell, Harry %A White, Harvey D %A Gao, He %A Stringham, Heather M %A Schmidt, Helena %A Li, Hengtong %A Brenner, Hermann %A Holm, Hilma %A Kirsten, Holgen %A Kramer, Holly %A Rudan, Igor %A Nolte, Ilja M %A Tzoulaki, Ioanna %A Olafsson, Isleifur %A Martins, Jade %A Cook, James P %A Wilson, James F %A Halbritter, Jan %A Felix, Janine F %A Divers, Jasmin %A Kooner, Jaspal S %A Lee, Jeannette Jen-Mai %A O'Connell, Jeffrey %A Rotter, Jerome I %A Liu, Jianjun %A Xu, Jie %A Thiery, Joachim %A Arnlöv, Johan %A Kuusisto, Johanna %A Jakobsdottir, Johanna %A Tremblay, Johanne %A Chambers, John C %A Whitfield, John B %A Gaziano, John M %A Marten, Jonathan %A Coresh, Josef %A Jonas, Jost B %A Mychaleckyj, Josyf C %A Christensen, Kaare %A Eckardt, Kai-Uwe %A Mohlke, Karen L %A Endlich, Karlhans %A Dittrich, Katalin %A Ryan, Kathleen A %A Rice, Kenneth M %A Taylor, Kent D %A Ho, Kevin %A Nikus, Kjell %A Matsuda, Koichi %A Strauch, Konstantin %A Miliku, Kozeta %A Hveem, Kristian %A Lind, Lars %A Wallentin, Lars %A Yerges-Armstrong, Laura M %A Raffield, Laura M %A Phillips, Lawrence S %A Launer, Lenore J %A Lyytikäinen, Leo-Pekka %A Lange, Leslie A %A Citterio, Lorena %A Klaric, Lucija %A Ikram, M Arfan %A Ising, Marcus %A Kleber, Marcus E %A Francescatto, Margherita %A Concas, Maria Pina %A Ciullo, Marina %A Piratsu, Mario %A Orho-Melander, Marju %A Laakso, Markku %A Loeffler, Markus %A Perola, Markus %A de Borst, Martin H %A Gögele, Martin %A Bianca, Martina La %A Lukas, Mary Ann %A Feitosa, Mary F %A Biggs, Mary L %A Wojczynski, Mary K %A Kavousi, Maryam %A Kanai, Masahiro %A Akiyama, Masato %A Yasuda, Masayuki %A Nauck, Matthias %A Waldenberger, Melanie %A Chee, Miao-Li %A Chee, Miao-Ling %A Boehnke, Michael %A Preuss, Michael H %A Stumvoll, Michael %A Province, Michael A %A Evans, Michele K %A O'Donoghue, Michelle L %A Kubo, Michiaki %A Kähönen, Mika %A Kastarinen, Mika %A Nalls, Mike A %A Kuokkanen, Mikko %A Ghanbari, Mohsen %A Bochud, Murielle %A Josyula, Navya Shilpa %A Martin, Nicholas G %A Tan, Nicholas Y Q %A Palmer, Nicholette D %A Pirastu, Nicola %A Schupf, Nicole %A Verweij, Niek %A Hutri-Kähönen, Nina %A Mononen, Nina %A Bansal, Nisha %A Devuyst, Olivier %A Melander, Olle %A Raitakari, Olli T %A Polasek, Ozren %A Manunta, Paolo %A Gasparini, Paolo %A Mishra, Pashupati P %A Sulem, Patrick %A Magnusson, Patrik K E %A Elliott, Paul %A Ridker, Paul M %A Hamet, Pavel %A Svensson, Per O %A Joshi, Peter K %A Kovacs, Peter %A Pramstaller, Peter P %A Rossing, Peter %A Vollenweider, Peter %A van der Harst, Pim %A Dorajoo, Rajkumar %A Sim, Ralene Z H %A Burkhardt, Ralph %A Tao, Ran %A Noordam, Raymond %A Mägi, Reedik %A Schmidt, Reinhold %A de Mutsert, Renée %A Rueedi, Rico %A van Dam, Rob M %A Carroll, Robert J %A Gansevoort, Ron T %A Loos, Ruth J F %A Felicita, Sala Cinzia %A Sedaghat, Sanaz %A Padmanabhan, Sandosh %A Freitag-Wolf, Sandra %A Pendergrass, Sarah A %A Graham, Sarah E %A Gordon, Scott D %A Hwang, Shih-Jen %A Kerr, Shona M %A Vaccargiu, Simona %A Patil, Snehal B %A Hallan, Stein %A Bakker, Stephan J L %A Lim, Su-Chi %A Lucae, Susanne %A Vogelezang, Suzanne %A Bergmann, Sven %A Corre, Tanguy %A Ahluwalia, Tarunveer S %A Lehtimäki, Terho %A Boutin, Thibaud S %A Meitinger, Thomas %A Wong, Tien-Yin %A Bergler, Tobias %A Rabelink, Ton J %A Esko, Tõnu %A Haller, Toomas %A Thorsteinsdottir, Unnur %A Völker, Uwe %A Foo, Valencia Hui Xian %A Salomaa, Veikko %A Vitart, Veronique %A Giedraitis, Vilmantas %A Gudnason, Vilmundur %A Jaddoe, Vincent W V %A Huang, Wei %A Zhang, Weihua %A Wei, Wen Bin %A Kiess, Wieland %A März, Winfried %A Koenig, Wolfgang %A Lieb, Wolfgang %A Gào, Xīn %A Sim, Xueling %A Wang, Ya Xing %A Friedlander, Yechiel %A Tham, Yih-Chung %A Kamatani, Yoichiro %A Okada, Yukinori %A Milaneschi, Yuri %A Yu, Zhi %A Stark, Klaus J %A Stefansson, Kari %A Böger, Carsten A %A Hung, Adriana M %A Kronenberg, Florian %A Köttgen, Anna %A Pattaro, Cristian %A Heid, Iris M %K Creatinine %K Diabetes Mellitus %K Diabetic Nephropathies %K Genome-Wide Association Study %K Glomerular Filtration Rate %K Humans %K Kidney %X

Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (n = 178,691, n = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.

%B Commun Biol %V 5 %P 580 %8 2022 Jun 13 %G eng %N 1 %R 10.1038/s42003-022-03448-z %0 Journal Article %J Nat Commun %D 2022 %T {DNA methylation signature of chronic low-grade inflammation and its role in cardio-respiratory diseases %A Wielscher, M. %A Mandaviya, P. R. %A Kuehnel, B. %A Joehanes, R. %A Mustafa, R. %A Robinson, O. %A Zhang, Y. %A Bodinier, B. %A Walton, E. %A Mishra, P. P. %A Schlosser, P. %A Wilson, R. %A Tsai, P. C. %A Palaniswamy, S. %A Marioni, R. E. %A Fiorito, G. %A Cugliari, G. %A Karhunen, V. %A Ghanbari, M. %A Psaty, B. M. %A Loh, M. %A Bis, J. C. %A Lehne, B. %A Sotoodehnia, N. %A Deary, I. J. %A Chadeau-Hyam, M. %A Brody, J. A. %A Cardona, A. %A Selvin, E. %A Smith, A. K. %A Miller, A. H. %A Torres, M. A. %A Marouli, E. %A Gào, X. %A van Meurs, J. B. J. %A Graf-Schindler, J. %A Rathmann, W. %A Koenig, W. %A Peters, A. %A Weninger, W. %A Farlik, M. %A Zhang, T. %A Chen, W. %A Xia, Y. %A Teumer, A. %A Nauck, M. %A Grabe, H. J. %A Doerr, M. %A Lehtimäki, T. %A Guan, W. %A Milani, L. %A Tanaka, T. %A Fisher, K. %A Waite, L. L. %A Kasela, S. %A Vineis, P. %A Verweij, N. %A van der Harst, P. %A Iacoviello, L. %A Sacerdote, C. %A Panico, S. %A Krogh, V. %A Tumino, R. %A Tzala, E. %A Matullo, G. %A Hurme, M. A. %A Raitakari, O. T. %A Colicino, E. %A Baccarelli, A. A. %A Kähönen, M. %A Herzig, K. H. %A Li, S. %A Conneely, K. N. %A Kooner, J. S. %A Köttgen, A. %A Heijmans, B. T. %A Deloukas, P. %A Relton, C. %A Ong, K. K. %A Bell, J. T. %A Boerwinkle, E. %A Elliott, P. %A Brenner, H. %A Beekman, M. %A Levy, D. %A Waldenberger, M. %A Chambers, J. C. %A Dehghan, A. %A Jarvelin, M. R. %X We performed a multi-ethnic Epigenome Wide Association study on 22,774 individuals to describe the DNA methylation signature of chronic low-grade inflammation as measured by C-Reactive protein (CRP). We find 1,511 independent differentially methylated loci associated with CRP. These CpG sites show correlation structures across chromosomes, and are primarily situated in euchromatin, depleted in CpG islands. These genomic loci are predominantly situated in transcription factor binding sites and genomic enhancer regions. Mendelian randomization analysis suggests altered CpG methylation is a consequence of increased blood CRP levels. Mediation analysis reveals obesity and smoking as important underlying driving factors for changed CpG methylation. Finally, we find that an activated CpG signature significantly increases the risk for cardiometabolic diseases and COPD. %B Nat Commun %V 13 %P 2408 %8 05 %G eng %0 Journal Article %J Nat Commun %D 2022 %T Endophenotype effect sizes support variant pathogenicity in monogenic disease susceptibility genes. %A Halford, Jennifer L %A Morrill, Valerie N %A Choi, Seung Hoan %A Jurgens, Sean J %A Melloni, Giorgio %A Marston, Nicholas A %A Weng, Lu-Chen %A Nauffal, Victor %A Hall, Amelia W %A Gunn, Sophia %A Austin-Tse, Christina A %A Pirruccello, James P %A Khurshid, Shaan %A Rehm, Heidi L %A Benjamin, Emelia J %A Boerwinkle, Eric %A Brody, Jennifer A %A Correa, Adolfo %A Fornwalt, Brandon K %A Gupta, Namrata %A Haggerty, Christopher M %A Harris, Stephanie %A Heckbert, Susan R %A Hong, Charles C %A Kooperberg, Charles %A Lin, Henry J %A Loos, Ruth J F %A Mitchell, Braxton D %A Morrison, Alanna C %A Post, Wendy %A Psaty, Bruce M %A Redline, Susan %A Rice, Kenneth M %A Rich, Stephen S %A Rotter, Jerome I %A Schnatz, Peter F %A Soliman, Elsayed Z %A Sotoodehnia, Nona %A Wong, Eugene K %A Sabatine, Marc S %A Ruff, Christian T %A Lunetta, Kathryn L %A Ellinor, Patrick T %A Lubitz, Steven A %K Disease Susceptibility %K Endophenotypes %K Humans %K Long QT Syndrome %K Virulence %X

Accurate and efficient classification of variant pathogenicity is critical for research and clinical care. Using data from three large studies, we demonstrate that population-based associations between rare variants and quantitative endophenotypes for three monogenic diseases (low-density-lipoprotein cholesterol for familial hypercholesterolemia, electrocardiographic QTc interval for long QT syndrome, and glycosylated hemoglobin for maturity-onset diabetes of the young) provide evidence for variant pathogenicity. Effect sizes are associated with pathogenic ClinVar assertions (P < 0.001 for each trait) and discriminate pathogenic from non-pathogenic variants (area under the curve 0.82-0.84 across endophenotypes). An effect size threshold of ≥ 0.5 times the endophenotype standard deviation nominates up to 35% of rare variants of uncertain significance or not in ClinVar in disease susceptibility genes with pathogenic potential. We propose that variant associations with quantitative endophenotypes for monogenic diseases can provide evidence supporting pathogenicity.

%B Nat Commun %V 13 %P 5106 %8 2022 08 30 %G eng %N 1 %R 10.1038/s41467-022-32009-5 %0 Journal Article %J Neurology %D 2022 %T Epilepsy, Vascular Risk Factors, and Cognitive Decline in Older Adults: The Cardiovascular Health Study. %A Choi, Hyunmi %A Elkind, Mitchell S V %A Longstreth, W T %A Boehme, Amelia K %A Hafen, Rebekah %A Hoyt, Emma J %A Thacker, Evan L %K Aged %K Cognition %K Cognitive Dysfunction %K Epilepsy %K Humans %K Longitudinal Studies %K Neuropsychological Tests %K Risk Factors %X

BACKGROUND AND OBJECTIVES: Recent studies have shown that global cognitive ability tends to decline faster over time in older adults (≥65 years) with epilepsy compared with older adults without epilepsy. Scarce data exist about the role of vascular risk factors (VRFs) on cognitive course in epilepsy. We assessed whether the associations of individual VRFs with cognitive trajectory differed depending on the presence of prevalent epilepsy.

METHODS: The Cardiovascular Health Study is a population-based longitudinal cohort study of 5,888 US adults aged ≥65 years. Cognitive function was assessed annually with modified Mini-Mental State Examination (3MS; global cognitive ability) and Digit Symbol Substitution Test (DSST; information processing speed). We used linear mixed models to estimate the individual and joint associations of epilepsy and VRFs with cognitive decline by modeling epilepsy × VRF interactions one by one, each adjusted for all other VRFs considered, including demographics, health behaviors, clinical characteristics, and comorbid diagnoses. From these models, we estimated excess mean cognitive decline due to interaction of epilepsy with each VRF.

RESULTS: We observed excess mean decline in global cognitive ability (3MS) due to interactions of epilepsy with hypertension (6.6 points greater mean 8-year decline than expected if no interaction; 95% CI 1.3-12.0) and with abstaining from alcohol (5.8 points greater than expected; 95% CI 0.3-11.3). We also observed excess mean decline in information processing speed (DSST) due to interactions of epilepsy with prior stroke (18.1 points greater mean 9-year decline than expected; 95% CI 7.6-28.5), with abstaining from alcohol (6.1 points greater than expected; 95% CI 2.5-9.8), and with higher triglyceride levels (2.4 points greater than expected per SD; 95% CI 0.4-4.3).

DISCUSSION: Associations of some VRFs with cognitive decline in older adults are stronger in the presence of epilepsy, suggesting a need for greater attention to vascular protection for preserving brain health in older adults with epilepsy.

%B Neurology %V 99 %P e2346-e2358 %8 2022 Nov 22 %G eng %N 21 %R 10.1212/WNL.0000000000201187 %0 Journal Article %J Brief Bioinform %D 2022 %T eSCAN: scan regulatory regions for aggregate association testing using whole-genome sequencing data. %A Yang, Yingxi %A Sun, Quan %A Huang, Le %A Broome, Jai G %A Correa, Adolfo %A Reiner, Alexander %A Raffield, Laura M %A Yang, Yuchen %A Li, Yun %K Genome %K Genome-Wide Association Study %K Genomics %K Regulatory Sequences, Nucleic Acid %K Whole Genome Sequencing %X

Multiple statistical methods for aggregate association testing have been developed for whole-genome sequencing (WGS) data. Many aggregate variants in a given genomic window and ignore existing knowledge to define test regions, resulting in many identified regions not clearly linked to genes, and thus, limiting biological understanding. Functional information from new technologies (such as Hi-C and its derivatives), which can help link enhancers to their effector genes, can be leveraged to predefine variant sets for aggregate testing in WGS data. Here, we propose the eSCAN (scan the enhancers) method for genome-wide assessment of enhancer regions in sequencing studies, combining the advantages of dynamic window selection in SCANG (SCAN the Genome), a previously developed method, with the advantages of incorporating putative regulatory regions from annotation. eSCAN, by searching in putative enhancers, increases statistical power and aids mechanistic interpretation, as demonstrated by extensive simulation studies. We also apply eSCAN for blood cell traits using NHLBI Trans-Omics for Precision Medicine WGS data. Results from real data analysis show that eSCAN is able to capture more significant signals, and these signals are of shorter length (indicating higher resolution fine-mapping capability) and drive association of larger regions detected by other methods.

%B Brief Bioinform %V 23 %8 2022 01 17 %G eng %N 1 %R 10.1093/bib/bbab497 %0 Journal Article %J Nutr Metab Cardiovasc Dis %D 2022 %T Fishing for health: Neighborhood variation in fish intake, fish quality and association with stroke risk among older adults in the Cardiovascular Health Study. %A Liang, Li-Jung %A Casillas, Alejandra %A Longstreth, W T %A PhanVo, Lynn %A Vassar, Stefanie D %A Brown, Arleen F %X

BACKGROUND AND AIMS: Fish consumption has been associated with better health outcomes. Dietary patterns may vary substantially by neighborhood of residence. However, it is unclear if the benefits of a healthy diet are equivalent in different communities. This study examines associations of fish consumption with stroke incidence and stroke risk factors, and whether these differ by neighborhood socioeconomic status (NSES).

METHODS AND RESULTS: We studied 4007 participants in the Cardiovascular Health Study who were 65 years or older and recruited between 1989 and 1990 from 4 US communities. Outcomes included fish consumption type (bakes/broiled vs. fried) and frequency, stroke incidence, and stroke risk factors. Multilevel regressions models were used to estimate fish consumption associations with clinical outcomes. Lower NSES was associated with higher consumption of fried fish (aOR = 1.47, 95% CI: 1.10-1.98) and lower consumption of non-fried fish (0.64, 0.47-0.86). Frequent fried fish (11.9 vs. 9.2 person-years for at least once weekly vs. less than once a month, respectively) and less frequent non-fried fish (17.7 vs. 9.6 person-years for less than once a month vs. at least once weekly, respectively) were independently associated with an increased risk of stroke (p-values < 0.05). However, among those with similar levels of healthy fish consumption, residents with low NSES had less benefit on stroke risk reduction, compared with high NSES.

CONCLUSION: Fish consumption type and frequency both impact stroke risk. Benefits of healthy fish consumption differ by neighborhood socioeconomic status.

%B Nutr Metab Cardiovasc Dis %8 2022 Mar 12 %G eng %R 10.1016/j.numecd.2022.03.005 %0 Journal Article %J Nat Methods %D 2022 %T A framework for detecting noncoding rare-variant associations of large-scale whole-genome sequencing studies. %A Li, Zilin %A Li, Xihao %A Zhou, Hufeng %A Gaynor, Sheila M %A Selvaraj, Margaret Sunitha %A Arapoglou, Theodore %A Quick, Corbin %A Liu, Yaowu %A Chen, Han %A Sun, Ryan %A Dey, Rounak %A Arnett, Donna K %A Auer, Paul L %A Bielak, Lawrence F %A Bis, Joshua C %A Blackwell, Thomas W %A Blangero, John %A Boerwinkle, Eric %A Bowden, Donald W %A Brody, Jennifer A %A Cade, Brian E %A Conomos, Matthew P %A Correa, Adolfo %A Cupples, L Adrienne %A Curran, Joanne E %A de Vries, Paul S %A Duggirala, Ravindranath %A Franceschini, Nora %A Freedman, Barry I %A Göring, Harald H H %A Guo, Xiuqing %A Kalyani, Rita R %A Kooperberg, Charles %A Kral, Brian G %A Lange, Leslie A %A Lin, Bridget M %A Manichaikul, Ani %A Manning, Alisa K %A Martin, Lisa W %A Mathias, Rasika A %A Meigs, James B %A Mitchell, Braxton D %A Montasser, May E %A Morrison, Alanna C %A Naseri, Take %A O'Connell, Jeffrey R %A Palmer, Nicholette D %A Peyser, Patricia A %A Psaty, Bruce M %A Raffield, Laura M %A Redline, Susan %A Reiner, Alexander P %A Reupena, Muagututi'a Sefuiva %A Rice, Kenneth M %A Rich, Stephen S %A Smith, Jennifer A %A Taylor, Kent D %A Taub, Margaret A %A Vasan, Ramachandran S %A Weeks, Daniel E %A Wilson, James G %A Yanek, Lisa R %A Zhao, Wei %A Rotter, Jerome I %A Willer, Cristen J %A Natarajan, Pradeep %A Peloso, Gina M %A Lin, Xihong %K Genetic Variation %K Genome %K Genome-Wide Association Study %K Humans %K Phenotype %K Whole Genome Sequencing %X

Large-scale whole-genome sequencing studies have enabled analysis of noncoding rare-variant (RV) associations with complex human diseases and traits. Variant-set analysis is a powerful approach to study RV association. However, existing methods have limited ability in analyzing the noncoding genome. We propose a computationally efficient and robust noncoding RV association detection framework, STAARpipeline, to automatically annotate a whole-genome sequencing study and perform flexible noncoding RV association analysis, including gene-centric analysis and fixed window-based and dynamic window-based non-gene-centric analysis by incorporating variant functional annotations. In gene-centric analysis, STAARpipeline uses STAAR to group noncoding variants based on functional categories of genes and incorporate multiple functional annotations. In non-gene-centric analysis, STAARpipeline uses SCANG-STAAR to incorporate dynamic window sizes and multiple functional annotations. We apply STAARpipeline to identify noncoding RV sets associated with four lipid traits in 21,015 discovery samples from the Trans-Omics for Precision Medicine (TOPMed) program and replicate several of them in an additional 9,123 TOPMed samples. We also analyze five non-lipid TOPMed traits.

%B Nat Methods %V 19 %P 1599-1611 %8 2022 Dec %G eng %N 12 %R 10.1038/s41592-022-01640-x %0 Journal Article %J Am J Ophthalmol %D 2022 %T {Gene Set Enrichment Analsyes Identify Pathways Involved in Genetic Risk for Diabetic Retinopathy %A Sobrin, L. %A Susarla, G. %A Stanwyck, L. %A Rouhana, J. M. %A Li, A. %A Pollack, S. %A Igo, R. P. %A Jensen, R. A. %A Li, X. %A Ng, M. C. Y. %A Smith, A. V. %A Kuo, J. Z. %A Taylor, K. D. %A Freedman, B. I. %A Bowden, D. W. %A Penman, A. %A Chen, C. J. %A Craig, J. E. %A Adler, S. G. %A Chew, E. Y. %A Cotch, M. F. %A Yaspan, B. %A Mitchell, P. %A Wang, J. J. %A Klein, B. E. K. %A Wong, T. Y. %A Rotter, J. I. %A Burdon, K. P. %A Iyengar, S. K. %A Segrè, A. V. %X {To identify functionally related genes associated with diabetic retinopathy (DR) risk using gene set enrichment analyses applied to genome-wide association study meta-analyses.\ .05.\ .05) in the other method. These pathways were regulation of the lipid catabolic process (2-fold enrichment %B Am J Ophthalmol %V 233 %P 111–123 %8 01 %G eng %0 Journal Article %J Brain %D 2022 %T {Gene-mapping study of extremes of cerebral small vessel disease reveals TRIM47 as a strong candidate %A Mishra, A. %A Duplaà, C. %A Vojinovic, D. %A Suzuki, H. %A Sargurupremraj, M. %A Zilhao, N. R. %A Li, S. %A Bartz, T. M. %A Jian, X. %A Zhao, W. %A Hofer, E. %A Wittfeld, K. %A Harris, S. E. %A van der Auwera-Palitschka, S. %A Luciano, M. %A Bis, J. C. %A Adams, H. H. H. %A Satizabal, C. L. %A Gottesman, R. F. %A Gampawar, P. G. %A Bülow, R. %A Weiss, S. %A Yu, M. %A Bastin, M. E. %A Lopez, O. L. %A Vernooij, M. W. %A Beiser, A. S. %A Völker, U. %A Kacprowski, T. %A Soumare, A. %A Smith, J. A. %A Knopman, D. S. %A Morris, Z. %A Zhu, Y. %A Rotter, J. I. %A Dufouil, C. %A Valdés Hernández, M. %A Muñoz Maniega, S. %A Lathrop, M. %A Boerwinkle, E. %A Schmidt, R. %A Ihara, M. %A Mazoyer, B. %A Yang, Q. %A Joutel, A. %A Tournier-Lasserve, E. %A Launer, L. J. %A Deary, I. J. %A Mosley, T. H. %A Amouyel, P. %A DeCarli, C. S. %A Psaty, B. M. %A Tzourio, C. %A Kardia, S. L. R. %A Grabe, H. J. %A Teumer, A. %A van Duijn, C. M. %A Schmidt, H. %A Wardlaw, J. M. %A Ikram, M. A. %A Fornage, M. %A Gudnason, V. %A Seshadri, S. %A Matthews, P. M. %A Longstreth, W. T. %A Couffinhal, T. %A Debette, S. %X Cerebral small vessel disease is a leading cause of stroke and a major contributor to cognitive decline and dementia, but our understanding of specific genes underlying the cause of sporadic cerebral small vessel disease is limited. We report a genome-wide association study and a whole-exome association study on a composite extreme phenotype of cerebral small vessel disease derived from its most common MRI features: white matter hyperintensities and lacunes. Seventeen population-based cohorts of older persons with MRI measurements and genome-wide genotyping (n = 41 326), whole-exome sequencing (n = 15 965), or exome chip (n = 5249) data contributed 13 776 and 7079 extreme small vessel disease samples for the genome-wide association study and whole-exome association study, respectively. The genome-wide association study identified significant association of common variants in 11 loci with extreme small vessel disease, of which the chr12q24.11 locus was not previously reported to be associated with any MRI marker of cerebral small vessel disease. The whole-exome association study identified significant associations of extreme small vessel disease with common variants in the 5' UTR region of EFEMP1 (chr2p16.1) and one probably damaging common missense variant in TRIM47 (chr17q25.1). Mendelian randomization supports the causal association of extensive small vessel disease severity with increased risk of stroke and Alzheimer's disease. Combined evidence from summary-based Mendelian randomization studies and profiling of human loss-of-function allele carriers showed an inverse relation between TRIM47 expression in the brain and blood vessels and extensive small vessel disease severity. We observed significant enrichment of Trim47 in isolated brain vessel preparations compared to total brain fraction in mice, in line with the literature showing Trim47 enrichment in brain endothelial cells at single cell level. Functional evaluation of TRIM47 by small interfering RNAs-mediated knockdown in human brain endothelial cells showed increased endothelial permeability, an important hallmark of cerebral small vessel disease pathology. Overall, our comprehensive gene-mapping study and preliminary functional evaluation suggests a putative role of TRIM47 in the pathophysiology of cerebral small vessel disease, making it an important candidate for extensive in vivo explorations and future translational work. %B Brain %V 145 %P 1992–2007 %8 Jun %G eng %0 Journal Article %J Nat Commun %D 2022 %T {Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways %A Young, W. J. %A Lahrouchi, N. %A Isaacs, A. %A Duong, T. %A Foco, L. %A Ahmed, F. %A Brody, J. A. %A Salman, R. %A Noordam, R. %A Benjamins, J. W. %A Haessler, J. %A Lyytikäinen, L. P. %A Repetto, L. %A Concas, M. P. %A van den Berg, M. E. %A Weiss, S. %A Baldassari, A. R. %A Bartz, T. M. %A Cook, J. P. %A Evans, D. S. %A Freudling, R. %A Hines, O. %A Isaksen, J. L. %A Lin, H. %A Mei, H. %A Moscati, A. %A Müller-Nurasyid, M. %A Nursyifa, C. %A Qian, Y. %A Richmond, A. %A Roselli, C. %A Ryan, K. A. %A Tarazona-Santos, E. %A Thériault, S. %A van Duijvenboden, S. %A Warren, H. R. %A Yao, J. %A Raza, D. %A Aeschbacher, S. %A Ahlberg, G. %A Alonso, A. %A Andreasen, L. %A Bis, J. C. %A Boerwinkle, E. %A Campbell, A. %A Catamo, E. %A Cocca, M. %A Cutler, M. J. %A Darbar, D. %A De Grandi, A. %A De Luca, A. %A Ding, J. %A Ellervik, C. %A Ellinor, P. T. %A Felix, S. B. %A Froguel, P. %A Fuchsberger, C. %A Gögele, M. %A Graff, C. %A Graff, M. %A Guo, X. %A Hansen, T. %A Heckbert, S. R. %A Huang, P. L. %A Huikuri, H. V. %A Hutri-Kähönen, N. %A Ikram, M. A. %A Jackson, R. D. %A Junttila, J. %A Kavousi, M. %A Kors, J. A. %A Leal, T. P. %A Lemaitre, R. N. %A Lin, H. J. %A Lind, L. %A Linneberg, A. %A Liu, S. %A Macfarlane, P. W. %A Mangino, M. %A Meitinger, T. %A Mezzavilla, M. %A Mishra, P. P. %A Mitchell, R. N. %A Mononen, N. %A Montasser, M. E. %A Morrison, A. C. %A Nauck, M. %A Nauffal, V. %A Navarro, P. %A Nikus, K. %A Pare, G. %A Patton, K. K. %A Pelliccione, G. %A Pittman, A. %A Porteous, D. J. %A Pramstaller, P. P. %A Preuss, M. H. %A Raitakari, O. T. %A Reiner, A. P. %A Ribeiro, A. L. P. %A Rice, K. M. %A Risch, L. %A Schlessinger, D. %A Schotten, U. %A Schurmann, C. %A Shen, X. %A Shoemaker, M. B. %A Sinagra, G. %A Sinner, M. F. %A Soliman, E. Z. %A Stoll, M. %A Strauch, K. %A Tarasov, K. %A Taylor, K. D. %A Tinker, A. %A Trompet, S. %A Uitterlinden, A. %A Völker, U. %A Völzke, H. %A Waldenberger, M. %A Weng, L. C. %A Whitsel, E. A. %A Wilson, J. G. %A Avery, C. L. %A Conen, D. %A Correa, A. %A Cucca, F. %A Dörr, M. %A Gharib, S. A. %A Girotto, G. %A Grarup, N. %A Hayward, C. %A Jamshidi, Y. %A Jarvelin, M. R. %A Jukema, J. W. %A Kääb, S. %A Kähönen, M. %A Kanters, J. K. %A Kooperberg, C. %A Lehtimäki, T. %A Lima-Costa, M. F. %A Liu, Y. %A Loos, R. J. F. %A Lubitz, S. A. %A Mook-Kanamori, D. O. %A Morris, A. P. %A O'Connell, J. R. %A Olesen, M. S. %A Orini, M. %A Padmanabhan, S. %A Pattaro, C. %A Peters, A. %A Psaty, B. M. %A Rotter, J. I. %A Stricker, B. %A van der Harst, P. %A van Duijn, C. M. %A Verweij, N. %A Wilson, J. F. %A Arking, D. E. %A Ramirez, J. %A Lambiase, P. D. %A Sotoodehnia, N. %A Mifsud, B. %A Newton-Cheh, C. %A Munroe, P. B. %X 250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization. %B Nat Commun %V 13 %P 5144 %8 09 %G eng %0 Journal Article %J Hum Mol Genet %D 2022 %T {Genetic and clinical determinants of abdominal aortic diameter: genome-wide association studies, exome array data and Mendelian randomization study %A Portilla-Fernandez, E. %A Klarin, D. %A Hwang, S. J. %A Biggs, M. L. %A Bis, J. C. %A Weiss, S. %A Rospleszcz, S. %A Natarajan, P. %A Hoffmann, U. %A Rogers, I. S. %A Truong, Q. A. %A lker, U. %A rr, M. %A low, R. %A Criqui, M. H. %A Allison, M. %A Ganesh, S. K. %A Yao, J. %A Waldenberger, M. %A Bamberg, F. %A Rice, K. M. %A Essers, J. %A Kapteijn, D. M. C. %A van der Laan, S. W. %A de Knegt, R. J. %A Ghanbari, M. %A Felix, J. F. %A Ikram, M. A. %A Kavousi, M. %A Uitterlinden, A. G. %A Roks, A. J. M. %A Danser, A. H. J. %A Tsao, P. S. %A Damrauer, S. M. %A Guo, X. %A Rotter, J. I. %A Psaty, B. M. %A Kathiresan, S. %A lzke, H. %A Peters, A. %A Johnson, C. %A Strauch, K. %A Meitinger, T. %A O'Donnell, C. J. %A Dehghan, A. %X 0.0001), known risk factors for AAA, consistent with a causal association with AAD. Our findings point to new biology as well as highlighting gene regions in mechanisms that have previously been implicated in the genetics of other vascular diseases. %B Hum Mol Genet %V 31 %P 3566–3579 %8 Oct %G eng %0 Journal Article %J Kidney Int %D 2022 %T Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies. %A Gorski, Mathias %A Rasheed, Humaira %A Teumer, Alexander %A Thomas, Laurent F %A Graham, Sarah E %A Sveinbjornsson, Gardar %A Winkler, Thomas W %A Günther, Felix %A Stark, Klaus J %A Chai, Jin-Fang %A Tayo, Bamidele O %A Wuttke, Matthias %A Li, Yong %A Tin, Adrienne %A Ahluwalia, Tarunveer S %A Arnlöv, Johan %A Åsvold, Bjørn Olav %A Bakker, Stephan J L %A Banas, Bernhard %A Bansal, Nisha %A Biggs, Mary L %A Biino, Ginevra %A Böhnke, Michael %A Boerwinkle, Eric %A Bottinger, Erwin P %A Brenner, Hermann %A Brumpton, Ben %A Carroll, Robert J %A Chaker, Layal %A Chalmers, John %A Chee, Miao-Li %A Chee, Miao-Ling %A Cheng, Ching-Yu %A Chu, Audrey Y %A Ciullo, Marina %A Cocca, Massimiliano %A Cook, James P %A Coresh, Josef %A Cusi, Daniele %A de Borst, Martin H %A Degenhardt, Frauke %A Eckardt, Kai-Uwe %A Endlich, Karlhans %A Evans, Michele K %A Feitosa, Mary F %A Franke, Andre %A Freitag-Wolf, Sandra %A Fuchsberger, Christian %A Gampawar, Piyush %A Gansevoort, Ron T %A Ghanbari, Mohsen %A Ghasemi, Sahar %A Giedraitis, Vilmantas %A Gieger, Christian %A Gudbjartsson, Daniel F %A Hallan, Stein %A Hamet, Pavel %A Hishida, Asahi %A Ho, Kevin %A Hofer, Edith %A Holleczek, Bernd %A Holm, Hilma %A Hoppmann, Anselm %A Horn, Katrin %A Hutri-Kähönen, Nina %A Hveem, Kristian %A Hwang, Shih-Jen %A Ikram, M Arfan %A Josyula, Navya Shilpa %A Jung, Bettina %A Kähönen, Mika %A Karabegović, Irma %A Khor, Chiea-Chuen %A Koenig, Wolfgang %A Kramer, Holly %A Krämer, Bernhard K %A Kuhnel, Brigitte %A Kuusisto, Johanna %A Laakso, Markku %A Lange, Leslie A %A Lehtimäki, Terho %A Li, Man %A Lieb, Wolfgang %A Lind, Lars %A Lindgren, Cecilia M %A Loos, Ruth J F %A Lukas, Mary Ann %A Lyytikäinen, Leo-Pekka %A Mahajan, Anubha %A Matias-Garcia, Pamela R %A Meisinger, Christa %A Meitinger, Thomas %A Melander, Olle %A Milaneschi, Yuri %A Mishra, Pashupati P %A Mononen, Nina %A Morris, Andrew P %A Mychaleckyj, Josyf C %A Nadkarni, Girish N %A Naito, Mariko %A Nakatochi, Masahiro %A Nalls, Mike A %A Nauck, Matthias %A Nikus, Kjell %A Ning, Boting %A Nolte, Ilja M %A Nutile, Teresa %A O'Donoghue, Michelle L %A O'Connell, Jeffrey %A Olafsson, Isleifur %A Orho-Melander, Marju %A Parsa, Afshin %A Pendergrass, Sarah A %A Penninx, Brenda W J H %A Pirastu, Mario %A Preuss, Michael H %A Psaty, Bruce M %A Raffield, Laura M %A Raitakari, Olli T %A Rheinberger, Myriam %A Rice, Kenneth M %A Rizzi, Federica %A Rosenkranz, Alexander R %A Rossing, Peter %A Rotter, Jerome I %A Ruggiero, Daniela %A Ryan, Kathleen A %A Sabanayagam, Charumathi %A Salvi, Erika %A Schmidt, Helena %A Schmidt, Reinhold %A Scholz, Markus %A Schöttker, Ben %A Schulz, Christina-Alexandra %A Sedaghat, Sanaz %A Shaffer, Christian M %A Sieber, Karsten B %A Sim, Xueling %A Sims, Mario %A Snieder, Harold %A Stanzick, Kira J %A Thorsteinsdottir, Unnur %A Stocker, Hannah %A Strauch, Konstantin %A Stringham, Heather M %A Sulem, Patrick %A Szymczak, Silke %A Taylor, Kent D %A Thio, Chris H L %A Tremblay, Johanne %A Vaccargiu, Simona %A van der Harst, Pim %A van der Most, Peter J %A Verweij, Niek %A Völker, Uwe %A Wakai, Kenji %A Waldenberger, Melanie %A Wallentin, Lars %A Wallner, Stefan %A Wang, Judy %A Waterworth, Dawn M %A White, Harvey D %A Willer, Cristen J %A Wong, Tien-Yin %A Woodward, Mark %A Yang, Qiong %A Yerges-Armstrong, Laura M %A Zimmermann, Martina %A Zonderman, Alan B %A Bergler, Tobias %A Stefansson, Kari %A Böger, Carsten A %A Pattaro, Cristian %A Köttgen, Anna %A Kronenberg, Florian %A Heid, Iris M %X

Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genome-wide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR-baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant-by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with age-dependency of genetic cross-section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in-silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03-1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.

%B Kidney Int %8 2022 Jun 16 %G eng %R 10.1016/j.kint.2022.05.021 %0 Journal Article %J iScience %D 2022 %T Genome-wide analyses identify as a susceptibility locus for premature atrial contraction frequency. %A Thériault, Sébastien %A Imboden, Medea %A Biggs, Mary L %A Austin, Thomas R %A Aeschbacher, Stefanie %A Schaffner, Emmanuel %A Brody, Jennifer A %A Bartz, Traci M %A Risch, Martin %A Grossmann, Kirsten %A Lin, Henry J %A Soliman, Elsayed Z %A Post, Wendy S %A Risch, Lorenz %A Krieger, Jose E %A Pereira, Alexandre C %A Heckbert, Susan R %A Sotoodehnia, Nona %A Probst-Hensch, Nicole M %A Conen, David %X

Premature atrial contractions (PACs) are frequently observed on electrocardiograms and are associated with increased risks of atrial fibrillation (AF), stroke, and mortality. In this study, we aimed to identify genetic susceptibility loci for PAC frequency. We performed a genome-wide association study meta-analysis with PAC frequency obtained from ambulatory cardiac monitoring in 4,831 individuals of European ancestry. We identified a genome-wide significant locus at the gene. The lead variant, rs7373862, located in an intron of , was associated with an increase of 0.12 [95% CI 0.08-0.16] standard deviations of the normalized PAC frequency per risk allele. Among genetic variants previously associated with AF, there was a significant enrichment in concordance of effect for PAC frequency (n = 73/106, p = 5.1 × 10). However, several AF risk loci, including , were not associated with PAC frequency. These findings suggest the existence of both shared and distinct genetic mechanisms for PAC frequency and AF.

%B iScience %V 25 %P 105210 %8 2022 Oct 21 %G eng %N 10 %R 10.1016/j.isci.2022.105210 %0 Journal Article %J Hum Genet %D 2022 %T {Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation %A Longchamps, R. J. %A Yang, S. Y. %A Castellani, C. A. %A Shi, W. %A Lane, J. %A Grove, M. L. %A Bartz, T. M. %A Sarnowski, C. %A Liu, C. %A Burrows, K. %A Guyatt, A. L. %A Gaunt, T. R. %A Kacprowski, T. %A Yang, J. %A De Jager, P. L. %A Yu, L. %A Bergman, A. %A Xia, R. %A Fornage, M. %A Feitosa, M. F. %A Wojczynski, M. K. %A Kraja, A. T. %A Province, M. A. %A Amin, N. %A Rivadeneira, F. %A Tiemeier, H. %A Uitterlinden, A. G. %A Broer, L. %A van Meurs, J. B. J. %A van Duijn, C. M. %A Raffield, L. M. %A Lange, L. %A Rich, S. S. %A Lemaitre, R. N. %A Goodarzi, M. O. %A Sitlani, C. M. %A Mak, A. C. Y. %A Bennett, D. A. %A Rodriguez, S. %A Murabito, J. M. %A Lunetta, K. L. %A Sotoodehnia, N. %A Atzmon, G. %A Ye, K. %A Barzilai, N. %A Brody, J. A. %A Psaty, B. M. %A Taylor, K. D. %A Rotter, J. I. %A Boerwinkle, E. %A Pankratz, N. %A Arking, D. E. %X ). %B Hum Genet %V 141 %P 127–146 %8 Jan %G eng %0 Journal Article %J Mol Psychiatry %D 2022 %T Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning. %A Lahti, Jari %A Tuominen, Samuli %A Yang, Qiong %A Pergola, Giulio %A Ahmad, Shahzad %A Amin, Najaf %A Armstrong, Nicola J %A Beiser, Alexa %A Bey, Katharina %A Bis, Joshua C %A Boerwinkle, Eric %A Bressler, Jan %A Campbell, Archie %A Campbell, Harry %A Chen, Qiang %A Corley, Janie %A Cox, Simon R %A Davies, Gail %A De Jager, Philip L %A Derks, Eske M %A Faul, Jessica D %A Fitzpatrick, Annette L %A Fohner, Alison E %A Ford, Ian %A Fornage, Myriam %A Gerring, Zachary %A Grabe, Hans J %A Grodstein, Francine %A Gudnason, Vilmundur %A Simonsick, Eleanor %A Holliday, Elizabeth G %A Joshi, Peter K %A Kajantie, Eero %A Kaprio, Jaakko %A Karell, Pauliina %A Kleineidam, Luca %A Knol, Maria J %A Kochan, Nicole A %A Kwok, John B %A Leber, Markus %A Lam, Max %A Lee, Teresa %A Li, Shuo %A Loukola, Anu %A Luck, Tobias %A Marioni, Riccardo E %A Mather, Karen A %A Medland, Sarah %A Mirza, Saira S %A Nalls, Mike A %A Nho, Kwangsik %A O'Donnell, Adrienne %A Oldmeadow, Christopher %A Painter, Jodie %A Pattie, Alison %A Reppermund, Simone %A Risacher, Shannon L %A Rose, Richard J %A Sadashivaiah, Vijay %A Scholz, Markus %A Satizabal, Claudia L %A Schofield, Peter W %A Schraut, Katharina E %A Scott, Rodney J %A Simino, Jeannette %A Smith, Albert V %A Smith, Jennifer A %A Stott, David J %A Surakka, Ida %A Teumer, Alexander %A Thalamuthu, Anbupalam %A Trompet, Stella %A Turner, Stephen T %A van der Lee, Sven J %A Villringer, Arno %A Völker, Uwe %A Wilson, Robert S %A Wittfeld, Katharina %A Vuoksimaa, Eero %A Xia, Rui %A Yaffe, Kristine %A Yu, Lei %A Zare, Habil %A Zhao, Wei %A Ames, David %A Attia, John %A Bennett, David A %A Brodaty, Henry %A Chasman, Daniel I %A Goldman, Aaron L %A Hayward, Caroline %A Ikram, M Arfan %A Jukema, J Wouter %A Kardia, Sharon L R %A Lencz, Todd %A Loeffler, Markus %A Mattay, Venkata S %A Palotie, Aarno %A Psaty, Bruce M %A Ramirez, Alfredo %A Ridker, Paul M %A Riedel-Heller, Steffi G %A Sachdev, Perminder S %A Saykin, Andrew J %A Scherer, Martin %A Schofield, Peter R %A Sidney, Stephen %A Starr, John M %A Trollor, Julian %A Ulrich, William %A Wagner, Michael %A Weir, David R %A Wilson, James F %A Wright, Margaret J %A Weinberger, Daniel R %A Debette, Stephanie %A Eriksson, Johan G %A Mosley, Thomas H %A Launer, Lenore J %A van Duijn, Cornelia M %A Deary, Ian J %A Seshadri, Sudha %A Räikkönen, Katri %X

Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.

%B Mol Psychiatry %8 2022 Aug 16 %G eng %R 10.1038/s41380-022-01710-8 %0 Journal Article %J JCI Insight %D 2022 %T {Genome-wide studies reveal factors associated with circulating uromodulin and its relationships to complex diseases %A Li, Y. %A Cheng, Y. %A Consolato, F. %A Schiano, G. %A Chong, M. R. %A Pietzner, M. %A Nguyen, N. Q. H. %A Scherer, N. %A Biggs, M. L. %A Kleber, M. E. %A Haug, S. %A Göçmen, B. %A Pigeyre, M. %A Sekula, P. %A Steinbrenner, I. %A Schlosser, P. %A Joseph, C. B. %A Brody, J. A. %A Grams, M. E. %A Hayward, C. %A Schultheiss, U. T. %A Krämer, B. K. %A Kronenberg, F. %A Peters, A. %A Seissler, J. %A Steubl, D. %A Then, C. %A Wuttke, M. %A März, W. %A Eckardt, K. U. %A Gieger, C. %A Boerwinkle, E. %A Psaty, B. M. %A Coresh, J. %A Oefner, P. J. %A Pare, G. %A Langenberg, C. %A Scherberich, J. E. %A Yu, B. %A Akilesh, S. %A Devuyst, O. %A Rampoldi, L. %A Köttgen, A. %X Uromodulin (UMOD) is a major risk gene for monogenic and complex forms of kidney disease. The encoded kidney-specific protein uromodulin is highly abundant in urine and related to chronic kidney disease, hypertension, and pathogen defense. To gain insights into potential systemic roles, we performed genome-wide screens of circulating uromodulin using complementary antibody-based and aptamer-based assays. We detected 3 and 10 distinct significant loci, respectively. Integration of antibody-based results at the UMOD locus with functional genomics data (RNA-Seq, ATAC-Seq, Hi-C) of primary human kidney tissue highlighted an upstream variant with differential accessibility and transcription in uromodulin-synthesizing kidney cells as underlying the observed cis effect. Shared association patterns with complex traits, including chronic kidney disease and blood pressure, placed the PRKAG2 locus in the same pathway as UMOD. Experimental validation of the third antibody-based locus, B4GALNT2, showed that the p.Cys466Arg variant of the encoded N-acetylgalactosaminyltransferase had a loss-of-function effect leading to higher serum uromodulin levels. Aptamer-based results pointed to enzymes writing glycan marks present on uromodulin and to their receptors in the circulation, suggesting that this assay permits investigating uromodulin's complex glycosylation rather than its quantitative levels. Overall, our study provides insights into circulating uromodulin and its emerging functions. %B JCI Insight %V 7 %8 05 %G eng %0 Journal Article %J Cardiovasc Diabetol %D 2022 %T Glucose dysregulation and subclinical cardiac dysfunction in older adults: The Cardiovascular Health Study. %A Garg, Parveen K %A Biggs, Mary L %A Kizer, Jorge R %A Shah, Sanjiv J %A Psaty, Bruce %A Carnethon, Mercedes %A Gottdiener, John S %A Siscovick, David %A Mukamal, Kenneth J %K Aged %K Cross-Sectional Studies %K Female %K Glucose %K Humans %K Insulin Resistance %K Male %K Ventricular Dysfunction, Left %K Ventricular Function, Left %X

OBJECTIVE: We evaluated whether measures of glucose dysregulation are associated with subclinical cardiac dysfunction, as assessed by speckle-tracking echocardiography, in an older population.

METHODS: Participants were men and women in the Cardiovascular Health Study, age 65+ years and without coronary heart disease, atrial fibrillation, or heart failure at baseline. We evaluated fasting insulin resistance (IR) with the homeostatic model of insulin resistance (HOMA-IR) and estimated the Matsuda insulin sensitivity index (ISI) and insulin secretion with an oral glucose tolerance test. Systolic and diastolic cardiac mechanics were measured with speckle-tracking analysis of echocardiograms. Multi-variable adjusted linear regression models were used to investigate associations of insulin measures and cardiac mechanics.

RESULTS: Mean age for the 2433 included participants was 72.0 years, 33.6% were male, and 3.7% were black. After adjustment for age, sex, race, site, speckle-tracking analyst, echo image and quality score, higher HOMA-IR, lower Matsuda ISI, and higher insulin secretion were each associated with worse left ventricular (LV) longitudinal strain and LV early diastolic strain rate (p-value < 0.005); however, associations were significantly attenuated after adjustment for waist circumference, with the exception of Matsuda ISI and LV longitudinal strain (increase in strain per standard deviation increment in Matsuda ISI = 0.18; 95% confidence interval = 0.03-0.33).

CONCLUSION: In this cross-sectional study of older adults, associations of glucose dysregulation with subclinical cardiac dysfunction were largely attenuated after adjusting for central adiposity.

%B Cardiovasc Diabetol %V 21 %P 112 %8 2022 Jun 20 %G eng %N 1 %R 10.1186/s12933-022-01547-z %0 Journal Article %J Genome Biol %D 2022 %T {Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis %A Kanoni, S. %A Graham, S. E. %A Wang, Y. %A Surakka, I. %A Ramdas, S. %A Zhu, X. %A Clarke, S. L. %A Bhatti, K. F. %A Vedantam, S. %A Winkler, T. W. %A Locke, A. E. %A Marouli, E. %A Zajac, G. J. M. %A Wu, K. H. %A Ntalla, I. %A Hui, Q. %A Klarin, D. %A Hilliard, A. T. %A Wang, Z. %A Xue, C. %A Thorleifsson, G. %A Helgadottir, A. %A Gudbjartsson, D. F. %A Holm, H. %A Olafsson, I. %A Hwang, M. Y. %A Han, S. %A Akiyama, M. %A Sakaue, S. %A Terao, C. %A Kanai, M. %A Zhou, W. %A Brumpton, B. M. %A Rasheed, H. %A Havulinna, A. S. %A Veturi, Y. %A Pacheco, J. A. %A Rosenthal, E. A. %A Lingren, T. %A Feng, Q. %A Kullo, I. J. %A Narita, A. %A Takayama, J. %A Martin, H. C. %A Hunt, K. A. %A Trivedi, B. %A Haessler, J. %A Giulianini, F. %A Bradford, Y. %A Miller, J. E. %A Campbell, A. %A Lin, K. %A Millwood, I. Y. %A Rasheed, A. %A Hindy, G. %A Faul, J. D. %A Zhao, W. %A Weir, D. R. %A Turman, C. %A Huang, H. %A Graff, M. %A Choudhury, A. %A Sengupta, D. %A Mahajan, A. %A Brown, M. R. %A Zhang, W. %A Yu, K. %A Schmidt, E. M. %A Pandit, A. %A Gustafsson, S. %A Yin, X. %A Luan, J. %A Zhao, J. H. %A Matsuda, F. %A Jang, H. M. %A Yoon, K. %A Medina-Gomez, C. %A Pitsillides, A. %A Hottenga, J. J. %A Wood, A. R. %A Ji, Y. %A Gao, Z. %A Haworth, S. %A Yousri, N. A. %A Mitchell, R. E. %A Chai, J. F. %A Aadahl, M. %A Bjerregaard, A. A. %A Yao, J. %A Manichaikul, A. %A Hwu, C. M. %A Hung, Y. J. %A Warren, H. R. %A Ramirez, J. %A Bork-Jensen, J. %A rhus, L. L. %A Goel, A. %A Sabater-Lleal, M. %A Noordam, R. %A Mauro, P. %A Matteo, F. %A McDaid, A. F. %A Marques-Vidal, P. %A Wielscher, M. %A Trompet, S. %A Sattar, N. %A llehave, L. T. %A Munz, M. %A Zeng, L. %A Huang, J. %A Yang, B. %A Poveda, A. %A Kurbasic, A. %A Lamina, C. %A Forer, L. %A Scholz, M. %A Galesloot, T. E. %A Bradfield, J. P. %A Ruotsalainen, S. E. %A Daw, E. %A Zmuda, J. M. %A Mitchell, J. S. %A Fuchsberger, C. %A Christensen, H. %A Brody, J. A. %A Vazquez-Moreno, M. %A Feitosa, M. F. %A Wojczynski, M. K. %A Wang, Z. %A Preuss, M. H. %A Mangino, M. %A Christofidou, P. %A Verweij, N. %A Benjamins, J. W. %A Engmann, J. %A Tsao, N. L. %A Verma, A. %A Slieker, R. C. %A Lo, K. S. %A Zilhao, N. R. %A Le, P. %A Kleber, M. E. %A Delgado, G. E. %A Huo, S. %A Ikeda, D. D. %A Iha, H. %A Yang, J. %A Liu, J. %A Demirkan, A. %A Leonard, H. L. %A Marten, J. %A Frank, M. %A Schmidt, B. %A Smyth, L. J. %A adas-Garre, M. %A Wang, C. %A Nakatochi, M. %A Wong, A. %A nen, N. %A Sim, X. %A Xia, R. %A Huerta-Chagoya, A. %A Fernandez-Lopez, J. C. %A Lyssenko, V. %A Nongmaithem, S. S. %A Bayyana, S. %A Stringham, H. M. %A Irvin, M. R. %A Oldmeadow, C. %A Kim, H. N. %A Ryu, S. %A Timmers, P. R. H. J. %A Arbeeva, L. %A Dorajoo, R. %A Lange, L. A. %A Prasad, G. %A s-Motta, L. %A Pauper, M. %A Long, J. %A Li, X. %A Theusch, E. %A Takeuchi, F. %A Spracklen, C. N. %A Loukola, A. %A Bollepalli, S. %A Warner, S. C. %A Wang, Y. X. %A Wei, W. B. %A Nutile, T. %A Ruggiero, D. %A Sung, Y. J. %A Chen, S. %A Liu, F. %A Yang, J. %A Kentistou, K. A. %A Banas, B. %A Nardone, G. G. %A Meidtner, K. %A Bielak, L. F. %A Smith, J. A. %A Hebbar, P. %A Farmaki, A. E. %A Hofer, E. %A Lin, M. %A Concas, M. P. %A Vaccargiu, S. %A van der Most, P. J. %A nen, N. %A Cade, B. E. %A van der Laan, S. W. %A Chitrala, K. N. %A Weiss, S. %A Bentley, A. R. %A Doumatey, A. P. %A Adeyemo, A. A. %A Lee, J. Y. %A Petersen, E. R. B. %A Nielsen, A. A. %A Choi, H. S. %A Nethander, M. %A Freitag-Wolf, S. %A Southam, L. %A Rayner, N. W. %A Wang, C. A. %A Lin, S. Y. %A Wang, J. S. %A Couture, C. %A inen, L. P. %A Nikus, K. %A Cuellar-Partida, G. %A Vestergaard, H. %A Hidalgo, B. %A Giannakopoulou, O. %A Cai, Q. %A Obura, M. O. %A van Setten, J. %A Li, X. %A Liang, J. %A Tang, H. %A Terzikhan, N. %A Shin, J. H. %A Jackson, R. D. %A Reiner, A. P. %A Martin, L. W. %A Chen, Z. %A Li, L. %A Kawaguchi, T. %A Thiery, J. %A Bis, J. C. %A Launer, L. J. %A Li, H. %A Nalls, M. A. %A Raitakari, O. T. %A Ichihara, S. %A Wild, S. H. %A Nelson, C. P. %A Campbell, H. %A ger, S. %A Nabika, T. %A Al-Mulla, F. %A Niinikoski, H. %A Braund, P. S. %A Kolcic, I. %A Kovacs, P. %A Giardoglou, T. %A Katsuya, T. %A de Kleijn, D. %A de Borst, G. J. %A Kim, E. K. %A Adams, H. H. H. %A Ikram, M. A. %A Zhu, X. %A Asselbergs, F. W. %A Kraaijeveld, A. O. %A Beulens, J. W. J. %A Shu, X. O. %A Rallidis, L. S. %A Pedersen, O. %A Hansen, T. %A Mitchell, P. %A Hewitt, A. W. %A nen, M. %A russe, L. %A Bouchard, C. %A njes, A. %A Chen, Y. I. %A Pennell, C. E. %A Mori, T. A. %A Lieb, W. %A Franke, A. %A Ohlsson, C. %A m, D. %A Cho, Y. S. %A Lee, H. %A Yuan, J. M. %A Koh, W. P. %A Rhee, S. Y. %A Woo, J. T. %A Heid, I. M. %A Stark, K. J. %A Zimmermann, M. E. %A lzke, H. %A Homuth, G. %A Evans, M. K. %A Zonderman, A. B. %A Polasek, O. %A Pasterkamp, G. %A Hoefer, I. E. %A Redline, S. %A Pahkala, K. %A Oldehinkel, A. J. %A Snieder, H. %A Biino, G. %A Schmidt, R. %A Schmidt, H. %A Bandinelli, S. %A Dedoussis, G. %A Thanaraj, T. A. %A Kardia, S. L. R. %A Peyser, P. A. %A Kato, N. %A Schulze, M. B. %A Girotto, G. %A ger, C. A. %A Jung, B. %A Joshi, P. K. %A Bennett, D. A. %A De Jager, P. L. %A Lu, X. %A Mamakou, V. %A Brown, M. %A Caulfield, M. J. %A Munroe, P. B. %A Guo, X. %A Ciullo, M. %A Jonas, J. B. %A Samani, N. J. %A Kaprio, J. %A Pajukanta, P. %A -Luna, T. %A Aguilar-Salinas, C. A. %A Adair, L. S. %A Bechayda, S. A. %A de Silva, H. J. %A Wickremasinghe, A. R. %A Krauss, R. M. %A Wu, J. Y. %A Zheng, W. %A Hollander, A. I. %A Bharadwaj, D. %A Correa, A. %A Wilson, J. G. %A Lind, L. %A Heng, C. K. %A Nelson, A. E. %A Golightly, Y. M. %A Wilson, J. F. %A Penninx, B. %A Kim, H. L. %A Attia, J. %A Scott, R. J. %A Rao, D. C. %A Arnett, D. K. %A Hunt, S. C. %A Walker, M. %A Koistinen, H. A. %A Chandak, G. R. %A Mercader, J. M. %A Costanzo, M. C. %A Jang, D. %A Burtt, N. P. %A Villalpando, C. G. %A Orozco, L. %A Fornage, M. %A Tai, E. %A van Dam, R. M. %A ki, T. %A Chaturvedi, N. %A Yokota, M. %A Liu, J. %A Reilly, D. F. %A McKnight, A. J. %A Kee, F. %A ckel, K. H. %A McCarthy, M. I. %A Palmer, C. N. A. %A Vitart, V. %A Hayward, C. %A Simonsick, E. %A van Duijn, C. M. %A Jin, Z. B. %A Qu, J. %A Hishigaki, H. %A Lin, X. %A rz, W. %A Gudnason, V. %A Tardif, J. C. %A Lettre, G. %A Hart, L. M. ' %A Elders, P. J. M. %A Damrauer, S. M. %A Kumari, M. %A Kivimaki, M. %A van der Harst, P. %A Spector, T. D. %A Loos, R. J. F. %A Province, M. A. %A Parra, E. J. %A Cruz, M. %A Psaty, B. M. %A Brandslund, I. %A Pramstaller, P. P. %A Rotimi, C. N. %A Christensen, K. %A Ripatti, S. %A n, E. %A Hakonarson, H. %A Grant, S. F. A. %A Kiemeney, L. A. L. M. %A de Graaf, J. %A Loeffler, M. %A Kronenberg, F. %A Gu, D. %A Erdmann, J. %A Schunkert, H. %A Franks, P. W. %A Linneberg, A. %A Jukema, J. W. %A Khera, A. V. %A ö, M. %A Jarvelin, M. R. %A Kutalik, Z. %A Francesco, C. %A Mook-Kanamori, D. O. %A van Dijk, K. W. %A Watkins, H. %A Strachan, D. P. %A Grarup, N. %A Sever, P. %A Poulter, N. %A Chuang, L. M. %A Rotter, J. I. %A Dantoft, T. M. %A Karpe, F. %A Neville, M. J. %A Timpson, N. J. %A Cheng, C. Y. %A Wong, T. Y. %A Khor, C. C. %A Li, H. %A Sabanayagam, C. %A Peters, A. %A Gieger, C. %A Hattersley, A. T. %A Pedersen, N. L. %A Magnusson, P. K. E. %A Boomsma, D. I. %A Willemsen, A. H. M. %A Cupples, L. %A van Meurs, J. B. J. %A Ghanbari, M. %A Gordon-Larsen, P. %A Huang, W. %A Kim, Y. J. %A Tabara, Y. %A Wareham, N. J. %A Langenberg, C. %A Zeggini, E. %A Kuusisto, J. %A Laakso, M. %A Ingelsson, E. %A Abecasis, G. %A Chambers, J. C. %A Kooner, J. S. %A de Vries, P. S. %A Morrison, A. C. %A Hazelhurst, S. %A Ramsay, M. %A North, K. E. %A Daviglus, M. %A Kraft, P. %A Martin, N. G. %A Whitfield, J. B. %A Abbas, S. %A Saleheen, D. %A Walters, R. G. %A Holmes, M. V. %A Black, C. %A Smith, B. H. %A Baras, A. %A Justice, A. E. %A Buring, J. E. %A Ridker, P. M. %A Chasman, D. I. %A Kooperberg, C. %A Tamiya, G. %A Yamamoto, M. %A van Heel, D. A. %A Trembath, R. C. %A Wei, W. Q. %A Jarvik, G. P. %A Namjou, B. %A Hayes, M. G. %A Ritchie, M. D. %A Jousilahti, P. %A Salomaa, V. %A Hveem, K. %A svold, B. O. %A Kubo, M. %A Kamatani, Y. %A Okada, Y. %A Murakami, Y. %A Kim, B. J. %A Thorsteinsdottir, U. %A Stefansson, K. %A Zhang, J. %A Chen, Y. %A Ho, Y. L. %A Lynch, J. A. %A Rader, D. J. %A Tsao, P. S. %A Chang, K. M. %A Cho, K. %A O'Donnell, C. J. %A Gaziano, J. M. %A Wilson, P. W. F. %A Frayling, T. M. %A Hirschhorn, J. N. %A Kathiresan, S. %A Mohlke, K. L. %A Sun, Y. V. %A Morris, A. P. %A Boehnke, M. %A Brown, C. D. %A Natarajan, P. %A Deloukas, P. %A Willer, C. J. %A Assimes, T. L. %A Peloso, G. M. %X Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.\ 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.\ Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk. %B Genome Biol %V 23 %P 268 %8 Dec %G eng %0 Journal Article %J Hypertension %D 2022 %T Insights From a Large-Scale Whole-Genome Sequencing Study of Systolic Blood Pressure, Diastolic Blood Pressure, and Hypertension. %A Kelly, Tanika N %A Sun, Xiao %A He, Karen Y %A Brown, Michael R %A Taliun, Sarah A Gagliano %A Hellwege, Jacklyn N %A Irvin, Marguerite R %A Mi, Xuenan %A Brody, Jennifer A %A Franceschini, Nora %A Guo, Xiuqing %A Hwang, Shih-Jen %A de Vries, Paul S %A Gao, Yan %A Moscati, Arden %A Nadkarni, Girish N %A Yanek, Lisa R %A Elfassy, Tali %A Smith, Jennifer A %A Chung, Ren-Hua %A Beitelshees, Amber L %A Patki, Amit %A Aslibekyan, Stella %A Blobner, Brandon M %A Peralta, Juan M %A Assimes, Themistocles L %A Palmas, Walter R %A Liu, Chunyu %A Bress, Adam P %A Huang, Zhijie %A Becker, Lewis C %A Hwa, Chii-Min %A O'Connell, Jeffrey R %A Carlson, Jenna C %A Warren, Helen R %A Das, Sayantan %A Giri, Ayush %A Martin, Lisa W %A Craig Johnson, W %A Fox, Ervin R %A Bottinger, Erwin P %A Razavi, Alexander C %A Vaidya, Dhananjay %A Chuang, Lee-Ming %A Chang, Yen-Pei C %A Naseri, Take %A Jain, Deepti %A Kang, Hyun Min %A Hung, Adriana M %A Srinivasasainagendra, Vinodh %A Snively, Beverly M %A Gu, Dongfeng %A Montasser, May E %A Reupena, Muagututi'a Sefuiva %A Heavner, Benjamin D %A LeFaive, Jonathon %A Hixson, James E %A Rice, Kenneth M %A Wang, Fei Fei %A Nielsen, Jonas B %A Huang, Jianfeng %A Khan, Alyna T %A Zhou, Wei %A Nierenberg, Jovia L %A Laurie, Cathy C %A Armstrong, Nicole D %A Shi, Mengyao %A Pan, Yang %A Stilp, Adrienne M %A Emery, Leslie %A Wong, Quenna %A Hawley, Nicola L %A Minster, Ryan L %A Curran, Joanne E %A Munroe, Patricia B %A Weeks, Daniel E %A North, Kari E %A Tracy, Russell P %A Kenny, Eimear E %A Shimbo, Daichi %A Chakravarti, Aravinda %A Rich, Stephen S %A Reiner, Alex P %A Blangero, John %A Redline, Susan %A Mitchell, Braxton D %A Rao, Dabeeru C %A Ida Chen, Yii-Der %A Kardia, Sharon L R %A Kaplan, Robert C %A Mathias, Rasika A %A He, Jiang %A Psaty, Bruce M %A Fornage, Myriam %A Loos, Ruth J F %A Correa, Adolfo %A Boerwinkle, Eric %A Rotter, Jerome I %A Kooperberg, Charles %A Edwards, Todd L %A Abecasis, Goncalo R %A Zhu, Xiaofeng %A Levy, Daniel %A Arnett, Donna K %A Morrison, Alanna C %X

BACKGROUND: The availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure.

METHODS: We conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383 145), Million Veteran Program (N=318 891), and Reasons for Geographic and Racial Differences in Stroke (N=10 643) participants, along with whole-exome sequencing data from UK Biobank (N=199 631) participants.

RESULTS: Two blood pressure signals achieved genome-wide significance in meta-analyses of stage-1 and stage-2 single variant findings (<5×10). Among them, a rare intergenic variant at novel locus, , was associated with lower systolic blood pressure in stage-1 (beta [SE]=-32.6 [6.0]; =4.99×10) but not stage-2 analysis (=0.11). Furthermore, a novel common variant at the known locus was suggestively associated with diastolic blood pressure in stage-1 (beta [SE]=-0.36 [0.07]; =4.18×10) and attained genome-wide significance in stage-2 (beta [SE]=-0.29 [0.03]; =7.28×10). Nineteen additional signals suggestively associated with blood pressure in meta-analysis of single and aggregate rare variant findings (<1×10 and <1×10, respectively).

DISCUSSION: We report one promising but unconfirmed rare variant for blood pressure and, more importantly, contribute insights for future blood pressure sequencing studies. Our findings suggest promise of aggregate analyses to complement single variant analysis strategies and the need for larger, diverse samples, and family studies to enable robust rare variant identification.

%B Hypertension %P 101161HYPERTENSIONAHA12219324 %8 2022 Jun 02 %G eng %R 10.1161/HYPERTENSIONAHA.122.19324 %0 Journal Article %J Aging Cell %D 2022 %T Integrative analysis of clinical and epigenetic biomarkers of mortality. %A Huan, Tianxiao %A Nguyen, Steve %A Colicino, Elena %A Ochoa-Rosales, Carolina %A Hill, W David %A Brody, Jennifer A %A Soerensen, Mette %A Zhang, Yan %A Baldassari, Antoine %A Elhadad, Mohamed Ahmed %A Toshiko, Tanaka %A Zheng, Yinan %A Domingo-Relloso, Arce %A Lee, Dong Heon %A Ma, Jiantao %A Yao, Chen %A Liu, Chunyu %A Hwang, Shih-Jen %A Joehanes, Roby %A Fornage, Myriam %A Bressler, Jan %A van Meurs, Joyce B J %A Debrabant, Birgit %A Mengel-From, Jonas %A Hjelmborg, Jacob %A Christensen, Kaare %A Vokonas, Pantel %A Schwartz, Joel %A Gahrib, Sina A %A Sotoodehnia, Nona %A Sitlani, Colleen M %A Kunze, Sonja %A Gieger, Christian %A Peters, Annette %A Waldenberger, Melanie %A Deary, Ian J %A Ferrucci, Luigi %A Qu, Yishu %A Greenland, Philip %A Lloyd-Jones, Donald M %A Hou, Lifang %A Bandinelli, Stefania %A Voortman, Trudy %A Hermann, Brenner %A Baccarelli, Andrea %A Whitsel, Eric %A Pankow, James S %A Levy, Daniel %K Biomarkers %K Cardiovascular Diseases %K DNA Methylation %K Epigenesis, Genetic %K Epigenomics %K Humans %K Male %K Neoplasms %X

DNA methylation (DNAm) has been reported to be associated with many diseases and with mortality. We hypothesized that the integration of DNAm with clinical risk factors would improve mortality prediction. We performed an epigenome-wide association study of whole blood DNAm in relation to mortality in 15 cohorts (n = 15,013). During a mean follow-up of 10 years, there were 4314 deaths from all causes including 1235 cardiovascular disease (CVD) deaths and 868 cancer deaths. Ancestry-stratified meta-analysis of all-cause mortality identified 163 CpGs in European ancestry (EA) and 17 in African ancestry (AA) participants at p < 1 × 10 , of which 41 (EA) and 16 (AA) were also associated with CVD death, and 15 (EA) and 9 (AA) with cancer death. We built DNAm-based prediction models for all-cause mortality that predicted mortality risk after adjusting for clinical risk factors. The mortality prediction model trained by integrating DNAm with clinical risk factors showed an improvement in prediction of cancer death with 5% increase in the C-index in a replication cohort, compared with the model including clinical risk factors alone. Mendelian randomization identified 15 putatively causal CpGs in relation to longevity, CVD, or cancer risk. For example, cg06885782 (in KCNQ4) was positively associated with risk for prostate cancer (Beta = 1.2, P  = 4.1 × 10 ) and negatively associated with longevity (Beta = -1.9, P  = 0.02). Pathway analysis revealed that genes associated with mortality-related CpGs are enriched for immune- and cancer-related pathways. We identified replicable DNAm signatures of mortality and demonstrated the potential utility of CpGs as informative biomarkers for prediction of mortality risk.

%B Aging Cell %V 21 %P e13608 %8 2022 Jun %G eng %N 6 %R 10.1111/acel.13608 %0 Journal Article %J Nat Med %D 2022 %T Large-scale genome-wide association study of coronary artery disease in genetically diverse populations. %A Tcheandjieu, Catherine %A Zhu, Xiang %A Hilliard, Austin T %A Clarke, Shoa L %A Napolioni, Valerio %A Ma, Shining %A Lee, Kyung Min %A Fang, Huaying %A Chen, Fei %A Lu, Yingchang %A Tsao, Noah L %A Raghavan, Sridharan %A Koyama, Satoshi %A Gorman, Bryan R %A Vujkovic, Marijana %A Klarin, Derek %A Levin, Michael G %A Sinnott-Armstrong, Nasa %A Wojcik, Genevieve L %A Plomondon, Mary E %A Maddox, Thomas M %A Waldo, Stephen W %A Bick, Alexander G %A Pyarajan, Saiju %A Huang, Jie %A Song, Rebecca %A Ho, Yuk-Lam %A Buyske, Steven %A Kooperberg, Charles %A Haessler, Jeffrey %A Loos, Ruth J F %A Do, Ron %A Verbanck, Marie %A Chaudhary, Kumardeep %A North, Kari E %A Avery, Christy L %A Graff, Mariaelisa %A Haiman, Christopher A %A Le Marchand, Loïc %A Wilkens, Lynne R %A Bis, Joshua C %A Leonard, Hampton %A Shen, Botong %A Lange, Leslie A %A Giri, Ayush %A Dikilitas, Ozan %A Kullo, Iftikhar J %A Stanaway, Ian B %A Jarvik, Gail P %A Gordon, Adam S %A Hebbring, Scott %A Namjou, Bahram %A Kaufman, Kenneth M %A Ito, Kaoru %A Ishigaki, Kazuyoshi %A Kamatani, Yoichiro %A Verma, Shefali S %A Ritchie, Marylyn D %A Kember, Rachel L %A Baras, Aris %A Lotta, Luca A %A Kathiresan, Sekar %A Hauser, Elizabeth R %A Miller, Donald R %A Lee, Jennifer S %A Saleheen, Danish %A Reaven, Peter D %A Cho, Kelly %A Gaziano, J Michael %A Natarajan, Pradeep %A Huffman, Jennifer E %A Voight, Benjamin F %A Rader, Daniel J %A Chang, Kyong-Mi %A Lynch, Julie A %A Damrauer, Scott M %A Wilson, Peter W F %A Tang, Hua %A Sun, Yan V %A Tsao, Philip S %A O'Donnell, Christopher J %A Assimes, Themistocles L %K Coronary Artery Disease %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Polymorphism, Single Nucleotide %K Risk Factors %X

We report a genome-wide association study (GWAS) of coronary artery disease (CAD) incorporating nearly a quarter of a million cases, in which existing studies are integrated with data from cohorts of white, Black and Hispanic individuals from the Million Veteran Program. We document near equivalent heritability of CAD across multiple ancestral groups, identify 95 novel loci, including nine on the X chromosome, detect eight loci of genome-wide significance in Black and Hispanic individuals, and demonstrate that two common haplotypes at the 9p21 locus are responsible for risk stratification in all populations except those of African origin, in which these haplotypes are virtually absent. Moreover, in the largest GWAS for angiographically derived coronary atherosclerosis performed to date, we find 15 loci of genome-wide significance that robustly overlap with established loci for clinical CAD. Phenome-wide association analyses of novel loci and polygenic risk scores (PRSs) augment signals related to insulin resistance, extend pleiotropic associations of these loci to include smoking and family history, and precisely document the markedly reduced transferability of existing PRSs to Black individuals. Downstream integrative analyses reinforce the critical roles of vascular endothelial, fibroblast, and smooth muscle cells in CAD susceptibility, but also point to a shared biology between atherosclerosis and oncogenesis. This study highlights the value of diverse populations in further characterizing the genetic architecture of CAD.

%B Nat Med %V 28 %P 1679-1692 %8 2022 08 %G eng %N 8 %R 10.1038/s41591-022-01891-3 %0 Journal Article %J JAMA Netw Open %D 2022 %T Longitudinal Changes in Hearing and Visual Impairments and Risk of Dementia in Older Adults in the United States. %A Hwang, Phillip H %A Longstreth, W T %A Thielke, Stephen M %A Francis, Courtney E %A Carone, Marco %A Kuller, Lewis H %A Fitzpatrick, Annette L %K Aged %K Alzheimer Disease %K Cohort Studies %K Female %K Hearing %K Hearing Loss %K Humans %K Male %K Medicare %K Prospective Studies %K United States %K Vision Disorders %X

Importance: Hearing and vision problems are individually associated with increased dementia risk, but the impact of having concurrent hearing and vision deficits, ie, dual sensory impairment (DSI), on risk of dementia, including its major subtypes Alzheimer disease (AD) and vascular dementia (VaD), is not well known.

Objective: To evaluate whether DSI is associated with incident dementia in older adults.

Design, Setting, and Participants: This prospective cohort study from the Cardiovascular Health Study (CHS) was conducted between 1992 and 1999, with as many as 8 years of follow-up. The multicenter, population-based sample was recruited from Medicare eligibility files in 4 US communities with academic medical centers. Of 5888 participants aged 65 years and older in CHS, 3602 underwent cranial magnetic resonance imaging and completed the modified Mini-Mental State Examination in 1992 to 1994 as part of the CHS Cognition Study. A total of 227 participants were excluded due to prevalent dementia, leaving a total of 3375 participants without dementia at study baseline. The study hypothesis was that DSI would be associated with increased risk of dementia compared with no sensory impairment. The association between the duration of DSI with risk of dementia was also evaluated. Data analysis was conducted from November 2019 to February 2020.

Exposures: Hearing and vision impairments were collected via self-report at baseline and as many as 5 follow-up visits.

Main Outcomes and Measures: All-cause dementia, AD, and VaD, classified by a multidisciplinary committee using standardized criteria.

Results: A total of 2927 participants with information on hearing and vision at all available study visits were included in the analysis (mean [SD] age, 74.6 [4.8] years; 1704 [58.2%] women; 455 [15.5%] African American or Black; 2472 [85.5%] White). Compared with no sensory impairment, DSI was associated with increased risk of all-cause dementia (hazard ratio [HR], 2.60; 95% CI, 1.66-2.06; P < .001), AD (HR, 3.67; 95% CI, 2.04-6.60; P < .001) but not VaD (HR, 2.03; 95% CI, 1.00-4.09; P = .05).

Conclusions and Relevance: In this cohort study, DSI was associated with increased risk of dementia, particularly AD. Evaluation of hearing and vision in older adults may help to identify those at high risk of developing dementia.

%B JAMA Netw Open %V 5 %P e2210734 %8 2022 05 02 %G eng %N 5 %R 10.1001/jamanetworkopen.2022.10734 %0 Journal Article %J Eur Heart J %D 2022 %T Lung function impairment and risk of incident heart failure: the NHLBI Pooled Cohorts Study. %A Eckhardt, Christina M %A Balte, Pallavi P %A Barr, Robert Graham %A Bertoni, Alain G %A Bhatt, Surya P %A Cuttica, Michael %A Cassano, Patricia A %A Chaves, Paolo %A Couper, David %A Jacobs, David R %A Kalhan, Ravi %A Kronmal, Richard %A Lange, Leslie %A Loehr, Laura %A London, Stephanie J %A O'Connor, George T %A Rosamond, Wayne %A Sanders, Jason %A Schwartz, Joseph E %A Shah, Amil %A Shah, Sanjiv J %A Smith, Lewis %A White, Wendy %A Yende, Sachin %A Oelsner, Elizabeth C %K Adult %K Heart Failure %K Hospitalization %K Humans %K Lung %K National Heart, Lung, and Blood Institute (U.S.) %K Prognosis %K Risk Factors %K Stroke Volume %K United States %X

AIMS: The aim is to evaluate associations of lung function impairment with risk of incident heart failure (HF).

METHODS AND RESULTS: Data were pooled across eight US population-based cohorts that enrolled participants from 1987 to 2004. Participants with self-reported baseline cardiovascular disease were excluded. Spirometry was used to define obstructive [forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) <0.70] or restrictive (FEV1/FVC ≥0.70, FVC <80%) lung physiology. The incident HF was defined as hospitalization or death caused by HF. In a sub-set, HF events were sub-classified as HF with reduced ejection fraction (HFrEF; EF <50%) or preserved EF (HFpEF; EF ≥50%). The Fine-Gray proportional sub-distribution hazards models were adjusted for sociodemographic factors, smoking, and cardiovascular risk factors. In models of incident HF sub-types, HFrEF, HFpEF, and non-HF mortality were treated as competing risks. Among 31 677 adults, there were 3344 incident HF events over a median follow-up of 21.0 years. Of 2066 classifiable HF events, 1030 were classified as HFrEF and 1036 as HFpEF. Obstructive [adjusted hazard ratio (HR) 1.17, 95% confidence interval (CI) 1.07-1.27] and restrictive physiology (adjusted HR 1.43, 95% CI 1.27-1.62) were associated with incident HF. Obstructive and restrictive ventilatory defects were associated with HFpEF but not HFrEF. The magnitude of the association between restrictive physiology and HFpEF was similar to associations with hypertension, diabetes, and smoking.

CONCLUSION: Lung function impairment was associated with increased risk of incident HF, and particularly incident HFpEF, independent of and to a similar extent as major known cardiovascular risk factors.

%B Eur Heart J %V 43 %P 2196-2208 %8 2022 06 14 %G eng %N 23 %R 10.1093/eurheartj/ehac205 %0 Journal Article %J Circulation %D 2022 %T Monogenic and Polygenic Contributions to QTc Prolongation in the Population. %A Nauffal, Victor %A Morrill, Valerie N %A Jurgens, Sean J %A Choi, Seung Hoan %A Hall, Amelia W %A Weng, Lu-Chen %A Halford, Jennifer L %A Austin-Tse, Christina %A Haggerty, Christopher M %A Harris, Stephanie L %A Wong, Eugene K %A Alonso, Alvaro %A Arking, Dan E %A Benjamin, Emelia J %A Boerwinkle, Eric %A Min, Yuan-I %A Correa, Adolfo %A Fornwalt, Brandon K %A Heckbert, Susan R %A Kooperberg, Charles %A Lin, Henry J %A Loos, Ruth J F %A Rice, Kenneth M %A Gupta, Namrata %A Blackwell, Thomas W %A Mitchell, Braxton D %A Morrison, Alanna C %A Psaty, Bruce M %A Post, Wendy S %A Redline, Susan %A Rehm, Heidi L %A Rich, Stephen S %A Rotter, Jerome I %A Soliman, Elsayed Z %A Sotoodehnia, Nona %A Lunetta, Kathryn L %A Ellinor, Patrick T %A Lubitz, Steven A %X

Rare sequence variation in genes underlying cardiac repolarization and common polygenic variation influence QT interval duration. However, current clinical genetic testing of individuals with unexplained QT prolongation is restricted to examination of monogenic rare variants. The recent emergence of large-scale biorepositories with sequence data enables examination of the joint contribution of rare and common variation to the QT interval in the population. We performed a genome wide association study (GWAS) of the QTc in 84,630 United Kingdom Biobank (UKB) participants and created a polygenic risk score (PRS). Among 26,976 participants with whole genome sequencing and electrocardiogram data in the Trans-Omics for Precision Medicine (TOPMed) program, we identified 160 carriers of putative pathogenic rare variants in 10 genes known to be associated with the QT interval. We examined QTc associations with the PRS and with rare variants in TOPMed. Fifty-four independent loci were identified by GWAS in the UKB. Twenty-one loci were novel, of which 12 were replicated in TOPMed. The PRS comprising 1,110,494 common variants was significantly associated with the QTc in TOPMed (ΔQTc/ = 1.4 ms, 95% CI 1.3 -1.5; p-value=1.1×10). Carriers of putative pathogenic rare variants had longer QTc than non-carriers (ΔQTc=10.9 ms [7.4-14.4]). 23.7% of individuals with QTc>480 ms carried either a monogenic rare variant or had a PRS in the top decile (3.4% monogenic, 21% top decile of PRS). QTc duration in the population is influenced by both rare variants in genes underlying cardiac repolarization and polygenic risk, with a sizeable contribution from polygenic risk. Comprehensive assessment of the genetic determinants of QTc prolongation includes incorporation of both polygenic and monogenic risk.

%B Circulation %8 2022 Apr 07 %G eng %R 10.1161/CIRCULATIONAHA.121.057261 %0 Journal Article %J Nat Genet %D 2022 %T Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation. %A Mahajan, Anubha %A Spracklen, Cassandra N %A Zhang, Weihua %A Ng, Maggie C Y %A Petty, Lauren E %A Kitajima, Hidetoshi %A Yu, Grace Z %A Rüeger, Sina %A Speidel, Leo %A Kim, Young Jin %A Horikoshi, Momoko %A Mercader, Josep M %A Taliun, Daniel %A Moon, Sanghoon %A Kwak, Soo-Heon %A Robertson, Neil R %A Rayner, Nigel W %A Loh, Marie %A Kim, Bong-Jo %A Chiou, Joshua %A Miguel-Escalada, Irene %A Della Briotta Parolo, Pietro %A Lin, Kuang %A Bragg, Fiona %A Preuss, Michael H %A Takeuchi, Fumihiko %A Nano, Jana %A Guo, Xiuqing %A Lamri, Amel %A Nakatochi, Masahiro %A Scott, Robert A %A Lee, Jung-Jin %A Huerta-Chagoya, Alicia %A Graff, Mariaelisa %A Chai, Jin-Fang %A Parra, Esteban J %A Yao, Jie %A Bielak, Lawrence F %A Tabara, Yasuharu %A Hai, Yang %A Steinthorsdottir, Valgerdur %A Cook, James P %A Kals, Mart %A Grarup, Niels %A Schmidt, Ellen M %A Pan, Ian %A Sofer, Tamar %A Wuttke, Matthias %A Sarnowski, Chloe %A Gieger, Christian %A Nousome, Darryl %A Trompet, Stella %A Long, Jirong %A Sun, Meng %A Tong, Lin %A Chen, Wei-Min %A Ahmad, Meraj %A Noordam, Raymond %A Lim, Victor J Y %A Tam, Claudia H T %A Joo, Yoonjung Yoonie %A Chen, Chien-Hsiun %A Raffield, Laura M %A Lecoeur, Cécile %A Prins, Bram Peter %A Nicolas, Aude %A Yanek, Lisa R %A Chen, Guanjie %A Jensen, Richard A %A Tajuddin, Salman %A Kabagambe, Edmond K %A An, Ping %A Xiang, Anny H %A Choi, Hyeok Sun %A Cade, Brian E %A Tan, Jingyi %A Flanagan, Jack %A Abaitua, Fernando %A Adair, Linda S %A Adeyemo, Adebowale %A Aguilar-Salinas, Carlos A %A Akiyama, Masato %A Anand, Sonia S %A Bertoni, Alain %A Bian, Zheng %A Bork-Jensen, Jette %A Brandslund, Ivan %A Brody, Jennifer A %A Brummett, Chad M %A Buchanan, Thomas A %A Canouil, Mickaël %A Chan, Juliana C N %A Chang, Li-Ching %A Chee, Miao-Li %A Chen, Ji %A Chen, Shyh-Huei %A Chen, Yuan-Tsong %A Chen, Zhengming %A Chuang, Lee-Ming %A Cushman, Mary %A Das, Swapan K %A de Silva, H Janaka %A Dedoussis, George %A Dimitrov, Latchezar %A Doumatey, Ayo P %A Du, Shufa %A Duan, Qing %A Eckardt, Kai-Uwe %A Emery, Leslie S %A Evans, Daniel S %A Evans, Michele K %A Fischer, Krista %A Floyd, James S %A Ford, Ian %A Fornage, Myriam %A Franco, Oscar H %A Frayling, Timothy M %A Freedman, Barry I %A Fuchsberger, Christian %A Genter, Pauline %A Gerstein, Hertzel C %A Giedraitis, Vilmantas %A González-Villalpando, Clicerio %A Gonzalez-Villalpando, Maria Elena %A Goodarzi, Mark O %A Gordon-Larsen, Penny %A Gorkin, David %A Gross, Myron %A Guo, Yu %A Hackinger, Sophie %A Han, Sohee %A Hattersley, Andrew T %A Herder, Christian %A Howard, Annie-Green %A Hsueh, Willa %A Huang, Mengna %A Huang, Wei %A Hung, Yi-Jen %A Hwang, Mi Yeong %A Hwu, Chii-Min %A Ichihara, Sahoko %A Ikram, Mohammad Arfan %A Ingelsson, Martin %A Islam, Md Tariqul %A Isono, Masato %A Jang, Hye-Mi %A Jasmine, Farzana %A Jiang, Guozhi %A Jonas, Jost B %A Jørgensen, Marit E %A Jørgensen, Torben %A Kamatani, Yoichiro %A Kandeel, Fouad R %A Kasturiratne, Anuradhani %A Katsuya, Tomohiro %A Kaur, Varinderpal %A Kawaguchi, Takahisa %A Keaton, Jacob M %A Kho, Abel N %A Khor, Chiea-Chuen %A Kibriya, Muhammad G %A Kim, Duk-Hwan %A Kohara, Katsuhiko %A Kriebel, Jennifer %A Kronenberg, Florian %A Kuusisto, Johanna %A Läll, Kristi %A Lange, Leslie A %A Lee, Myung-Shik %A Lee, Nanette R %A Leong, Aaron %A Li, Liming %A Li, Yun %A Li-Gao, Ruifang %A Ligthart, Symen %A Lindgren, Cecilia M %A Linneberg, Allan %A Liu, Ching-Ti %A Liu, Jianjun %A Locke, Adam E %A Louie, Tin %A Luan, Jian'an %A Luk, Andrea O %A Luo, Xi %A Lv, Jun %A Lyssenko, Valeriya %A Mamakou, Vasiliki %A Mani, K Radha %A Meitinger, Thomas %A Metspalu, Andres %A Morris, Andrew D %A Nadkarni, Girish N %A Nadler, Jerry L %A Nalls, Michael A %A Nayak, Uma %A Nongmaithem, Suraj S %A Ntalla, Ioanna %A Okada, Yukinori %A Orozco, Lorena %A Patel, Sanjay R %A Pereira, Mark A %A Peters, Annette %A Pirie, Fraser J %A Porneala, Bianca %A Prasad, Gauri %A Preissl, Sebastian %A Rasmussen-Torvik, Laura J %A Reiner, Alexander P %A Roden, Michael %A Rohde, Rebecca %A Roll, Kathryn %A Sabanayagam, Charumathi %A Sander, Maike %A Sandow, Kevin %A Sattar, Naveed %A Schönherr, Sebastian %A Schurmann, Claudia %A Shahriar, Mohammad %A Shi, Jinxiu %A Shin, Dong Mun %A Shriner, Daniel %A Smith, Jennifer A %A So, Wing Yee %A Stančáková, Alena %A Stilp, Adrienne M %A Strauch, Konstantin %A Suzuki, Ken %A Takahashi, Atsushi %A Taylor, Kent D %A Thorand, Barbara %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Tomlinson, Brian %A Torres, Jason M %A Tsai, Fuu-Jen %A Tuomilehto, Jaakko %A Tusié-Luna, Teresa %A Udler, Miriam S %A Valladares-Salgado, Adan %A van Dam, Rob M %A van Klinken, Jan B %A Varma, Rohit %A Vujkovic, Marijana %A Wacher-Rodarte, Niels %A Wheeler, Eleanor %A Whitsel, Eric A %A Wickremasinghe, Ananda R %A van Dijk, Ko Willems %A Witte, Daniel R %A Yajnik, Chittaranjan S %A Yamamoto, Ken %A Yamauchi, Toshimasa %A Yengo, Loic %A Yoon, Kyungheon %A Yu, Canqing %A Yuan, Jian-Min %A Yusuf, Salim %A Zhang, Liang %A Zheng, Wei %A Raffel, Leslie J %A Igase, Michiya %A Ipp, Eli %A Redline, Susan %A Cho, Yoon Shin %A Lind, Lars %A Province, Michael A %A Hanis, Craig L %A Peyser, Patricia A %A Ingelsson, Erik %A Zonderman, Alan B %A Psaty, Bruce M %A Wang, Ya-Xing %A Rotimi, Charles N %A Becker, Diane M %A Matsuda, Fumihiko %A Liu, Yongmei %A Zeggini, Eleftheria %A Yokota, Mitsuhiro %A Rich, Stephen S %A Kooperberg, Charles %A Pankow, James S %A Engert, James C %A Chen, Yii-Der Ida %A Froguel, Philippe %A Wilson, James G %A Sheu, Wayne H H %A Kardia, Sharon L R %A Wu, Jer-Yuarn %A Hayes, M Geoffrey %A Ma, Ronald C W %A Wong, Tien-Yin %A Groop, Leif %A Mook-Kanamori, Dennis O %A Chandak, Giriraj R %A Collins, Francis S %A Bharadwaj, Dwaipayan %A Paré, Guillaume %A Sale, Michèle M %A Ahsan, Habibul %A Motala, Ayesha A %A Shu, Xiao-Ou %A Park, Kyong-Soo %A Jukema, J Wouter %A Cruz, Miguel %A McKean-Cowdin, Roberta %A Grallert, Harald %A Cheng, Ching-Yu %A Bottinger, Erwin P %A Dehghan, Abbas %A Tai, E-Shyong %A Dupuis, Josée %A Kato, Norihiro %A Laakso, Markku %A Köttgen, Anna %A Koh, Woon-Puay %A Palmer, Colin N A %A Liu, Simin %A Abecasis, Goncalo %A Kooner, Jaspal S %A Loos, Ruth J F %A North, Kari E %A Haiman, Christopher A %A Florez, Jose C %A Saleheen, Danish %A Hansen, Torben %A Pedersen, Oluf %A Mägi, Reedik %A Langenberg, Claudia %A Wareham, Nicholas J %A Maeda, Shiro %A Kadowaki, Takashi %A Lee, Juyoung %A Millwood, Iona Y %A Walters, Robin G %A Stefansson, Kari %A Myers, Simon R %A Ferrer, Jorge %A Gaulton, Kyle J %A Meigs, James B %A Mohlke, Karen L %A Gloyn, Anna L %A Bowden, Donald W %A Below, Jennifer E %A Chambers, John C %A Sim, Xueling %A Boehnke, Michael %A Rotter, Jerome I %A McCarthy, Mark I %A Morris, Andrew P %K Diabetes Mellitus, Type 2 %K Ethnicity %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Polymorphism, Single Nucleotide %K Risk Factors %X

We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 × 10), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background.

%B Nat Genet %V 54 %P 560-572 %8 2022 May %G eng %N 5 %R 10.1038/s41588-022-01058-3 %0 Journal Article %J Nat Commun %D 2022 %T A multi-ethnic polygenic risk score is associated with hypertension prevalence and progression throughout adulthood. %A Kurniansyah, Nuzulul %A Goodman, Matthew O %A Kelly, Tanika N %A Elfassy, Tali %A Wiggins, Kerri L %A Bis, Joshua C %A Guo, Xiuqing %A Palmas, Walter %A Taylor, Kent D %A Lin, Henry J %A Haessler, Jeffrey %A Gao, Yan %A Shimbo, Daichi %A Smith, Jennifer A %A Yu, Bing %A Feofanova, Elena V %A Smit, Roelof A J %A Wang, Zhe %A Hwang, Shih-Jen %A Liu, Simin %A Wassertheil-Smoller, Sylvia %A Manson, JoAnn E %A Lloyd-Jones, Donald M %A Rich, Stephen S %A Loos, Ruth J F %A Redline, Susan %A Correa, Adolfo %A Kooperberg, Charles %A Fornage, Myriam %A Kaplan, Robert C %A Psaty, Bruce M %A Rotter, Jerome I %A Arnett, Donna K %A Morrison, Alanna C %A Franceschini, Nora %A Levy, Daniel %A Sofer, Tamar %K Adult %K Diabetes Mellitus, Type 2 %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Hypertension %K Multifactorial Inheritance %K Prevalence %K Risk Factors %X

In a multi-stage analysis of 52,436 individuals aged 17-90 across diverse cohorts and biobanks, we train, test, and evaluate a polygenic risk score (PRS) for hypertension risk and progression. The PRS is trained using genome-wide association studies (GWAS) for systolic, diastolic blood pressure, and hypertension, respectively. For each trait, PRS is selected by optimizing the coefficient of variation (CV) across estimated effect sizes from multiple potential PRS using the same GWAS, after which the 3 trait-specific PRSs are combined via an unweighted sum called "PRSsum", forming the HTN-PRS. The HTN-PRS is associated with both prevalent and incident hypertension at 4-6 years of follow up. This association is further confirmed in age-stratified analysis. In an independent biobank of 40,201 individuals, the HTN-PRS is confirmed to be predictive of increased risk for coronary artery disease, ischemic stroke, type 2 diabetes, and chronic kidney disease.

%B Nat Commun %V 13 %P 3549 %8 2022 Jun 21 %G eng %N 1 %R 10.1038/s41467-022-31080-2 %0 Journal Article %J Diabetes %D 2022 %T Multi-Scalar Data Integration Links Glomerular Angiopoietin-Tie Signaling Pathway Activation With Progression of Diabetic Kidney Disease. %A Liu, Jiahao %A Nair, Viji %A Zhao, Yi-Yang %A Chang, Dong-Yuan %A Limonte, Christine %A Bansal, Nisha %A Fermin, Damian %A Eichinger, Felix %A Tanner, Emily C %A Bellovich, Keith A %A Steigerwalt, Susan %A Bhat, Zeenat %A Hawkins, Jennifer J %A Subramanian, Lalita %A Rosas, Sylvia E %A Sedor, John R %A Vasquez, Miguel A %A Waikar, Sushrut S %A Bitzer, Markus %A Pennathur, Subramaniam %A Brosius, Frank C %A de Boer, Ian %A Chen, Min %A Kretzler, Matthias %A Ju, Wenjun %K Angiopoietin-1 %K Angiopoietin-2 %K Angiopoietins %K Biomarkers %K Cohort Studies %K Diabetes Mellitus %K Diabetic Nephropathies %K Disease Progression %K Endothelial Cells %K Humans %K Kidney Failure, Chronic %K Receptor, TIE-2 %K Signal Transduction %X

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease (ESKD). Prognostic biomarkers reflective of underlying molecular mechanisms are critically needed for effective management of DKD. A three-marker panel was derived from a proteomics analysis of plasma samples by an unbiased machine learning approach from participants (N = 58) in the Clinical Phenotyping and Resource Biobank study. In combination with standard clinical parameters, this panel improved prediction of the composite outcome of ESKD or a 40% decline in glomerular filtration rate. The panel was validated in an independent group (N = 68), who also had kidney transcriptomic profiles. One marker, plasma angiopoietin 2 (ANGPT2), was significantly associated with outcomes in cohorts from the Cardiovascular Health Study (N = 3,183) and the Chinese Cohort Study of Chronic Kidney Disease (N = 210). Glomerular transcriptional angiopoietin/Tie (ANG-TIE) pathway scores, derived from the expression of 154 ANG-TIE signaling mediators, correlated positively with plasma ANGPT2 levels and kidney outcomes. Higher receptor expression in glomeruli and higher ANG-TIE pathway scores in endothelial cells corroborated potential functional effects in the kidney from elevated plasma ANGPT2 levels. Our work suggests that ANGPT2 is a promising prognostic endothelial biomarker with likely functional impact on glomerular pathogenesis in DKD.

%B Diabetes %V 71 %P 2664-2676 %8 2022 Dec 01 %G eng %N 12 %R 10.2337/db22-0169 %0 Journal Article %J Nat Genet %D 2022 %T New insights into the genetic etiology of Alzheimer's disease and related dementias. %A Bellenguez, Céline %A Küçükali, Fahri %A Jansen, Iris E %A Kleineidam, Luca %A Moreno-Grau, Sonia %A Amin, Najaf %A Naj, Adam C %A Campos-Martin, Rafael %A Grenier-Boley, Benjamin %A Andrade, Victor %A Holmans, Peter A %A Boland, Anne %A Damotte, Vincent %A van der Lee, Sven J %A Costa, Marcos R %A Kuulasmaa, Teemu %A Yang, Qiong %A de Rojas, Itziar %A Bis, Joshua C %A Yaqub, Amber %A Prokic, Ivana %A Chapuis, Julien %A Ahmad, Shahzad %A Giedraitis, Vilmantas %A Aarsland, Dag %A Garcia-Gonzalez, Pablo %A Abdelnour, Carla %A Alarcón-Martín, Emilio %A Alcolea, Daniel %A Alegret, Montserrat %A Alvarez, Ignacio %A Alvarez, Victoria %A Armstrong, Nicola J %A Tsolaki, Anthoula %A Antunez, Carmen %A Appollonio, Ildebrando %A Arcaro, Marina %A Archetti, Silvana %A Pastor, Alfonso Arias %A Arosio, Beatrice %A Athanasiu, Lavinia %A Bailly, Henri %A Banaj, Nerisa %A Baquero, Miquel %A Barral, Sandra %A Beiser, Alexa %A Pastor, Ana Belén %A Below, Jennifer E %A Benchek, Penelope %A Benussi, Luisa %A Berr, Claudine %A Besse, Céline %A Bessi, Valentina %A Binetti, Giuliano %A Bizarro, Alessandra %A Blesa, Rafael %A Boada, Merce %A Boerwinkle, Eric %A Borroni, Barbara %A Boschi, Silvia %A Bossù, Paola %A Bråthen, Geir %A Bressler, Jan %A Bresner, Catherine %A Brodaty, Henry %A Brookes, Keeley J %A Brusco, Luis Ignacio %A Buiza-Rueda, Dolores %A Bûrger, Katharina %A Burholt, Vanessa %A Bush, William S %A Calero, Miguel %A Cantwell, Laura B %A Chene, Geneviève %A Chung, Jaeyoon %A Cuccaro, Michael L %A Carracedo, Angel %A Cecchetti, Roberta %A Cervera-Carles, Laura %A Charbonnier, Camille %A Chen, Hung-Hsin %A Chillotti, Caterina %A Ciccone, Simona %A Claassen, Jurgen A H R %A Clark, Christopher %A Conti, Elisa %A Corma-Gómez, Anaïs %A Costantini, Emanuele %A Custodero, Carlo %A Daian, Delphine %A Dalmasso, Maria Carolina %A Daniele, Antonio %A Dardiotis, Efthimios %A Dartigues, Jean-François %A de Deyn, Peter Paul %A de Paiva Lopes, Katia %A de Witte, Lot D %A Debette, Stephanie %A Deckert, Jürgen %A Del Ser, Teodoro %A Denning, Nicola %A DeStefano, Anita %A Dichgans, Martin %A Diehl-Schmid, Janine %A Diez-Fairen, Monica %A Rossi, Paolo Dionigi %A Djurovic, Srdjan %A Duron, Emmanuelle %A Düzel, Emrah %A Dufouil, Carole %A Eiriksdottir, Gudny %A Engelborghs, Sebastiaan %A Escott-Price, Valentina %A Espinosa, Ana %A Ewers, Michael %A Faber, Kelley M %A Fabrizio, Tagliavini %A Nielsen, Sune Fallgaard %A Fardo, David W %A Farotti, Lucia %A Fenoglio, Chiara %A Fernández-Fuertes, Marta %A Ferrari, Raffaele %A Ferreira, Catarina B %A Ferri, Evelyn %A Fin, Bertrand %A Fischer, Peter %A Fladby, Tormod %A Fließbach, Klaus %A Fongang, Bernard %A Fornage, Myriam %A Fortea, Juan %A Foroud, Tatiana M %A Fostinelli, Silvia %A Fox, Nick C %A Franco-Macías, Emlio %A Bullido, María J %A Frank-García, Ana %A Froelich, Lutz %A Fulton-Howard, Brian %A Galimberti, Daniela %A García-Alberca, Jose Maria %A Garcia-Gonzalez, Pablo %A Garcia-Madrona, Sebastian %A Garcia-Ribas, Guillermo %A Ghidoni, Roberta %A Giegling, Ina %A Giorgio, Giaccone %A Goate, Alison M %A Goldhardt, Oliver %A Gomez-Fonseca, Duber %A González-Perez, Antonio %A Graff, Caroline %A Grande, Giulia %A Green, Emma %A Grimmer, Timo %A Grünblatt, Edna %A Grunin, Michelle %A Gudnason, Vilmundur %A Guetta-Baranes, Tamar %A Haapasalo, Annakaisa %A Hadjigeorgiou, Georgios %A Haines, Jonathan L %A Hamilton-Nelson, Kara L %A Hampel, Harald %A Hanon, Olivier %A Hardy, John %A Hartmann, Annette M %A Hausner, Lucrezia %A Harwood, Janet %A Heilmann-Heimbach, Stefanie %A Helisalmi, Seppo %A Heneka, Michael T %A Hernandez, Isabel %A Herrmann, Martin J %A Hoffmann, Per %A Holmes, Clive %A Holstege, Henne %A Vilas, Raquel Huerto %A Hulsman, Marc %A Humphrey, Jack %A Biessels, Geert Jan %A Jian, Xueqiu %A Johansson, Charlotte %A Jun, Gyungah R %A Kastumata, Yuriko %A Kauwe, John %A Kehoe, Patrick G %A Kilander, Lena %A Ståhlbom, Anne Kinhult %A Kivipelto, Miia %A Koivisto, Anne %A Kornhuber, Johannes %A Kosmidis, Mary H %A Kukull, Walter A %A Kuksa, Pavel P %A Kunkle, Brian W %A Kuzma, Amanda B %A Lage, Carmen %A Laukka, Erika J %A Launer, Lenore %A Lauria, Alessandra %A Lee, Chien-Yueh %A Lehtisalo, Jenni %A Lerch, Ondrej %A Lleo, Alberto %A Longstreth, William %A Lopez, Oscar %A de Munain, Adolfo Lopez %A Love, Seth %A Löwemark, Malin %A Luckcuck, Lauren %A Lunetta, Kathryn L %A Ma, Yiyi %A Macías, Juan %A MacLeod, Catherine A %A Maier, Wolfgang %A Mangialasche, Francesca %A Spallazzi, Marco %A Marquié, Marta %A Marshall, Rachel %A Martin, Eden R %A Montes, Angel Martín %A Rodríguez, Carmen Martínez %A Masullo, Carlo %A Mayeux, Richard %A Mead, Simon %A Mecocci, Patrizia %A Medina, Miguel %A Meggy, Alun %A Mehrabian, Shima %A Mendoza, Silvia %A Menéndez-González, Manuel %A Mir, Pablo %A Moebus, Susanne %A Mol, Merel %A Molina-Porcel, Laura %A Montrreal, Laura %A Morelli, Laura %A Moreno, Fermin %A Morgan, Kevin %A Mosley, Thomas %A Nöthen, Markus M %A Muchnik, Carolina %A Mukherjee, Shubhabrata %A Nacmias, Benedetta %A Ngandu, Tiia %A Nicolas, Gaël %A Nordestgaard, Børge G %A Olaso, Robert %A Orellana, Adelina %A Orsini, Michela %A Ortega, Gemma %A Padovani, Alessandro %A Paolo, Caffarra %A Papenberg, Goran %A Parnetti, Lucilla %A Pasquier, Florence %A Pastor, Pau %A Peloso, Gina %A Pérez-Cordón, Alba %A Pérez-Tur, Jordi %A Pericard, Pierre %A Peters, Oliver %A Pijnenburg, Yolande A L %A Pineda, Juan A %A Piñol-Ripoll, Gerard %A Pisanu, Claudia %A Polak, Thomas %A Popp, Julius %A Posthuma, Danielle %A Priller, Josef %A Puerta, Raquel %A Quenez, Olivier %A Quintela, Inés %A Thomassen, Jesper Qvist %A Rábano, Alberto %A Rainero, Innocenzo %A Rajabli, Farid %A Ramakers, Inez %A Real, Luis M %A Reinders, Marcel J T %A Reitz, Christiane %A Reyes-Dumeyer, Dolly %A Ridge, Perry %A Riedel-Heller, Steffi %A Riederer, Peter %A Roberto, Natalia %A Rodriguez-Rodriguez, Eloy %A Rongve, Arvid %A Allende, Irene Rosas %A Rosende-Roca, Maitée %A Royo, Jose Luis %A Rubino, Elisa %A Rujescu, Dan %A Sáez, María Eugenia %A Sakka, Paraskevi %A Saltvedt, Ingvild %A Sanabria, Ángela %A Sánchez-Arjona, María Bernal %A Sanchez-Garcia, Florentino %A Juan, Pascual Sánchez %A Sánchez-Valle, Raquel %A Sando, Sigrid B %A Sarnowski, Chloe %A Satizabal, Claudia L %A Scamosci, Michela %A Scarmeas, Nikolaos %A Scarpini, Elio %A Scheltens, Philip %A Scherbaum, Norbert %A Scherer, Martin %A Schmid, Matthias %A Schneider, Anja %A Schott, Jonathan M %A Selbæk, Geir %A Seripa, Davide %A Serrano, Manuel %A Sha, Jin %A Shadrin, Alexey A %A Skrobot, Olivia %A Slifer, Susan %A Snijders, Gijsje J L %A Soininen, Hilkka %A Solfrizzi, Vincenzo %A Solomon, Alina %A Song, Yeunjoo %A Sorbi, Sandro %A Sotolongo-Grau, Oscar %A Spalletta, Gianfranco %A Spottke, Annika %A Squassina, Alessio %A Stordal, Eystein %A Tartan, Juan Pablo %A Tarraga, Lluis %A Tesí, Niccolo %A Thalamuthu, Anbupalam %A Thomas, Tegos %A Tosto, Giuseppe %A Traykov, Latchezar %A Tremolizzo, Lucio %A Tybjærg-Hansen, Anne %A Uitterlinden, Andre %A Ullgren, Abbe %A Ulstein, Ingun %A Valero, Sergi %A Valladares, Otto %A Broeckhoven, Christine Van %A Vance, Jeffery %A Vardarajan, Badri N %A van der Lugt, Aad %A Dongen, Jasper Van %A van Rooij, Jeroen %A van Swieten, John %A Vandenberghe, Rik %A Verhey, Frans %A Vidal, Jean-Sébastien %A Vogelgsang, Jonathan %A Vyhnalek, Martin %A Wagner, Michael %A Wallon, David %A Wang, Li-San %A Wang, Ruiqi %A Weinhold, Leonie %A Wiltfang, Jens %A Windle, Gill %A Woods, Bob %A Yannakoulia, Mary %A Zare, Habil %A Zhao, Yi %A Zhang, Xiaoling %A Zhu, Congcong %A Zulaica, Miren %A Farrer, Lindsay A %A Psaty, Bruce M %A Ghanbari, Mohsen %A Raj, Towfique %A Sachdev, Perminder %A Mather, Karen %A Jessen, Frank %A Ikram, M Arfan %A de Mendonça, Alexandre %A Hort, Jakub %A Tsolaki, Magda %A Pericak-Vance, Margaret A %A Amouyel, Philippe %A Williams, Julie %A Frikke-Schmidt, Ruth %A Clarimon, Jordi %A Deleuze, Jean-Francois %A Rossi, Giacomina %A Seshadri, Sudha %A Andreassen, Ole A %A Ingelsson, Martin %A Hiltunen, Mikko %A Sleegers, Kristel %A Schellenberg, Gerard D %A van Duijn, Cornelia M %A Sims, Rebecca %A van der Flier, Wiesje M %A Ruiz, Agustin %A Ramirez, Alfredo %A Lambert, Jean-Charles %K Alzheimer Disease %K Cognitive Dysfunction %K Genome-Wide Association Study %K Humans %K tau Proteins %X

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

%B Nat Genet %V 54 %P 412-436 %8 2022 Apr %G eng %N 4 %R 10.1038/s41588-022-01024-z %0 Journal Article %J Commun Biol %D 2022 %T Non-linear machine learning models incorporating SNPs and PRS improve polygenic prediction in diverse human populations. %A Elgart, Michael %A Lyons, Genevieve %A Romero-Brufau, Santiago %A Kurniansyah, Nuzulul %A Brody, Jennifer A %A Guo, Xiuqing %A Lin, Henry J %A Raffield, Laura %A Gao, Yan %A Chen, Han %A de Vries, Paul %A Lloyd-Jones, Donald M %A Lange, Leslie A %A Peloso, Gina M %A Fornage, Myriam %A Rotter, Jerome I %A Rich, Stephen S %A Morrison, Alanna C %A Psaty, Bruce M %A Levy, Daniel %A Redline, Susan %A Sofer, Tamar %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Machine Learning %K Multifactorial Inheritance %K Polymorphism, Single Nucleotide %X

Polygenic risk scores (PRS) are commonly used to quantify the inherited susceptibility for a trait, yet they fail to account for non-linear and interaction effects between single nucleotide polymorphisms (SNPs). We address this via a machine learning approach, validated in nine complex phenotypes in a multi-ancestry population. We use an ensemble method of SNP selection followed by gradient boosted trees (XGBoost) to allow for non-linearities and interaction effects. We compare our results to the standard, linear PRS model developed using PRSice, LDpred2, and lassosum2. Combining a PRS as a feature in an XGBoost model results in a relative increase in the percentage variance explained compared to the standard linear PRS model by 22% for height, 27% for HDL cholesterol, 43% for body mass index, 50% for sleep duration, 58% for systolic blood pressure, 64% for total cholesterol, 66% for triglycerides, 77% for LDL cholesterol, and 100% for diastolic blood pressure. Multi-ancestry trained models perform similarly to specific racial/ethnic group trained models and are consistently superior to the standard linear PRS models. This work demonstrates an effective method to account for non-linearities and interaction effects in genetics-based prediction models.

%B Commun Biol %V 5 %P 856 %8 2022 08 22 %G eng %N 1 %R 10.1038/s42003-022-03812-z %0 Journal Article %J Diabetes Care %D 2022 %T {Obesity Partially Mediates the Diabetogenic Effect of Lowering LDL Cholesterol %A Wu, P. %A Moon, J. Y. %A Daghlas, I. %A Franco, G. %A Porneala, B. C. %A Ahmadizar, F. %A Richardson, T. G. %A Isaksen, J. L. %A Hindy, G. %A Yao, J. %A Sitlani, C. M. %A Raffield, L. M. %A Yanek, L. R. %A Feitosa, M. F. %A Cuadrat, R. R. C. %A Qi, Q. %A Arfan Ikram, M. %A Ellervik, C. %A Ericson, U. %A Goodarzi, M. O. %A Brody, J. A. %A Lange, L. %A Mercader, J. M. %A Vaidya, D. %A An, P. %A Schulze, M. B. %A Masana, L. %A Ghanbari, M. %A Olesen, M. S. %A Cai, J. %A Guo, X. %A Floyd, J. S. %A Jäger, S. %A Province, M. A. %A Kalyani, R. R. %A Psaty, B. M. %A Orho-Melander, M. %A Ridker, P. M. %A Kanters, J. K. %A Uitterlinden, A. %A Davey Smith, G. %A Gill, D. %A Kaplan, R. C. %A Kavousi, M. %A Raghavan, S. %A Chasman, D. I. %A Rotter, J. I. %A Meigs, J. B. %A Florez, J. C. %A Dupuis, J. %A Liu, C. T. %A Merino, J. %X LDL cholesterol (LDLc)-lowering drugs modestly increase body weight and type 2 diabetes risk, but the extent to which the diabetogenic effect of lowering LDLc is mediated through increased BMI is unknown.\ We conducted summary-level univariable and multivariable Mendelian randomization (MR) analyses in 921,908 participants to investigate the effect of lowering LDLc on type 2 diabetes risk and the proportion of this effect mediated through BMI. We used data from 92,532 participants from 14 observational studies to replicate findings in individual-level MR analyses.\ A 1-SD decrease in genetically predicted LDLc was associated with increased type 2 diabetes odds (odds ratio [OR] 1.12 [95% CI 1.01, 1.24]) and BMI (β = 0.07 SD units [95% CI 0.02, 0.12]) in univariable MR analyses. The multivariable MR analysis showed evidence of an indirect effect of lowering LDLc on type 2 diabetes through BMI (OR 1.04 [95% CI 1.01, 1.08]) with a proportion mediated of 38% of the total effect (P = 0.03). Total and indirect effect estimates were similar across a number of sensitivity analyses. Individual-level MR analyses confirmed the indirect effect of lowering LDLc on type 2 diabetes through BMI with an estimated proportion mediated of 8% (P = 0.04).\ These findings suggest that the diabetogenic effect attributed to lowering LDLc is partially mediated through increased BMI. Our results could help advance understanding of adipose tissue and lipids in type 2 diabetes pathophysiology and inform strategies to reduce diabetes risk among individuals taking LDLc-lowering medications. %B Diabetes Care %V 45 %P 232–240 %8 Jan %G eng %0 Journal Article %J Am J Hum Genet %D 2022 %T Polygenic transcriptome risk scores for COPD and lung function improve cross-ethnic portability of prediction in the NHLBI TOPMed program. %A Hu, Xiaowei %A Qiao, Dandi %A Kim, Wonji %A Moll, Matthew %A Balte, Pallavi P %A Lange, Leslie A %A Bartz, Traci M %A Kumar, Rajesh %A Li, Xingnan %A Yu, Bing %A Cade, Brian E %A Laurie, Cecelia A %A Sofer, Tamar %A Ruczinski, Ingo %A Nickerson, Deborah A %A Muzny, Donna M %A Metcalf, Ginger A %A Doddapaneni, Harshavardhan %A Gabriel, Stacy %A Gupta, Namrata %A Dugan-Perez, Shannon %A Cupples, L Adrienne %A Loehr, Laura R %A Jain, Deepti %A Rotter, Jerome I %A Wilson, James G %A Psaty, Bruce M %A Fornage, Myriam %A Morrison, Alanna C %A Vasan, Ramachandran S %A Washko, George %A Rich, Stephen S %A O'Connor, George T %A Bleecker, Eugene %A Kaplan, Robert C %A Kalhan, Ravi %A Redline, Susan %A Gharib, Sina A %A Meyers, Deborah %A Ortega, Victor %A Dupuis, Josée %A London, Stephanie J %A Lappalainen, Tuuli %A Oelsner, Elizabeth C %A Silverman, Edwin K %A Barr, R Graham %A Thornton, Timothy A %A Wheeler, Heather E %A Cho, Michael H %A Im, Hae Kyung %A Manichaikul, Ani %X

While polygenic risk scores (PRSs) enable early identification of genetic risk for chronic obstructive pulmonary disease (COPD), predictive performance is limited when the discovery and target populations are not well matched. Hypothesizing that the biological mechanisms of disease are shared across ancestry groups, we introduce a PrediXcan-derived polygenic transcriptome risk score (PTRS) to improve cross-ethnic portability of risk prediction. We constructed the PTRS using summary statistics from application of PrediXcan on large-scale GWASs of lung function (forced expiratory volume in 1 s [FEV] and its ratio to forced vital capacity [FEV/FVC]) in the UK Biobank. We examined prediction performance and cross-ethnic portability of PTRS through smoking-stratified analyses both on 29,381 multi-ethnic participants from TOPMed population/family-based cohorts and on 11,771 multi-ethnic participants from TOPMed COPD-enriched studies. Analyses were carried out for two dichotomous COPD traits (moderate-to-severe and severe COPD) and two quantitative lung function traits (FEV and FEV/FVC). While the proposed PTRS showed weaker associations with disease than PRS for European ancestry, the PTRS showed stronger association with COPD than PRS for African Americans (e.g., odds ratio [OR] = 1.24 [95% confidence interval [CI]: 1.08-1.43] for PTRS versus 1.10 [0.96-1.26] for PRS among heavy smokers with ≥ 40 pack-years of smoking) for moderate-to-severe COPD. Cross-ethnic portability of the PTRS was significantly higher than the PRS (paired t test p < 2.2 × 10 with portability gains ranging from 5% to 28%) for both dichotomous COPD traits and across all smoking strata. Our study demonstrates the value of PTRS for improved cross-ethnic portability compared to PRS in predicting COPD risk.

%B Am J Hum Genet %8 2022 Mar 31 %G eng %R 10.1016/j.ajhg.2022.03.007 %0 Journal Article %J Ann Am Thorac Soc %D 2022 %T Pooled Cohort Probability Score for Subclinical Airflow Obstruction. %A Bhatt, Surya P %A Balte, Pallavi P %A Schwartz, Joseph E %A Jaeger, Byron C %A Cassano, Patricia A %A Chaves, Paulo H %A Couper, David %A Jacobs, David R %A Kalhan, Ravi %A Kaplan, Robert %A Lloyd-Jones, Donald %A Newman, Anne B %A O'Connor, George %A Sanders, Jason L %A Smith, Benjamin M %A Sun, Yifei %A Umans, Jason G %A White, Wendy B %A Yende, Sachin %A Oelsner, Elizabeth C %K Adult %K Female %K Forced Expiratory Volume %K Humans %K Lung %K Male %K Middle Aged %K Nutrition Surveys %K Pulmonary Disease, Chronic Obstructive %K Risk Factors %K Spirometry %K Vital Capacity %X

Early detection of chronic obstructive pulmonary disease (COPD) is a public health priority. Airflow obstruction is the single most important risk factor for adverse COPD outcomes, but spirometry is not routinely recommended for screening. To describe the burden of subclinical airflow obstruction (SAO) and to develop a probability score for SAO to inform potential detection and prevention programs. Lung function and clinical data were harmonized and pooled across nine U.S. general population cohorts. Adults with respiratory symptoms, inhaler use, or prior diagnosis of COPD or asthma were excluded. A probability score for prevalent SAO (forced expiratory volume in 1 second/forced vital capacity < 0.70) was developed via hierarchical group-lasso regularization from clinical variables in strata of sex and smoking status, and its discriminative accuracy for SAO was assessed in the pooled cohort as well as in an external validation cohort (NHANES [National Health and Nutrition Examination Survey] 2011-2012). Incident hospitalizations and deaths due to COPD (respiratory events) were defined by adjudication or administrative criteria in four of nine cohorts. Of 33,546 participants (mean age 52 yr, 54% female, 44% non-Hispanic White), 4,424 (13.2%) had prevalent SAO. The incidence of respiratory events ( = 14,024) was threefold higher in participants with SAO versus those without (152 vs. 39 events/10,000 person-years). The probability score, which was based on six commonly available variables (age, sex, race and/or ethnicity, body mass index, smoking status, and smoking pack-years) was well calibrated and showed excellent discrimination in both the testing sample (C-statistic, 0.81; 95% confidence interval [CI], 0.80-0.82) and in NHANES (C-statistic, 0.83; 95% CI, 0.80-0.86). Among participants with predicted probabilities ⩾ 15%, 3.2 would need to undergo spirometry to detect one case of SAO. Adults with SAO demonstrate excess respiratory hospitalization and mortality. A probability score for SAO using commonly available clinical risk factors may be suitable for targeting screening and primary prevention strategies.

%B Ann Am Thorac Soc %V 19 %P 1294-1304 %8 2022 08 %G eng %N 8 %R 10.1513/AnnalsATS.202109-1020OC %0 Journal Article %J Am J Clin Nutr %D 2022 %T Prospective study of breakfast frequency and timing and the risk of incident type 2 diabetes in community-dwelling older adults: The Cardiovascular Health Study. %A Carew, Allie S %A Mekary, Rania A %A Kirkland, Susan %A Theou, Olga %A Siddiqi, Ferhan %A Urquhart, Robin %A George, Michelle %A Blanchard, Chris %A Biggs, Mary L %A Djoussé, Luc %A Mukamal, Kenneth J %A Cahill, Leah E %X

BACKGROUND: No evidence-based recommendations regarding optimal breakfast frequency and timing and type 2 diabetes mellitus (T2DM) exist for older adults due to limited studies.

OBJECTIVE: We sought to prospectively assess relationships between breakfast frequency and timing and T2DM risk among older adults and determine whether these depended on gender or cardiometabolic risk factors.

METHODS: Weekly breakfast frequency and usual daily breakfast time were assessed by questionnaire at baseline in 3,747 older adults (aged ≥65 years) from the Cardiovascular Health Study (CHS) who were free of cancer and T2DM and followed for 17.6 years. Multivariable-adjusted hazard ratios (aHR) with 95% confidence intervals (CI) estimated from Cox proportional hazards models were used to quantify associations with T2DM.

RESULTS: Most CHS participants (median age: 74 years; interquartile range: 71, 78) consumed breakfast daily (85.5%), and 73% had their first daily eating occasion between 07:00-09:00 hours, which were associated with higher socioeconomic status, factors that are indicative of a healthier lifestyle, and lower levels of cardiometabolic risk indicators at baseline. During follow-up, 547 T2DM cases were documented. No strong evidence was observed between breakfast frequency and risk of T2DM. Compared to participants whose breakfast timing (first eating occasion of the day) was 07:00-09:00, those who broke fast after 09:00 had an aHR for T2DM of 0.71 (95% CI: 0.51, 0.99). This association was present in participants with impaired fasting glucose at baseline (0.61; 0.39, 0.95) but not in those without (0.83; 0.50, 1.38)). No associations between eating frequency or timing and T2DM were observed within other pre-specified subgroups.

CONCLUSIONS: Eating breakfast daily was not associated with either higher or lower risk of T2DM in this cohort of older adults, while a later (after 09:00) daily first eating occasion time was associated with lower T2DM risk in participants with impaired fasting glucose at baseline.

%B Am J Clin Nutr %8 2022 Apr 05 %G eng %R 10.1093/ajcn/nqac087 %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 Am J Clin Nutr %D 2022 %T PUFA ω-3 and ω-6 biomarkers and sleep: a pooled analysis of cohort studies on behalf of the Fatty Acids and Outcomes Research Consortium (FORCE). %A Murphy, Rachel A %A Tintle, Nathan %A Harris, William S %A Darvishian, Maryam %A Marklund, Matti %A Virtanen, Jyrki K %A Hantunen, Sari %A de Mello, Vanessa D %A Tuomilehto, Jaakko %A Lindström, Jaana %A Bolt, Matthew A %A Brouwer, Ingeborg A %A Wood, Alexis C %A Senn, Mackenzie %A Redline, Susan %A Tsai, Michael Y %A Gudnason, Vilmundur %A Eiriksdottir, Gudny %A Lindberg, Eva %A Shadyab, Aladdin H %A Liu, Buyun %A Carnethon, Mercedes %A Uusitupa, Matti %A Djoussé, Luc %A Riserus, Ulf %A Lind, Lars %A van Dam, Rob M %A Koh, Woon-Puay %A Shi, Peilin %A Siscovick, David %A Lemaitre, Rozenn N %A Mozaffarian, Dariush %K Biomarkers %K Cohort Studies %K Cross-Sectional Studies %K Fatty Acids %K Fatty Acids, Omega-3 %K Humans %K Outcome Assessment, Health Care %K Sleep %X

BACKGROUND: n-3 and n-6 PUFAs have physiologic roles in sleep processes, but little is known regarding circulating n-3 and n-6 PUFA and sleep parameters.

OBJECTIVES: We sought to assess associations between biomarkers of n-3 and n-6 PUFA intake with self-reported sleep duration and difficulty falling sleeping in the Fatty Acids and Outcome Research Consortium.

METHODS: Harmonized, de novo, individual-level analyses were performed and pooled across 12 cohorts. Participants were 35-96 y old and from 5 nations. Circulating measures included α-linolenic acid (ALA), EPA, docosapentaenoic acid (DPA), DHA, EPA + DPA + DHA, linoleic acid, and arachidonic acid. Sleep duration (10 cohorts, n = 18,791) was categorized as short (≤6 h), 7-8 h (reference), or long (≥9 h). Difficulty falling asleep (8 cohorts, n = 12,500) was categorized as yes or no. Associations between PUFAs, sleep duration, and difficulty falling sleeping were assessed by cross-sectional multinomial logistic regression using standardized protocols and covariates. Cohort-specific multivariable-adjusted ORs per quintile of PUFAs were pooled with inverse-variance weighted meta-analysis.

RESULTS: In pooled analysis adjusted for sociodemographic characteristics and health status, participants with higher very long-chain n-3 PUFAs were less likely to have long sleep duration. In the top compared with the bottom quintiles, the multivariable-adjusted ORs (95% CIs) for long sleep were 0.78 (95% CI: 0.65, 0.95) for DHA and 0.76 (95% CI: 0.63, 0.93) for EPA + DPA + DHA. Significant associations for ALA and n-6 PUFA with short sleep duration or difficulty falling sleeping were not identified.

CONCLUSIONS: Participants with higher concentrations of very long-chain n-3 PUFAs were less likely to have long sleep duration. While objective biomarkers reduce recall bias and misclassification, the cross-sectional design limits assessment of the temporal nature of this relation. These novel findings across 12 cohorts highlight the need for experimental and biological assessments of very long-chain n-3 PUFAs and sleep duration.

%B Am J Clin Nutr %V 115 %P 864-876 %8 2022 Mar 04 %G eng %N 3 %R 10.1093/ajcn/nqab408 %0 Journal Article %J Am J Hum Genet %D 2022 %T Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes. %A Hindy, George %A Dornbos, Peter %A Chaffin, Mark D %A Liu, Dajiang J %A Wang, Minxian %A Selvaraj, Margaret Sunitha %A Zhang, David %A Park, Joseph %A Aguilar-Salinas, Carlos A %A Antonacci-Fulton, Lucinda %A Ardissino, Diego %A Arnett, Donna K %A Aslibekyan, Stella %A Atzmon, Gil %A Ballantyne, Christie M %A Barajas-Olmos, Francisco %A Barzilai, Nir %A Becker, Lewis C %A Bielak, Lawrence F %A Bis, Joshua C %A Blangero, John %A Boerwinkle, Eric %A Bonnycastle, Lori L %A Bottinger, Erwin %A Bowden, Donald W %A Bown, Matthew J %A Brody, Jennifer A %A Broome, Jai G %A Burtt, Noel P %A Cade, Brian E %A Centeno-Cruz, Federico %A Chan, Edmund %A Chang, Yi-Cheng %A Chen, Yii-der I %A Cheng, Ching-Yu %A Choi, Won Jung %A Chowdhury, Rajiv %A Contreras-Cubas, Cecilia %A Córdova, Emilio J %A Correa, Adolfo %A Cupples, L Adrienne %A Curran, Joanne E %A Danesh, John %A de Vries, Paul S %A DeFronzo, Ralph A %A Doddapaneni, Harsha %A Duggirala, Ravindranath %A Dutcher, Susan K %A Ellinor, Patrick T %A Emery, Leslie S %A Florez, Jose C %A Fornage, Myriam %A Freedman, Barry I %A Fuster, Valentin %A Garay-Sevilla, Ma Eugenia %A García-Ortiz, Humberto %A Germer, Soren %A Gibbs, Richard A %A Gieger, Christian %A Glaser, Benjamin %A Gonzalez, Clicerio %A Gonzalez-Villalpando, Maria Elena %A Graff, Mariaelisa %A Graham, Sarah E %A Grarup, Niels %A Groop, Leif C %A Guo, Xiuqing %A Gupta, Namrata %A Han, Sohee %A Hanis, Craig L %A Hansen, Torben %A He, Jiang %A Heard-Costa, Nancy L %A Hung, Yi-Jen %A Hwang, Mi Yeong %A Irvin, Marguerite R %A Islas-Andrade, Sergio %A Jarvik, Gail P %A Kang, Hyun Min %A Kardia, Sharon L R %A Kelly, Tanika %A Kenny, Eimear E %A Khan, Alyna T %A Kim, Bong-Jo %A Kim, Ryan W %A Kim, Young Jin %A Koistinen, Heikki A %A Kooperberg, Charles %A Kuusisto, Johanna %A Kwak, Soo Heon %A Laakso, Markku %A Lange, Leslie A %A Lee, Jiwon %A Lee, Juyoung %A Lee, Seonwook %A Lehman, Donna M %A Lemaitre, Rozenn N %A Linneberg, Allan %A Liu, Jianjun %A Loos, Ruth J F %A Lubitz, Steven A %A Lyssenko, Valeriya %A Ma, Ronald C W %A Martin, Lisa Warsinger %A Martínez-Hernández, Angélica %A Mathias, Rasika A %A McGarvey, Stephen T %A McPherson, Ruth %A Meigs, James B %A Meitinger, Thomas %A Melander, Olle %A Mendoza-Caamal, Elvia %A Metcalf, Ginger A %A Mi, Xuenan %A Mohlke, Karen L %A Montasser, May E %A Moon, Jee-Young %A Moreno-Macias, Hortensia %A Morrison, Alanna C %A Muzny, Donna M %A Nelson, Sarah C %A Nilsson, Peter M %A O'Connell, Jeffrey R %A Orho-Melander, Marju %A Orozco, Lorena %A Palmer, Colin N A %A Palmer, Nicholette D %A Park, Cheol Joo %A Park, Kyong Soo %A Pedersen, Oluf %A Peralta, Juan M %A Peyser, Patricia A %A Post, Wendy S %A Preuss, Michael %A Psaty, Bruce M %A Qi, Qibin %A Rao, D C %A Redline, Susan %A Reiner, Alexander P %A Revilla-Monsalve, Cristina %A Rich, Stephen S %A Samani, Nilesh %A Schunkert, Heribert %A Schurmann, Claudia %A Seo, Daekwan %A Seo, Jeong-Sun %A Sim, Xueling %A Sladek, Rob %A Small, Kerrin S %A So, Wing Yee %A Stilp, Adrienne M %A Tai, E Shyong %A Tam, Claudia H T %A Taylor, Kent D %A Teo, Yik Ying %A Thameem, Farook %A Tomlinson, Brian %A Tsai, Michael Y %A Tuomi, Tiinamaija %A Tuomilehto, Jaakko %A Tusié-Luna, Teresa %A Udler, Miriam S %A van Dam, Rob M %A Vasan, Ramachandran S %A Viaud Martinez, Karine A %A Wang, Fei Fei %A Wang, Xuzhi %A Watkins, Hugh %A Weeks, Daniel E %A Wilson, James G %A Witte, Daniel R %A Wong, Tien-Yin %A Yanek, Lisa R %A Kathiresan, Sekar %A Rader, Daniel J %A Rotter, Jerome I %A Boehnke, Michael %A McCarthy, Mark I %A Willer, Cristen J %A Natarajan, Pradeep %A Flannick, Jason A %A Khera, Amit V %A Peloso, Gina M %K Alleles %K Blood Glucose %K Case-Control Studies %K Computational Biology %K Databases, Genetic %K Diabetes Mellitus, Type 2 %K Exome %K Genetic Predisposition to Disease %K Genetic Variation %K Genetics, Population %K Genome-Wide Association Study %K Humans %K Lipid Metabolism %K Lipids %K Liver %K Molecular Sequence Annotation %K Multifactorial Inheritance %K Open Reading Frames %K Phenotype %K Polymorphism, Single Nucleotide %X

Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency < 1%) predicted damaging coding variation by using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels; some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples. We prioritize 32 genes in array-based genome-wide association study (GWAS) loci based on aggregations of rare coding variants; three (EVI5, SH2B3, and PLIN1) had no prior association of rare coding variants with lipid levels. Most of our associated genes showed evidence of association among multiple ancestries. Finally, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes and for genes closest to GWAS index single-nucleotide polymorphisms (SNPs). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.

%B Am J Hum Genet %V 109 %P 81-96 %8 2022 01 06 %G eng %N 1 %R 10.1016/j.ajhg.2021.11.021 %0 Journal Article %J Nat Hum Behav %D 2022 %T Rare genetic variants explain missing heritability in smoking. %A Jang, Seon-Kyeong %A Evans, Luke %A Fialkowski, Allison %A Arnett, Donna K %A Ashley-Koch, Allison E %A Barnes, Kathleen C %A Becker, Diane M %A Bis, Joshua C %A Blangero, John %A Bleecker, Eugene R %A Boorgula, Meher Preethi %A Bowden, Donald W %A Brody, Jennifer A %A Cade, Brian E %A Jenkins, Brenda W Campbell %A Carson, April P %A Chavan, Sameer %A Cupples, L Adrienne %A Custer, Brian %A Damrauer, Scott M %A David, Sean P %A de Andrade, Mariza %A Dinardo, Carla L %A Fingerlin, Tasha E %A Fornage, Myriam %A Freedman, Barry I %A Garrett, Melanie E %A Gharib, Sina A %A Glahn, David C %A Haessler, Jeffrey %A Heckbert, Susan R %A Hokanson, John E %A Hou, Lifang %A Hwang, Shih-Jen %A Hyman, Matthew C %A Judy, Renae %A Justice, Anne E %A Kaplan, Robert C %A Kardia, Sharon L R %A Kelly, Shannon %A Kim, Wonji %A Kooperberg, Charles %A Levy, Daniel %A Lloyd-Jones, Donald M %A Loos, Ruth J F %A Manichaikul, Ani W %A Gladwin, Mark T %A Martin, Lisa Warsinger %A Nouraie, Mehdi %A Melander, Olle %A Meyers, Deborah A %A Montgomery, Courtney G %A North, Kari E %A Oelsner, Elizabeth C %A Palmer, Nicholette D %A Payton, Marinelle %A Peljto, Anna L %A Peyser, Patricia A %A Preuss, Michael %A Psaty, Bruce M %A Qiao, Dandi %A Rader, Daniel J %A Rafaels, Nicholas %A Redline, Susan %A Reed, Robert M %A Reiner, Alexander P %A Rich, Stephen S %A Rotter, Jerome I %A Schwartz, David A %A Shadyab, Aladdin H %A Silverman, Edwin K %A Smith, Nicholas L %A Smith, J Gustav %A Smith, Albert V %A Smith, Jennifer A %A Tang, Weihong %A Taylor, Kent D %A Telen, Marilyn J %A Vasan, Ramachandran S %A Gordeuk, Victor R %A Wang, Zhe %A Wiggins, Kerri L %A Yanek, Lisa R %A Yang, Ivana V %A Young, Kendra A %A Young, Kristin L %A Zhang, Yingze %A Liu, Dajiang J %A Keller, Matthew C %A Vrieze, Scott %X

Common genetic variants explain less variation in complex phenotypes than inferred from family-based studies, and there is a debate on the source of this 'missing heritability'. We investigated the contribution of rare genetic variants to tobacco use with whole-genome sequences from up to 26,257 unrelated individuals of European ancestries and 11,743 individuals of African ancestries. Across four smoking traits, single-nucleotide-polymorphism-based heritability ([Formula: see text]) was estimated from 0.13 to 0.28 (s.e., 0.10-0.13) in European ancestries, with 35-74% of it attributable to rare variants with minor allele frequencies between 0.01% and 1%. These heritability estimates are 1.5-4 times higher than past estimates based on common variants alone and accounted for 60% to 100% of our pedigree-based estimates of narrow-sense heritability ([Formula: see text], 0.18-0.34). In the African ancestry samples, [Formula: see text] was estimated from 0.03 to 0.33 (s.e., 0.09-0.14) across the four smoking traits. These results suggest that rare variants are important contributors to the heritability of smoking.

%B Nat Hum Behav %8 2022 Aug 04 %G eng %R 10.1038/s41562-022-01408-5 %0 Journal Article %J Alzheimers Dement %D 2022 %T {Replication study of AD-associated rare variants %A Neupane, A. %A Lenny, B. %A Budde, J. P. %A Wang, F. %A Norton, J. %A Morris, J. C. %A Cruchaga, C. %A Fernández, M. V. %B Alzheimers Dement %V 18 %P 858–862 %8 Apr %G eng %0 Journal Article %J Nature %D 2022 %T {A saturated map of common genetic variants associated with human height %A Yengo, L. %A Vedantam, S. %A Marouli, E. %A Sidorenko, J. %A Bartell, E. %A Sakaue, S. %A Graff, M. %A Eliasen, A. U. %A Jiang, Y. %A Raghavan, S. %A Miao, J. %A Arias, J. D. %A Graham, S. E. %A Mukamel, R. E. %A Spracklen, C. N. %A Yin, X. %A Chen, S. H. %A Ferreira, T. %A Highland, H. H. %A Ji, Y. %A Karaderi, T. %A Lin, K. %A ll, K. %A Malden, D. E. %A Medina-Gomez, C. %A Machado, M. %A Moore, A. %A eger, S. %A Sim, X. %A Vrieze, S. %A Ahluwalia, T. S. %A Akiyama, M. %A Allison, M. A. %A Alvarez, M. %A Andersen, M. 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F. %A Wu, J. Y. %A Xu, H. %A Yajnik, C. S. %A Yokota, M. %A Yuan, J. M. %A Zeggini, E. %A Zemel, B. S. %A Zheng, W. %A Zhu, X. %A Zmuda, J. M. %A Zonderman, A. B. %A Zwart, J. A. %A Chasman, D. I. %A Cho, Y. S. %A Heid, I. M. %A McCarthy, M. I. %A Ng, M. C. Y. %A O'Donnell, C. J. %A Rivadeneira, F. %A Thorsteinsdottir, U. %A Sun, Y. V. %A Tai, E. S. %A Boehnke, M. %A Deloukas, P. %A Justice, A. E. %A Lindgren, C. M. %A Loos, R. J. F. %A Mohlke, K. L. %A North, K. E. %A Stefansson, K. %A Walters, R. G. %A Winkler, T. W. %A Young, K. L. %A Loh, P. R. %A Yang, J. %A Esko, T. %A Assimes, T. L. %A Auton, A. %A Abecasis, G. R. %A Willer, C. J. %A Locke, A. E. %A Berndt, S. I. %A Lettre, G. %A Frayling, T. M. %A Okada, Y. %A Wood, A. R. %A Visscher, P. M. %A Hirschhorn, J. N. %A Partida, G. C. %A Sun, Y. %A Croteau-Chonka, D. %A Vonk, J. M. %A Chanock, S. %A Le Marchand, L. %X ) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries. %B Nature %V 610 %P 704–712 %8 Oct %G eng %0 Journal Article %J J Am Geriatr Soc %D 2022 %T Sex- and race-specific associations of bone mineral density with incident heart failure and its subtypes in older adults. %A Gao, Hans %A Patel, Sheena %A Fohtung, Raymond B %A Cawthon, Peggy M %A Newman, Anne B %A Cauley, Jane A %A Carbone, Laura %A Chaves, Paulo H M %A Stein, Phyllis K %A Civitelli, Roberto %A Kizer, Jorge R %X

BACKGROUND: Previous studies have suggested an association between bone mineral density (BMD) and heart failure (HF) risk that may be race-dependent.

METHODS: We evaluated the relationship between BMD and incident HF in a cohort of older adults, the Health, Aging, and Body Composition (Health ABC) study (n = 2835), and next performed a pooled analysis involving a second older cohort, the Cardiovascular Health Study (n = 1268). Hip BMD was measured by dual-energy X-ray absorptiometry in both cohorts and spine BMD by computed tomography in a subset from Health ABC.

RESULTS: In Health ABC, lower BMD at the total hip was associated with higher incident HF in Black women after multivariable adjustment. Similar associations were found for BMD at the femoral neck and spine. In both cohorts, pooled analysis again revealed an association between lower total hip BMD and increased risk of HF in Black women (HR = 1.41 per 0.1-g/cm decrement [95% CI = 1.23-1.62]), and showed the same to be true for White men (HR = 1.12 [1.03-1.21]). There was a decreased risk of HF in Black men (HR 0.80 [0.70-0.91]), but no relationship in White women. The associations were numerically stronger with HFpEF for Black women and White men, and with HFrEF for Black men. Findings were similar for femoral neck BMD. Sensitivity analyses delaying HF follow-up by 2 years eliminated the association in Black men.

CONCLUSIONS: Lower BMD was associated with higher risk of HF and especially HFpEF in older Black women and White men, highlighting the need for additional investigation into underlying mechanisms.

%B J Am Geriatr Soc %8 2022 Nov 05 %G eng %R 10.1111/jgs.18121 %0 Journal Article %J Nature %D 2022 %T Stroke genetics informs drug discovery and risk prediction across ancestries. %A Mishra, Aniket %A Malik, Rainer %A Hachiya, Tsuyoshi %A Jürgenson, Tuuli %A Namba, Shinichi %A Posner, Daniel C %A Kamanu, Frederick K %A Koido, Masaru %A Le Grand, Quentin %A Shi, Mingyang %A He, Yunye %A Georgakis, Marios K %A Caro, Ilana %A Krebs, Kristi %A Liaw, Yi-Ching %A Vaura, Felix C %A Lin, Kuang %A Winsvold, Bendik Slagsvold %A Srinivasasainagendra, Vinodh %A Parodi, Livia %A Bae, Hee-Joon %A Chauhan, Ganesh %A Chong, Michael R %A Tomppo, Liisa %A Akinyemi, Rufus %A Roshchupkin, Gennady V %A Habib, Naomi %A Jee, Yon Ho %A Thomassen, Jesper Qvist %A Abedi, Vida %A Cárcel-Márquez, Jara %A Nygaard, Marianne %A Leonard, Hampton L %A Yang, Chaojie %A Yonova-Doing, Ekaterina %A Knol, Maria J %A Lewis, Adam J %A Judy, Renae L %A Ago, Tetsuro %A Amouyel, Philippe %A Armstrong, Nicole D %A Bakker, Mark K %A Bartz, Traci M %A Bennett, David A %A Bis, Joshua C %A Bordes, Constance %A Børte, Sigrid %A Cain, Anael %A Ridker, Paul M %A Cho, Kelly %A Chen, Zhengming %A Cruchaga, Carlos %A Cole, John W %A De Jager, Phil L %A de Cid, Rafael %A Endres, Matthias %A Ferreira, Leslie E %A Geerlings, Mirjam I %A Gasca, Natalie C %A Gudnason, Vilmundur %A Hata, Jun %A He, Jing %A Heath, Alicia K %A Ho, Yuk-Lam %A Havulinna, Aki S %A Hopewell, Jemma C %A Hyacinth, Hyacinth I %A Inouye, Michael %A Jacob, Mina A %A Jeon, Christina E %A Jern, Christina %A Kamouchi, Masahiro %A Keene, Keith L %A Kitazono, Takanari %A Kittner, Steven J %A Konuma, Takahiro %A Kumar, Amit %A Lacaze, Paul %A Launer, Lenore J %A Lee, Keon-Joo %A Lepik, Kaido %A Li, Jiang %A Li, Liming %A Manichaikul, Ani %A Markus, Hugh S %A Marston, Nicholas A %A Meitinger, Thomas %A Mitchell, Braxton D %A Montellano, Felipe A %A Morisaki, Takayuki %A Mosley, Thomas H %A Nalls, Mike A %A Nordestgaard, Børge G %A O'Donnell, Martin J %A Okada, Yukinori %A Onland-Moret, N Charlotte %A Ovbiagele, Bruce %A Peters, Annette %A Psaty, Bruce M %A Rich, Stephen S %A Rosand, Jonathan %A Sabatine, Marc S %A Sacco, Ralph L %A Saleheen, Danish %A Sandset, Else Charlotte %A Salomaa, Veikko %A Sargurupremraj, Muralidharan %A Sasaki, Makoto %A Satizabal, Claudia L %A Schmidt, Carsten O %A Shimizu, Atsushi %A Smith, Nicholas L %A Sloane, Kelly L %A Sutoh, Yoichi %A Sun, Yan V %A Tanno, Kozo %A Tiedt, Steffen %A Tatlisumak, Turgut %A Torres-Aguila, Nuria P %A Tiwari, Hemant K %A Trégouët, David-Alexandre %A Trompet, Stella %A Tuladhar, Anil Man %A Tybjærg-Hansen, Anne %A van Vugt, Marion %A Vibo, Riina %A Verma, Shefali S %A Wiggins, Kerri L %A Wennberg, Patrik %A Woo, Daniel %A Wilson, Peter W F %A Xu, Huichun %A Yang, Qiong %A Yoon, Kyungheon %A Millwood, Iona Y %A Gieger, Christian %A Ninomiya, Toshiharu %A Grabe, Hans J %A Jukema, J Wouter %A Rissanen, Ina L %A Strbian, Daniel %A Kim, Young Jin %A Chen, Pei-Hsin %A Mayerhofer, Ernst %A Howson, Joanna M M %A Irvin, Marguerite R %A Adams, Hieab %A Wassertheil-Smoller, Sylvia %A Christensen, Kaare %A Ikram, Mohammad A %A Rundek, Tatjana %A Worrall, Bradford B %A Lathrop, G Mark %A Riaz, Moeen %A Simonsick, Eleanor M %A Kõrv, Janika %A França, Paulo H C %A Zand, Ramin %A Prasad, Kameshwar %A Frikke-Schmidt, Ruth %A de Leeuw, Frank-Erik %A Liman, Thomas %A Haeusler, Karl Georg %A Ruigrok, Ynte M %A Heuschmann, Peter Ulrich %A Longstreth, W T %A Jung, Keum Ji %A Bastarache, Lisa %A Paré, Guillaume %A Damrauer, Scott M %A Chasman, Daniel I %A Rotter, Jerome I %A Anderson, Christopher D %A Zwart, John-Anker %A Niiranen, Teemu J %A Fornage, Myriam %A Liaw, Yung-Po %A Seshadri, Sudha %A Fernandez-Cadenas, Israel %A Walters, Robin G %A Ruff, Christian T %A Owolabi, Mayowa O %A Huffman, Jennifer E %A Milani, Lili %A Kamatani, Yoichiro %A Dichgans, Martin %A Debette, Stephanie %X

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

%B Nature %8 2022 Sep 30 %G eng %R 10.1038/s41586-022-05165-3 %0 Journal Article %J Am J Respir Crit Care Med %D 2022 %T Targeted Genome Sequencing Identifies Multiple Rare Variants in Caveolin-1 Associated with Obstructive Sleep Apnea. %A Liang, Jingjing %A Wang, Heming %A Cade, Brian E %A Kurniansyah, Nuzulul %A He, Karen Y %A Lee, Jiwon %A Sands, Scott A %A Brody, Jennifer %A Chen, Han %A Gottlieb, Daniel J %A Evans, Daniel S %A Guo, Xiuqing %A Gharib, Sina A %A Hale, Lauren %A Hillman, David R %A Lutsey, Pamela L %A Mukherjee, Sutapa %A Ochs-Balcom, Heather M %A Palmer, Lyle J %A Purcell, Shaun %A Saxena, Richa %A Patel, Sanjay R %A Stone, Katie L %A Tranah, Gregory J %A Boerwinkle, Eric %A Lin, Xihong %A Liu, Yongmei %A Psaty, Bruce M %A Vasan, Ramachandran S %A Manichaikul, Ani %A Rich, Stephen S %A Rotter, Jerome I %A Sofer, Tamar %A Redline, Susan %A Zhu, Xiaofeng %X

INTRODUCTION: Obstructive sleep apnea (OSA) is a common disorder associated with increased risk for cardiovascular disease, diabetes, and premature mortality. There is strong clinical and epi-demiologic evidence supporting the importance of genetic factors influencing OSA, but limited data implicating specific genes.

METHODS: Leveraging high depth genomic sequencing data from the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program and imputed genotype data from multiple population-based studies, we performed linkage analysis in the Cleve-land Family Study (CFS) followed by multi-stage gene-based association analyses in independent cohorts to search for rare variants contributing to OSA severity as assessed by the apnea-hypopnea index (AHI) in a total of 7,708 individuals of European ancestry.

RESULTS: Linkage analysis in CFS identified a suggestive linkage peak on chromosome 7q31 (LOD=2.31). Gene-based analysis identified 21 non-coding rare variants in Caveolin-1 (CAV1) associated with lower AHI after accounting for multiple comparisons (p=7.4×10-8). These non-coding variants together significantly contributed to the linkage evidence (p<10-3). Follow-up anal-ysis revealed significant associations between these variants and increased CAV1 expression, and increased CAV1 expression in peripheral monocytes was associated with lower AHI (p=0.024) and higher minimum overnight oxygen saturation (p=0.007).

CONCLUSION: Rare variants in CAV1, a membrane scaffolding protein essential in multiple cellular and metabolic functions, are associated with higher CAV1 gene expression and lower OSA severity, suggesting a novel target for modulating OSA severity.

%B Am J Respir Crit Care Med %8 2022 Jul 13 %G eng %R 10.1164/rccm.202203-0618OC %0 Journal Article %J Diabetes Care %D 2022 %T {Trans Fatty Acid Biomarkers and Incident Type 2 Diabetes: Pooled Analysis of 12 Prospective Cohort Studies in the Fatty Acids and Outcomes Research Consortium (FORCE) %A Lai, H. T. M. %A Imamura, F. %A Korat, A. V. A. %A Murphy, R. A. %A Tintle, N. %A Bassett, J. K. %A Chen, J. %A ger, J. %A Chien, K. L. %A Senn, M. %A Wood, A. C. %A Forouhi, N. G. %A Schulze, M. B. %A Harris, W. S. %A Vasan, R. S. %A Hu, F. %A Giles, G. G. %A Hodge, A. %A Djousse, L. %A Brouwer, I. A. %A Qian, F. %A Sun, Q. %A Wu, J. H. Y. %A Marklund, M. %A Lemaitre, R. N. %A Siscovick, D. S. %A Fretts, A. M. %A Shadyab, A. H. %A Manson, J. E. %A Howard, B. V. %A Robinson, J. G. %A Wallace, R. B. %A Wareham, N. J. %A Chen, Y. I. %A Rotter, J. I. %A Tsai, M. Y. %A Micha, R. %A Mozaffarian, D. %X Trans fatty acids (TFAs) have harmful biologic effects that could increase the risk of type 2 diabetes (T2D), but evidence remains uncertain. We aimed to investigate the prospective associations of TFA biomarkers and T2D by conducting an individual participant-level pooled analysis.\ 18 years without prevalent diabetes. Each cohort conducted de novo harmonized analyses using a prespecified protocol, and findings were pooled using inverse-variance weighted meta-analysis. Heterogeneity was explored by prespecified between-study and within-study characteristics.\ 0.1).\ Circulating individual trans-18:2 TFA biomarkers were not associated with risk of T2D, while trans-16:1n-9, total trans-18:1, and total trans-18:2 were inversely associated. Findings may reflect the influence of mixed TFA sources (industrial vs. natural ruminant), a general decline in TFA exposure due to policy changes during this period, or the relatively limited range of TFA levels. %B Diabetes Care %V 45 %P 854–863 %8 Apr %G eng %0 Journal Article %J Bone %D 2022 %T Trimethylamine N-oxide and hip fracture and bone mineral density in older adults: The cardiovascular health study. %A Elam, Rachel E %A Bůzková, Petra %A Barzilay, Joshua I %A Wang, Zeneng %A Nemet, Ina %A Budoff, Matthew J %A Cauley, Jane A %A Fink, Howard A %A Lee, Yujin %A Robbins, John A %A Wang, Meng %A Hazen, Stanley L %A Mozaffarian, Dariush %A Carbone, Laura D %K Absorptiometry, Photon %K Aged %K Bone Density %K Female %K Hip Fractures %K Humans %K Male %K Methylamines %K Risk Factors %X

CONTEXT: Gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) may adversely affect bone by inducing oxidative stress. Whether this translates into increased fracture risk in older adults is uncertain.

OBJECTIVE: Determine the associations of plasma TMAO with hip fracture and bone mineral density (BMD) in older adults.

DESIGN AND SETTING: Cox hazard models and linear regression stratified by sex examined the associations of TMAO with hip fracture and BMD in the longitudinal cohort of the Cardiovascular Health Study.

PARTICIPANTS: 5019 U.S. adults aged ≥65 years.

EXPOSURE: Plasma TMAO.

MAIN OUTCOME MEASURES: Incident hip fractures; total hip BMD dual x-ray absorptiometry in a subset (n = 1400).

RESULTS: Six hundred sixty-six incident hip fractures occurred during up to 26 years of follow-up (67,574 person-years). After multivariable adjustment, TMAO was not significantly associated with hip fracture (women: hazard ratio (HR) [95% confidence interval (CI)] of 1.00[0.92,1.09] per TMAO doubling; men: 1.12[0.95,1.33]). TMAO was also not associated with total hip BMD (women: BMD difference [95% CI] of 0.42 g/cm*100 [-0.34,1.17] per TMAO doubling; men: 0.19[-1.04,1.42]). In exploratory analyses, we found an interaction between body mass index (BMI) and the association of TMAO with hip fracture (P < 0.01). Higher TMAO was significantly associated with risk of hip fracture in adults with overweight or obesity (BMI ≥ 25) (HR [95% CI]:1.17[1.05,1.31]), but not normal or underweight.

CONCLUSIONS: Among older US men and women, TMAO was not significantly associated with risk of hip fracture or BMD overall. Exploratory analyses suggested a significant association between higher TMAO and hip fracture when BMI was elevated, which merits further study.

%B Bone %V 161 %P 116431 %8 2022 08 %G eng %R 10.1016/j.bone.2022.116431 %0 Journal Article %J Front Endocrinol (Lausanne) %D 2022 %T The Value of Rare Genetic Variation in the Prediction of Common Obesity in European Ancestry Populations. %A Wang, Zhe %A Choi, Shing Wan %A Chami, Nathalie %A Boerwinkle, Eric %A Fornage, Myriam %A Redline, Susan %A Bis, Joshua C %A Brody, Jennifer A %A Psaty, Bruce M %A Kim, Wonji %A McDonald, Merry-Lynn N %A Regan, Elizabeth A %A Silverman, Edwin K %A Liu, Ching-Ti %A Vasan, Ramachandran S %A Kalyani, Rita R %A Mathias, Rasika A %A Yanek, Lisa R %A Arnett, Donna K %A Justice, Anne E %A North, Kari E %A Kaplan, Robert %A Heckbert, Susan R %A de Andrade, Mariza %A Guo, Xiuqing %A Lange, Leslie A %A Rich, Stephen S %A Rotter, Jerome I %A Ellinor, Patrick T %A Lubitz, Steven A %A Blangero, John %A Shoemaker, M Benjamin %A Darbar, Dawood %A Gladwin, Mark T %A Albert, Christine M %A Chasman, Daniel I %A Jackson, Rebecca D %A Kooperberg, Charles %A Reiner, Alexander P %A O'Reilly, Paul F %A Loos, Ruth J F %K Gene Frequency %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Obesity %K Whole Genome Sequencing %X

Polygenic risk scores (PRSs) aggregate the effects of genetic variants across the genome and are used to predict risk of complex diseases, such as obesity. Current PRSs only include common variants (minor allele frequency (MAF) ≥1%), whereas the contribution of rare variants in PRSs to predict disease remains unknown. Here, we examine whether augmenting the standard common variant PRS (PRS) with a rare variant PRS (PRS) improves prediction of obesity. We used genome-wide genotyped and imputed data on 451,145 European-ancestry participants of the UK Biobank, as well as whole exome sequencing (WES) data on 184,385 participants. We performed single variant analyses (for both common and rare variants) and gene-based analyses (for rare variants) for association with BMI (kg/m), obesity (BMI ≥ 30 kg/m), and extreme obesity (BMI ≥ 40 kg/m). We built PRSs and PRSs using a range of methods (Clumping+Thresholding [C+T], PRS-CS, lassosum, gene-burden test). We selected the best-performing PRSs and assessed their performance in 36,757 European-ancestry unrelated participants with whole genome sequencing (WGS) data from the Trans-Omics for Precision Medicine (TOPMed) program. The best-performing PRS explained 10.1% of variation in BMI, and 18.3% and 22.5% of the susceptibility to obesity and extreme obesity, respectively, whereas the best-performing PRS explained 1.49%, and 2.97% and 3.68%, respectively. The PRS was associated with an increased risk of obesity and extreme obesity (OR = 1.37 per SD, = 1.7x10; OR = 1.55 per SD, = 3.8x10), which was attenuated, after adjusting for PRS (OR = 1.08 per SD, = 9.8x10; OR= 1.09 per SD, = 0.02). When PRS and PRS are combined, the increase in explained variance attributed to PRS was small (incremental Nagelkerke R = 0.24% for obesity and 0.51% for extreme obesity). Consistently, combining PRS to PRS provided little improvement to the prediction of obesity (PRS AUC = 0.591; PRS AUC = 0.708; PRS AUC = 0.710). In summary, while rare variants show convincing association with BMI, obesity and extreme obesity, the PRS provides limited improvement over PRS in the prediction of obesity risk, based on these large populations.

%B Front Endocrinol (Lausanne) %V 13 %P 863893 %8 2022 %G eng %R 10.3389/fendo.2022.863893 %0 Journal Article %J Hum Mol Genet %D 2022 %T Whole exome sequencing of 14 389 individuals from the ESP and CHARGE consortia identifies novel rare variation associated with hemostatic factors. %A Pankratz, Nathan %A Wei, Peng %A Brody, Jennifer A %A Chen, Ming-Huei %A Vries, Paul S %A Huffman, Jennifer E %A Stimson, Mary Rachel %A Auer, Paul L %A Boerwinkle, Eric %A Cushman, Mary %A Maat, Moniek P M %A Folsom, Aaron R %A Franco, Oscar H %A Gibbs, Richard A %A Haagenson, Kelly K %A Hofman, Albert %A Johnsen, Jill M %A Kovar, Christie L %A Kraaij, Robert %A McKnight, Barbara %A Metcalf, Ginger A %A Muzny, Donna %A Psaty, Bruce M %A Tang, Weihong %A Uitterlinden, André G %A Rooij, Jeroen G J %A Dehghan, Abbas %A O'Donnell, Christopher J %A Reiner, Alex P %A Morrison, Alanna C %A Smith, Nicholas L %X

Plasma levels of fibrinogen, coagulation factors VII and VIII, and von Willebrand factor (vWF) are four intermediate phenotypes that are heritable and have been associated with the risk of clinical thrombotic events. To identify rare and low-frequency variants associated with these hemostatic factors, we conducted whole exome sequencing in 10 860 individuals of European ancestry (EA) and 3529 African Americans (AAs) from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium and the National Heart, Lung, and Blood Institute's Exome Sequencing Project (ESP). Gene-based tests demonstrated significant associations with rare variation (minor allele frequency < 5%) in FGG (with fibrinogen, p = 9.1x10-13), F7 (with factor VII, p = 1.3x10-72; seven novel variants), and VWF (with factor VIII and vWF; p = 3.2x10-14; one novel variant). These eight novel rare variant associations were independent of the known common variants at these loci and tended to have much larger effect sizes. In addition, one of the rare novel variants in F7 was significantly associated with an increased risk of venous thromboembolism in AAs (Ile200Ser; rs141219108; p = 4.2x10-5). After restricting gene-based analyses to only loss-of-function variants, a novel significant association was detected and replicated between factor VIII levels and a stop-gain mutation exclusive to African Americans (rs3211938) in CD36. This variant has previously been linked to dyslipidemia but not with levels of a hemostatic factor. These efforts represent the largest integration of whole exome sequence data from two national projects to identify genetic variation associated with plasma hemostatic factors.

%B Hum Mol Genet %8 2022 May 12 %G eng %R 10.1093/hmg/ddac100 %0 Journal Article %J Commun Biol %D 2022 %T Whole genome sequence association analysis of fasting glucose and fasting insulin levels in diverse cohorts from the NHLBI TOPMed program. %A DiCorpo, Daniel %A Gaynor, Sheila M %A Russell, Emily M %A Westerman, Kenneth E %A Raffield, Laura M %A Majarian, Timothy D %A Wu, Peitao %A Sarnowski, Chloe %A Highland, Heather M %A Jackson, Anne %A Hasbani, Natalie R %A de Vries, Paul S %A Brody, Jennifer A %A Hidalgo, Bertha %A Guo, Xiuqing %A Perry, James A %A O'Connell, Jeffrey R %A Lent, Samantha %A Montasser, May E %A Cade, Brian E %A Jain, Deepti %A Wang, Heming %A D'Oliveira Albanus, Ricardo %A Varshney, Arushi %A Yanek, Lisa R %A Lange, Leslie %A Palmer, Nicholette D %A Almeida, Marcio %A Peralta, Juan M %A Aslibekyan, Stella %A Baldridge, Abigail S %A Bertoni, Alain G %A Bielak, Lawrence F %A Chen, Chung-Shiuan %A Chen, Yii-Der Ida %A Choi, Won Jung %A Goodarzi, Mark O %A Floyd, James S %A Irvin, Marguerite R %A Kalyani, Rita R %A Kelly, Tanika N %A Lee, Seonwook %A Liu, Ching-Ti %A Loesch, Douglas %A Manson, JoAnn E %A Minster, Ryan L %A Naseri, Take %A Pankow, James S %A Rasmussen-Torvik, Laura J %A Reiner, Alexander P %A Reupena, Muagututi'a Sefuiva %A Selvin, Elizabeth %A Smith, Jennifer A %A Weeks, Daniel E %A Xu, Huichun %A Yao, Jie %A Zhao, Wei %A Parker, Stephen %A Alonso, Alvaro %A Arnett, Donna K %A Blangero, John %A Boerwinkle, Eric %A Correa, Adolfo %A Cupples, L Adrienne %A Curran, Joanne E %A Duggirala, Ravindranath %A He, Jiang %A Heckbert, Susan R %A Kardia, Sharon L R %A Kim, Ryan W %A Kooperberg, Charles %A Liu, Simin %A Mathias, Rasika A %A McGarvey, Stephen T %A Mitchell, Braxton D %A Morrison, Alanna C %A Peyser, Patricia A %A Psaty, Bruce M %A Redline, Susan %A Shuldiner, Alan R %A Taylor, Kent D %A Vasan, Ramachandran S %A Viaud-Martinez, Karine A %A Florez, Jose C %A Wilson, James G %A Sladek, Robert %A Rich, Stephen S %A Rotter, Jerome I %A Lin, Xihong %A Dupuis, Josée %A Meigs, James B %A Wessel, Jennifer %A Manning, Alisa K %K Diabetes Mellitus, Type 2 %K Fasting %K Glucose %K Humans %K Insulin %K National Heart, Lung, and Blood Institute (U.S.) %K Nerve Tissue Proteins %K Polymorphism, Single Nucleotide %K Precision Medicine %K Receptors, Immunologic %K United States %X

The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI's Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, PTPRT, and ROBO1. Functional annotation resources including the Diabetes Epigenome Atlas were compiled for each signal (chromatin states, annotation principal components, and others) to elucidate variant-to-function hypotheses. We provide a catalog of nucleotide-resolution genomic variation spanning intergenic and intronic regions creating a foundation for future sequencing-based investigations of glycemic traits.

%B Commun Biol %V 5 %P 756 %8 2022 07 28 %G eng %N 1 %R 10.1038/s42003-022-03702-4 %0 Journal Article %J Nat Commun %D 2022 %T Whole genome sequencing identifies structural variants contributing to hematologic traits in the NHLBI TOPMed program. %A Wheeler, Marsha M %A Stilp, Adrienne M %A Rao, Shuquan %A Halldorsson, Bjarni V %A Beyter, Doruk %A Wen, Jia %A Mihkaylova, Anna V %A McHugh, Caitlin P %A Lane, John %A Jiang, Min-Zhi %A Raffield, Laura M %A Jun, Goo %A Sedlazeck, Fritz J %A Metcalf, Ginger %A Yao, Yao %A Bis, Joshua B %A Chami, Nathalie %A de Vries, Paul S %A Desai, Pinkal %A Floyd, James S %A Gao, Yan %A Kammers, Kai %A Kim, Wonji %A Moon, Jee-Young %A Ratan, Aakrosh %A Yanek, Lisa R %A Almasy, Laura %A Becker, Lewis C %A Blangero, John %A Cho, Michael H %A Curran, Joanne E %A Fornage, Myriam %A Kaplan, Robert C %A Lewis, Joshua P %A Loos, Ruth J F %A Mitchell, Braxton D %A Morrison, Alanna C %A Preuss, Michael %A Psaty, Bruce M %A Rich, Stephen S %A Rotter, Jerome I %A Tang, Hua %A Tracy, Russell P %A Boerwinkle, Eric %A Abecasis, Goncalo R %A Blackwell, Thomas W %A Smith, Albert V %A Johnson, Andrew D %A Mathias, Rasika A %A Nickerson, Deborah A %A Conomos, Matthew P %A Li, Yun %A Þorsteinsdottir, Unnur %A Magnússon, Magnús K %A Stefansson, Kari %A Pankratz, Nathan D %A Bauer, Daniel E %A Auer, Paul L %A Reiner, Alex P %K Blood Cells %K Genome-Wide Association Study %K Humans %K Whole Genome Sequencing %X

Genome-wide association studies have identified thousands of single nucleotide variants and small indels that contribute to variation in hematologic traits. While structural variants are known to cause rare blood or hematopoietic disorders, the genome-wide contribution of structural variants to quantitative blood cell trait variation is unknown. Here we utilized whole genome sequencing data in ancestrally diverse participants of the NHLBI Trans Omics for Precision Medicine program (N = 50,675) to detect structural variants associated with hematologic traits. Using single variant tests, we assessed the association of common and rare structural variants with red cell-, white cell-, and platelet-related quantitative traits and observed 21 independent signals (12 common and 9 rare) reaching genome-wide significance. The majority of these associations (N = 18) replicated in independent datasets. In genome-editing experiments, we provide evidence that a deletion associated with lower monocyte counts leads to disruption of an S1PR3 monocyte enhancer and decreased S1PR3 expression.

%B Nat Commun %V 13 %P 7592 %8 2022 Dec 08 %G eng %N 1 %R 10.1038/s41467-022-35354-7 %0 Journal Article %J Hum Mol Genet %D 2022 %T Whole-Exome Sequencing Study Identifies Four Novel Gene Loci Associated with Diabetic Kidney Disease. %A Pan, Yang %A Sun, Xiao %A Mi, Xuenan %A Huang, Zhijie %A Hsu, Yenchih %A Hixson, James E %A Munzy, Donna %A Metcalf, Ginger %A Franceschini, Nora %A Tin, Adrienne %A Köttgen, Anna %A Francis, Michael %A Brody, Jennifer A %A Kestenbaum, Bryan %A Sitlani, Colleen M %A Mychaleckyj, Josyf C %A Kramer, Holly %A Lange, Leslie A %A Guo, Xiuqing %A Hwang, Shih-Jen %A Irvin, Marguerite R %A Smith, Jennifer A %A Yanek, Lisa R %A Vaidya, Dhananjay %A Chen, Yii-Der Ida %A Fornage, Myriam %A Lloyd-Jones, Donald M %A Hou, Lifang %A Mathias, Rasika A %A Mitchell, Braxton D %A Peyser, Patricia A %A Kardia, Sharon L R %A Arnett, Donna K %A Correa, Adolfo %A Raffield, Laura M %A Vasan, Ramachandran S %A Cupple, L Adrienne %A Levy, Daniel %A Kaplan, Robert C %A North, Kari E %A Rotter, Jerome I %A Kooperberg, Charles %A Reiner, Alexander P %A Psaty, Bruce M %A Tracy, Russell P %A Gibbs, Richard A %A Morrison, Alanna C %A Feldman, Harold %A Boerwinkle, Eric %A He, Jiang %A Kelly, Tanika N %X

Diabetic kidney disease (DKD) is recognized as an important public health challenge. However, its genomic mechanisms are poorly understood. To identify rare variants for DKD, we conducted a whole-exome sequencing (WES) study leveraging large cohorts well-phenotyped for chronic kidney disease (CKD) and diabetes. Our two-stage whole-exome sequencing study included 4372 European and African ancestry participants from the Chronic Renal Insufficiency Cohort (CRIC) and Atherosclerosis Risk in Communities (ARIC) studies (stage-1) and 11 487 multi-ancestry Trans-Omics for Precision Medicine (TOPMed) participants (stage-2). Generalized linear mixed models, which accounted for genetic relatedness and adjusted for age, sex, and ancestry, were used to test associations between single variants and DKD. Gene-based aggregate rare variant analyses were conducted using an optimized sequence kernel association test (SKAT-O) implemented within our mixed model framework. We identified four novel exome-wide significant DKD-related loci through initiating diabetes. In single variant analyses, participants carrying a rare, in-frame insertion in the DIS3L2 gene (rs141560952) exhibited a 193-fold increased odds (95% confidence interval: 33.6, 1105) of DKD compared with non-carriers (P = 3.59 × 10-9). Likewise, each copy of a low-frequency KRT6B splice-site variant (rs425827) conferred a 5.31-fold higher odds (95% confidence interval: 3.06, 9.21) of DKD (P = 2.72 × 10-9). Aggregate gene-based analyses further identified ERAP2 (P = 4.03 × 10-8) and NPEPPS (P = 1.51 × 10-7), which are both expressed in the kidney and implicated in renin-angiotensin-aldosterone system modulated immune response. In the largest WES study of DKD, we identified novel rare variant loci attaining exome-wide significance. These findings provide new insights into the molecular mechanisms underlying DKD.

%B Hum Mol Genet %8 2022 Nov 29 %G eng %R 10.1093/hmg/ddac290 %0 Journal Article %J Stroke %D 2022 %T {Whole-Genome Sequencing Association Analyses of Stroke and Its Subtypes in Ancestrally Diverse Populations From Trans-Omics for Precision Medicine Project %A Hu, Y. %A Haessler, J. W. %A Manansala, R. %A Wiggins, K. L. %A Moscati, A. %A Beiser, A. %A Heard-Costa, N. L. %A Sarnowski, C. %A Raffield, L. M. %A Chung, J. %A Marini, S. %A Anderson, C. D. %A Rosand, J. %A Xu, H. %A Sun, X. %A Kelly, T. N. %A Wong, Q. %A Lange, L. A. %A Rotter, J. I. %A Correa, A. %A Vasan, R. S. %A Seshadri, S. %A Rich, S. S. %A Do, R. %A Loos, R. J. F. %A Longstreth, W. T. %A Bis, J. C. %A Psaty, B. M. %A Tirschwell, D. L. %A Assimes, T. L. %A Silver, B. %A Liu, S. %A Jackson, R. %A Wassertheil-Smoller, S. %A Mitchell, B. D. %A Fornage, M. %A Auer, P. L. %A Reiner, A. P. %A Kooperberg, C. %X Stroke is the leading cause of death and long-term disability worldwide. Previous genome-wide association studies identified 51 loci associated with stroke (mostly ischemic) and its subtypes among predominantly European populations. Using whole-genome sequencing in ancestrally diverse populations from the Trans-Omics for Precision Medicine (TOPMed) Program, we aimed to identify novel variants, especially low-frequency or ancestry-specific variants, associated with all stroke, ischemic stroke and its subtypes (large artery, cardioembolic, and small vessel), and hemorrhagic stroke and its subtypes (intracerebral and subarachnoid).\ Whole-genome sequencing data were available for 6833 stroke cases and 27 116 controls, including 22 315 European, 7877 Black, 2616 Hispanic/Latino, 850 Asian, 54 Native American, and 237 other ancestry participants. In TOPMed, we performed single variant association analysis examining 40 million common variants and aggregated association analysis focusing on rare variants. We also combined TOPMed European populations with over 28 000 additional European participants from the UK BioBank genome-wide array data through meta-analysis.\ .\ We represent the first association analysis for stroke and its subtypes using whole-genome sequencing data from ancestrally diverse populations. While our findings suggest the potential benefits of combining whole-genome sequencing data with populations of diverse genetic backgrounds to identify possible low-frequency or ancestry-specific variants, they also highlight the need to increase genome coverage and sample sizes. %B Stroke %V 53 %P 875–885 %8 Mar %G eng %0 Journal Article %J Nature %D 2023 %T Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis. %A Weinstock, Joshua S %A Gopakumar, Jayakrishnan %A Burugula, Bala Bharathi %A Uddin, Md Mesbah %A Jahn, Nikolaus %A Belk, Julia A %A Bouzid, Hind %A Daniel, Bence %A Miao, Zhuang %A Ly, Nghi %A Mack, Taralynn M %A Luna, Sofia E %A Prothro, Katherine P %A Mitchell, Shaneice R %A Laurie, Cecelia A %A Broome, Jai G %A Taylor, Kent D %A Guo, Xiuqing %A Sinner, Moritz F %A von Falkenhausen, Aenne S %A Kääb, Stefan %A Shuldiner, Alan R %A O'Connell, Jeffrey R %A Lewis, Joshua P %A Boerwinkle, Eric %A Barnes, Kathleen C %A Chami, Nathalie %A Kenny, Eimear E %A Loos, Ruth J F %A Fornage, Myriam %A Hou, Lifang %A Lloyd-Jones, Donald M %A Redline, Susan %A Cade, Brian E %A Psaty, Bruce M %A Bis, Joshua C %A Brody, Jennifer A %A Silverman, Edwin K %A Yun, Jeong H %A Qiao, Dandi %A Palmer, Nicholette D %A Freedman, Barry I %A Bowden, Donald W %A Cho, Michael H %A DeMeo, Dawn L %A Vasan, Ramachandran S %A Yanek, Lisa R %A Becker, Lewis C %A Kardia, Sharon L R %A Peyser, Patricia A %A He, Jiang %A Rienstra, Michiel %A van der Harst, Pim %A Kaplan, Robert %A Heckbert, Susan R %A Smith, Nicholas L %A Wiggins, Kerri L %A Arnett, Donna K %A Irvin, Marguerite R %A Tiwari, Hemant %A Cutler, Michael J %A Knight, Stacey %A Muhlestein, J Brent %A Correa, Adolfo %A Raffield, Laura M %A Gao, Yan %A de Andrade, Mariza %A Rotter, Jerome I %A Rich, Stephen S %A Tracy, Russell P %A Konkle, Barbara A %A Johnsen, Jill M %A Wheeler, Marsha M %A Smith, J Gustav %A Melander, Olle %A Nilsson, Peter M %A Custer, Brian S %A Duggirala, Ravindranath %A Curran, Joanne E %A Blangero, John %A McGarvey, Stephen %A Williams, L Keoki %A Xiao, Shujie %A Yang, Mao %A Gu, C Charles %A Chen, Yii-Der Ida %A Lee, Wen-Jane %A Marcus, Gregory M %A Kane, John P %A Pullinger, Clive R %A Shoemaker, M Benjamin %A Darbar, Dawood %A Roden, Dan M %A Albert, Christine %A Kooperberg, Charles %A Zhou, Ying %A Manson, JoAnn E %A Desai, Pinkal %A Johnson, Andrew D %A Mathias, Rasika A %A Blackwell, Thomas W %A Abecasis, Goncalo R %A Smith, Albert V %A Kang, Hyun M %A Satpathy, Ansuman T %A Natarajan, Pradeep %A Kitzman, Jacob O %A Whitsel, Eric A %A Reiner, Alexander P %A Bick, Alexander G %A Jaiswal, Siddhartha %K Alleles %K Animals %K Clonal Hematopoiesis %K Genome-Wide Association Study %K Hematopoiesis %K Hematopoietic Stem Cells %K Humans %K Mice %K Mutation %K Promoter Regions, Genetic %X

Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis. These lesions are precursors for blood cancers, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but this effect was not seen in clones with driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.

%B Nature %V 616 %P 755-763 %8 2023 Apr %G eng %N 7958 %R 10.1038/s41586-023-05806-1 %0 Journal Article %J Endocr Pract %D 2023 %T Age-Related Factors Associated with Hip Fracture Risk. %A Bůzková, Petra %A Cauley, Jane A %A Fink, Howard A %A Robbins, John A %A Mukamal, Kenneth J %A Barzilay, Joshua I %X

OBJECTIVES: Advancing age is a powerful risk factor for hip fracture. The biological mechanisms through which aging impacts hip fracture risk have not been well studied.

METHODS: Biological factors associated with "advancing age" that help to explain how aging is associated with hip fracture risk are reviewed. The findings are based on analyses of the Cardiovascular Health Study, an ongoing observational study of adults ages >65 years with 25 years of follow up.

RESULTS: Five age-related factors were found to be significantly associated with hip fracture risk: (1) microvascular disease of the kidney (albuminuria and / or elevated urine albumin to creatinine ratio) and of the brain (abnormal white matter disease on brain MRI); (2) increased serum levels of carboxymethyl-lysine (CML), an advanced glycation end-product that reflects glycation and oxidative stress; (3) reduced parasympathetic tone, as derived from 24-hour Holter monitoring; (4) carotid artery atherosclerosis in the absence of clinical cardiovascular disease; and (5) increased trans-fatty acid levels in the blood. Each of these factors was associated with a 10-25%. increased risk of fracture. These associations were independent of traditional risk factors for hip fracture.

CONCLUSION: Several factors associated with older age help to explain how "aging" may be associated with hip fracture risk. These same factors may also explain the high risk for mortality following hip fracture.

%B Endocr Pract %8 2023 Mar 06 %G eng %R 10.1016/j.eprac.2023.03.001 %0 Journal Article %J J Am Heart Assoc %D 2023 %T Association Between Whole Blood-Derived Mitochondrial DNA Copy Number, Low-Density Lipoprotein Cholesterol, and Cardiovascular Disease Risk. %A Liu, Xue %A Sun, Xianbang %A Zhang, Yuankai %A Jiang, Wenqing %A Lai, Meng %A Wiggins, Kerri L %A Raffield, Laura M %A Bielak, Lawrence F %A Zhao, Wei %A Pitsillides, Achilleas %A Haessler, Jeffrey %A Zheng, Yinan %A Blackwell, Thomas W %A Yao, Jie %A Guo, Xiuqing %A Qian, Yong %A Thyagarajan, Bharat %A Pankratz, Nathan %A Rich, Stephen S %A Taylor, Kent D %A Peyser, Patricia A %A Heckbert, Susan R %A Seshadri, Sudha %A Boerwinkle, Eric %A Grove, Megan L %A Larson, Nicholas B %A Smith, Jennifer A %A Vasan, Ramachandran S %A Fitzpatrick, Annette L %A Fornage, Myriam %A Ding, Jun %A Carson, April P %A Abecasis, Goncalo %A Dupuis, Josée %A Reiner, Alexander %A Kooperberg, Charles %A Hou, Lifang %A Psaty, Bruce M %A Wilson, James G %A Levy, Daniel %A Rotter, Jerome I %A Bis, Joshua C %A Satizabal, Claudia L %A Arking, Dan E %A Liu, Chunyu %X

Background The relationship between mitochondrial DNA copy number (mtDNA CN) and cardiovascular disease remains elusive. Methods and Results We performed cross-sectional and prospective association analyses of blood-derived mtDNA CN and cardiovascular disease outcomes in 27 316 participants in 8 cohorts of multiple racial and ethnic groups with whole-genome sequencing. We also performed Mendelian randomization to explore causal relationships of mtDNA CN with coronary heart disease (CHD) and cardiometabolic risk factors (obesity, diabetes, hypertension, and hyperlipidemia). <0.01 was used for significance. We validated most of the previously reported associations between mtDNA CN and cardiovascular disease outcomes. For example, 1-SD unit lower level of mtDNA CN was associated with 1.08 (95% CI, 1.04-1.12; <0.001) times the hazard for developing incident CHD, adjusting for covariates. Mendelian randomization analyses showed no causal effect from a lower level of mtDNA CN to a higher CHD risk (β=0.091; =0.11) or in the reverse direction (β=-0.012; =0.076). Additional bidirectional Mendelian randomization analyses revealed that low-density lipoprotein cholesterol had a causal effect on mtDNA CN (β=-0.084; <0.001), but the reverse direction was not significant (=0.059). No causal associations were observed between mtDNA CN and obesity, diabetes, and hypertension, in either direction. Multivariable Mendelian randomization analyses showed no causal effect of CHD on mtDNA CN, controlling for low-density lipoprotein cholesterol level (=0.52), whereas there was a strong direct causal effect of higher low-density lipoprotein cholesterol on lower mtDNA CN, adjusting for CHD status (β=-0.092; <0.001). Conclusions Our findings indicate that high low-density lipoprotein cholesterol may underlie the complex relationships between mtDNA CN and vascular atherosclerosis.

%B J Am Heart Assoc %P e029090 %8 2023 Oct 07 %G eng %R 10.1161/JAHA.122.029090 %0 Journal Article %J Osteoporos Int %D 2023 %T Association of covert brain infarcts and white matter hyperintensities with risk of hip fracture in older adults: the Cardiovascular Health Study. %A Sheets, Kerry M %A Bůzková, Petra %A Chen, Zhao %A Carbone, Laura D %A Cauley, Jane A %A Barzilay, Joshua I %A Starks, Jamie L %A Miller, Lindsay M %A Fink, Howard A %K Aged %K Brain Infarction %K Frailty %K Hip Fractures %K Humans %K Prospective Studies %K Risk Factors %K White Matter %X

UNLABELLED: Covert brain infarcts and white matter hyperintensities (WMHs), incidental markers of brain microvascular disease commonly seen on brain MRIs in older adults, have been associated with falls and lower bone mineral density. We found covert infarcts and WMHs may also be associated with an increased risk of future hip fracture.

INTRODUCTION: To determine whether covert infarcts and white matter hyperintensities (WMHs) are associated with increased risk of incident hip fracture.

METHODS: A prospective cohort of 3373 community-dwelling adults aged ≥ 65 years enrolled in the Cardiovascular Health Study with a brain MRI (1992-1993) was analyzed. Covert infarcts were categorized by number of infarcts and largest infarct size. WMH burden was assessed by radiologists and graded qualitatively from 0 (no WMHs) to 9 (extensive).

RESULTS: Participants had 465 incident hip fractures during a mean follow-up of 12.8 years. The demographic-adjusted hazard of incident hip fracture was 32% higher among participants with ≥ 1 covert infarct compared to those without infarcts (hazard ratio (HR) 1.32; 95% CI, 1.08-1.62). The hazard of incident hip fracture was similar after further adjustment for medications and medical history (HR = 1.34; 95% CI, 1.08-1.65), but attenuated following additional adjustment for functional status, frailty, and falls (HR = 1.25; 95% CI, 0.99-1.57). Fully adjusted hazard of incident hip fracture per increase in infarct number was 1.10 (95% CI, 0.98-1.23); risk in individuals whose largest infarct was ≥ 20 mm versus 3 to < 20 mm was similar. Compared with WMH grades 0-1, the demographic-adjusted hazard of hip fracture was 1.34 (95% CI, 1.09-1.66) and 1.83 (95% CI, 1.37-2.46), respectively, for WMH grades 2-3 and 4-9. The hazard was similar following adjustment for medications and medical history (grades 2-3: HR = 1.32; 95% CI, 1.05-1.64; grades 4-9: HR = 1.69; 95% CI, 1.23-2.30), but attenuated following additional adjustment for functional status, frailty, and falls (grades 2-3: HR = 1.24; 95% CI, 0.98-1.56; grades 4-9: HR = 1.34; 95% CI, 0.95-1.90).

CONCLUSION: Older, community-dwelling adults with covert infarcts or WMHs may be at increased risk of hip fracture.

%B Osteoporos Int %V 34 %P 91-99 %8 2023 Jan %G eng %N 1 %R 10.1007/s00198-022-06565-x %0 Journal Article %J Calcif Tissue Int %D 2023 %T Association of Immune Cell Subsets with Incident Hip Fracture: The Cardiovascular Health Study. %A Elam, Rachel E %A Bůzková, Petra %A Delaney, Joseph A C %A Fink, Howard A %A Barzilay, Joshua I %A Carbone, Laura D %A Saha, Rick %A Robbins, John A %A Mukamal, Kenneth J %A Valderrábano, Rodrigo J %A Psaty, Bruce M %A Tracy, Russell P %A Olson, Nels C %A Huber, Sally A %A Doyle, Margaret F %A Landay, Alan L %A Cauley, Jane A %X

In this study, we aimed to evaluate the association of innate and adaptive immune cell subsets in peripheral blood mononuclear cells (PBMCs) with hip fracture. To conduct this study, we used data from the Cardiovascular Health Study (CHS), a U.S. multicenter observational cohort of community-dwelling men and women aged ≥ 65 years. Twenty-five immune cell phenotypes were measured by flow cytometry from cryopreserved PBMCs of CHS participants collected in 1998-1999. The natural killer (NK), γδ T, T helper 17 (Th17), and differentiated/senescent CD4CD28 T cell subsets were pre-specified as primary subsets of interest. Hip fracture incidence was assessed prospectively by review of hospitalization records. Multivariable Cox hazard models evaluated associations of immune cell phenotypes with incident hip fracture in sex-stratified and combined analyses. Among 1928 persons, 259 hip fractures occurred over a median 9.7 years of follow-up. In women, NK cells were inversely associated with hip fracture [hazard ratio (HR) 0.77, 95% confidence interval (CI) 0.60-0.99 per one standard deviation higher value] and Th17 cells were positively associated with hip fracture [HR 1.18, 95% CI 1.01-1.39]. In men, γδ T cells were inversely associated with hip fracture [HR 0.60, 95% CI 0.37-0.98]. None of the measured immune cell phenotypes were significantly associated with hip fracture incidence in combined analyses. In this large prospective cohort of older adults, potentially important sex differences in the associations of immune cell phenotypes and hip fracture were identified. However, immune cell phenotypes had no association with hip fracture in analyses combining men and women.

%B Calcif Tissue Int %8 2023 Aug 31 %G eng %R 10.1007/s00223-023-01126-8 %0 Journal Article %J Neurology %D 2023 %T Association of Mitochondrial DNA Copy Number With Brain MRI Markers and Cognitive Function: A Meta-analysis of Community-Based Cohorts. %A Zhang, Yuankai %A Liu, Xue %A Wiggins, Kerri L %A Kurniansyah, Nuzulul %A Guo, Xiuqing %A Rodrigue, Amanda L %A Zhao, Wei %A Yanek, Lisa R %A Ratliff, Scott M %A Pitsillides, Achilleas %A Aguirre Patiño, Juan Sebastian %A Sofer, Tamar %A Arking, Dan E %A Austin, Thomas R %A Beiser, Alexa S %A Blangero, John %A Boerwinkle, Eric %A Bressler, Jan %A Curran, Joanne E %A Hou, Lifang %A Hughes, Timothy M %A Kardia, Sharon L %A Launer, Lenore %A Levy, Daniel %A Mosley, Tom H %A Nasrallah, Ilya M %A Rich, Stephen S %A Rotter, Jerome I %A Seshadri, Sudha %A Tarraf, Wassim %A González, Kevin A %A Ramachandran, Vasan %A Yaffe, Kristine %A Nyquist, Paul A %A Psaty, Bruce M %A DeCarli, Charles S %A Smith, Jennifer A %A Glahn, David C %A González, Hector M %A Bis, Joshua C %A Fornage, Myriam %A Heckbert, Susan R %A Fitzpatrick, Annette L %A Liu, Chunyu %A Satizabal, Claudia L %X

BACKGROUND AND OBJECTIVES: Previous studies suggest lower mitochondrial DNA (mtDNA) copy number (CN) is associated with neurodegenerative diseases. However, whether mtDNA CN in whole blood is related to endophenotypes of Alzheimer's disease (AD) and AD related dementia (AD/ADRD) needs further investigation. We assessed the association of mtDNA CN with cognitive function and MRI measures in community-based samples of middle-aged to older adults.

METHODS: We included dementia-free participants from nine diverse community-based cohorts with whole-genome sequencing in the Trans-Omics for Precision Medicine (TOPMed) program. Circulating mtDNA CN was estimated as twice the ratio of the average coverage of mtDNA to nuclear DNA. Brain MRI markers included total brain, hippocampal, and white matter hyperintensity volumes. General cognitive function was derived from distinct cognitive domains. We performed cohort-specific association analyses of mtDNA CN with AD/ADRD endophenotypes assessed within ±5 years (i.e., cross-sectional analyses) or 5 to 20 years after blood draw (i.e., prospective analyses) adjusting for potential confounders. We further explored associations stratified by sex and age (<60 vs. ≥60 years). Fixed-effects or sample size-weighted meta-analyses were performed to combine results. Finally, we performed Mendelian randomization (MR) analyses to assess causality.

RESULTS: We included up to 19,152 participants (mean age 59 years, 57% women). Higher mtDNA CN was cross-sectionally associated with better general cognitive function (Beta=0.04; 95% CI 0.02, 0.06) independent of age, sex, batch effects, race/ethnicity, time between blood draw and cognitive evaluation, cohort-specific variables, and education. Additional adjustment for blood cell counts or cardiometabolic traits led to slightly attenuated results. We observed similar significant associations with cognition in prospective analyses, although of reduced magnitude. We found no significant associations between mtDNA CN and brain MRI measures in meta-analyses. MR analyses did not reveal a causal relation between mtDNA CN in blood and cognition.

DISCUSSION: Higher mtDNA CN in blood is associated with better current and future general cognitive function in large and diverse communities across the US. Although MR analyses did not support a causal role, additional research is needed to assess causality. Circulating mtDNA CN could serve nevertheless as a biomarker of current and future cognitive function in the community.

%B Neurology %8 2023 Mar 16 %G eng %R 10.1212/WNL.0000000000207157 %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 Circulation %D 2023 %T Association of Severe Hypercholesterolemia and Familial Hypercholesterolemia Genotype With Risk of Coronary Heart Disease. %A Zhang, Yiyi %A Dron, Jacqueline S %A Bellows, Brandon K %A Khera, Amit V %A Liu, Junxiu %A Balte, Pallavi P %A Oelsner, Elizabeth C %A Amr, Sami Samir %A Lebo, Matthew S %A Nagy, Anna %A Peloso, Gina M %A Natarajan, Pradeep %A Rotter, Jerome I %A Willer, Cristen %A Boerwinkle, Eric %A Ballantyne, Christie M %A Lutsey, Pamela L %A Fornage, Myriam %A Lloyd-Jones, Donald M %A Hou, Lifang %A Psaty, Bruce M %A Bis, Joshua C %A Floyd, James S %A Vasan, Ramachandran S %A Heard-Costa, Nancy L %A Carson, April P %A Hall, Michael E %A Rich, Stephen S %A Guo, Xiuqing %A Kazi, Dhruv S %A de Ferranti, Sarah D %A Moran, Andrew E %K Coronary Disease %K Genotype %K Humans %K Hypercholesterolemia %K Hyperlipoproteinemia Type II %B Circulation %V 147 %P 1556-1559 %8 2023 May 16 %G eng %N 20 %R 10.1161/CIRCULATIONAHA.123.064168 %0 Journal Article %J JBMR Plus %D 2023 %T The Association of Tryptophan and Its Metabolites With Incident Hip Fractures, Mortality, and Prevalent Frailty in Older Adults: The Cardiovascular Health Study. %A Carbone, Laura %A Bůzková, Petra %A Fink, Howard A %A Robbins, John A %A Barzilay, Joshua I %A Elam, Rachel E %A Isales, Carlos %X

Amino acids are the building blocks of proteins, and sufficient protein intake is important for skeletal health. We utilized stored serum from the Cardiovascular Health Study in 1992-1993 to examine the relationship between levels of the essential amino acid tryptophan (trp) and its oxidized and nonoxidized metabolites to risk for incident hip fractures and mortality over 12 years of follow-up. We included 131 persons who sustained a hip fracture during this time period and 131 without a hip fracture over these same 12 years of follow-up; 58% female and 95% White. Weighted multivariable Cox hazards models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) of incident hip fracture associated with a one standard deviation (SD) higher trp or its metabolites exposure. Relative risk regression was used to evaluate the cross-sectional association of trp and its metabolites with frailty. Higher serum levels of trp were significantly associated with lower risk of incident hip fractures (HR = 0.75 per SD of trp (95% CI 0.57-0.99) but were not significantly associated with mortality or frailty status by Freid's frailty index. There were no statistically significant associations between any of the oxidized or nonoxidized products of trp with incident hip fractures ( ≥ 0.64), mortality ( ≥ 0.20), or cross-sectional frailty status ( ≥ 0.13) after multiple testing adjustment. Randomized clinical trials examining whether increasing trp intake is beneficial for osteoporosis are needed. © 2023 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

%B JBMR Plus %V 7 %P e10801 %8 2023 Oct %G eng %N 10 %R 10.1002/jbm4.10801 %0 Journal Article %J JAMA Netw Open %D 2023 %T {Associations Between Vascular Risk Factor Levels and Cognitive Decline Among Stroke Survivors %A Levine, D. A. %A Chen, B. %A Galecki, A. T. %A Gross, A. L. %A o, E. M. %A Whitney, R. T. %A Ploutz-Snyder, R. J. %A Giordani, B. J. %A Sussman, J. B. %A Burke, J. F. %A Lazar, R. M. %A Howard, V. J. %A Aparicio, H. J. %A Beiser, A. S. %A Elkind, M. S. V. %A Gottesman, R. F. %A Koton, S. %A Pendlebury, S. T. %A Sharma, A. %A Springer, M. V. %A Seshadri, S. %A Romero, J. R. %A Hayward, R. A. %X Incident stroke is associated with accelerated cognitive decline. Whether poststroke vascular risk factor levels are associated with faster cognitive decline is uncertain.\ To evaluate associations of poststroke systolic blood pressure (SBP), glucose, and low-density lipoprotein (LDL) cholesterol levels with cognitive decline.\ Individual participant data meta-analysis of 4 US cohort studies (conducted 1971-2019). Linear mixed-effects models estimated changes in cognition after incident stroke. Median (IQR) follow-up was 4.7 (2.6-7.9) years. Analysis began August 2021 and was completed March 2023.\ Time-dependent cumulative mean poststroke SBP, glucose, and LDL cholesterol levels.\ The primary outcome was change in global cognition. Secondary outcomes were change in executive function and memory. Outcomes were standardized as t scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1-SD difference in cognition.\ .002) but not executive function or memory declines.\ In this cohort study, higher poststroke glucose levels were associated with faster global cognitive decline. We found no evidence that poststroke LDL cholesterol and SBP levels were associated with cognitive decline. %B JAMA Netw Open %V 6 %P e2313879 %8 May %G eng %0 Journal Article %J Arch Osteoporos %D 2023 %T The associations of markers of endothelial dysfunction with hip fracture risk. %A Barzilay, Joshua I %A Bůzková, Petra %A Fink, Howard A %A Cauley, Jane A %A Carbone, Laura %A Elam, Rachel %A Robbins, John A %A Stein, Phyllis %A Sheets, Kerry %A Jalal, Diana %A Mukamal, Kenneth J %K Aged %K Forearm %K Hip Fractures %K Humans %K Osteoporotic Fractures %K Vascular Diseases %X

UNLABELLED: Endothelial dysfunction underlies the development of atherosclerotic vascular disease, which in turn is associated with osteoporotic fractures. Here, we examined the association of two markers of endothelial dysfunction with incident hip fracture risk in older adults but found no statistically significant associations between them.

PURPOSE/INTRODUCTION: Endothelial dysfunction underlies the development of atherosclerotic vascular disease. Vascular disease, in turn, is associated with the risk of osteoporotic fractures, such as hip fractures. Here, we examine whether two measures of endothelial dysfunction are related to hip fracture risk.

METHODS: Participants for this study were 2792 individuals (mean age 78.6 years) who had flow-mediated dilation (FMD) measured after ischemia in the forearm and 2255 adults (mean age 73.3 years) with measured soluble intercellular adhesion molecule (siCAM) levels, a constitutive endothelial cell membrane protein associated with the initiation of atherosclerosis. Mean follow-up was 9.7 and 11.7 years, respectively. There were 375 and 265 incident hip fractures, respectively, in each group.

RESULTS: In Cox proportional hazards models, there was no significant association between FMD response and incident hip fracture (HR per 1% higher FMD was 0.98 [0.93, 1.04]; p = 0.44). In exploratory analyses, when data were examined dichotomously, participants in the lowest 80% of FMD (≤ 4.5%) had an adjusted 1.29 (0.98, 1.68; p = 0.067) higher hazard of hip fracture compared to participants in the upper 20% of FMD change. There were no significant associations between siCAM and incident hip fracture whether examined as a continuous or dichotomized variable.

CONCLUSIONS: Among older adults, two measures of endothelial dysfunction were not significantly associated with hip fracture risk. There was a trend for higher fracture risk with lower FMD.

%B Arch Osteoporos %V 18 %P 39 %8 2023 Mar 02 %G eng %N 1 %R 10.1007/s11657-023-01226-w %0 Journal Article %J Kidney360 %D 2023 %T Cardiac Mechanics and Kidney Function Decline in the Cardiovascular Health Study. %A Mehta, Rupal %A Bůzková, Petra %A Patel, Harnish %A Cheng, Jeanette %A Kizer, Jorge R %A Gottdiener, John S %A Psaty, Bruce %A Khan, Sadiya S %A Ix, Joachim H %A Isakova, Tamara %A Shlipak, Michael G %A Bansal, Nisha %A Shah, Sanjiv J %X

BACKGROUND: Clinical heart failure frequently coexists with chronic kidney disease (CKD) and may precipitate kidney function decline. However, whether earlier-stage myocardial dysfunction assessable by speckle tracking echocardiography is a contributor to kidney function decline remains unknown.

METHODS: We studied 2135 Cardiovascular Health Study (CHS) participants who were free of clinical heart failure and had Year 2-baseline 2D speckle tracking echocardiography and two measurements of estimated glomerular filtration rate (eGFR) (Year 2 and Year 9). "Archival" speckle tracking of digitized echocardiogram videotapes was utilized to measure left ventricular longitudinal strain (LVLS), LV early diastolic strain rate (EDSR), left atrial reservoir strain (LARS), right ventricular free wall strain (RVFWS), and mitral annular velocity (e'). Multivariable Poisson regression models that adjusted for demographics and cardiovascular risk factors were used to investigate the independent associations of cardiac mechanics indices and decline in kidney function defined as a 30% decline in eGFR over 7 years.

RESULTS: In risk factor (RF) models LVLS, EDSR, RVFWS, and e' were all significantly associated with the prevalence of kidney disease. After multivariable adjustment, left atrial dysfunction (RR 1.18 [95% CI 1.01, 1.38] per SD lower LARS] and left ventricular diastolic dysfunction (RR 1.21 [95% CI 1.04, 1.41] per SD lower EDSR) were each significantly associated with 30% decline in eGFR.

CONCLUSIONS: Subclinical myocardial dysfunction suggesting abnormal diastolic function detected by 2D speckle-tracking echocardiography was independently associated with decline in kidney function over time. Further studies are needed to understand the mechanisms of these associations and to test whether interventions that may improve subclinical myocardial dysfunction can prevent decline of kidney function.

%B Kidney360 %8 2023 Mar 08 %G eng %R 10.34067/KID.0000000000000100 %0 Journal Article %J medRxiv %D 2023 %T Carriers of rare damaging genetic variants are at lower risk of atherosclerotic disease. %A Georgakis, Marios K %A Malik, Rainer %A Hasbani, Natalie R %A Shakt, Gabrielle %A Morrison, Alanna C %A Tsao, Noah L %A Judy, Renae %A Mitchell, Braxton D %A Xu, Huichun %A Montasser, May E %A Do, Ron %A Kenny, Eimear E %A Loos, Ruth J F %A Terry, James G %A Carr, John Jeffrey %A Bis, Joshua C %A Psaty, Bruce M %A Longstreth, W T %A Young, Kendra A %A Lutz, Sharon M %A Cho, Michael H %A Broome, Jai %A Khan, Alyna T %A Wang, Fei Fei %A Heard-Costa, Nancy %A Seshadri, Sudha %A Vasan, Ramachandran S %A Palmer, Nicholette D %A Freedman, Barry I %A Bowden, Donald W %A Yanek, Lisa R %A Kral, Brian G %A Becker, Lewis C %A Peyser, Patricia A %A Bielak, Lawrence F %A Ammous, Farah %A Carson, April P %A Hall, Michael E %A Raffield, Laura M %A Rich, Stephen S %A Post, Wendy S %A Tracy, Russel P %A Taylor, Kent D %A Guo, Xiuqing %A Mahaney, Michael C %A Curran, Joanne E %A Blangero, John %A Clarke, Shoa L %A Haessler, Jeffrey W %A Hu, Yao %A Assimes, Themistocles L %A Kooperberg, Charles %A Damrauer, Scott M %A Rotter, Jerome I %A de Vries, Paul S %A Dichgans, Martin %X

BACKGROUND: The CCL2/CCR2 axis governs monocyte trafficking and recruitment to atherosclerotic lesions. Human genetic analyses and population-based studies support an association between circulating CCL2 levels and atherosclerosis. Still, it remains unknown whether pharmacological targeting of CCR2, the main CCL2 receptor, would provide protection against human atherosclerotic disease.

METHODS: In whole-exome sequencing data from 454,775 UK Biobank participants (40-69 years), we identified predicted loss-of-function (LoF) or damaging missense (REVEL score >0.5) variants within the gene. We prioritized variants associated with lower monocyte count (p<0.05) and tested associations with vascular risk factors and risk of atherosclerotic disease over a mean follow-up of 14 years. The results were replicated in a pooled cohort of three independent datasets (TOPMed, deCODE and Penn Medicine BioBank; total n=441,445) and the effect of the most frequent damaging variant was experimentally validated.

RESULTS: A total of 45 predicted LoF or damaging missense variants were identified in the gene, 4 of which were also significantly associated with lower monocyte count, but not with other white blood cell counts. Heterozygous carriers of these variants were at a lower risk of a combined atherosclerosis outcome, showed a lower burden of atherosclerosis across four vascular beds, and were at a lower lifetime risk of coronary artery disease and myocardial infarction. There was no evidence of association with vascular risk factors including LDL-cholesterol, blood pressure, glycemic status, or C-reactive protein. Using a cAMP assay, we found that cells transfected with the most frequent damaging variant (3:46358273:T:A, M249K, 547 carriers, frequency: 0.14%) show a decrease in signaling in response to CCL2. The associations of the M249K variant with myocardial infarction were consistent across cohorts (OR : 0.62 95%CI: 0.39-0.96; OR : 0.64 95%CI: 0.34-1.19; OR : 0.64 95%CI: 0.45-0.90). In a phenome-wide association study, we found no evidence for higher risk of common infections or mortality among carriers of damaging variants.

CONCLUSIONS: Heterozygous carriers of damaging variants have a lower burden of atherosclerosis and lower lifetime risk of myocardial infarction. In conjunction with previous evidence from experimental and epidemiological studies, our findings highlight the translational potential of CCR2-targeting as an atheroprotective approach.

%B medRxiv %8 2023 Aug 16 %G eng %R 10.1101/2023.08.14.23294063 %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2023 %T Circulating Growth Differentiation Factors 11 and 8, Their Antagonists Follistatin and Follistatin-like-3, and Risk of Heart Failure in Elders. %A Kizer, Jorge R %A Patel, Sheena %A Ganz, Peter %A Newman, Anne B %A Bhasin, Shalender %A Lee, Se-Jin %A Cawthon, Peggy M %A LeBrasseur, Nathan %A Shah, Sanjiv J %A Psaty, Bruce M %A Tracy, Russell P %A Cummings, Steven R %X

BACKGROUND: Heterochronic parabiosis has identified growth differentiation factor (GDF)-11 as a potential means of cardiac rejuvenation, but findings have been inconsistent. A major barrier has been lack of assay specificity for GDF-11 and its homolog GDF-8.

METHODS: We tested the hypothesis that GDF-11 and GDF-8, and their major antagonists follistatin and follistatin-like (FSTL)-3, are associated with incident heart failure (HF) and its subtypes in elders. Based on validation experiments, we used liquid chromatography tandem mass spectrometry to measure total serum GDF-11 and GDF-8, along with follistatin and follistatin-like (FSTL)-3 by immunoassay, in two longitudinal cohorts of older adults.

RESULTS: In 2,599 participants (age 75.2±4.3) followed for 10.8±5.6 years, 721 HF events occurred. After adjustment, neither GDF-11 (HR per doubling: 0.93 [0.67, 1.30]) nor GDF-8 (HR: 1.02 per doubling [0.83, 1.27]) was associated with incident HF or its subtypes. Positive associations with HF were detected for follistatin (HR: 1.15 [1.00, 1.32]) and FLST-3 (HR: 1.38 [1.03, 1.85]), and with HF with preserved ejection fraction for FSTL-3 (HR: 1.77 [1.03, 3.02]). (All HRs per doubling of biomarker.) FSTL-3 associations with HF appeared stronger at higher follistatin levels and vice versa, and also for men, Blacks and lower kidney function.

CONCLUSIONS: Among older adults, serum follistatin and FSTL-3, but not GDF-11 or GDF-8, were associated with incident HF. These findings do not support the concept that low serum levels of total GDF-11 or GDF-8 contribute to HF late in life, but do implicate transforming growth factor-βsuperfamily pathways as potential therapeutic targets.

%B J Gerontol A Biol Sci Med Sci %8 2023 Aug 25 %G eng %R 10.1093/gerona/glad206 %0 Journal Article %J Nat Med %D 2023 %T Clonal hematopoiesis is associated with protection from Alzheimer's disease. %A Bouzid, Hind %A Belk, Julia A %A Jan, Max %A Qi, Yanyan %A Sarnowski, Chloe %A Wirth, Sara %A Ma, Lisa %A Chrostek, Matthew R %A Ahmad, Herra %A Nachun, Daniel %A Yao, Winnie %A Beiser, Alexa %A Bick, Alexander G %A Bis, Joshua C %A Fornage, Myriam %A Longstreth, William T %A Lopez, Oscar L %A Natarajan, Pradeep %A Psaty, Bruce M %A Satizabal, Claudia L %A Weinstock, Joshua %A Larson, Eric B %A Crane, Paul K %A Keene, C Dirk %A Seshadri, Sudha %A Satpathy, Ansuman T %A Montine, Thomas J %A Jaiswal, Siddhartha %X

Clonal hematopoiesis of indeterminate potential (CHIP) is a premalignant expansion of mutated hematopoietic stem cells. As CHIP-associated mutations are known to alter the development and function of myeloid cells, we hypothesized that CHIP may also be associated with the risk of Alzheimer's disease (AD), a disease in which brain-resident myeloid cells are thought to have a major role. To perform association tests between CHIP and AD dementia, we analyzed blood DNA sequencing data from 1,362 individuals with AD and 4,368 individuals without AD. Individuals with CHIP had a lower risk of AD dementia (meta-analysis odds ratio (OR) = 0.64, P = 3.8 × 10), and Mendelian randomization analyses supported a potential causal association. We observed that the same mutations found in blood were also detected in microglia-enriched fraction of the brain in seven of eight CHIP carriers. Single-nucleus chromatin accessibility profiling of brain-derived nuclei in six CHIP carriers revealed that the mutated cells comprised a large proportion of the microglial pool in the samples examined. While additional studies are required to validate the mechanistic findings, these results suggest that CHIP may have a role in attenuating the risk of AD.

%B Nat Med %V 29 %P 1662-1670 %8 2023 Jul %G eng %N 7 %R 10.1038/s41591-023-02397-2 %0 Journal Article %J Diabetes Care %D 2023 %T Clonal Hematopoiesis of Indeterminate Potential (CHIP) and Incident Type 2 Diabetes Risk. %A Tobias, Deirdre K %A Manning, Alisa K %A Wessel, Jennifer %A Raghavan, Sridharan %A Westerman, Kenneth E %A Bick, Alexander G %A DiCorpo, Daniel %A Whitsel, Eric A %A Collins, Jason %A Correa, Adolfo %A Cupples, L Adrienne %A Dupuis, Josée %A Goodarzi, Mark O %A Guo, Xiuqing %A Howard, Barbara %A Lange, Leslie A %A Liu, Simin %A Raffield, Laura M %A Reiner, Alex P %A Rich, Stephen S %A Taylor, Kent D %A Tinker, Lesley %A Wilson, James G %A Wu, Peitao %A Carson, April P %A Vasan, Ramachandran S %A Fornage, Myriam %A Psaty, Bruce M %A Kooperberg, Charles %A Rotter, Jerome I %A Meigs, James %A Manson, JoAnn E %X

OBJECTIVE: Clonal hematopoiesis of indeterminate potential (CHIP) is an aging-related accumulation of somatic mutations in hematopoietic stem cells, leading to clonal expansion. CHIP presence has been implicated in atherosclerotic coronary heart disease (CHD) and all-cause mortality, but its association with incident type 2 diabetes (T2D) is unknown. We hypothesized that CHIP is associated with elevated risk of T2D.

RESEARCH DESIGN AND METHODS: CHIP was derived from whole-genome sequencing of blood DNA in the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine (TOPMed) prospective cohorts. We performed analysis for 17,637 participants from six cohorts, without prior T2D, cardiovascular disease, or cancer. We evaluated baseline CHIP versus no CHIP prevalence with incident T2D, including associations with DNMT3A, TET2, ASXL1, JAK2, and TP53 variants. We estimated multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) with adjustment for age, sex, BMI, smoking, alcohol, education, self-reported race/ethnicity, and combined cohorts' estimates via fixed-effects meta-analysis.

RESULTS: Mean (SD) age was 63.4 (11.5) years, 76% were female, and CHIP prevalence was 6.0% (n = 1,055) at baseline. T2D was diagnosed in n = 2,467 over mean follow-up of 9.8 years. Participants with CHIP had 23% (CI = 1.04, 1.45) higher risk of T2D than those with no CHIP. Specifically, higher risk was for TET2 (HR 1.48; CI = 1.05, 2.08) and ASXL1 (HR 1.76; CI = 1.03, 2.99) mutations; DNMT3A was nonsignificant (HR 1.15; CI = 0.93, 1.43). Statistical power was limited for JAK2 and TP53 analyses.

CONCLUSIONS: CHIP was associated with higher incidence of T2D. CHIP mutations located on genes implicated in CHD and mortality were also related to T2D, suggesting shared aging-related pathology.

%B Diabetes Care %8 2023 Sep 27 %G eng %R 10.2337/dc23-0805 %0 Journal Article %J medRxiv %D 2023 %T Clonal Hematopoiesis of Indeterminate Potential is Associated with Acute Kidney Injury. %A Vlasschaert, Caitlyn %A Robinson-Cohen, Cassianne %A Kestenbaum, Bryan %A Silver, Samuel A %A Chen, Jian-Chun %A Akwo, Elvis %A Bhatraju, Pavan K %A Zhang, Ming-Zhi %A Cao, Shirong %A Jiang, Ming %A Wang, Yinqiu %A Niu, Aolei %A Siew, Edward %A Kramer, Holly J %A Köttgen, Anna %A Franceschini, Nora %A Psaty, Bruce M %A Tracy, Russell P %A Alonso, Alvaro %A Arking, Dan E %A Coresh, Josef %A Ballantyne, Christie M %A Boerwinkle, Eric %A Grams, Morgan %A Lanktree, Matthew B %A Rauh, Michael J %A Harris, Raymond C %A Bick, Alexander G %X

Age is a predominant risk factor for acute kidney injury (AKI), yet the biological mechanisms underlying this risk are largely unknown and to date no genetic mechanisms for AKI have been established. Clonal hematopoiesis of indeterminate potential (CHIP) is a recently recognized biological mechanism conferring risk of several chronic aging diseases including cardiovascular disease, pulmonary disease and liver disease. In CHIP, blood stem cells acquire mutations in myeloid cancer driver genes such as and and the myeloid progeny of these mutated cells contribute to end-organ damage through inflammatory dysregulation. We sought to establish whether CHIP causes acute kidney injury (AKI). To address this question, we first evaluated associations with incident AKI events in three population-based epidemiology cohorts (N = 442,153). We found that CHIP was associated with a greater risk of AKI (adjusted HR 1.26, 95% CI: 1.19-1.34, p<0.0001), which was more pronounced in patients with AKI requiring dialysis (adjusted HR 1.65, 95% CI: 1.24-2.20, p=0.001). The risk was particularly high in the subset of individuals where CHIP was driven by mutations in genes other than (HR: 1.49, 95% CI: 1.37-1.61, p<0.0001). We then examined the association between CHIP and recovery from AKI in the ASSESS-AKI cohort and identified that non- CHIP was more common among those with a non-resolving pattern of injury (HR 2.3, 95% CI: 1.14-4.64, p = 0.03). To gain mechanistic insight, we evaluated the role of -CHIP to AKI in ischemia-reperfusion injury (IRI) and unilateral ureteral obstruction (UUO) mouse models. In both models, we observed more severe AKI and greater post-AKI kidney fibrosis in -CHIP mice. Kidney macrophage infiltration was markedly increased in -CHIP mice and -CHIP mutant renal macrophages displayed greater pro-inflammatory responses. In summary, this work establishes CHIP as a genetic mechanism conferring risk of AKI and impaired kidney function recovery following AKI via an aberrant inflammatory response in CHIP derived renal macrophages.

%B medRxiv %8 2023 May 17 %G eng %R 10.1101/2023.05.16.23290051 %0 Journal Article %J JAMA Netw Open %D 2023 %T CogDrisk, ANU-ADRI, CAIDE, and LIBRA Risk Scores for Estimating Dementia Risk. %A Huque, Md Hamidul %A Kootar, Scherazad %A Eramudugolla, Ranmalee %A Han, S Duke %A Carlson, Michelle C %A Lopez, Oscar L %A Bennett, David A %A Peters, Ruth %A Anstey, Kaarin J %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Australia %K Cohort Studies %K Female %K Heart Disease Risk Factors %K Humans %K Male %K Risk Factors %X

IMPORTANCE: While the Australian National University-Alzheimer Disease Risk Index (ANU-ADRI), Cardiovascular Risk Factors, Aging, and Dementia (CAIDE), and Lifestyle for Brain Health (LIBRA) dementia risk tools have been widely used, a large body of new evidence has emerged since their publication. Recently, Cognitive Health and Dementia Risk Index (CogDrisk) and CogDrisk for Alzheimer disease (CogDrisk-AD) risk tools have been developed for the assessment of dementia and AD risk, respectively, using contemporary evidence; comparison of the relative performance of these risk tools is limited.

OBJECTIVE: To evaluate the performance of CogDrisk, ANU-ADRI, CAIDE, LIBRA, and modified LIBRA (LIBRA with age and sex estimates from ANU-ADRI) in estimating dementia and AD risks (with CogDrisk-AD and ANU-ADRI).

DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study obtained data from the Rush Memory and Aging Project (MAP), the Cardiovascular Health Study Cognition Study (CHS-CS), and the Health and Retirement Study-Aging, Demographics and Memory Study (HRS-ADAMS). Participants who were free of dementia at baseline were included. The factors were component variables in the risk tools that included self-reported baseline demographics, medical risk factors, and lifestyle habits. The study was conducted between November 2021 and March 2023, and statistical analysis was performed from January to June 2023.

MAIN OUTCOMES AND MEASURES: Risk scores were calculated based on available factors in each of these cohorts. Area under the receiver operating characteristic curve (AUC) was calculated to measure the performance of each risk score. Multiple imputation was used to assess whether missing data may have affected estimates for dementia risk.

RESULTS: Among the 6107 participants in 3 validation cohorts included for this study, 2184 participants without dementia at baseline were available from MAP (mean [SD] age, 80.0 [7.6] years; 1606 [73.5%] female), 548 participants without dementia at baseline were available from HRS-ADAMS (mean [SD] age, 79.5 [6.3] years; 288 [52.5%] female), and 3375 participants without dementia at baseline were available from CHS-CS (mean [SD] age, 74.8 [4.9] years; 1994 [59.1%] female). In all 3 cohorts, a similar AUC for dementia was obtained using CogDrisk, ANU-ADRI, and modified LIBRA (MAP cohort: CogDrisk AUC, 0.65 [95% CI, 0.61-0.69]; ANU-ADRI AUC, 0.65 [95% CI, 0.61-0.69]; modified LIBRA AUC, 0.65 [95% CI, 0.61-0.69]; HRS-ADAMS cohort: CogDrisk AUC, 0.75 [95% CI, 0.71-0.79]; ANU-ADRI AUC, 0.74 [95% CI, 0.70-0.78]; modified LIBRA AUC, 0.75 [95% CI, 0.71-0.79]; CHS-CS cohort: CogDrisk AUC, 0.70 [95% CI, 0.67-0.72]; ANU-ADRI AUC, 0.69 [95% CI, 0.66-0.72]; modified LIBRA AUC, 0.70 [95% CI, 0.68-0.73]). The CAIDE and LIBRA also provided similar but lower AUCs than the 3 aforementioned tools (eg, MAP cohort: CAIDE AUC, 0.50 [95% CI, 0.46-0.54]; LIBRA AUC, 0.53 [95% CI, 0.48-0.57]). The performance of CogDrisk-AD and ANU-ADRI in estimating AD risks was also similar.

CONCLUSIONS AND RELEVANCE: CogDrisk and CogDrisk-AD performed similarly to ANU-ADRI in estimating dementia and AD risks. These results suggest that CogDrisk and CogDrisk-AD, with a greater range of modifiable risk factors compared with other risk tools in this study, may be more informative for risk reduction.

%B JAMA Netw Open %V 6 %P e2331460 %8 2023 Aug 01 %G eng %N 8 %R 10.1001/jamanetworkopen.2023.31460 %0 Journal Article %J medRxiv %D 2023 %T Complexities of cerebral small vessel disease, blood pressure, and dementia relationship: new insights from genetics. %A Sargurupremraj, Muralidharan %A Soumaré, Aïcha %A Bis, Joshua C %A Surakka, Ida %A Jürgenson, Tuuli %A Joly, Pierre %A Knol, Maria J %A Wang, Ruiqi %A Yang, Qiong %A Satizabal, Claudia L %A Gudjonsson, Alexander %A Mishra, Aniket %A Bouteloup, Vincent %A Phuah, Chia-Ling %A van Duijn, Cornelia M %A Cruchaga, Carlos %A Dufouil, Carole %A Chene, Geneviève %A Lopez, Oscar %A Psaty, Bruce M %A Tzourio, Christophe %A Amouyel, Philippe %A Adams, Hieab H %A Jacqmin-Gadda, Hélène %A Ikram, Mohammad Arfan %A Gudnason, Vilmundur %A Milani, Lili %A Winsvold, Bendik S %A Hveem, Kristian %A Matthews, Paul M %A Longstreth, W T %A Seshadri, Sudha %A Launer, Lenore J %A Debette, Stephanie %X

IMPORTANCE: There is increasing recognition that vascular disease, which can be treated, is a key contributor to dementia risk. However, the contribution of specific markers of vascular disease is unclear and, as a consequence, optimal prevention strategies remain unclear.

OBJECTIVE: To disentangle the causal relation of several key vascular traits to dementia risk: (i) white matter hyperintensity (WMH) burden, a highly prevalent imaging marker of covert cerebral small vessel disease (cSVD); (ii) clinical stroke; and (iii) blood pressure (BP), the leading risk factor for cSVD and stroke, for which efficient therapies exist. To account for potential epidemiological biases inherent to late-onset conditions like dementia.

DESIGN SETTING AND PARTICIPANTS: This study first explored the association of genetically determined WMH, BP levels and stroke risk with AD using summary-level data from large genome-wide association studies (GWASs) in a two-sample Mendelian randomization (MR) framework. Second, leveraging individual-level data from large longitudinal population-based cohorts and biobanks with prospective dementia surveillance, the association of weighted genetic risk scores (wGRSs) for WMH, BP, and stroke with incident all-cause-dementia was explored using Cox-proportional hazard and multi-state models. The data analysis was performed from July 26, 2020, through July 24, 2022.

EXPOSURES: Genetically determined levels of WMH volume and BP (systolic, diastolic and pulse blood pressures) and genetic liability to stroke.

MAIN OUTCOMES AND MEASURES: The summary-level MR analyses focused on the outcomes from GWAS of clinically diagnosed AD (n-cases=21,982) and GWAS additionally including self-reported parental history of dementia as a proxy for AD diagnosis (AD , n-cases=53,042). For the longitudinal analyses, individual-level data of 157,698 participants with 10,699 incident all-cause-dementia were studied, exploring AD, vascular or mixed dementia in secondary analyses.

RESULTS: In the two-sample MR analyses, WMH showed strong evidence for a causal association with increased risk of AD (OR, 1.16; 95%CI:1.05-1.28; P=.003) and AD (OR, 1.28; 95%CI:1.07-1.53; P=.008), after accounting for genetically determined pulse pressure for the latter. Genetically predicted BP traits showed evidence for a protective association with both clinically defined AD and AD , with evidence for confounding by shared genetic instruments. In longitudinal analyses the wGRSs for WMH, but not BP or stroke, showed suggestive association with incident all-cause-dementia (HR, 1.02; 95%CI:1.00-1.04; P=.06). BP and stroke wGRSs were strongly associated with mortality but there was no evidence for selective survival bias during follow-up. In secondary analyses, polygenic scores with more liberal instrument definition showed association of both WMH and stroke with all-cause-dementia, AD, and vascular or mixed dementia; associations of stroke, but not WMH, with dementia outcomes were markedly attenuated after adjusting for interim stroke.

CONCLUSION: These findings provide converging evidence that WMH is a leading vascular contributor to dementia risk, which may better capture the brain damage caused by BP (and other etiologies) than BP itself and should be targeted in priority for dementia prevention in the population.

KEY POINTS: Do instrumental variable analyses leveraging genetic information provide evidence for a causal association of various vascular traits with Alzheimer's disease (AD) and all-cause-dementia? How do these associations compare for white matter hyperintensity (WMH) burden, a highly prevalent marker of covert cerebral small vessel disease (cSVD), stroke, and blood pressure traits, the strongest known risk factor for cSVD and stroke? Using Mendelian randomization (MR) leveraging large, published genome-wide association studies, this study showed a putative causal association of larger WMH burden with increased AD risk after accounting for pulse pressure effects, and some evidence for association of lower BP with AD risk with possible confounding by shared genetic instruments. Longitudinal analyses on individual-level data also supported association of genetically determined WMH with incident all-cause-dementia and AD, independently of interim stroke. This study using complementary genetic epidemiology approaches, identified increasing WMH burden to be associated with dementia and AD risk, suggesting the association as specific for cSVD and independent of BP and stroke.

%B medRxiv %8 2023 Aug 13 %G eng %R 10.1101/2023.08.08.23293761 %0 Journal Article %J medRxiv %D 2023 %T Determinants of mosaic chromosomal alteration fitness. %A Pershad, Yash %A Mack, Taralynn %A Poisner, Hannah %A Jakubek, Yasminka A %A Stilp, Adrienne M %A Mitchell, Braxton D %A Lewis, Joshua P %A Boerwinkle, Eric %A Loos, Ruth J %A Chami, Nathalie %A Wang, Zhe %A Barnes, Kathleen %A Pankratz, Nathan %A Fornage, Myriam %A Redline, Susan %A Psaty, Bruce M %A Bis, Joshua C %A Shojaie, Ali %A Silverman, Edwin K %A Cho, Michael H %A Yun, Jeong %A DeMeo, Dawn %A Levy, Daniel %A Johnson, Andrew %A Mathias, Rasika %A Taub, Margaret %A Arnett, Donna %A North, Kari %A Raffield, Laura M %A Carson, April %A Doyle, Margaret F %A Rich, Stephen S %A Rotter, Jerome I %A Guo, Xiuqing %A Cox, Nancy %A Roden, Dan M %A Franceschini, Nora %A Desai, Pinkal %A Reiner, Alex %A Auer, Paul L %A Scheet, Paul %A Jaiswal, Siddhartha %A Weinstock, Joshua S %A Bick, Alexander G %X

Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well-understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our estimates of mCA fitness were correlated (R = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using a theoretical probability distribution. Individuals with lymphoid-associated mCAs had a significantly higher white blood cell count and faster clonal expansion rate. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified , , and locus variants as modulators of mCA clonal expansion rate.

%B medRxiv %8 2023 Oct 21 %G eng %R 10.1101/2023.10.20.23297280 %0 Journal Article %J Alzheimers Dement (Amst) %D 2023 %T {Early-onset Alzheimer's disease explained by polygenic risk of late-onset disease? %A Mantyh, W. G. %A Cochran, J. N. %A Taylor, J. W. %A Broce, I. J. %A Geier, E. G. %A Bonham, L. W. %A Anderson, A. G. %A Sirkis, D. W. %A Joie, R. %A Iaccarino, L. %A Chaudhary, K. %A Edwards, L. %A Strom, A. %A Grant, H. %A Allen, I. E. %A Miller, Z. A. %A Gorno-Tempini, M. L. %A Kramer, J. H. %A Miller, B. L. %A Desikan, R. S. %A Rabinovici, G. D. %A Yokoyama, J. S. %X There is a unique genetic architecture of early- versus late-onset Alzheimer's disease (AD).Late-onset AD polygenic risk is not an explanation for early-onset AD.Polygenic risk of late-onset AD does not predict early-onset AD biology.Unique genetic architecture of early- versus late-onset AD parallels AD heterogeneity. %B Alzheimers Dement (Amst) %V 15 %P e12482 %G eng %0 Journal Article %J J Am Heart Assoc %D 2023 %T Elevated Plasma Levels of Ketone Bodies Are Associated With All-Cause Mortality and Incidence of Heart Failure in Older Adults: The CHS. %A Niezen, Sebastian %A Connelly, Margery A %A Hirsch, Calvin %A Kizer, Jorge R %A Benitez, Maria E %A Minchenberg, Scott %A Perez-Matos, Maria Camila %A Jiang, Zhenghui Gordon %A Mukamal, Kenneth J %K Aged %K Aging %K Cardiovascular Diseases %K Heart Failure %K Humans %K Incidence %K Ketone Bodies %X

Background Chronic disease, such as heart failure, influences cellular metabolism and shapes circulating metabolites. The relationships between key energy metabolites and chronic diseases in aging are not well understood. This study aims to determine the relationship between main components of energy metabolism with all-cause mortality and incident heart failure. Methods and Results We analyzed the association between plasma metabolite levels with all-cause mortality and incident heart failure among US older adults in the CHS (Cardiovascular Health Study). We followed 1758 participants without heart failure at baseline with hazard ratios (HRs) of analyte levels and metabolic profiles characterized by high levels of ketone bodies for all-cause mortality and incident heart failure. Multivariable Cox analyses revealed a dose-response relationship of 50% increase in all-cause mortality between lowest and highest quintiles of ketone body concentrations (HR, 1.5 [95% CI, 1.0-1.9]; =0.007). Ketone body levels remained associated with incident heart failure after adjusting for cardiovascular disease confounders (HR, 1.2 [95% CI, 1.0-1.3]; =0.02). Using K-means cluster analysis, we identified a cluster with higher levels of ketone bodies, citrate, interleukin-6, and B-type natriuretic peptide but lower levels of pyruvate, body mass index, and estimated glomerular filtration rate. The cluster with elevated ketone body levels was associated with higher all-cause mortality (HR, 1.7 [95% CI, 1.1-2.7]; =0.01). Conclusions Higher concentrations of ketone bodies predict incident heart failure and all-cause mortality in an older US population, independent of metabolic and cardiovascular confounders. This association suggests a potentially important relationship between ketone body metabolism and aging.

%B J Am Heart Assoc %V 12 %P e029960 %8 2023 Sep 05 %G eng %N 17 %R 10.1161/JAHA.123.029960 %0 Journal Article %J Nat Commun %D 2023 %T Evaluating the use of blood pressure polygenic risk scores across race/ethnic background groups. %A Kurniansyah, Nuzulul %A Goodman, Matthew O %A Khan, Alyna T %A Wang, Jiongming %A Feofanova, Elena %A Bis, Joshua C %A Wiggins, Kerri L %A Huffman, Jennifer E %A Kelly, Tanika %A Elfassy, Tali %A Guo, Xiuqing %A Palmas, Walter %A Lin, Henry J %A Hwang, Shih-Jen %A Gao, Yan %A Young, Kendra %A Kinney, Gregory L %A Smith, Jennifer A %A Yu, Bing %A Liu, Simin %A Wassertheil-Smoller, Sylvia %A Manson, JoAnn E %A Zhu, Xiaofeng %A Chen, Yii-Der Ida %A Lee, I-Te %A Gu, C Charles %A Lloyd-Jones, Donald M %A Zöllner, Sebastian %A Fornage, Myriam %A Kooperberg, Charles %A Correa, Adolfo %A Psaty, Bruce M %A Arnett, Donna K %A Isasi, Carmen R %A Rich, Stephen S %A Kaplan, Robert C %A Redline, Susan %A Mitchell, Braxton D %A Franceschini, Nora %A Levy, Daniel %A Rotter, Jerome I %A Morrison, Alanna C %A Sofer, Tamar %K Blood Pressure %K Ethnicity %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Male %K Multifactorial Inheritance %K Population Health %K Risk Factors %X

We assess performance and limitations of polygenic risk scores (PRSs) for multiple blood pressure (BP) phenotypes in diverse population groups. We compare "clumping-and-thresholding" (PRSice2) and LD-based (LDPred2) methods to construct PRSs from each of multiple GWAS, as well as multi-PRS approaches that sum PRSs with and without weights, including PRS-CSx. We use datasets from the MGB Biobank, TOPMed study, UK biobank, and from All of Us to train, assess, and validate PRSs in groups defined by self-reported race/ethnic background (Asian, Black, Hispanic/Latino, and White). For both SBP and DBP, the PRS-CSx based PRS, constructed as a weighted sum of PRSs developed from multiple independent GWAS, perform best across all race/ethnic backgrounds. Stratified analysis in All of Us shows that PRSs are better predictive of BP in females compared to males, individuals without obesity, and middle-aged (40-60 years) compared to older and younger individuals.

%B Nat Commun %V 14 %P 3202 %8 2023 Jun 02 %G eng %N 1 %R 10.1038/s41467-023-38990-9 %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2023 %T Evaluation of Associations of Growth Differentiation Factor-11, Growth Differentiation Factor-8 and their Binding Proteins Follistatin and Follistatin-like protein-3 with Dementia and Cognition. %A Newman, Anne B %A Patel, Sheena %A Kizer, Jorge %A Lee, Se-Jin %A Bhasin, Shalinder %A Cawthon, Peggy %A LeBrasseur, Nathan %A Tracy, Russel P %A Ganz, Peter %A Cummings, Steve %X

BACKGROUND: Studies using heterochronic parabiosis discovered that circulating factors mediate brain aging in animal models.

METHODS: We assessed Growth Differentiation Factor (GDF)-11 and GDF-8 using mass spectrometry and inhibitors follistatin and follistatin-like protein-3 (FSTL-3) with ELISA in in the Cardiovascular Health Study (N=1506) and the Health ABC study (N=1237). CLL-11 and Beta 2 microglobulin (B2M) were measured with ELISA in a subset of 400 individuals in Health ABC. Associations were assessed with cognitive function, brain magnetic resonance imaging (MRI) findings (CHS only) and incident dementia using correlations, linear regression and Cox proportional hazards models.

RESULTS: In CHS, levels of GDF-11, GDF-8 and follistatin were not correlated cross sectionally with the 3MSE or DSST, brain MRI findings of white matter hyperintensity, atrophy or small infarcts, nor were they associated with incident dementia. FSTL-3 was modestly correlated with poorer cognitive function, greater white matter hyperintensities and atrophy on MRI as well as with incident dementia with an adjusted HR of 1.72 (95% CI=1.13, 2.61) per doubling of FSTL-3. FSTL-3 was not associated with cognition or dementia in Health ABC, but GDF-8 was associated with both. The adjusted HR for incident dementia was 1.50 (95%CI 1.07, 2.10) per doubling of GDF-8.

CONCLUSIONS: Total GDF-11 level was not related to cognition or dementia in older adults. Associations of GDF-8 with cognitive outcomes in Health ABC were not expected, but consistent with animal models. Associations of FSTL-3 with cognition, brain abnormalities, and incident dementia in CHS implicates TGF-B superfamily inhibition in the pathogenesis of dementia.

%B J Gerontol A Biol Sci Med Sci %8 2023 Jan 20 %G eng %R 10.1093/gerona/glad019 %0 Journal Article %J Ann Intern Med %D 2023 %T Factors Associated With Circulating Sex Hormones in Men : Individual Participant Data Meta-analyses. %A Marriott, Ross J %A Murray, Kevin %A Adams, Robert J %A Antonio, Leen %A Ballantyne, Christie M %A Bauer, Douglas C %A Bhasin, Shalender %A Biggs, Mary L %A Cawthon, Peggy M %A Couper, David J %A Dobs, Adrian S %A Flicker, Leon %A Handelsman, David J %A Hankey, Graeme J %A Hannemann, Anke %A Haring, Robin %A Hsu, Benjumin %A Karlsson, Magnus %A Martin, Sean A %A Matsumoto, Alvin M %A Mellström, Dan %A Ohlsson, Claes %A O'Neill, Terence W %A Orwoll, Eric S %A Quartagno, Matteo %A Shores, Molly M %A Steveling, Antje %A Tivesten, Åsa %A Travison, Thomas G %A Vanderschueren, Dirk %A Wittert, Gary A %A Wu, Frederick C W %A Yeap, Bu B %X

BACKGROUND: Various factors modulate circulating testosterone in men, affecting interpretation of testosterone measurements.

PURPOSE: To clarify factors associated with variations in sex hormone concentrations.

DATA SOURCES: Systematic literature searches (to July 2019).

STUDY SELECTION: Prospective cohort studies of community-dwelling men with total testosterone measured using mass spectrometry.

DATA EXTRACTION: Individual participant data (IPD) (9 studies;  = 21 074) and aggregate data (2 studies;  = 4075). Sociodemographic, lifestyle, and health factors and concentrations of total testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone, and estradiol were extracted.

DATA SYNTHESIS: Two-stage random-effects IPD meta-analyses found a nonlinear association of testosterone with age, with negligible change among men aged 17 to 70 years (change per SD increase about the midpoint, -0.27 nmol/L [-7.8 ng/dL] [CI, -0.71 to 0.18 nmol/L {-20.5 to 5.2 ng/dL}]) and decreasing testosterone levels with age for men older than 70 years (-1.55 nmol/L [-44.7 ng/dL] [CI, -2.05 to -1.06 nmol/L {-59.1 to -30.6 ng/dL}]). Testosterone was inversely associated with body mass index (BMI) (change per SD increase, -2.42 nmol/L [-69.7 ng/dL] [CI, -2.70 to -2.13 nmol/L {-77.8 to -61.4 ng/dL}]). Testosterone concentrations were lower for men who were married (mean difference, -0.57 nmol/L [-16.4 ng/dL] [CI, -0.89 to -0.26 nmol/L {-25.6 to -7.5 ng/dL}]); undertook at most 75 minutes of vigorous physical activity per week (-0.51 nmol/L [-14.7 ng/dL] [CI, -0.90 to -0.13 nmol/L {-25.9 to -3.7 ng/dL}]); were former smokers (-0.34 nmol/L [-9.8 ng/dL] [CI, -0.55 to -0.12 nmol/L {-15.9 to -3.5 ng/dL}]); or had hypertension (-0.53 nmol/L [-15.3 ng/dL] [CI, -0.82 to -0.24 nmol/L {-23.6 to -6.9 ng/dL}]), cardiovascular disease (-0.35 nmol/L [-10.1 ng/dL] [CI, -0.55 to -0.15 nmol/L {-15.9 to -4.3 ng/dL}]), cancer (-1.39 nmol/L [-40.1 ng/dL] [CI, -1.79 to -0.99 nmol/L {-51.6 to -28.5 ng/dL}]), or diabetes (-1.43 nmol/L [-41.2 ng/dL] [CI, -1.65 to -1.22 nmol/L {-47.6 to -35.2 ng/dL}]). Sex hormone-binding globulin was directly associated with age and inversely associated with BMI. Luteinizing hormone was directly associated with age in men older than 70 years.

LIMITATION: Cross-sectional analysis, heterogeneity between studies and in timing of blood sampling, and imputation for missing data.

CONCLUSION: Multiple factors are associated with variation in male testosterone, SHBG, and LH concentrations. Reduced testosterone and increased LH concentrations may indicate impaired testicular function after age 70 years. Interpretation of individual testosterone measurements should account particularly for age older than 70 years, obesity, diabetes, and cancer.

PRIMARY FUNDING SOURCE: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).

%B Ann Intern Med %8 2023 Aug 29 %G eng %R 10.7326/M23-0342 %0 Journal Article %J Front Genet %D 2023 %T Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci. %A de Las Fuentes, Lisa %A Schwander, Karen L %A Brown, Michael R %A Bentley, Amy R %A Winkler, Thomas W %A Sung, Yun Ju %A Munroe, Patricia B %A Miller, Clint L %A Aschard, Hugo %A Aslibekyan, Stella %A Bartz, Traci M %A Bielak, Lawrence F %A Chai, Jin Fang %A Cheng, Ching-Yu %A Dorajoo, Rajkumar %A Feitosa, Mary F %A Guo, Xiuqing %A Hartwig, Fernando P %A Horimoto, Andrea %A Kolcic, Ivana %A Lim, Elise %A Liu, Yongmei %A Manning, Alisa K %A Marten, Jonathan %A Musani, Solomon K %A Noordam, Raymond %A Padmanabhan, Sandosh %A Rankinen, Tuomo %A Richard, Melissa A %A Ridker, Paul M %A Smith, Albert V %A Vojinovic, Dina %A Zonderman, Alan B %A Alver, Maris %A Boissel, Mathilde %A Christensen, Kaare %A Freedman, Barry I %A Gao, Chuan %A Giulianini, Franco %A Harris, Sarah E %A He, Meian %A Hsu, Fang-Chi %A Kuhnel, Brigitte %A Laguzzi, Federica %A Li, Xiaoyin %A Lyytikäinen, Leo-Pekka %A Nolte, Ilja M %A Poveda, Alaitz %A Rauramaa, Rainer %A Riaz, Muhammad %A Robino, Antonietta %A Sofer, Tamar %A Takeuchi, Fumihiko %A Tayo, Bamidele O %A van der Most, Peter J %A Verweij, Niek %A Ware, Erin B %A Weiss, Stefan %A Wen, Wanqing %A Yanek, Lisa R %A Zhan, Yiqiang %A Amin, Najaf %A Arking, Dan E %A Ballantyne, Christie %A Boerwinkle, Eric %A Brody, Jennifer A %A Broeckel, Ulrich %A Campbell, Archie %A Canouil, Mickaël %A Chai, Xiaoran %A Chen, Yii-Der Ida %A Chen, Xu %A Chitrala, Kumaraswamy Naidu %A Concas, Maria Pina %A de Faire, Ulf %A de Mutsert, Renée %A de Silva, H Janaka %A de Vries, Paul S %A Do, Ahn %A Faul, Jessica D %A Fisher, Virginia %A Floyd, James S %A Forrester, Terrence %A Friedlander, Yechiel %A Girotto, Giorgia %A Gu, C Charles %A Hallmans, Göran %A Heikkinen, Sami %A Heng, Chew-Kiat %A Homuth, Georg %A Hunt, Steven %A Ikram, M Arfan %A Jacobs, David R %A Kavousi, Maryam %A Khor, Chiea Chuen %A Kilpeläinen, Tuomas O %A Koh, Woon-Puay %A Komulainen, Pirjo %A Langefeld, Carl D %A Liang, Jingjing %A Liu, Kiang %A Liu, Jianjun %A Lohman, Kurt %A Mägi, Reedik %A Manichaikul, Ani W %A McKenzie, Colin A %A Meitinger, Thomas %A Milaneschi, Yuri %A Nauck, Matthias %A Nelson, Christopher P %A O'Connell, Jeffrey R %A Palmer, Nicholette D %A Pereira, Alexandre C %A Perls, Thomas %A Peters, Annette %A Polasek, Ozren %A Raitakari, Olli T %A Rice, Kenneth %A Rice, Treva K %A Rich, Stephen S %A Sabanayagam, Charumathi %A Schreiner, Pamela J %A Shu, Xiao-Ou %A Sidney, Stephen %A Sims, Mario %A Smith, Jennifer A %A Starr, John M %A Strauch, Konstantin %A Tai, E Shyong %A Taylor, Kent D %A Tsai, Michael Y %A Uitterlinden, André G %A van Heemst, Diana %A Waldenberger, Melanie %A Wang, Ya-Xing %A Wei, Wen-Bin %A Wilson, Gregory %A Xuan, Deng %A Yao, Jie %A Yu, Caizheng %A Yuan, Jian-Min %A Zhao, Wei %A Becker, Diane M %A Bonnefond, Amélie %A Bowden, Donald W %A Cooper, Richard S %A Deary, Ian J %A Divers, Jasmin %A Esko, Tõnu %A Franks, Paul W %A Froguel, Philippe %A Gieger, Christian %A Jonas, Jost B %A Kato, Norihiro %A Lakka, Timo A %A Leander, Karin %A Lehtimäki, Terho %A Magnusson, Patrik K E %A North, Kari E %A Ntalla, Ioanna %A Penninx, Brenda %A Samani, Nilesh J %A Snieder, Harold %A Spedicati, Beatrice %A van der Harst, Pim %A Völzke, Henry %A Wagenknecht, Lynne E %A Weir, David R %A Wojczynski, Mary K %A Wu, Tangchun %A Zheng, Wei %A Zhu, Xiaofeng %A Bouchard, Claude %A Chasman, Daniel I %A Evans, Michele K %A Fox, Ervin R %A Gudnason, Vilmundur %A Hayward, Caroline %A Horta, Bernardo L %A Kardia, Sharon L R %A Krieger, Jose Eduardo %A Mook-Kanamori, Dennis O %A Peyser, Patricia A %A Province, Michael M %A Psaty, Bruce M %A Rudan, Igor %A Sim, Xueling %A Smith, Blair H %A van Dam, Rob M %A van Duijn, Cornelia M %A Wong, Tien Yin %A Arnett, Donna K %A Rao, Dabeeru C %A Gauderman, James %A Liu, Ching-Ti %A Morrison, Alanna C %A Rotter, Jerome I %A Fornage, Myriam %X

Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes. A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: "Some College" (yes/no, for any education beyond high school) and "Graduated College" (yes/no, for completing a 4-year college degree). Genome-wide significant ( < 5 × 10) and suggestive ( < 1 × 10) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals). In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (), brain (), and liver () biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue. Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects.

%B Front Genet %V 14 %P 1235337 %8 2023 %G eng %R 10.3389/fgene.2023.1235337 %0 Journal Article %J Nat Commun %D 2023 %T Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease. %A Young, William J %A Haessler, Jeffrey %A Benjamins, Jan-Walter %A Repetto, Linda %A Yao, Jie %A Isaacs, Aaron %A Harper, Andrew R %A Ramirez, Julia %A Garnier, Sophie %A Van Duijvenboden, Stefan %A Baldassari, Antoine R %A Concas, Maria Pina %A Duong, ThuyVy %A Foco, Luisa %A Isaksen, Jonas L %A Mei, Hao %A Noordam, Raymond %A Nursyifa, Casia %A Richmond, Anne %A Santolalla, Meddly L %A Sitlani, Colleen M %A Soroush, Negin %A Thériault, Sébastien %A Trompet, Stella %A Aeschbacher, Stefanie %A Ahmadizar, Fariba %A Alonso, Alvaro %A Brody, Jennifer A %A Campbell, Archie %A Correa, Adolfo %A Darbar, Dawood %A De Luca, Antonio %A Deleuze, Jean-Francois %A Ellervik, Christina %A Fuchsberger, Christian %A Goel, Anuj %A Grace, Christopher %A Guo, Xiuqing %A Hansen, Torben %A Heckbert, Susan R %A Jackson, Rebecca D %A Kors, Jan A %A Lima-Costa, Maria Fernanda %A Linneberg, Allan %A Macfarlane, Peter W %A Morrison, Alanna C %A Navarro, Pau %A Porteous, David J %A Pramstaller, Peter P %A Reiner, Alexander P %A Risch, Lorenz %A Schotten, Ulrich %A Shen, Xia %A Sinagra, Gianfranco %A Soliman, Elsayed Z %A Stoll, Monika %A Tarazona-Santos, Eduardo %A Tinker, Andrew %A Trajanoska, Katerina %A Villard, Eric %A Warren, Helen R %A Whitsel, Eric A %A Wiggins, Kerri L %A Arking, Dan E %A Avery, Christy L %A Conen, David %A Girotto, Giorgia %A Grarup, Niels %A Hayward, Caroline %A Jukema, J Wouter %A Mook-Kanamori, Dennis O %A Olesen, Morten Salling %A Padmanabhan, Sandosh %A Psaty, Bruce M %A Pattaro, Cristian %A Ribeiro, Antonio Luiz P %A Rotter, Jerome I %A Stricker, Bruno H %A van der Harst, Pim %A van Duijn, Cornelia M %A Verweij, Niek %A Wilson, James G %A Orini, Michele %A Charron, Philippe %A Watkins, Hugh %A Kooperberg, Charles %A Lin, Henry J %A Wilson, James F %A Kanters, Jørgen K %A Sotoodehnia, Nona %A Mifsud, Borbala %A Lambiase, Pier D %A Tereshchenko, Larisa G %A Munroe, Patricia B %K Arrhythmias, Cardiac %K Atrioventricular Block %K Biomarkers %K Cardiovascular Diseases %K Electrocardiography %K Genome-Wide Association Study %K Humans %K Risk Factors %X

The 3-dimensional spatial and 2-dimensional frontal QRS-T angles are measures derived from the vectorcardiogram. They are independent risk predictors for arrhythmia, but the underlying biology is unknown. Using multi-ancestry genome-wide association studies we identify 61 (58 previously unreported) loci for the spatial QRS-T angle (N = 118,780) and 11 for the frontal QRS-T angle (N = 159,715). Seven out of the 61 spatial QRS-T angle loci have not been reported for other electrocardiographic measures. Enrichments are observed in pathways related to cardiac and vascular development, muscle contraction, and hypertrophy. Pairwise genome-wide association studies with classical ECG traits identify shared genetic influences with PR interval and QRS duration. Phenome-wide scanning indicate associations with atrial fibrillation, atrioventricular block and arterial embolism and genetically determined QRS-T angle measures are associated with fascicular and bundle branch block (and also atrioventricular block for the frontal QRS-T angle). We identify potential biology involved in the QRS-T angle and their genetic relationships with cardiovascular traits and diseases, may inform future research and risk prediction.

%B Nat Commun %V 14 %P 1411 %8 2023 Mar 14 %G eng %N 1 %R 10.1038/s41467-023-36997-w %0 Journal Article %J bioRxiv %D 2023 %T Genetic control of mRNA splicing as a potential mechanism for incomplete penetrance of rare coding variants. %A Einson, Jonah %A Glinos, Dafni %A Boerwinkle, Eric %A Castaldi, Peter %A Darbar, Dawood %A de Andrade, Mariza %A Ellinor, Patrick %A Fornage, Myriam %A Gabriel, Stacey %A Germer, Soren %A Gibbs, Richard %A Hersh, Craig P %A Johnsen, Jill %A Kaplan, Robert %A Konkle, Barbara A %A Kooperberg, Charles %A Nassir, Rami %A Loos, Ruth J F %A Meyers, Deborah A %A Mitchell, Braxton D %A Psaty, Bruce %A Vasan, Ramachandran S %A Rich, Stephen S %A Rienstra, Michael %A Rotter, Jerome I %A Saferali, Aabida %A Shoemaker, M Benjamin %A Silverman, Edwin %A Smith, Albert Vernon %A Mohammadi, Pejman %A Castel, Stephane E %A Iossifov, Ivan %A Lappalainen, Tuuli %X

Exonic variants present some of the strongest links between genotype and phenotype. However, these variants can have significant inter-individual pathogenicity differences, known as variable penetrance. In this study, we propose a model where genetically controlled mRNA splicing modulates the pathogenicity of exonic variants. By first cataloging exonic inclusion from RNA-seq data in GTEx v8, we find that pathogenic alleles are depleted on highly included exons. Using a large-scale phased WGS data from the TOPMed consortium, we observe that this effect may be driven by common splice-regulatory genetic variants, and that natural selection acts on haplotype configurations that reduce the transcript inclusion of putatively pathogenic variants, especially when limiting to haploinsufficient genes. Finally, we test if this effect may be relevant for autism risk using families from the Simons Simplex Collection, but find that splicing of pathogenic alleles has a penetrance reducing effect here as well. Overall, our results indicate that common splice-regulatory variants may play a role in reducing the damaging effects of rare exonic variants.

%B bioRxiv %8 2023 Jan 31 %G eng %R 10.1101/2023.01.31.526505 %0 Journal Article %J Sci Adv %D 2023 %T The genetic determinants of recurrent somatic mutations in 43,693 blood genomes. %A Weinstock, Joshua S %A Laurie, Cecelia A %A Broome, Jai G %A Taylor, Kent D %A Guo, Xiuqing %A Shuldiner, Alan R %A O'Connell, Jeffrey R %A Lewis, Joshua P %A Boerwinkle, Eric %A Barnes, Kathleen C %A Chami, Nathalie %A Kenny, Eimear E %A Loos, Ruth J F %A Fornage, Myriam %A Redline, Susan %A Cade, Brian E %A Gilliland, Frank D %A Chen, Zhanghua %A Gauderman, W James %A Kumar, Rajesh %A Grammer, Leslie %A Schleimer, Robert P %A Psaty, Bruce M %A Bis, Joshua C %A Brody, Jennifer A %A Silverman, Edwin K %A Yun, Jeong H %A Qiao, Dandi %A Weiss, Scott T %A Lasky-Su, Jessica %A DeMeo, Dawn L %A Palmer, Nicholette D %A Freedman, Barry I %A Bowden, Donald W %A Cho, Michael H %A Vasan, Ramachandran S %A Johnson, Andrew D %A Yanek, Lisa R %A Becker, Lewis C %A Kardia, Sharon %A He, Jiang %A Kaplan, Robert %A Heckbert, Susan R %A Smith, Nicholas L %A Wiggins, Kerri L %A Arnett, Donna K %A Irvin, Marguerite R %A Tiwari, Hemant %A Correa, Adolfo %A Raffield, Laura M %A Gao, Yan %A de Andrade, Mariza %A Rotter, Jerome I %A Rich, Stephen S %A Manichaikul, Ani W %A Konkle, Barbara A %A Johnsen, Jill M %A Wheeler, Marsha M %A Custer, Brian S %A Duggirala, Ravindranath %A Curran, Joanne E %A Blangero, John %A Gui, Hongsheng %A Xiao, Shujie %A Williams, L Keoki %A Meyers, Deborah A %A Li, Xingnan %A Ortega, Victor %A McGarvey, Stephen %A Gu, C Charles %A Chen, Yii-Der Ida %A Lee, Wen-Jane %A Shoemaker, M Benjamin %A Darbar, Dawood %A Roden, Dan %A Albert, Christine %A Kooperberg, Charles %A Desai, Pinkal %A Blackwell, Thomas W %A Abecasis, Goncalo R %A Smith, Albert V %A Kang, Hyun M %A Mathias, Rasika %A Natarajan, Pradeep %A Jaiswal, Siddhartha %A Reiner, Alexander P %A Bick, Alexander G %K Germ-Line Mutation %K Hematopoiesis %K Humans %K Middle Aged %K Mutation %K Mutation, Missense %K Phenotype %X

Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid lineage commitment. In addition, the presence of eight specific RNMSMs associated with blood cell traits at effect sizes comparable to Mendelian genetic mutations. Overall, we found that somatic mutations in blood are an unexpectedly common phenomenon with ancestry-specific determinants and human health consequences.

%B Sci Adv %V 9 %P eabm4945 %8 2023 Apr 28 %G eng %N 17 %R 10.1126/sciadv.abm4945 %0 Journal Article %J Res Sq %D 2023 %T Genome-Wide Association Studies and fine-mapping of genomic loci for n-3 and n-6 Polyunsaturated Fatty Acids in Hispanic American and African American Cohorts. %A Yang, Chaojie %A Veenstra, Jenna %A Bartz, Traci %A Pahl, Matthew %A Hallmark, Brian %A Chen, Yii-Der Ida %A Westra, Jason %A Steffen, Lyn %A Brown, Christopher %A Siscovick, David %A Tsai, Michael %A Wood, Alexis %A Rich, Stephen %A Smith, Caren %A O'Connor, Timothy %A Mozaffarian, Dariush %A Grant, Struan %A Chilton, Floyd %A Tintle, Nathan %A Lemaitre, Rozenn %A Manichaikul, Ani %X

Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) play critical roles in human health. Prior genome-wide association studies (GWAS) of n-3 and n-6 PUFAs in European Americans from the CHARGE Consortium have documented strong genetic signals in/near the locus on chromosome 11. We performed a GWAS of four n-3 and four n-6 PUFAs in Hispanic American (n = 1454) and African American (n = 2278) participants from three CHARGE cohorts. Applying a genome-wide significance threshold of  < 5 x 10 , we confirmed association of the signal and found evidence of two additional signals (in and ) within 200 kb of the originally reported signal. Outside of the region, we identified novel signals for arachidonic acid (AA) in Hispanic Americans located in/near genes including , , and spanning a > 9 Mb region on chromosome 11 (57.5Mb ~ 67.1Mb). Among these novel signals, we found associations unique to Hispanic Americans, including rs28364240, a missense variant for AA that is common in CHARGE Hispanic Americans but absent in other race/ancestry groups. Our study sheds light on the genetics of PUFAs and the value of investigating complex trait genetics across diverse ancestry populations.

%B Res Sq %8 2023 Feb 24 %G eng %R 10.21203/rs.3.rs-2073736/v1 %0 Journal Article %J medRxiv %D 2023 %T Genome-Wide Interaction Analysis with DASH Diet Score Identified Novel Loci for Systolic Blood Pressure. %A Guirette, Melanie %A Lan, Jessie %A McKeown, Nicola %A Brown, Michael R %A Chen, Han %A de Vries, Paul S %A Kim, Hyunju %A Rebholz, Casey M %A Morrison, Alanna C %A Bartz, Traci M %A Fretts, Amanda M %A Guo, Xiuqing %A Lemaitre, Rozenn N %A Liu, Ching-Ti %A Noordam, Raymond %A de Mutsert, Renée %A Rosendaal, Frits R %A Wang, Carol A %A Beilin, Lawrence %A Mori, Trevor A %A Oddy, Wendy H %A Pennell, Craig E %A Chai, Jin Fang %A Whitton, Clare %A van Dam, Rob M %A Liu, Jianjun %A Tai, E Shyong %A Sim, Xueling %A Neuhouser, Marian L %A Kooperberg, Charles %A Tinker, Lesley %A Franceschini, Nora %A Huan, Tianxiao %A Winkler, Thomas W %A Bentley, Amy R %A Gauderman, W James %A Heerkens, Luc %A Tanaka, Toshiko %A van Rooij, Jeroen %A Munroe, Patricia B %A Warren, Helen R %A Voortman, Trudy %A Chen, Honglei %A Rao, D C %A Levy, Daniel %A Ma, Jiantao %X

OBJECTIVE: We examined interactions between genotype and a Dietary Approaches to Stop Hypertension (DASH) diet score in relation to systolic blood pressure (SBP).

METHODS: We analyzed up to 9,420,585 biallelic imputed single nucleotide polymorphisms (SNPs) in up to 127,282 individuals of six population groups (91% of European population) from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (CHARGE; n=35,660) and UK Biobank (n=91,622) and performed European population-specific and cross-population meta-analyses.

RESULTS: We identified three loci in European-specific analyses and an additional four loci in cross-population analyses at P for interaction < 5e-8. We observed a consistent interaction between rs117878928 at 15q25.1 (minor allele frequency = 0.03) and the DASH diet score (P for interaction = 4e-8; P for heterogeneity = 0.35) in European population, where the interaction effect size was 0.42±0.09 mm Hg (P for interaction = 9.4e-7) and 0.20±0.06 mm Hg (P for interaction = 0.001) in CHARGE and the UK Biobank, respectively. The 1 Mb region surrounding rs117878928 was enriched with -expression quantitative trait loci (eQTL) variants (P = 4e-273) and -DNA methylation quantitative trait loci (mQTL) variants (P = 1e-300). While the closest gene for rs117878928 is , the highest narrow sense heritability accounted by SNPs potentially interacting with the DASH diet score in this locus was for gene at 15q25.1.

CONCLUSION: We demonstrated gene-DASH diet score interaction effects on SBP in several loci. Studies with larger diverse populations are needed to validate our findings.

%B medRxiv %8 2023 Nov 11 %G eng %R 10.1101/2023.11.10.23298402 %0 Journal Article %J Cerebrovasc Dis %D 2023 %T Hospital-Acquired Infection at Time of Stroke and Cognitive Decline: The Cardiovascular Health Study. %A Cole, Kyril L %A Boehme, Amelia K %A Thacker, Evan L %A Longstreth, W T %A Brown, Bruce L %A Gale, Shawn D %A Hedges, Dawson W %A Anderson, Jacqueline K %A Elkind, Mitchell S V %X

Introduction Hospital-acquired infections (HAIs) after stroke are associated with additional morbidity and mortality, but whether HAIs increase long-term cognitive decline in stroke patients is unknown. We hypothesized that older adults with incident stroke with HAI experience faster cognitive decline than those having stroke without HAI and those without stroke. Methods We performed a longitudinal analysis in the population-based prospective Cardiovascular Health Study. Medicare-eligible participants aged >65 years with and without incident stroke had cognition assessed annually. HAIs were assessed by hospital discharge codes. Global cognitive function was assessed annually by Modified Mini-Mental State Examination (3MSE) and executive function by Digit Symbol Substitution Test (DSST). We used linear mixed models to estimate the mean decline and 95% confidence intervals (95% CI) for 3MSE and DSST scores by incident stroke and HAI status, adjusted for demographics and vascular risk factors. Results Among 5,443 participants >65 years without previous history of stroke, 393 participants had stroke with HAI (SI), 766 had a stroke only (SO), and 4,284 had no stroke (NS) throughout a maximum 9-year follow-up. For 3MSE, compared with NS participants, SO participants had a similar adjusted mean decline (additional 0.08 points/year, 95%CI -0.15, 0.31), while SI participants had a more rapid decline (additional 0.28 points/year, 95%CI 0.16, 0.40). Adjusted mean decline was 0.20 points/year faster (95%CI -0.05, 0.45) among SI than SO participants. For DSST, compared with NS participants, SO participants had a faster adjusted mean decline (additional 0.17 points/year (95%CI 0.003, 0.33), as did SI participants (additional 0.27 points/year (95%CI 0.19, 0.35). Conclusion Stroke, when accompanied by HAI, leads to a faster long-term decline in cognitive ability than in those without stroke. The clinical and public health implications of the effect of infection on post-stroke cognitive decline warrant further attention.

%B Cerebrovasc Dis %8 2023 Oct 23 %G eng %R 10.1159/000533568 %0 Journal Article %J Commun Biol %D 2023 %T {Identification of circulating proteins associated with general cognitive function among middle-aged and older adults %A Tin, A. %A Fohner, A. E. %A Yang, Q. %A Brody, J. A. %A Davies, G. %A Yao, J. %A Liu, D. %A Caro, I. %A Lindbohm, J. V. %A Duggan, M. R. %A Meirelles, O. %A Harris, S. E. %A Gudmundsdottir, V. %A Taylor, A. M. %A Henry, A. %A Beiser, A. S. %A Shojaie, A. %A Coors, A. %A Fitzpatrick, A. L. %A Langenberg, C. %A Satizabal, C. L. %A Sitlani, C. M. %A Wheeler, E. %A Tucker-Drob, E. M. %A Bressler, J. %A Coresh, J. %A Bis, J. C. %A Candia, J. %A Jennings, L. L. %A Pietzner, M. %A Lathrop, M. %A Lopez, O. L. %A Redmond, P. %A Gerszten, R. E. %A Rich, S. S. %A Heckbert, S. R. %A Austin, T. R. %A Hughes, T. M. %A Tanaka, T. %A Emilsson, V. %A Vasan, R. S. %A Guo, X. %A Zhu, Y. %A Tzourio, C. %A Rotter, J. I. %A Walker, K. A. %A Ferrucci, L. %A ki, M. %A Breteler, M. M. B. %A Cox, S. R. %A Debette, S. %A Mosley, T. H. %A Gudnason, V. G. %A Launer, L. J. %A Psaty, B. M. %A Seshadri, S. %A Fornage, M. %X 2.0E-4). Proteins implicated as causes or consequences of AD susceptibility may provide new insight into the potential relationship between immunity and AD susceptibility as well as potential therapeutic targets. %B Commun Biol %V 6 %P 1117 %8 Nov %G eng %0 Journal Article %J Aging Cell %D 2023 %T Late-life plasma proteins associated with prevalent and incident frailty: A proteomic analysis. %A Liu, Fangyu %A Austin, Thomas R %A Schrack, Jennifer A %A Chen, Jingsha %A Walston, Jeremy %A Mathias, Rasika A %A Grams, Morgan %A Odden, Michelle C %A Newman, Anne %A Psaty, Bruce M %A Ramonfaur, Diego %A Shah, Amil M %A Windham, B Gwen %A Coresh, Josef %A Walker, Keenan A %X

Proteomic approaches have unique advantages in the identification of biological pathways that influence physical frailty, a multifactorial geriatric syndrome predictive of adverse health outcomes in older adults. To date, proteomic studies of frailty are scarce, and few evaluated prefrailty as a separate state or examined predictors of incident frailty. Using plasma proteins measured by 4955 SOMAmers in the Atherosclerosis Risk in Community study, we identified 134 and 179 proteins cross-sectionally associated with prefrailty and frailty, respectively, after Bonferroni correction (p < 1 × 10 ) among 3838 older adults aged ≥65 years, adjusting for demographic and physiologic factors and chronic diseases. Among them, 23 (17%) and 82 (46%) were replicated in the Cardiovascular Health Study using the same models (FDR p < 0.05). Notably, higher odds of prefrailty and frailty were observed with higher levels of growth differentiation factor 15 (GDF15; p  = 1 × 10 , p  = 2 × 10 ), transgelin (TAGLN; p  = 2 × 10 , p  = 6 × 10 ), and insulin-like growth factor-binding protein 2 (IGFBP2; p  = 5 × 10 , p  = 1 × 10 ) and with a lower level of growth hormone receptor (GHR, p  = 3 × 10 , p  = 2 × 10 ). Longitudinally, we identified 4 proteins associated with incident frailty (p < 1 × 10 ). Higher levels of triggering receptor expressed on myeloid cells 1 (TREM1), TAGLN, and heart and adipocyte fatty-acid binding proteins predicted incident frailty. Differentially regulated proteins were enriched in pathways and upstream regulators related to lipid metabolism, angiogenesis, inflammation, and cell senescence. Our findings provide a set of plasma proteins and biological mechanisms that were dysregulated in both the prodromal and the clinical stage of frailty, offering new insights into frailty etiology and targets for intervention.

%B Aging Cell %8 2023 Sep 11 %G eng %R 10.1111/acel.13975 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Longitudinal Patterns of Brain Changes in a Community Sample in Relation to Aging and Cognitive Status. %A Chwa, Won Jong %A Lopez, Oscar L %A Longstreth, W T %A Dai, Weiying %A Raji, Cyrus A %X

BACKGROUND: Aging and Alzheimer's disease (AD) are characterized by widespread cortical and subcortical atrophy. Though atrophy patterns between aging and AD overlap considerably, regional differences between these two conditions may exist. Few studies, however, have investigated these patterns in large community samples.

OBJECTIVE: Elaborate longitudinal changes in brain morphometry in relation to aging and cognitive status in a well-characterized community cohort.

METHODS: Clinical and neuroimaging data were compiled from 72 participants from the Cardiovascular Health Study-Cognition Study, a community cohort of healthy aging and probable AD participants. Two time points were identified for each participant with a mean follow-up time of 5.36 years. MRI post-processing, morphometric measurements, and statistical analyses were performed using FreeSurfer, Version 7.1.1.

RESULTS: Cortical volume was significantly decreased in the bilateral superior frontal, bilateral inferior parietal, and left superior parietal regions, among others. Cortical thickness was significantly reduced in the bilateral superior frontal and left inferior parietal regions, among others. Overall gray and white matter volumes and hippocampal subfields also demonstrated significant reductions. Cortical volume atrophy trajectories between cognitively stable and cognitively declined participants were significantly different in the right postcentral region.

CONCLUSION: Observed volume reductions were consistent with previous studies investigating morphometric brain changes. Patterns of brain atrophy between AD and aging may be different in magnitude but exhibit widespread spatial overlap. These findings help characterize patterns of brain atrophy that may reflect the general population. Larger studies may more definitively establish population norms of aging and AD-related neuroimaging changes.

%B J Alzheimers Dis %8 2023 Jun 20 %G eng %R 10.3233/JAD-230080 %0 Journal Article %J medRxiv %D 2023 %T loss-of-function variants: Compatible with longevity and associated with resistance to Alzheimer's Disease pathology %A Chemparathy, A. %A Guen, Y. L. %A Chen, S. %A Lee, E. G. %A Leong, L. %A Gorzynski, J. %A Xu, G. %A Belloy, M. %A Kasireddy, N. %A Tauber, A. P. %A Williams, K. %A Stewart, I. %A Wingo, T. %A Lah, J. %A Jayadev, S. %A Hales, C. %A Peskind, E. %A Child, D. D. %A Keene, C. D. %A Cong, L. %A Ashley, E. %A Yu, C. E. %A Greicius, M. D. %X 4 or its protein product as a viable therapeutic option. %B medRxiv %8 Jul %G eng %0 Journal Article %J medRxiv %D 2023 %T Machine learning models for blood pressure phenotypes combining multiple polygenic risk scores. %A Hrytsenko, Yana %A Shea, Benjamin %A Elgart, Michael %A Kurniansyah, Nuzulul %A Lyons, Genevieve %A Morrison, Alanna C %A Carson, April P %A Haring, Bernhard %A Mitchel, Braxton D %A Psaty, Bruce M %A Jaeger, Byron C %A Gu, C Charles %A Kooperberg, Charles %A Levy, Daniel %A Lloyd-Jones, Donald %A Choi, Eunhee %A Brody, Jennifer A %A Smith, Jennifer A %A Rotter, Jerome I %A Moll, Matthew %A Fornage, Myriam %A Simon, Noah %A Castaldi, Peter %A Casanova, Ramon %A Chung, Ren-Hua %A Kaplan, Robert %A Loos, Ruth J F %A Kardia, Sharon L R %A Rich, Stephen S %A Redline, Susan %A Kelly, Tanika %A O'Connor, Timothy %A Zhao, Wei %A Kim, Wonji %A Guo, Xiuqing %A Der Ida Chen, Yii %A Sofer, Tamar %X

We construct non-linear machine learning (ML) prediction models for systolic and diastolic blood pressure (SBP, DBP) using demographic and clinical variables and polygenic risk scores (PRSs). We developed a two-model ensemble, consisting of a baseline model, where prediction is based on demographic and clinical variables only, and a genetic model, where we also include PRSs. We evaluate the use of a linear versus a non-linear model at both the baseline and the genetic model levels and assess the improvement in performance when incorporating multiple PRSs. We report the ensemble model's performance as percentage variance explained (PVE) on a held-out test dataset. A non-linear baseline model improved the PVEs from 28.1% to 30.1% (SBP) and 14.3% to 17.4% (DBP) compared with a linear baseline model. Including seven PRSs in the genetic model computed based on the largest available GWAS of SBP/DBP improved the genetic model PVE from 4.8% to 5.1% (SBP) and 4.7% to 5% (DBP) compared to using a single PRS. Adding additional 14 PRSs computed based on two independent GWASs further increased the genetic model PVE to 6.3% (SBP) and 5.7% (DBP). PVE differed across self-reported race/ethnicity groups, with primarily all non-White groups benefitting from the inclusion of additional PRSs.

%B medRxiv %8 2023 Dec 14 %G eng %R 10.1101/2023.12.13.23299909 %0 Journal Article %J Am J Med %D 2023 %T Mortality Following Hip Fracture in Older Adults With and Without Coronary Heart Disease. %A Robbins, John A %A Bůzková, Petra %A Barzilay, Joshua I %A Cauley, Jane A %A Fink, Howard A %A Carbone, Laura D %A Chen, Zhao %A Stein, Phyllis K %A Elam, Rachel %A Sheets, Kerry %A Mukamal, Kenneth J %X

BACKGROUND: Comorbidities like coronary heart disease are common among older people who sustain an osteoporotic hip fracture. However, their impact on short- and long-term mortality post-hip fracture is not well quantified.

METHODS: We examined 4092 and 1173 older adults without and with prevalent coronary heart disease, respectively. Post-hip fracture mortality rates were computed with Poisson models and hazard ratios with Cox regression. For perspective, we compared mortality rates among participants with prevalent coronary heart disease who had either a hip fracture or incident heart failure (but no hip fracture).

RESULTS: Among participants without prevalent coronary heart disease, the mortality rate post-hip fracture was 21.83 per 100 participant years, including 49.27 per 100 participant years in the first 6 months following hip fracture. Among participants with prevalent coronary heart disease, the corresponding mortality rates were 32.52 and 79.44 per 100 participant years, respectively. Participants with prevalent coronary heart disease and incident heart failure (but no hip fracture) had corresponding post-incident heart failure mortality rates per 100 participant years of 25.62 overall and 46.4 in the first 6 months. In all 3 groups, the hazard ratio for mortality was similarly elevated: 5- to 7-fold at 6 months and 1.7- to 2.5-fold beyond 5 years.

CONCLUSION: As a case study in the absolute effects of a comorbidity on post-hip fracture mortality, hip fracture in a person with coronary heart disease carries an exceedingly high mortality rate, even higher than that following incident heart failure in individuals with coronary heart disease.

%B Am J Med %8 2023 Apr 24 %G eng %R 10.1016/j.amjmed.2023.03.036 %0 Journal Article %J Nat Genet %D 2023 %T Mosaic chromosomal alterations in blood across ancestries using whole-genome sequencing. %A Jakubek, Yasminka A %A Zhou, Ying %A Stilp, Adrienne %A Bacon, Jason %A Wong, Justin W %A Ozcan, Zuhal %A Arnett, Donna %A Barnes, Kathleen %A Bis, Joshua C %A Boerwinkle, Eric %A Brody, Jennifer A %A Carson, April P %A Chasman, Daniel I %A Chen, Jiawen %A Cho, Michael %A Conomos, Matthew P %A Cox, Nancy %A Doyle, Margaret F %A Fornage, Myriam %A Guo, Xiuqing %A Kardia, Sharon L R %A Lewis, Joshua P %A Loos, Ruth J F %A Ma, Xiaolong %A Machiela, Mitchell J %A Mack, Taralynn M %A Mathias, Rasika A %A Mitchell, Braxton D %A Mychaleckyj, Josyf C %A North, Kari %A Pankratz, Nathan %A Peyser, Patricia A %A Preuss, Michael H %A Psaty, Bruce %A Raffield, Laura M %A Vasan, Ramachandran S %A Redline, Susan %A Rich, Stephen S %A Rotter, Jerome I %A Silverman, Edwin K %A Smith, Jennifer A %A Smith, Aaron P %A Taub, Margaret %A Taylor, Kent D %A Yun, Jeong %A Li, Yun %A Desai, Pinkal %A Bick, Alexander G %A Reiner, Alexander P %A Scheet, Paul %A Auer, Paul L %K Black People %K Genome, Human %K Genome-Wide Association Study %K Hispanic or Latino %K Humans %K Mosaicism %K Precision Medicine %X

Megabase-scale mosaic chromosomal alterations (mCAs) in blood are prognostic markers for a host of human diseases. Here, to gain a better understanding of mCA rates in genetically diverse populations, we analyzed whole-genome sequencing data from 67,390 individuals from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program. We observed higher sensitivity with whole-genome sequencing data, compared with array-based data, in uncovering mCAs at low mutant cell fractions and found that individuals of European ancestry have the highest rates of autosomal mCAs and the lowest rates of chromosome X mCAs, compared with individuals of African or Hispanic ancestry. Although further studies in diverse populations will be needed to replicate our findings, we report three loci associated with loss of chromosome X, associations between autosomal mCAs and rare variants in DCPS, ADM17, PPP1R16B and TET2 and ancestry-specific variants in ATM and MPL with mCAs in cis.

%B Nat Genet %V 55 %P 1912-1919 %8 2023 Nov %G eng %N 11 %R 10.1038/s41588-023-01553-1 %0 Journal Article %J Nat Genet %D 2023 %T Multi-ancestry genome-wide study identifies effector genes and druggable pathways for coronary artery calcification. %A Kavousi, Maryam %A Bos, Maxime M %A Barnes, Hanna J %A Lino Cardenas, Christian L %A Wong, Doris %A Lu, Haojie %A Hodonsky, Chani J %A Landsmeer, Lennart P L %A Turner, Adam W %A Kho, Minjung %A Hasbani, Natalie R %A de Vries, Paul S %A Bowden, Donald W %A Chopade, Sandesh %A Deelen, Joris %A Benavente, Ernest Diez %A Guo, Xiuqing %A Hofer, Edith %A Hwang, Shih-Jen %A Lutz, Sharon M %A Lyytikäinen, Leo-Pekka %A Slenders, Lotte %A Smith, Albert V %A Stanislawski, Maggie A %A van Setten, Jessica %A Wong, Quenna %A Yanek, Lisa R %A Becker, Diane M %A Beekman, Marian %A Budoff, Matthew J %A Feitosa, Mary F %A Finan, Chris %A Hilliard, Austin T %A Kardia, Sharon L R %A Kovacic, Jason C %A Kral, Brian G %A Langefeld, Carl D %A Launer, Lenore J %A Malik, Shaista %A Hoesein, Firdaus A A Mohamed %A Mokry, Michal %A Schmidt, Reinhold %A Smith, Jennifer A %A Taylor, Kent D %A Terry, James G %A van der Grond, Jeroen %A van Meurs, Joyce %A Vliegenthart, Rozemarijn %A Xu, Jianzhao %A Young, Kendra A %A Zilhão, Nuno R %A Zweiker, Robert %A Assimes, Themistocles L %A Becker, Lewis C %A Bos, Daniel %A Carr, J Jeffrey %A Cupples, L Adrienne %A de Kleijn, Dominique P V %A de Winther, Menno %A den Ruijter, Hester M %A Fornage, Myriam %A Freedman, Barry I %A Gudnason, Vilmundur %A Hingorani, Aroon D %A Hokanson, John E %A Ikram, M Arfan %A Išgum, Ivana %A Jacobs, David R %A Kähönen, Mika %A Lange, Leslie A %A Lehtimäki, Terho %A Pasterkamp, Gerard %A Raitakari, Olli T %A Schmidt, Helena %A Slagboom, P Eline %A Uitterlinden, André G %A Vernooij, Meike W %A Bis, Joshua C %A Franceschini, Nora %A Psaty, Bruce M %A Post, Wendy S %A Rotter, Jerome I %A Björkegren, Johan L M %A O'Donnell, Christopher J %A Bielak, Lawrence F %A Peyser, Patricia A %A Malhotra, Rajeev %A van der Laan, Sander W %A Miller, Clint L %X

Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC.

%B Nat Genet %V 55 %P 1651-1664 %8 2023 Oct %G eng %N 10 %R 10.1038/s41588-023-01518-4 %0 Journal Article %J medRxiv %D 2023 %T Multi-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications. %A Suzuki, Ken %A Hatzikotoulas, Konstantinos %A Southam, Lorraine %A Taylor, Henry J %A Yin, Xianyong %A Lorenz, Kim M %A Mandla, Ravi %A Huerta-Chagoya, Alicia %A Rayner, Nigel W %A Bocher, Ozvan %A Ana Luiza de, S V Arruda %A Sonehara, Kyuto %A Namba, Shinichi %A Lee, Simon S K %A Preuss, Michael H %A Petty, Lauren E %A Schroeder, Philip %A Vanderwerff, Brett %A Kals, Mart %A Bragg, Fiona %A Lin, Kuang %A Guo, Xiuqing %A Zhang, Weihua %A Yao, Jie %A Kim, Young Jin %A Graff, Mariaelisa %A Takeuchi, Fumihiko %A Nano, Jana %A Lamri, Amel %A Nakatochi, Masahiro %A Moon, Sanghoon %A Scott, Robert A %A Cook, James P %A Lee, Jung-Jin %A Pan, Ian %A Taliun, Daniel %A Parra, Esteban J %A Chai, Jin-Fang %A Bielak, Lawrence F %A Tabara, Yasuharu %A Hai, Yang %A Thorleifsson, Gudmar %A Grarup, Niels %A Sofer, Tamar %A Wuttke, Matthias %A Sarnowski, Chloe %A Gieger, Christian %A Nousome, Darryl %A Trompet, Stella %A Kwak, Soo-Heon %A Long, Jirong %A Sun, Meng %A Tong, Lin %A Chen, Wei-Min %A Nongmaithem, Suraj S %A Noordam, Raymond %A Lim, Victor J Y %A Tam, Claudia H T %A Joo, Yoonjung Yoonie %A Chen, Chien-Hsiun %A Raffield, Laura M %A Prins, Bram Peter %A Nicolas, Aude %A Yanek, Lisa R %A Chen, Guanjie %A Brody, Jennifer A %A Kabagambe, Edmond %A An, Ping %A Xiang, Anny H %A Choi, Hyeok Sun %A Cade, Brian E %A Tan, Jingyi %A Alaine Broadaway, K %A Williamson, Alice %A Kamali, Zoha %A Cui, Jinrui %A Adair, Linda S %A Adeyemo, Adebowale %A Aguilar-Salinas, Carlos A %A Ahluwalia, Tarunveer S %A Anand, Sonia S %A Bertoni, Alain %A Bork-Jensen, Jette %A Brandslund, Ivan %A Buchanan, Thomas A %A Burant, Charles F %A Butterworth, Adam S %A Canouil, Mickaël %A Chan, Juliana C N %A Chang, Li-Ching %A Chee, Miao-Li %A Chen, Ji %A Chen, Shyh-Huei %A Chen, Yuan-Tsong %A Chen, Zhengming %A Chuang, Lee-Ming %A Cushman, Mary %A Danesh, John %A Das, Swapan K %A Janaka de Silva, H %A Dedoussis, George %A Dimitrov, Latchezar %A Doumatey, Ayo P %A Du, Shufa %A Duan, Qing %A Eckardt, Kai-Uwe %A Emery, Leslie S %A Evans, Daniel S %A Evans, Michele K %A Fischer, Krista %A Floyd, James S %A Ford, Ian %A Franco, Oscar H %A Frayling, Timothy M %A Freedman, Barry I %A Genter, Pauline %A Gerstein, Hertzel C %A Giedraitis, Vilmantas %A González-Villalpando, Clicerio %A Gonzalez-Villalpando, Maria Elena %A Gordon-Larsen, Penny %A Gross, Myron %A Guare, Lindsay A %A Hackinger, Sophie %A Han, Sohee %A Hattersley, Andrew T %A Herder, Christian %A Horikoshi, Momoko %A Howard, Annie-Green %A Hsueh, Willa %A Huang, Mengna %A Huang, Wei %A Hung, Yi-Jen %A Hwang, Mi Yeong %A Hwu, Chii-Min %A Ichihara, Sahoko %A Ikram, Mohammad Arfan %A Ingelsson, Martin %A Islam, Md Tariqul %A Isono, Masato %A Jang, Hye-Mi %A Jasmine, Farzana %A Jiang, Guozhi %A Jonas, Jost B %A Jørgensen, Torben %A Kandeel, Fouad R %A Kasturiratne, Anuradhani %A Katsuya, Tomohiro %A Kaur, Varinderpal %A Kawaguchi, Takahisa %A Keaton, Jacob M %A Kho, Abel N %A Khor, Chiea-Chuen %A Kibriya, Muhammad G %A Kim, Duk-Hwan %A Kronenberg, Florian %A Kuusisto, Johanna %A Läll, Kristi %A Lange, Leslie A %A Lee, Kyung Min %A Lee, Myung-Shik %A Lee, Nanette R %A Leong, Aaron %A Li, Liming %A Li, Yun %A Li-Gao, Ruifang %A Lithgart, Symen %A Lindgren, Cecilia M %A Linneberg, Allan %A Liu, Ching-Ti %A Liu, Jianjun %A Locke, Adam E %A Louie, Tin %A Luan, Jian'an %A Luk, Andrea O %A Luo, Xi %A Lv, Jun %A Lynch, Julie A %A Lyssenko, Valeriya %A Maeda, Shiro %A Mamakou, Vasiliki %A Mansuri, Sohail Rafik %A Matsuda, Koichi %A Meitinger, Thomas %A Metspalu, Andres %A Mo, Huan %A Morris, Andrew D %A Nadler, Jerry L %A Nalls, Michael A %A Nayak, Uma %A Ntalla, Ioanna %A Okada, Yukinori %A Orozco, Lorena %A Patel, Sanjay R %A Patil, Snehal %A Pei, Pei %A Pereira, Mark A %A Peters, Annette %A Pirie, Fraser J %A Polikowsky, Hannah G %A Porneala, Bianca %A Prasad, Gauri %A Rasmussen-Torvik, Laura J %A Reiner, Alexander P %A Roden, Michael %A Rohde, Rebecca %A Roll, Katheryn %A Sabanayagam, Charumathi %A Sandow, Kevin %A Sankareswaran, Alagu %A Sattar, Naveed %A Schönherr, Sebastian %A Shahriar, Mohammad %A Shen, Botong %A Shi, Jinxiu %A Shin, Dong Mun %A Shojima, Nobuhiro %A Smith, Jennifer A %A So, Wing Yee %A Stančáková, Alena %A Steinthorsdottir, Valgerdur %A Stilp, Adrienne M %A Strauch, Konstantin %A Taylor, Kent D %A Thorand, Barbara %A Thorsteinsdottir, Unnur %A Tomlinson, Brian %A Tran, Tam C %A Tsai, Fuu-Jen %A Tuomilehto, Jaakko %A Tusié-Luna, Teresa %A Udler, Miriam S %A Valladares-Salgado, Adan %A van Dam, Rob M %A van Klinken, Jan B %A Varma, Rohit %A Wacher-Rodarte, Niels %A Wheeler, Eleanor %A Wickremasinghe, Ananda R %A van Dijk, Ko Willems %A Witte, Daniel R %A Yajnik, Chittaranjan S %A Yamamoto, Ken %A Yamamoto, Kenichi %A Yoon, Kyungheon %A Yu, Canqing %A Yuan, Jian-Min %A Yusuf, Salim %A Zawistowski, Matthew %A Zhang, Liang %A Zheng, Wei %A Project, Biobank Japan %A BioBank, Penn Medicine %A Center, Regeneron Genetics %A Consortium, eMERGE %A Raffel, Leslie J %A Igase, Michiya %A Ipp, Eli %A Redline, Susan %A Cho, Yoon Shin %A Lind, Lars %A Province, Michael A %A Fornage, Myriam %A Hanis, Craig L %A Ingelsson, Erik %A Zonderman, Alan B %A Psaty, Bruce M %A Wang, Ya-Xing %A Rotimi, Charles N %A Becker, Diane M %A Matsuda, Fumihiko %A Liu, Yongmei %A Yokota, Mitsuhiro %A Kardia, Sharon L R %A Peyser, Patricia A %A Pankow, James S %A Engert, James C %A Bonnefond, Amélie %A Froguel, Philippe %A Wilson, James G %A Sheu, Wayne H H %A Wu, Jer-Yuarn %A Geoffrey Hayes, M %A Ma, Ronald C W %A Wong, Tien-Yin %A Mook-Kanamori, Dennis O %A Tuomi, Tiinamaija %A Chandak, Giriraj R %A Collins, Francis S %A Bharadwaj, Dwaipayan %A Paré, Guillaume %A Sale, Michèle M %A Ahsan, Habibul %A Motala, Ayesha A %A Shu, Xiao-Ou %A Park, Kyong-Soo %A Jukema, J Wouter %A Cruz, Miguel %A Chen, Yii-Der Ida %A Rich, Stephen S %A McKean-Cowdin, Roberta %A Grallert, Harald %A Cheng, Ching-Yu %A Ghanbari, Mohsen %A Tai, E-Shyong %A Dupuis, Josée %A Kato, Norihiro %A Laakso, Markku %A Köttgen, Anna %A Koh, Woon-Puay %A Bowden, Donald W %A Palmer, Colin N A %A Kooner, Jaspal S %A Kooperberg, Charles %A Liu, Simin %A North, Kari E %A Saleheen, Danish %A Hansen, Torben %A Pedersen, Oluf %A Wareham, Nicholas J %A Lee, Juyoung %A Kim, Bong-Jo %A Millwood, Iona Y %A Walters, Robin G %A Stefansson, Kari %A Goodarzi, Mark O %A Mohlke, Karen L %A Langenberg, Claudia %A Haiman, Christopher A %A Loos, Ruth J F %A Florez, Jose C %A Rader, Daniel J %A Ritchie, Marylyn D %A Zöllner, Sebastian %A Mägi, Reedik %A Denny, Joshua C %A Yamauchi, Toshimasa %A Kadowaki, Takashi %A Chambers, John C %A Ng, Maggie C Y %A Sim, Xueling %A Below, Jennifer E %A Tsao, Philip S %A Chang, Kyong-Mi %A McCarthy, Mark I %A Meigs, James B %A Mahajan, Anubha %A Spracklen, Cassandra N %A Mercader, Josep M %A Boehnke, Michael %A Rotter, Jerome I %A Vujkovic, Marijana %A Voight, Benjamin F %A Morris, Andrew P %A Zeggini, Eleftheria %X

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes. To characterise the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study (GWAS) data from 2,535,601 individuals (39.7% non-European ancestry), including 428,452 T2D cases. We identify 1,289 independent association signals at genome-wide significance (P<5×10 ) that map to 611 loci, of which 145 loci are previously unreported. We define eight non-overlapping clusters of T2D signals characterised by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial, and enteroendocrine cells. We build cluster-specific partitioned genetic risk scores (GRS) in an additional 137,559 individuals of diverse ancestry, including 10,159 T2D cases, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned GRS are more strongly associated with coronary artery disease and end-stage diabetic nephropathy than an overall T2D GRS across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings demonstrate the value of integrating multi-ancestry GWAS with single-cell epigenomics to disentangle the aetiological heterogeneity driving the development and progression of T2D, which may offer a route to optimise global access to genetically-informed diabetes care.

%B medRxiv %8 2023 Mar 31 %G eng %R 10.1101/2023.03.31.23287839 %0 Journal Article %J Nat Genet %D 2023 %T Multi-ancestry transcriptome-wide association analyses yield insights into tobacco use biology and drug repurposing. %A Chen, Fang %A Wang, Xingyan %A Jang, Seon-Kyeong %A Quach, Bryan C %A Weissenkampen, J Dylan %A Khunsriraksakul, Chachrit %A Yang, Lina %A Sauteraud, Renan %A Albert, Christine M %A Allred, Nicholette D D %A Arnett, Donna K %A Ashley-Koch, Allison E %A Barnes, Kathleen C %A Barr, R Graham %A Becker, Diane M %A Bielak, Lawrence F %A Bis, Joshua C %A Blangero, John %A Boorgula, Meher Preethi %A Chasman, Daniel I %A Chavan, Sameer %A Chen, Yii-der I %A Chuang, Lee-Ming %A Correa, Adolfo %A Curran, Joanne E %A David, Sean P %A Fuentes, Lisa de Las %A Deka, Ranjan %A Duggirala, Ravindranath %A Faul, Jessica D %A Garrett, Melanie E %A Gharib, Sina A %A Guo, Xiuqing %A Hall, Michael E %A Hawley, Nicola L %A He, Jiang %A Hobbs, Brian D %A Hokanson, John E %A Hsiung, Chao A %A Hwang, Shih-Jen %A Hyde, Thomas M %A Irvin, Marguerite R %A Jaffe, Andrew E %A Johnson, Eric O %A Kaplan, Robert %A Kardia, Sharon L R %A Kaufman, Joel D %A Kelly, Tanika N %A Kleinman, Joel E %A Kooperberg, Charles %A Lee, I-Te %A Levy, Daniel %A Lutz, Sharon M %A Manichaikul, Ani W %A Martin, Lisa W %A Marx, Olivia %A McGarvey, Stephen T %A Minster, Ryan L %A Moll, Matthew %A Moussa, Karine A %A Naseri, Take %A North, Kari E %A Oelsner, Elizabeth C %A Peralta, Juan M %A Peyser, Patricia A %A Psaty, Bruce M %A Rafaels, Nicholas %A Raffield, Laura M %A Reupena, Muagututi'a Sefuiva %A Rich, Stephen S %A Rotter, Jerome I %A Schwartz, David A %A Shadyab, Aladdin H %A Sheu, Wayne H-H %A Sims, Mario %A Smith, Jennifer A %A Sun, Xiao %A Taylor, Kent D %A Telen, Marilyn J %A Watson, Harold %A Weeks, Daniel E %A Weir, David R %A Yanek, Lisa R %A Young, Kendra A %A Young, Kristin L %A Zhao, Wei %A Hancock, Dana B %A Jiang, Bibo %A Vrieze, Scott %A Liu, Dajiang J %K Biology %K Drug Repositioning %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Polymorphism, Single Nucleotide %K Tobacco Use %K Transcriptome %X

Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction.

%B Nat Genet %V 55 %P 291-300 %8 2023 Feb %G eng %N 2 %R 10.1038/s41588-022-01282-x %0 Journal Article %J J Card Fail %D 2023 %T Multiple Prior Live Births are Associated with Cardiac Remodeling and Heart Failure Risk in Women. %A Sarma, Amy A %A Paniagua, Samantha M %A Lau, Emily S %A Wang, Dongyu %A Liu, Elizabeth E %A Larson, Martin G %A Hamburg, Naomi M %A Mitchell, Gary F %A Kizer, Jorge %A Psaty, Bruce M %A Allen, Norrina B %A Lely, A Titia %A Gansevoort, Ronald T %A Rosenberg, Emily %A Mukamal, Kenneth %A Benjamin, Emelia J %A Vasan, Ramachandran S %A Cheng, Susan %A Levy, Daniel %A de Boer, Rudolf A %A Gottdiener, John S %A Shah, Sanjiv J %A Ho, Jennifer E %X

INTRODUCTION: Greater parity has been associated with cardiovascular disease risk, though effects on cardiac remodeling and heart failure risk remain unclear.

METHODS: We examined the association of number of live births and echocardiographic measures of cardiac structure and function in participants of the Framingham Heart Study (FHS) using multivariable linear regression. We next examined the association of parity with incident heart failure with preserved (HFpEF) or reduced (HFrEF) ejection fraction using a Fine-Gray subdistribution hazards model in a pooled analysis of n=12,635 participants of FHS, the Cardiovascular Health Study, the Multi-Ethnic Study of Atherosclerosis, and Prevention of Renal and Vascular Endstage Disease. Secondary analyses included major CVD, MI, and stroke.

RESULTS: Among n=3931 FHS participants (mean age 48 ± 13 years), higher number of live births was associated with worse LV fractional shortening (multivariable β -1.11 (0.31), p= 0.0005 in ≥ 5 live births vs nulliparous women) and worse cardiac mechanics including global circumferential strain and longitudinal and radial dyssynchrony (p< 0.01 for all comparing ≥ 5 live births vs nulliparity). When examining HF subtypes, women with ≥5 live births were at higher risk of developing future HFrEF compared with nulliparous women (HR 1.93, 95% CI 1.19-3.12, p=0.008); by contrast, a lower risk of HFpEF was observed (HR 0.58, 95% CI 0.37-0.91, p=0.02).

CONCLUSIONS: Greater number of live births are associated with worse cardiac structure and function. While there was no association with overall HF, a higher number of live births was associated with greater risk for incident HFrEF.

%B J Card Fail %8 2023 Jan 10 %G eng %R 10.1016/j.cardfail.2022.12.014 %0 Journal Article %J Health Place %D 2023 %T Neighborhood greenspace and cognition: The cardiovascular health study. %A Godina, Sara L %A Rosso, Andrea L %A Hirsch, Jana A %A Besser, Lilah M %A Lovasi, Gina S %A Donovan, Geoffrey H %A Garg, Parveen K %A Platt, Jonathan M %A Fitzpatrick, Annette L %A Lopez, Oscar L %A Carlson, Michelle C %A Michael, Yvonne L %X

OBJECTIVES: We examined whether greenspace measures (overall percent greenspace and forest, and number of greenspace types) were associated with clinically adjudicated dementia status.

METHODS: In a sample of non-demented older adults (n = 2141, average age = 75.3 years) from the Cardiovascular Health and Cognition Study, Cox proportional hazard and logistic regression analyses were used to estimate associations of baseline greenspace with risks of incident dementia and MCI, respectively, while adjusting for demographics, co-morbidities, and other neighborhood factors. We derived quartiles of percent greenness (greenspace), forest (percent tree canopy cover), and tertiles of greenspace diversity (number of greenspace types) for 5-km radial buffers around participant's residences at study entry (1989-1990) from the 1992 National Land Cover Dataset. Dementia status and mild cognitive impairment (MCI) over 10 years was clinically adjudicated.

RESULTS: We observed no significant association between overall percent greenspace and risk of mild cognitive impairment or dementia and mostly null results for forest and greenspace diversity. Forest greenspace was associated with lower odds of MCI (OR quartile 4 versus 1: 0.54, 95% CI: 0.29-0.98) and greenspace diversity was associated with lower hazard of incident dementia (HR tertile 2 versus 1: 0.70, 95% CI = 0.50-0.99).

DISCUSSION: We found divergent results for different types of greenspace and mild cognitive impairment or dementia. Improved greenspace type and diversity measurement could better characterize the association between greenspace and cognition.

%B Health Place %V 79 %P 102960 %8 2023 Jan 03 %G eng %R 10.1016/j.healthplace.2022.102960 %0 Journal Article %J Alzheimers Dement (Amst) %D 2023 %T Neighborhood greenspace and neighborhood income associated with white matter grade worsening: Cardiovascular Health Study. %A Besser, Lilah M %A Lovasi, Gina S %A Zambrano, Joyce Jimenez %A Camacho, Simone %A Dhanekula, Devi %A Michael, Yvonne L %A Garg, Parveen %A Hirsch, Jana A %A Siscovick, David %A Hurvitz, Philip M %A Biggs, Mary L %A Galvin, James E %A Bartz, Traci M %A Longstreth, W T %X

INTRODUCTION: We examined whether a combined measure of neighborhood greenspace and neighborhood median income was associated with white matter hyperintensity (WMH) and ventricle size changes.

METHODS: The sample included 1260 cognitively normal ≥ 65-year-olds with two magnetic resonance images (MRI; ≈ 5 years apart). WMH and ventricular size were graded from 0 (least) to 9 (most) abnormal (worsening = increase of ≥1 grade from initial to follow-up MRI scans). The four-category neighborhood greenspace-income measure was based on median neighborhood greenspace and income values at initial MRI. Multivariable logistic regression tested associations between neighborhood greenspace-income and MRI measures (worsening vs. not).

RESULTS: White matter grade worsening was more likely for those in lower greenspace-lower income neighborhoods than higher greenspace-higher income neighborhoods (odds ratio = 1.73; 95% confidence interval = 1.19-2.51).

DISCUSSION: The combination of lower neighborhood income and lower greenspace may be a risk factor for worsening white matter grade on MRI. However, findings need to be replicated in more diverse cohorts.

HIGHLIGHTS: Population-based cohort of older adults (≥ 65 years) with greenspace and MRI dataCombined measure of neighborhood greenspace and neighborhood income at initial MRIMRI outcomes included white matter hyperintensities (WMH) and ventricular sizeLongitudinal change in MRI outcomes measured approximately 5 years apartWorsening WMH over time more likely for lower greenspace-lower income neighborhoods.

%B Alzheimers Dement (Amst) %V 15 %P e12484 %8 2023 Oct-Dec %G eng %N 4 %R 10.1002/dad2.12484 %0 Journal Article %J Atherosclerosis %D 2023 %T Non-esterified fatty acids and risk of peripheral artery disease in older adults: The cardiovascular health study. %A Ahiawodzi, Peter %A Solaru, Khendi White %A Chaves, Paulo H M %A Ix, Joachim H %A Kizer, Jorge R %A Tracy, Russell P %A Newman, Anne %A Siscovick, David %A Djoussé, Luc %A Mukamal, Kenneth J %X

BACKGROUND AND AIMS: Non-esterified fatty acids have been implicated in the pathogenesis of diabetes and cardiovascular disease. No longitudinal study has assessed their effects on peripheral artery disease (PAD). We determined the relationships between NEFAs and incident clinical PAD and abnormal ankle-brachial index (ABI) in a population-based cohort of older persons.

METHODS: We evaluated 4575 community living participants aged >65 years who underwent measurement of circulating NEFAs in fasting specimens and ABI in 1992-1993. Participants were assessed annually for clinical PAD until 2015 and underwent repeat ABI in 1998-1999. We used Cox proportional hazards regression to model the associations between NEFAs and risk of clinical PAD and logistic regression to model the associations of NEFAs with incident abnormal ABI.

RESULTS: Mean age was 74.8 years, 59% were female, and 17% were Black. NEFAs were associated with higher risk of clinical PAD in unadjusted and adjusted models. The adjusted hazard ratios for incident clinical PAD were 1.51 (95%CI = 1.06-2.13, p = 0.02) across extreme tertiles, and 1.14 (95%CI = 0.99-1.31, p = 0.08) per standard deviation higher NEFA. The corresponding odds ratios for abnormal ABI were 0.95 (95%CI = 0.69-1.32, p = 0.76) across extreme tertiles, and 1.03 (95%CI = 0.89-1.20, p = 0.68) per standard deviation higher NEFA. Relationships appeared similar irrespective of sex, race, or pre-existing cardiovascular disease, but were stronger later than earlier in follow-up.

CONCLUSIONS: Higher serum levels of NEFAs are significantly associated with increased likelihood of clinical PAD over long-term follow-up but not with 6-year decline in ABI. NEFAs may offer a potential target for intervention against clinical PAD.

%B Atherosclerosis %8 2023 Jan 29 %G eng %R 10.1016/j.atherosclerosis.2023.01.020 %0 Journal Article %J J Clin Endocrinol Metab %D 2023 %T Plasma Levels of Branched Chain Amino Acids, Incident Hip Fractures and Bone Mineral Density of the Hip and Spine. %A Carbone, Laura %A Bůzková, Petra %A Fink, Howard A %A Robbins, John A %A Barzilay, Joshua I %A Elam, Rachel E %A Isales, Carlos %A Connelly, Margery A %A Mukamal, Kenneth J %X

OBJECTIVE: Branched chain amino acids (BCAA) are building blocks for protein, an essential component of bone. However, the association of plasma levels of BCAA with fractures in populations outside of Hong Kong or with hip fractures in particular is not known. The purpose of these analyses was to determine the relationship of BCAA including valine, leucine and isoleucine and total BCAA (standard deviation of the sum of Z-scores for each BCAA) with incident hip fractures and bone mineral density (BMD) of the hip and lumbar spine in older African American and Caucasian men and women in the Cardiovascular Health Study (CHS).

DESIGN: Longitudinal analyses of association of plasma levels of BCAA with incident hip fractures and cross-sectional BMD of the hip and lumbar spine from the CHS.

SETTING: Community.

PARTICIPANTS: 1850 men (38% of cohort) and women; mean age 73.

MAIN OUTCOME MEASURES: Incident hip fractures and cross-sectional BMD of the total hip, femoral neck and lumbar spine.

RESULTS: In fully adjusted models, over 12 years of follow-up, we observed no significant association between incident hip fracture and plasma values of valine, leucine, isoleucine or total BCAA per 1 standard deviation higher of each BCAA. Plasma values of leucine but not valine, isoleucine or total BCAA, were positively and significantly associated with BMD of the total hip (p = 0.03) and femoral neck (p = 0.02), but not the lumbar spine (p = 0.07).

CONCLUSIONS: Plasma levels of the BCAA leucine may be associated with higher BMD in older men and women. However, given lack of a significant association with hip fracture risk, further information is needed to determine whether BCAAs would be novel targets for osteoporosis therapies.

%B J Clin Endocrinol Metab %8 2023 May 18 %G eng %R 10.1210/clinem/dgad275 %0 Journal Article %J Nat Genet %D 2023 %T Powerful, scalable and resource-efficient meta-analysis of rare variant associations in large whole genome sequencing studies. %A Li, Xihao %A Quick, Corbin %A Zhou, Hufeng %A Gaynor, Sheila M %A Liu, Yaowu %A Chen, Han %A Selvaraj, Margaret Sunitha %A Sun, Ryan %A Dey, Rounak %A Arnett, Donna K %A Bielak, Lawrence F %A Bis, Joshua C %A Blangero, John %A Boerwinkle, Eric %A Bowden, Donald W %A Brody, Jennifer A %A Cade, Brian E %A Correa, Adolfo %A Cupples, L Adrienne %A Curran, Joanne E %A de Vries, Paul S %A Duggirala, Ravindranath %A Freedman, Barry I %A Göring, Harald H H %A Guo, Xiuqing %A Haessler, Jeffrey %A Kalyani, Rita R %A Kooperberg, Charles %A Kral, Brian G %A Lange, Leslie A %A Manichaikul, Ani %A Martin, Lisa W %A McGarvey, Stephen T %A Mitchell, Braxton D %A Montasser, May E %A Morrison, Alanna C %A Naseri, Take %A O'Connell, Jeffrey R %A Palmer, Nicholette D %A Peyser, Patricia A %A Psaty, Bruce M %A Raffield, Laura M %A Redline, Susan %A Reiner, Alexander P %A Reupena, Muagututi'a Sefuiva %A Rice, Kenneth M %A Rich, Stephen S %A Sitlani, Colleen M %A Smith, Jennifer A %A Taylor, Kent D %A Vasan, Ramachandran S %A Willer, Cristen J %A Wilson, James G %A Yanek, Lisa R %A Zhao, Wei %A Rotter, Jerome I %A Natarajan, Pradeep %A Peloso, Gina M %A Li, Zilin %A Lin, Xihong %K Exome Sequencing %K Genome-Wide Association Study %K Lipids %K Phenotype %K Whole Genome Sequencing %X

Meta-analysis of whole genome sequencing/whole exome sequencing (WGS/WES) studies provides an attractive solution to the problem of collecting large sample sizes for discovering rare variants associated with complex phenotypes. Existing rare variant meta-analysis approaches are not scalable to biobank-scale WGS data. Here we present MetaSTAAR, a powerful and resource-efficient rare variant meta-analysis framework for large-scale WGS/WES studies. MetaSTAAR accounts for relatedness and population structure, can analyze both quantitative and dichotomous traits and boosts the power of rare variant tests by incorporating multiple variant functional annotations. Through meta-analysis of four lipid traits in 30,138 ancestrally diverse samples from 14 studies of the Trans Omics for Precision Medicine (TOPMed) Program, we show that MetaSTAAR performs rare variant meta-analysis at scale and produces results comparable to using pooled data. Additionally, we identified several conditionally significant rare variant associations with lipid traits. We further demonstrate that MetaSTAAR is scalable to biobank-scale cohorts through meta-analysis of TOPMed WGS data and UK Biobank WES data of ~200,000 samples.

%B Nat Genet %V 55 %P 154-164 %8 2023 Jan %G eng %N 1 %R 10.1038/s41588-022-01225-6 %0 Journal Article %J medRxiv %D 2023 %T Rare variants in long non-coding RNAs are associated with blood lipid levels in the TOPMed Whole Genome Sequencing Study. %A Wang, Yuxuan %A Selvaraj, Margaret Sunitha %A Li, Xihao %A Li, Zilin %A Holdcraft, Jacob A %A Arnett, Donna K %A Bis, Joshua C %A Blangero, John %A Boerwinkle, Eric %A Bowden, Donald W %A Cade, Brian E %A Carlson, Jenna C %A Carson, April P %A Chen, Yii-Der Ida %A Curran, Joanne E %A de Vries, Paul S %A Dutcher, Susan K %A Ellinor, Patrick T %A Floyd, James S %A Fornage, Myriam %A Freedman, Barry I %A Gabriel, Stacey %A Germer, Soren %A Gibbs, Richard A %A Guo, Xiuqing %A He, Jiang %A Heard-Costa, Nancy %A Hildalgo, Bertha %A Hou, Lifang %A Irvin, Marguerite R %A Joehanes, Roby %A Kaplan, Robert C %A Kardia, Sharon Lr %A Kelly, Tanika N %A Kim, Ryan %A Kooperberg, Charles %A Kral, Brian G %A Levy, Daniel %A Li, Changwei %A Liu, Chunyu %A Lloyd-Jone, Don %A Loos, Ruth Jf %A Mahaney, Michael C %A Martin, Lisa W %A Mathias, Rasika A %A Minster, Ryan L %A Mitchell, Braxton D %A Montasser, May E %A Morrison, Alanna C %A Murabito, Joanne M %A Naseri, Take %A O'Connell, Jeffrey R %A Palmer, Nicholette D %A Preuss, Michael H %A Psaty, Bruce M %A Raffield, Laura M %A Rao, Dabeeru C %A Redline, Susan %A Reiner, Alexander P %A Rich, Stephen S %A Ruepena, Muagututi'a Sefuiva %A Sheu, Wayne H-H %A Smith, Jennifer A %A Smith, Albert %A Tiwari, Hemant K %A Tsai, Michael Y %A Viaud-Martinez, Karine A %A Wang, Zhe %A Yanek, Lisa R %A Zhao, Wei %A Rotter, Jerome I %A Lin, Xihong %A Natarajan, Pradeep %A Peloso, Gina M %X

Long non-coding RNAs (lncRNAs) are known to perform important regulatory functions. Large-scale whole genome sequencing (WGS) studies and new statistical methods for variant set tests now provide an opportunity to assess the associations between rare variants in lncRNA genes and complex traits across the genome. In this study, we used high-coverage WGS from 66,329 participants of diverse ancestries with blood lipid levels (LDL-C, HDL-C, TC, and TG) in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program to investigate the role of lncRNAs in lipid variability. We aggregated rare variants for 165,375 lncRNA genes based on their genomic locations and conducted rare variant aggregate association tests using the STAAR (variant-Set Test for Association using Annotation infoRmation) framework. We performed STAAR conditional analysis adjusting for common variants in known lipid GWAS loci and rare coding variants in nearby protein coding genes. Our analyses revealed 83 rare lncRNA variant sets significantly associated with blood lipid levels, all of which were located in known lipid GWAS loci (in a ±500 kb window of a Global Lipids Genetics Consortium index variant). Notably, 61 out of 83 signals (73%) were conditionally independent of common regulatory variations and rare protein coding variations at the same loci. We replicated 34 out of 61 (56%) conditionally independent associations using the independent UK Biobank WGS data. Our results expand the genetic architecture of blood lipids to rare variants in lncRNA, implicating new therapeutic opportunities.

%B medRxiv %8 2023 Jun 29 %G eng %R 10.1101/2023.06.28.23291966 %0 Journal Article %J JAMA Netw Open %D 2023 %T Sleep Architecture, Obstructive Sleep Apnea, and Cognitive Function in Adults. %A Pase, Matthew P %A Harrison, Stephanie %A Misialek, Jeffrey R %A Kline, Christopher E %A Cavuoto, Marina %A Baril, Andree-Ann %A Yiallourou, Stephanie %A Bisson, Alycia %A Himali, Dibya %A Leng, Yue %A Yang, Qiong %A Seshadri, Sudha %A Beiser, Alexa %A Gottesman, Rebecca F %A Redline, Susan %A Lopez, Oscar %A Lutsey, Pamela L %A Yaffe, Kristine %A Stone, Katie L %A Purcell, Shaun M %A Himali, Jayandra J %X

IMPORTANCE: Good sleep is essential for health, yet associations between sleep and dementia risk remain incompletely understood. The Sleep and Dementia Consortium was established to study associations between polysomnography (PSG)-derived sleep and the risk of dementia and related cognitive and brain magnetic resonance imaging endophenotypes.

OBJECTIVE: To investigate association of sleep architecture and obstructive sleep apnea (OSA) with cognitive function in the Sleep and Dementia Consortium.

DESIGN, SETTING, AND PARTICIPANTS: The Sleep and Dementia Consortium curated data from 5 population-based cohorts across the US with methodologically consistent, overnight, home-based type II PSG and neuropsychological assessments over 5 years of follow-up: the Atherosclerosis Risk in Communities study, Cardiovascular Health Study, Framingham Heart Study (FHS), Osteoporotic Fractures in Men Study, and Study of Osteoporotic Fractures. Sleep metrics were harmonized centrally and then distributed to participating cohorts for cohort-specific analysis using linear regression; study-level estimates were pooled in random effects meta-analyses. Results were adjusted for demographic variables, the time between PSG and neuropsychological assessment (0-5 years), body mass index, antidepressant use, and sedative use. There were 5946 participants included in the pooled analyses without stroke or dementia. Data were analyzed from March 2020 to June 2023.

EXPOSURES: Measures of sleep architecture and OSA derived from in-home PSG.

MAIN OUTCOMES AND MEASURES: The main outcomes were global cognitive composite z scores derived from principal component analysis, with cognitive domains investigated as secondary outcomes. Higher scores indicated better performance.

RESULTS: Across cohorts, 5946 adults (1875 females [31.5%]; mean age range, 58-89 years) were included. The median (IQR) wake after sleep onset time ranged from 44 (27-73) to 101 (66-147) minutes, and the prevalence of moderate to severe OSA ranged from 16.9% to 28.9%. Across cohorts, higher sleep maintenance efficiency (pooled β per 1% increase, 0.08; 95% CI, 0.03 to 0.14; P < .01) and lower wake after sleep onset (pooled β per 1-min increase, -0.07; 95% CI, -0.13 to -0.01 per 1-min increase; P = .02) were associated with better global cognition. Mild to severe OSA (apnea-hypopnea index [AHI] ≥5) was associated with poorer global cognition (pooled β, -0.06; 95% CI, -0.11 to -0.01; P = .01) vs AHI less than 5; comparable results were found for moderate to severe OSA (pooled β, -0.06; 95% CI, -0.11 to -0.01; P = .02) vs AHI less than 5. Differences in sleep stages were not associated with cognition.

CONCLUSIONS AND RELEVANCE: This study found that better sleep consolidation and the absence of OSA were associated with better global cognition over 5 years of follow-up. These findings suggest that the role of interventions to improve sleep for maintaining cognitive function requires investigation.

%B JAMA Netw Open %V 6 %P e2325152 %8 2023 Jul 03 %G eng %N 7 %R 10.1001/jamanetworkopen.2023.25152 %0 Journal Article %J bioRxiv %D 2023 %T A statistical framework for powerful multi-trait rare variant analysis in large-scale whole-genome sequencing studies. %A Li, Xihao %A Chen, Han %A Selvaraj, Margaret Sunitha %A Van Buren, Eric %A Zhou, Hufeng %A Wang, Yuxuan %A Sun, Ryan %A McCaw, Zachary R %A Yu, Zhi %A Arnett, Donna K %A Bis, Joshua C %A Blangero, John %A Boerwinkle, Eric %A Bowden, Donald W %A Brody, Jennifer A %A Cade, Brian E %A Carson, April P %A Carlson, Jenna C %A Chami, Nathalie %A Chen, Yii-Der Ida %A Curran, Joanne E %A de Vries, Paul S %A Fornage, Myriam %A Franceschini, Nora %A Freedman, Barry I %A Gu, Charles %A Heard-Costa, Nancy L %A He, Jiang %A Hou, Lifang %A Hung, Yi-Jen %A Irvin, Marguerite R %A Kaplan, Robert C %A Kardia, Sharon L R %A Kelly, Tanika %A Konigsberg, Iain %A Kooperberg, Charles %A Kral, Brian G %A Li, Changwei %A Loos, Ruth J F %A Mahaney, Michael C %A Martin, Lisa W %A Mathias, Rasika A %A Minster, Ryan L %A Mitchell, Braxton D %A Montasser, May E %A Morrison, Alanna C %A Palmer, Nicholette D %A Peyser, Patricia A %A Psaty, Bruce M %A Raffield, Laura M %A Redline, Susan %A Reiner, Alexander P %A Rich, Stephen S %A Sitlani, Colleen M %A Smith, Jennifer A %A Taylor, Kent D %A Tiwari, Hemant %A Vasan, Ramachandran S %A Wang, Zhe %A Yanek, Lisa R %A Yu, Bing %A Rice, Kenneth M %A Rotter, Jerome I %A Peloso, Gina M %A Natarajan, Pradeep %A Li, Zilin %A Liu, Zhonghua %A Lin, Xihong %X

Large-scale whole-genome sequencing (WGS) studies have improved our understanding of the contributions of coding and noncoding rare variants to complex human traits. Leveraging association effect sizes across multiple traits in WGS rare variant association analysis can improve statistical power over single-trait analysis, and also detect pleiotropic genes and regions. Existing multi-trait methods have limited ability to perform rare variant analysis of large-scale WGS data. We propose MultiSTAAR, a statistical framework and computationally-scalable analytical pipeline for functionally-informed multi-trait rare variant analysis in large-scale WGS studies. MultiSTAAR accounts for relatedness, population structure and correlation among phenotypes by jointly analyzing multiple traits, and further empowers rare variant association analysis by incorporating multiple functional annotations. We applied MultiSTAAR to jointly analyze three lipid traits (low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides) in 61,861 multi-ethnic samples from the Trans-Omics for Precision Medicine (TOPMed) Program. We discovered new associations with lipid traits missed by single-trait analysis, including rare variants within an enhancer of and an intergenic region on chromosome 1.

%B bioRxiv %8 2023 Nov 02 %G eng %R 10.1101/2023.10.30.564764 %0 Journal Article %J Res Sq %D 2023 %T {Structural Variation Detection and Association Analysis of Whole-Genome-Sequence Data from 16,905 Alzheimer's Diseases Sequencing Project Subjects %A Lee, W. P. %A Wang, H. %A Dombroski, B. %A Cheng, P. L. %A Tucci, A. %A Si, Y. Q. %A Farrell, J. %A Tzeng, J. Y. %A Leung, Y. Y. %A Malamon, J. %A Wang, L. S. %A Vardarajan, B. %A Farrer, L. %A Schellenberg, G. %X . We also identified 16 SVs associated with AD and 13 SVs linked to AD-related pathological/cognitive endophenotypes. This study highlights the pivotal role of SVs in shaping our understanding of AD genetics. %B Res Sq %8 Oct %G eng %0 Journal Article %J medRxiv %D 2023 %T {Structural Variation Detection and Association Analysis of Whole-Genome-Sequence Data from 16,905 Alzheimer's Diseases Sequencing Project Subjects %A Wang, H. %A Dombroski, B. A. %A Cheng, P. L. %A Tucci, A. %A Si, Y. Q. %A Farrell, J. J. %A Tzeng, J. Y. %A Leung, Y. Y. %A Malamon, J. S. %A Wang, L. S. %A Vardarajan, B. N. %A Farrer, L. A. %A Schellenberg, G. D. %A Lee, W. P. %X . We also identified 16 SVs associated with AD and 13 SVs associated with AD-related pathological/cognitive endophenotypes. Our findings demonstrate the broad impact of SVs on AD genetics.\ Alzheimer's disease, Structural variation, Copy number variation. %B medRxiv %8 Sep %G eng %0 Journal Article %J medRxiv %D 2023 %T Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People with Type 2 Diabetes Mellitus. %A Kwak, Soo Heon %A Hernandez-Cancela, Ryan B %A DiCorpo, Daniel A %A Condon, David E %A Merino, Jordi %A Wu, Peitao %A Brody, Jennifer A %A Yao, Jie %A Guo, Xiuqing %A Ahmadizar, Fariba %A Meyer, Mariah %A Sincan, Murat %A Mercader, Josep M %A Lee, Sujin %A Haessler, Jeffrey %A Vy, Ha My T %A Lin, Zhaotong %A Armstrong, Nicole D %A Gu, Shaopeng %A Tsao, Noah L %A Lange, Leslie A %A Wang, Ningyuan %A Wiggins, Kerri L %A Trompet, Stella %A Liu, Simin %A Loos, Ruth J F %A Judy, Renae %A Schroeder, Philip H %A Hasbani, Natalie R %A Bos, Maxime M %A Morrison, Alanna C %A Jackson, Rebecca D %A Reiner, Alexander P %A Manson, JoAnn E %A Chaudhary, Ninad S %A Carmichael, Lynn K %A Chen, Yii-Der Ida %A Taylor, Kent D %A Ghanbari, Mohsen %A van Meurs, Joyce %A Pitsillides, Achilleas N %A Psaty, Bruce M %A Noordam, Raymond %A Do, Ron %A Park, Kyong Soo %A Jukema, J Wouter %A Kavousi, Maryam %A Correa, Adolfo %A Rich, Stephen S %A Damrauer, Scott M %A Hajek, Catherine %A Cho, Nam H %A Irvin, Marguerite R %A Pankow, James S %A Nadkarni, Girish N %A Sladek, Robert %A Goodarzi, Mark O %A Florez, Jose C %A Chasman, Daniel I %A Heckbert, Susan R %A Kooperberg, Charles %A Dupuis, Josée %A Malhotra, Rajeev %A de Vries, Paul S %A Liu, Ching-Ti %A Rotter, Jerome I %A Meigs, James B %X

BACKGROUND: Type 2 diabetes mellitus (T2D) confers a two- to three-fold increased risk of cardiovascular disease (CVD). However, the mechanisms underlying increased CVD risk among people with T2D are only partially understood. We hypothesized that a genetic association study among people with T2D at risk for developing incident cardiovascular complications could provide insights into molecular genetic aspects underlying CVD.

METHODS: From 16 studies of the Cohorts for Heart & Aging Research in Genomic Epidemiology (CHARGE) Consortium, we conducted a multi-ancestry time-to-event genome-wide association study (GWAS) for incident CVD among people with T2D using Cox proportional hazards models. Incident CVD was defined based on a composite of coronary artery disease (CAD), stroke, and cardiovascular death that occurred at least one year after the diagnosis of T2D. Cohort-level estimated effect sizes were combined using inverse variance weighted fixed effects meta-analysis. We also tested 204 known CAD variants for association with incident CVD among patients with T2D.

RESULTS: A total of 49,230 participants with T2D were included in the analyses (31,118 European ancestries and 18,112 non-European ancestries) which consisted of 8,956 incident CVD cases over a range of mean follow-up duration between 3.2 and 33.7 years (event rate 18.2%). We identified three novel, distinct genetic loci for incident CVD among individuals with T2D that reached the threshold for genome-wide significance ( <5.0×10 ): rs147138607 (intergenic variant between and ) with a hazard ratio (HR) 1.23, 95% confidence interval (CI) 1.15 - 1.32, =3.6×10 , rs11444867 (intergenic variant near ) with HR 1.89, 95% CI 1.52 - 2.35, =9.9×10 , and rs335407 (intergenic variant between and ) HR 1.25, 95% CI 1.16 - 1.35, =1.5×10 . Among 204 known CAD loci, 32 were associated with incident CVD in people with T2D with <0.05, and 5 were significant after Bonferroni correction ( <0.00024, 0.05/204). A polygenic score of these 204 variants was significantly associated with incident CVD with HR 1.14 (95% CI 1.12 - 1.16) per 1 standard deviation increase ( =1.0×10 ).

CONCLUSIONS: The data point to novel and known genomic regions associated with incident CVD among individuals with T2D.

CLINICAL PERSPECTIVE: We conducted a large-scale multi-ancestry time-to-event GWAS to identify genetic variants associated with CVD among people with T2D. Three variants were significantly associated with incident CVD in people with T2D: rs147138607 (intergenic variant between and ), rs11444867 (intergenic variant near ), and rs335407 (intergenic variant between and ). A polygenic score composed of known CAD variants identified in the general population was significantly associated with the risk of CVD in people with T2D. There are genetic risk factors specific to T2D that could at least partially explain the excess risk of CVD in people with T2D.In addition, we show that people with T2D have enrichment of known CAD association signals which could also explain the excess risk of CVD.

%B medRxiv %8 2023 Jul 28 %G eng %R 10.1101/2023.07.25.23293180 %0 Journal Article %J Circ Genom Precis Med %D 2023 %T Type 2 Diabetes Modifies the Association of CAD Genomic Risk Variants With Subclinical Atherosclerosis. %A Hasbani, Natalie R %A Westerman, Kenneth E %A Heon Kwak, Soo %A Chen, Han %A Li, Xihao %A DiCorpo, Daniel %A Wessel, Jennifer %A Bis, Joshua C %A Sarnowski, Chloe %A Wu, Peitao %A Bielak, Lawrence F %A Guo, Xiuqing %A Heard-Costa, Nancy %A Kinney, Gregory %A Mahaney, Michael C %A Montasser, May E %A Palmer, Nicholette D %A Raffield, Laura M %A Terry, James G %A Yanek, Lisa R %A Bon, Jessica %A Bowden, Donald W %A Brody, Jennifer A %A Duggirala, Ravindranath %A Jacobs, David R %A Kalyani, Rita R %A Lange, Leslie A %A Mitchell, Braxton D %A Smith, Jennifer A %A Taylor, Kent D %A Carson, April %A Curran, Joanne E %A Fornage, Myriam %A Freedman, Barry I %A Gabriel, Stacey %A Gibbs, Richard A %A Gupta, Namrata %A Kardia, Sharon L R %A Kral, Brian G %A Momin, Zeineen %A Newman, Anne B %A Post, Wendy S %A Viaud-Martinez, Karine A %A Young, Kendra A %A Becker, Lewis C %A Bertoni, Alain %A Blangero, John %A Carr, John J %A Pratte, Katherine %A Psaty, Bruce M %A Rich, Stephen S %A Wu, Joseph C %A Malhotra, Rajeev %A Peyser, Patricia A %A Morrison, Alanna C %A Vasan, Ramachandran S %A Lin, Xihong %A Rotter, Jerome I %A Meigs, James B %A Manning, Alisa K %A de Vries, Paul S %X

BACKGROUND: Individuals with type 2 diabetes (T2D) have an increased risk of coronary artery disease (CAD), but questions remain about the underlying pathology. Identifying which CAD loci are modified by T2D in the development of subclinical atherosclerosis (coronary artery calcification [CAC], carotid intima-media thickness, or carotid plaque) may improve our understanding of the mechanisms leading to the increased CAD in T2D.

METHODS: We compared the common and rare variant associations of known CAD loci from the literature on CAC, carotid intima-media thickness, and carotid plaque in up to 29 670 participants, including up to 24 157 normoglycemic controls and 5513 T2D cases leveraging whole-genome sequencing data from the Trans-Omics for Precision Medicine program. We included first-order T2D interaction terms in each model to determine whether CAD loci were modified by T2D. The genetic main and interaction effects were assessed using a joint test to determine whether a CAD variant, or gene-based rare variant set, was associated with the respective subclinical atherosclerosis measures and then further determined whether these loci had a significant interaction test.

RESULTS: Using a Bonferroni-corrected significance threshold of <1.6×10, we identified 3 genes (, , and ) associated with CAC and 2 genes ( and ) associated with carotid intima-media thickness and carotid plaque, respectively, through gene-based rare variant set analysis. Both and also had significantly different associations for CAC in T2D cases versus controls. No significant interaction tests were identified through the candidate single-variant analysis.

CONCLUSIONS: These results highlight T2D as an important modifier of rare variant associations in CAD loci with CAC.

%B Circ Genom Precis Med %P e004176 %8 2023 Nov 28 %G eng %R 10.1161/CIRCGEN.123.004176 %0 Journal Article %J J Prev Alzheimers Dis %D 2023 %T Validation of the CogDrisk Instrument as Predictive of Dementia in Four General Community-Dwelling Populations. %A Kootar, S %A Huque, M H %A Eramudugolla, R %A Rizzuto, D %A Carlson, M C %A Odden, M C %A Lopez, O L %A Qiu, C %A Fratiglioni, L %A Han, S D %A Bennett, D A %A Peters, R %A Anstey, K J %K Aging %K Alzheimer Disease %K Cohort Studies %K Dementia %K Humans %K Independent Living %X

BACKGROUND: Lack of external validation of dementia risk tools is a major limitation for generalizability and translatability of prediction scores in clinical practice and research.

OBJECTIVES: We aimed to validate a new dementia prediction risk tool called CogDrisk and a version, CogDrisk-AD for predicting Alzheimer's disease (AD) using cohort studies.

DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: Four cohort studies were identified that included majority of the dementia risk factors from the CogDrisk tool. Participants who were free of dementia at baseline were included. The predictors were component variables in the CogDrisk tool that include self-reported demographics, medical risk factors and lifestyle habits. Risk scores for Any Dementia and AD were computed and Area Under the Curve (AUC) was assessed. To examine modifiable risk factors for dementia, the CogDrisk tool was tested by excluding age and sex estimates from the model.

RESULTS: The performance of the tool varied between studies. The overall AUC and 95% CI for predicting dementia was 0.77 (0.57, 0.97) for the Swedish National study on Aging and Care in Kungsholmen, 0.76 (0.70, 0.83) for the Health and Retirement Study - Aging, Demographics and Memory Study, 0.70 (0.67,0.72) for the Cardiovascular Health Study Cognition Study, and 0.66 (0.62,0.70) for the Rush Memory and Aging Project.

CONCLUSIONS: The CogDrisk and CogDrisk-AD performed well in the four studies. Overall, this tool can be used to assess individualized risk factors of dementia and AD in various population settings.

%B J Prev Alzheimers Dis %V 10 %P 478-487 %8 2023 %G eng %N 3 %R 10.14283/jpad.2023.38 %0 Journal Article %J medRxiv %D 2023 %T Whole genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles. %A Huffman, Jennifer E %A Nicolas, Jayna %A Hahn, Julie %A Heath, Adam S %A Raffield, Laura M %A Yanek, Lisa R %A Brody, Jennifer A %A Thibord, Florian %A Almasy, Laura %A Bartz, Traci M %A Bielak, Lawrence F %A Bowler, Russell P %A Carrasquilla, Germán D %A Chasman, Daniel I %A Chen, Ming-Huei %A Emmert, David B %A Ghanbari, Mohsen %A Haessle, Jeffery %A Hottenga, Jouke-Jan %A Kleber, Marcus E %A Le, Ngoc-Quynh %A Lee, Jiwon %A Lewis, Joshua P %A Li-Gao, Ruifang %A Luan, Jian'an %A Malmberg, Anni %A Mangino, Massimo %A Marioni, Riccardo E %A Martinez-Perez, Angel %A Pankratz, Nathan %A Polasek, Ozren %A Richmond, Anne %A Rodriguez, Benjamin At %A Rotter, Jerome I %A Steri, Maristella %A Suchon, Pierre %A Trompet, Stella %A Weiss, Stefan %A Zare, Marjan %A Auer, Paul %A Cho, Michael H %A Christofidou, Paraskevi %A Davies, Gail %A de Geus, Eco %A Deleuze, Jean-Francois %A Delgado, Graciela E %A Ekunwe, Lynette %A Faraday, Nauder %A Gögele, Martin %A Greinacher, Andreas %A He, Gao %A Howard, Tom %A Joshi, Peter K %A Kilpeläinen, Tuomas O %A Lahti, Jari %A Linneberg, Allan %A Naitza, Silvia %A Noordam, Raymond %A Paüls-Vergés, Ferran %A Rich, Stephen S %A Rosendaal, Frits R %A Rudan, Igor %A Ryan, Kathleen A %A Souto, Juan Carlos %A van Rooij, Frank Ja %A Wang, Heming %A Zhao, Wei %A Becker, Lewis C %A Beswick, Andrew %A Brown, Michael R %A Cade, Brian E %A Campbell, Harry %A Cho, Kelly %A Crapo, James D %A Curran, Joanne E %A de Maat, Moniek Pm %A Doyle, Margaret %A Elliott, Paul %A Floyd, James S %A Fuchsberger, Christian %A Grarup, Niels %A Guo, Xiuqing %A Harris, Sarah E %A Hou, Lifang %A Kolcic, Ivana %A Kooperberg, Charles %A Menni, Cristina %A Nauck, Matthias %A O'Connell, Jeffrey R %A Orrù, Valeria %A Psaty, Bruce M %A Räikkönen, Katri %A Smith, Jennifer A %A Soria, José Manuel %A Stott, David J %A van Hylckama Vlieg, Astrid %A Watkins, Hugh %A Willemsen, Gonneke %A Wilson, Peter %A Ben-Shlomo, Yoav %A Blangero, John %A Boomsma, Dorret %A Cox, Simon R %A Dehghan, Abbas %A Eriksson, Johan G %A Fiorillo, Edoardo %A Fornage, Myriam %A Hansen, Torben %A Hayward, Caroline %A Ikram, M Arfan %A Jukema, J Wouter %A Kardia, Sharon Lr %A Lange, Leslie A %A März, Winfried %A Mathias, Rasika A %A Mitchell, Braxton D %A Mook-Kanamori, Dennis O %A Morange, Pierre-Emmanuel %A Pedersen, Oluf %A Pramstaller, Peter P %A Redline, Susan %A Reiner, Alexander %A Ridker, Paul M %A Silverman, Edwin K %A Spector, Tim D %A Völker, Uwe %A Wareham, Nick %A Wilson, James F %A Yao, Jie %A Trégouët, David-Alexandre %A Johnson, Andrew D %A Wolberg, Alisa S %A de Vries, Paul S %A Sabater-Lleal, Maria %A Morrison, Alanna C %A Smith, Nicholas L %X

UNLABELLED: Genetic studies have identified numerous regions associated with plasma fibrinogen levels in Europeans, yet missing heritability and limited inclusion of non-Europeans necessitates further studies with improved power and sensitivity. Compared with array-based genotyping, whole genome sequencing (WGS) data provides better coverage of the genome and better representation of non-European variants. To better understand the genetic landscape regulating plasma fibrinogen levels, we meta-analyzed WGS data from the NHLBI's Trans-Omics for Precision Medicine (TOPMed) program (n=32,572), with array-based genotype data from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium (n=131,340) imputed to the TOPMed or Haplotype Reference Consortium panel. We identified 18 loci that have not been identified in prior genetic studies of fibrinogen. Of these, four are driven by common variants of small effect with reported MAF at least 10% higher in African populations. Three ( , and signals contain predicted deleterious missense variants. Two loci, and , each harbor two conditionally distinct, non-coding variants. The gene region encoding the protein chain subunits ( ), contains 7 distinct signals, including one novel signal driven by rs28577061, a variant common (MAF=0.180) in African reference panels but extremely rare (MAF=0.008) in Europeans. Through phenome-wide association studies in the VA Million Veteran Program, we found associations between fibrinogen polygenic risk scores and thrombotic and inflammatory disease phenotypes, including an association with gout. Our findings demonstrate the utility of WGS to augment genetic discovery in diverse populations and offer new insights for putative mechanisms of fibrinogen regulation.

KEY POINTS: Largest and most diverse genetic study of plasma fibrinogen identifies 54 regions (18 novel), housing 69 conditionally distinct variants (20 novel).Sufficient power achieved to identify signal driven by African population variant.Links to (1) liver enzyme, blood cell and lipid genetic signals, (2) liver regulatory elements, and (3) thrombotic and inflammatory disease.

%B medRxiv %8 2023 Jun 12 %G eng %R 10.1101/2023.06.07.23291095 %0 Journal Article %J Circ Genom Precis Med %D 2023 %T Whole Genome Analysis of Venous Thromboembolism: the Trans-Omics for Precision Medicine Program. %A Seyerle, Amanda A %A Laurie, Cecelia A %A Coombes, Brandon J %A Jain, Deepti %A Conomos, Matthew P %A Brody, Jennifer %A Chen, Ming-Huei %A Gogarten, Stephanie M %A Beutel, Kathleen M %A Gupta, Namrata %A Heckbert, Susan R %A Jackson, Rebecca D %A Johnson, Andrew D %A Ko, Darae %A Manson, JoAnn E %A McKnight, Barbara %A Metcalf, Ginger A %A Morrison, Alanna C %A Reiner, Alexander P %A Sofer, Tamar %A Tang, Weihong %A Wiggins, Kerri L %A Boerwinkle, Eric %A Andrade, Mariza de %A Gabriel, Stacey B %A Gibbs, Richard A %A Laurie, Cathy C %A Psaty, Bruce M %A Vasan, Ramachandran S %A Rice, Ken %A Kooperberg, Charles %A Pankow, James S %A Smith, Nicholas L %A Pankratz, Nathan %X

Background Risk for venous thromboembolism has a strong genetic component. Whole genome sequencingfrom the Trans-Omics for Precision Medicine program allowed us to look for new associations, particularly rare variants missed by standard genome-wide association studies. Methods The 3793 cases and 7834 controls (11.6% of cases were Black, Hispanic/Latino, or Asian American) were analyzed using a single variant approach and an aggregate gene-based approach using our primary filter (included only loss-of-function and missense variants predicted to be deleterious) and our secondary filter (included all missense variants). Results Single variant analyses identified associations at 5 known loci. Aggregate gene-based analyses identified only (odds ratio, 6.2 for carriers of rare variants; =7.4×10) when using our primary filter. Employing our secondary variant filter led to a smaller effect size at (odds ratio, 3.8; =1.6×10), while excluding variants found only in rare isoforms led to a larger one (odds ratio, 7.5). Different filtering strategies improved the signal for 2 other known genes: became significant (minimum =1.8×10 with the secondary filter), while did not (minimum =4.4×10 with minor allele frequency <0.0005). Results were largely the same when restricting the analyses to include only unprovoked cases; however, one novel gene, , became significant (=4.4×10 using all missense variants with minor allele frequency <0.0005). Conclusions Here, we have demonstrated the importance of using multiple variant filtering strategies, as we detected additional genes when filtering variants based on their predicted deleteriousness, frequency, and presence on the most expressed isoforms. Our primary analyses did not identify new candidate loci; thus larger follow-up studies are needed to replicate the novel locus and to identify additional rare variation associated with venous thromboembolism.

%B Circ Genom Precis Med %P e003532 %8 2023 Mar 24 %G eng %R 10.1161/CIRCGEN.121.003532 %0 Journal Article %J Front Genet %D 2023 %T Whole genome sequence analysis of apparent treatment resistant hypertension status in participants from the Trans-Omics for Precision Medicine program. %A Armstrong, Nicole D %A Srinivasasainagendra, Vinodh %A Ammous, Farah %A Assimes, Themistocles L %A Beitelshees, Amber L %A Brody, Jennifer %A Cade, Brian E %A Ida Chen, Yii-Der %A Chen, Han %A de Vries, Paul S %A Floyd, James S %A Franceschini, Nora %A Guo, Xiuqing %A Hellwege, Jacklyn N %A House, John S %A Hwu, Chii-Min %A Kardia, Sharon L R %A Lange, Ethan M %A Lange, Leslie A %A McDonough, Caitrin W %A Montasser, May E %A O'Connell, Jeffrey R %A Shuey, Megan M %A Sun, Xiao %A Tanner, Rikki M %A Wang, Zhe %A Zhao, Wei %A Carson, April P %A Edwards, Todd L %A Kelly, Tanika N %A Kenny, Eimear E %A Kooperberg, Charles %A Loos, Ruth J F %A Morrison, Alanna C %A Motsinger-Reif, Alison %A Psaty, Bruce M %A Rao, Dabeeru C %A Redline, Susan %A Rich, Stephen S %A Rotter, Jerome I %A Smith, Jennifer A %A Smith, Albert V %A Irvin, Marguerite R %A Arnett, Donna K %X

Apparent treatment-resistant hypertension (aTRH) is characterized by the use of four or more antihypertensive (AHT) classes to achieve blood pressure (BP) control. In the current study, we conducted single-variant and gene-based analyses of aTRH among individuals from 12 Trans-Omics for Precision Medicine cohorts with whole-genome sequencing data. Cases were defined as individuals treated for hypertension (HTN) taking three different AHT classes, with average systolic BP ≥ 140 or diastolic BP ≥ 90 mmHg, or four or more medications regardless of BP ( = 1,705). A normotensive control group was defined as individuals with BP < 140/90 mmHg ( = 22,079), not on AHT medication. A second control group comprised individuals who were treatment responsive on one AHT medication with BP < 140/ 90 mmHg ( = 5,424). Logistic regression with kinship adjustment using the Scalable and Accurate Implementation of Generalized mixed models (SAIGE) was performed, adjusting for age, sex, and genetic ancestry. We assessed variants using SKAT-O in rare-variant analyses. Single-variant and gene-based tests were conducted in a pooled multi-ethnicity stratum, as well as self-reported ethnic/racial strata (European and African American). One variant in the known HTN locus, , was a top finding in the multi-ethnic analysis ( = 8.23E-07) for the normotensive control group [rs12476527, odds ratio (95% confidence interval) = 0.80 (0.74-0.88)]. This variant was replicated in the Vanderbilt University Medical Center's DNA repository data. Aggregate gene-based signals included the genes and . Additional work validating these loci in larger, more diverse populations, is warranted to determine whether these regions influence the pathobiology of aTRH.

%B Front Genet %V 14 %P 1278215 %8 2023 %G eng %R 10.3389/fgene.2023.1278215 %0 Journal Article %J medRxiv %D 2023 %T WHOLE GENOME SEQUENCING ANALYSIS OF BODY MASS INDEX IDENTIFIES NOVEL AFRICAN ANCESTRY-SPECIFIC RISK ALLELE. %A Zhang, Xinruo %A Brody, Jennifer A %A Graff, Mariaelisa %A Highland, Heather M %A Chami, Nathalie %A Xu, Hanfei %A Wang, Zhe %A Ferrier, Kendra %A Chittoor, Geetha %A Josyula, Navya S %A Li, Xihao %A Li, Zilin %A Allison, Matthew A %A Becker, Diane M %A Bielak, Lawrence F %A Bis, Joshua C %A Boorgula, Meher Preethi %A Bowden, Donald W %A Broome, Jai G %A Buth, Erin J %A Carlson, Christopher S %A Chang, Kyong-Mi %A Chavan, Sameer %A Chiu, Yen-Feng %A Chuang, Lee-Ming %A Conomos, Matthew P %A DeMeo, Dawn L %A Du, Margaret %A Duggirala, Ravindranath %A Eng, Celeste %A Fohner, Alison E %A Freedman, Barry I %A Garrett, Melanie E %A Guo, Xiuqing %A Haiman, Chris %A Heavner, Benjamin D %A Hidalgo, Bertha %A Hixson, James E %A Ho, Yuk-Lam %A Hobbs, Brian D %A Hu, Donglei %A Hui, Qin %A Hwu, Chii-Min %A Jackson, Rebecca D %A Jain, Deepti %A Kalyani, Rita R %A Kardia, Sharon L R %A Kelly, Tanika N %A Lange, Ethan M %A LeNoir, Michael %A Li, Changwei %A Marchand, Loic Le %A McDonald, Merry-Lynn N %A McHugh, Caitlin P %A Morrison, Alanna C %A Naseri, Take %A O'Connell, Jeffrey %A O'Donnell, Christopher J %A Palmer, Nicholette D %A Pankow, James S %A Perry, James A %A Peters, Ulrike %A Preuss, Michael H %A Rao, D C %A Regan, Elizabeth A %A Reupena, Sefuiva M %A Roden, Dan M %A Rodriguez-Santana, Jose %A Sitlani, Colleen M %A Smith, Jennifer A %A Tiwari, Hemant K %A Vasan, Ramachandran S %A Wang, Zeyuan %A Weeks, Daniel E %A Wessel, Jennifer %A Wiggins, Kerri L %A Wilkens, Lynne R %A Wilson, Peter W F %A Yanek, Lisa R %A Yoneda, Zachary T %A Zhao, Wei %A Zöllner, Sebastian %A Arnett, Donna K %A Ashley-Koch, Allison E %A Barnes, Kathleen C %A Blangero, John %A Boerwinkle, Eric %A Burchard, Esteban G %A Carson, April P %A Chasman, Daniel I %A Chen, Yii-Der Ida %A Curran, Joanne E %A Fornage, Myriam %A Gordeuk, Victor R %A He, Jiang %A Heckbert, Susan R %A Hou, Lifang %A Irvin, Marguerite R %A Kooperberg, Charles %A Minster, Ryan L %A Mitchell, Braxton D %A Nouraie, Mehdi %A Psaty, Bruce M %A Raffield, Laura M %A Reiner, Alexander P %A Rich, Stephen S %A Rotter, Jerome I %A Shoemaker, M Benjamin %A Smith, Nicholas L %A Taylor, Kent D %A Telen, Marilyn J %A Weiss, Scott T %A Zhang, Yingze %A Costa, Nancy Heard- %A Sun, Yan V %A Lin, Xihong %A Cupples, L Adrienne %A Lange, Leslie A %A Liu, Ching-Ti %A Loos, Ruth J F %A North, Kari E %A Justice, Anne E %X

Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals ( < 5 × 10 ). Notably, we identified and replicated a novel low frequency single nucleotide polymorphism (SNP) in that was common in individuals of African descent. Using a diverse study population, we further identified two novel secondary signals in known BMI loci and pinpointed two likely causal variants in the and loci. Our work demonstrates the benefits of combining WGS and diverse cohorts in expanding current catalog of variants and genes confer risk for obesity, bringing us one step closer to personalized medicine.

%B medRxiv %8 2023 Aug 22 %G eng %R 10.1101/2023.08.21.23293271 %0 Journal Article %J bioRxiv %D 2023 %T Whole Genome Sequencing Based Analysis of Inflammation Biomarkers in the Trans-Omics for Precision Medicine (TOPMed) Consortium. %A Jiang, Min-Zhi %A Gaynor, Sheila M %A Li, Xihao %A Van Buren, Eric %A Stilp, Adrienne %A Buth, Erin %A Wang, Fei Fei %A Manansala, Regina %A Gogarten, Stephanie M %A Li, Zilin %A Polfus, Linda M %A Salimi, Shabnam %A Bis, Joshua C %A Pankratz, Nathan %A Yanek, Lisa R %A Durda, Peter %A Tracy, Russell P %A Rich, Stephen S %A Rotter, Jerome I %A Mitchell, Braxton D %A Lewis, Joshua P %A Psaty, Bruce M %A Pratte, Katherine A %A Silverman, Edwin K %A Kaplan, Robert C %A Avery, Christy %A North, Kari %A Mathias, Rasika A %A Faraday, Nauder %A Lin, Honghuang %A Wang, Biqi %A Carson, April P %A Norwood, Arnita F %A Gibbs, Richard A %A Kooperberg, Charles %A Lundin, Jessica %A Peters, Ulrike %A Dupuis, Josée %A Hou, Lifang %A Fornage, Myriam %A Benjamin, Emelia J %A Reiner, Alexander P %A Bowler, Russell P %A Lin, Xihong %A Auer, Paul L %A Raffield, Laura M %X

Inflammation biomarkers can provide valuable insight into the role of inflammatory processes in many diseases and conditions. Sequencing based analyses of such biomarkers can also serve as an exemplar of the genetic architecture of quantitative traits. To evaluate the biological insight, which can be provided by a multi-ancestry, whole-genome based association study, we performed a comprehensive analysis of 21 inflammation biomarkers from up to 38,465 individuals with whole-genome sequencing from the Trans-Omics for Precision Medicine (TOPMed) program. We identified 22 distinct single-variant associations across 6 traits - E-selectin, intercellular adhesion molecule 1, interleukin-6, lipoprotein-associated phospholipase A2 activity and mass, and P-selectin - that remained significant after conditioning on previously identified associations for these inflammatory biomarkers. We further expanded upon known biomarker associations by pairing the single-variant analysis with a rare variant set-based analysis that further identified 19 significant rare variant set-based associations with 5 traits. These signals were distinct from both significant single variant association signals within TOPMed and genetic signals observed in prior studies, demonstrating the complementary value of performing both single and rare variant analyses when analyzing quantitative traits. We also confirm several previously reported signals from semi-quantitative proteomics platforms. Many of these signals demonstrate the extensive allelic heterogeneity and ancestry-differentiated variant-trait associations common for inflammation biomarkers, a characteristic we hypothesize will be increasingly observed with well-powered, large-scale analyses of complex traits.

%B bioRxiv %8 2023 Sep 12 %G eng %R 10.1101/2023.09.10.555215 %0 Journal Article %J Nat Commun %D 2023 %T Whole-Genome Sequencing Analysis of Human Metabolome in Multi-Ethnic Populations. %A Feofanova, Elena V %A Brown, Michael R %A Alkis, Taryn %A Manuel, Astrid M %A Li, Xihao %A Tahir, Usman A %A Li, Zilin %A Mendez, Kevin M %A Kelly, Rachel S %A Qi, Qibin %A Chen, Han %A Larson, Martin G %A Lemaitre, Rozenn N %A Morrison, Alanna C %A Grieser, Charles %A Wong, Kari E %A Gersztern, Robert E %A Zhao, Zhongming %A Lasky-Su, Jessica %A Yu, Bing %K Ethnicity %K Genome-Wide Association Study %K Humans %K Metabolome %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %X

Circulating metabolite levels may reflect the state of the human organism in health and disease, however, the genetic architecture of metabolites is not fully understood. We have performed a whole-genome sequencing association analysis of both common and rare variants in up to 11,840 multi-ethnic participants from five studies with up to 1666 circulating metabolites. We have discovered 1985 novel variant-metabolite associations, and validated 761 locus-metabolite associations reported previously. Seventy-nine novel variant-metabolite associations have been replicated, including three genetic loci located on the X chromosome that have demonstrated its involvement in metabolic regulation. Gene-based analysis have provided further support for seven metabolite-replicated loci pairs and their biologically plausible genes. Among those novel replicated variant-metabolite pairs, follow-up analyses have revealed that 26 metabolites have colocalized with 21 tissues, seven metabolite-disease outcome associations have been putatively causal, and 7 metabolites might be regulated by plasma protein levels. Our results have depicted the genetic contribution to circulating metabolite levels, providing additional insights into understanding human disease.

%B Nat Commun %V 14 %P 3111 %8 2023 May 30 %G eng %N 1 %R 10.1038/s41467-023-38800-2 %0 Journal Article %J medRxiv %D 2024 %T Association analysis of mitochondrial DNA heteroplasmic variants: methods and application. %A Sun, Xianbang %A Bulekova, Katia %A Yang, Jian %A Lai, Meng %A Pitsillides, Achilleas N %A Liu, Xue %A Zhang, Yuankai %A Guo, Xiuqing %A Yong, Qian %A Raffield, Laura M %A Rotter, Jerome I %A Rich, Stephen S %A Abecasis, Goncalo %A Carson, April P %A Vasan, Ramachandran S %A Bis, Joshua C %A Psaty, Bruce M %A Boerwinkle, Eric %A Fitzpatrick, Annette L %A Satizabal, Claudia L %A Arking, Dan E %A Ding, Jun %A Levy, Daniel %A Liu, Chunyu %X

We rigorously assessed a comprehensive association testing framework for heteroplasmy, employing both simulated and real-world data. This framework employed a variant allele fraction (VAF) threshold and harnessed multiple gene-based tests for robust identification and association testing of heteroplasmy. Our simulation studies demonstrated that gene-based tests maintained an appropriate type I error rate at α=0.001. Notably, when 5% or more heteroplasmic variants within a target region were linked to an outcome, burden-extension tests (including the adaptive burden test, variable threshold burden test, and z-score weighting burden test) outperformed the sequence kernel association test (SKAT) and the original burden test. Applying this framework, we conducted association analyses on whole-blood derived heteroplasmy in 17,507 individuals of African and European ancestries (31% of African Ancestry, mean age of 62, with 58% women) with whole genome sequencing data. We performed both cohort- and ancestry-specific association analyses, followed by meta-analysis on bothpooled samples and within each ancestry group. Our results suggest that mtDNA-Enco ded genes/regions are likely to exhibit varying rates in somatic aging, with the notably strong associations observed between heteroplasmy in the and genes ( <0.001) and advance aging by the Original Burden test. In contrast, SKAT identified significant associations ( <0.001) between diabetes and the aggregated effects of heteroplasmy in several protein-coding genes. Further research is warranted to validate these findings. In summary, our proposed statistical framework represents a valuable tool for facilitating association testing of heteroplasmy with disease traits in large human populations.

%B medRxiv %8 2024 Jan 13 %G eng %R 10.1101/2024.01.12.24301233 %0 Journal Article %J J Clin Endocrinol Metab %D 2024 %T Association of thyroid dysfunction in individuals ≥ 65 years of age with subclinical cardiac abnormalities. %A Barasch, Eddy %A Gottdiener, John %A Bůzková, Petra %A Cappola, Anne %A Shah, Sanjiv %A DeFilippi, Christopher %A Gardin, Julius %A Kizer, Jorge R %X

CONTEXT: The relationship between thyroid dysfunction and measures of myocardial disease in older individuals remains to be defined.

OBJECTIVE: To evaluate the impact of thyroid dysfunction on structure and function of the left-heart chambers and blood markers of cardiac disease.

DESIGN: Cross-sectional analysis.

SETTING: The Cardiovascular Health Study, a community-based cohort of older individuals recruited from four urban areas in the United States.

PATIENTS: Of 3163 participants studied, 2477 were euthyroid, 465 had subclinical hypothyroidism (SCH), 47 overt hypothyroidism (OH), 45 endogenous (endo) subclinical hyperthyroidism (endo-SCT), and 129 had exogenous (exo) SCT due to thyroid hormone supplementation.

INTERVENTIONS: Clinical evaluation, blood sampling and biomarker measurement, 2-dimensional and speckle-tracking echocardiography.

MAIN OUTCOME MEASURE(S): Left heart myocardial deformation, circulating biomarkers of diastolic overload (NT-proBNP), fibrosis (sST2, gal-3), and cardiomyocyte injury (hs-cTnT).

RESULTS: SCH was associated with higher NT-proBNP (beta = 0.17, p = 0.004), whereas OH was associated with higher hs-cTnT (beta = 0.29, p = 0.005). There were also suggestive associations of SCH with higher sST2, as well as endo-SCT with higher gal-3 and lower (worse) left atrial reservoir strain. Left ventricular longitudinal strain and end-diastolic strain rate did not differ significantly from euthyroid participants in SCH, OH, or exo-SCT.

CONCLUSIONS: In this free-living elderly cohort, subclinical and overt hypothyroidism were associated with abnormalities of blood biomarkers consistent with diastolic overload and myocardial necrosis respectively, whereas subclinical hyperthyroidism tended to be associated with myocardial fibrosis and decreased left atrial strain. Our findings could represent stage B heart failure and illuminate distinct aspects of the pathobiology of heart disease related to thyroid gland dysfunction with potential clinical implications.

%B J Clin Endocrinol Metab %8 2024 Jan 06 %G eng %R 10.1210/clinem/dgae001 %0 Journal Article %J JAMA Cardiol %D 2024 %T Familial Hypercholesterolemia Variant and Cardiovascular Risk in Individuals With Elevated Cholesterol. %A Zhang, Yiyi %A Dron, Jacqueline S %A Bellows, Brandon K %A Khera, Amit V %A Liu, Junxiu %A Balte, Pallavi P %A Oelsner, Elizabeth C %A Amr, Sami Samir %A Lebo, Matthew S %A Nagy, Anna %A Peloso, Gina M %A Natarajan, Pradeep %A Rotter, Jerome I %A Willer, Cristen %A Boerwinkle, Eric %A Ballantyne, Christie M %A Lutsey, Pamela L %A Fornage, Myriam %A Lloyd-Jones, Donald M %A Hou, Lifang %A Psaty, Bruce M %A Bis, Joshua C %A Floyd, James S %A Vasan, Ramachandran S %A Heard-Costa, Nancy L %A Carson, April P %A Hall, Michael E %A Rich, Stephen S %A Guo, Xiuqing %A Kazi, Dhruv S %A de Ferranti, Sarah D %A Moran, Andrew E %X

IMPORTANCE: Familial hypercholesterolemia (FH) is a genetic disorder that often results in severely high low-density lipoprotein cholesterol (LDL-C) and high risk of premature coronary heart disease (CHD). However, the impact of FH variants on CHD risk among individuals with moderately elevated LDL-C is not well quantified.

OBJECTIVE: To assess CHD risk associated with FH variants among individuals with moderately (130-189 mg/dL) and severely (≥190 mg/dL) elevated LDL-C and to quantify excess CHD deaths attributable to FH variants in US adults.

DESIGN, SETTING, AND PARTICIPANTS: A total of 21 426 individuals without preexisting CHD from 6 US cohort studies (Atherosclerosis Risk in Communities study, Coronary Artery Risk Development in Young Adults study, Cardiovascular Health Study, Framingham Heart Study Offspring cohort, Jackson Heart Study, and Multi-Ethnic Study of Atherosclerosis) were included, 63 of whom had an FH variant. Data were collected from 1971 to 2018, and the median (IQR) follow-up was 18 (13-28) years. Data were analyzed from March to May 2023.

EXPOSURES: LDL-C, cumulative past LDL-C, FH variant status.

MAIN OUTCOMES AND MEASURES: Cox proportional hazards models estimated associations between FH variants and incident CHD. The Cardiovascular Disease Policy Model projected excess CHD deaths associated with FH variants in US adults.

RESULTS: Of the 21 426 individuals without preexisting CHD (mean [SD] age 52.1 [15.5] years; 12 041 [56.2%] female), an FH variant was found in 22 individuals with moderately elevated LDL-C (0.3%) and in 33 individuals with severely elevated LDL-C (2.5%). The adjusted hazard ratios for incident CHD comparing those with and without FH variants were 2.9 (95% CI, 1.4-6.0) and 2.6 (95% CI, 1.4-4.9) among individuals with moderately and severely elevated LDL-C, respectively. The association between FH variants and CHD was slightly attenuated when further adjusting for baseline LDL-C level, whereas the association was no longer statistically significant after adjusting for cumulative past LDL-C exposure. Among US adults 20 years and older with no history of CHD and LDL-C 130 mg/dL or higher, more than 417 000 carry an FH variant and were projected to experience more than 12 000 excess CHD deaths in those with moderately elevated LDL-C and 15 000 in those with severely elevated LDL-C compared with individuals without an FH variant.

CONCLUSIONS AND RELEVANCE: In this pooled cohort study, the presence of FH variants was associated with a 2-fold higher CHD risk, even when LDL-C was only moderately elevated. The increased CHD risk appeared to be largely explained by the higher cumulative LDL-C exposure in individuals with an FH variant compared to those without. Further research is needed to assess the value of adding genetic testing to traditional phenotypic FH screening.

%B JAMA Cardiol %8 2024 Jan 31 %G eng %R 10.1001/jamacardio.2023.5366 %0 Journal Article %J Nature %D 2024 %T Genetic drivers of heterogeneity in type 2 diabetes pathophysiology. %A Suzuki, Ken %A Hatzikotoulas, Konstantinos %A Southam, Lorraine %A Taylor, Henry J %A Yin, Xianyong %A Lorenz, Kim M %A Mandla, Ravi %A Huerta-Chagoya, Alicia %A Melloni, Giorgio E M %A Kanoni, Stavroula %A Rayner, Nigel W %A Bocher, Ozvan %A Arruda, Ana Luiza %A Sonehara, Kyuto %A Namba, Shinichi %A Lee, Simon S K %A Preuss, Michael H %A Petty, Lauren E %A Schroeder, Philip %A Vanderwerff, Brett %A Kals, Mart %A Bragg, Fiona %A Lin, Kuang %A Guo, Xiuqing %A Zhang, Weihua %A Yao, Jie %A Kim, Young Jin %A Graff, Mariaelisa %A Takeuchi, Fumihiko %A Nano, Jana %A Lamri, Amel %A Nakatochi, Masahiro %A Moon, Sanghoon %A Scott, Robert A %A Cook, James P %A Lee, Jung-Jin %A Pan, Ian %A Taliun, Daniel %A Parra, Esteban J %A Chai, Jin-Fang %A Bielak, Lawrence F %A Tabara, Yasuharu %A Hai, Yang %A Thorleifsson, Gudmar %A Grarup, Niels %A Sofer, Tamar %A Wuttke, Matthias %A Sarnowski, Chloe %A Gieger, Christian %A Nousome, Darryl %A Trompet, Stella %A Kwak, Soo-Heon %A Long, Jirong %A Sun, Meng %A Tong, Lin %A Chen, Wei-Min %A Nongmaithem, Suraj S %A Noordam, Raymond %A Lim, Victor J Y %A Tam, Claudia H T %A Joo, Yoonjung Yoonie %A Chen, Chien-Hsiun %A Raffield, Laura M %A Prins, Bram Peter %A Nicolas, Aude %A Yanek, Lisa R %A Chen, Guanjie %A Brody, Jennifer A %A Kabagambe, Edmond %A An, Ping %A Xiang, Anny H %A Choi, Hyeok Sun %A Cade, Brian E %A Tan, Jingyi %A Broadaway, K Alaine %A Williamson, Alice %A Kamali, Zoha %A Cui, Jinrui %A Thangam, Manonanthini %A Adair, Linda S %A Adeyemo, Adebowale %A Aguilar-Salinas, Carlos A %A Ahluwalia, Tarunveer S %A Anand, Sonia S %A Bertoni, Alain %A Bork-Jensen, Jette %A Brandslund, Ivan %A Buchanan, Thomas A %A Burant, Charles F %A Butterworth, Adam S %A Canouil, Mickaël %A Chan, Juliana C N %A Chang, Li-Ching %A Chee, Miao-Li %A Chen, Ji %A Chen, Shyh-Huei %A Chen, Yuan-Tsong %A Chen, Zhengming %A Chuang, Lee-Ming %A Cushman, Mary %A Danesh, John %A Das, Swapan K %A de Silva, H Janaka %A Dedoussis, George %A Dimitrov, Latchezar %A Doumatey, Ayo P %A Du, Shufa %A Duan, Qing %A Eckardt, Kai-Uwe %A Emery, Leslie S %A Evans, Daniel S %A Evans, Michele K %A Fischer, Krista %A Floyd, James S %A Ford, Ian %A Franco, Oscar H %A Frayling, Timothy M %A Freedman, Barry I %A Genter, Pauline %A Gerstein, Hertzel C %A Giedraitis, Vilmantas %A González-Villalpando, Clicerio %A Gonzalez-Villalpando, Maria Elena %A Gordon-Larsen, Penny %A Gross, Myron %A Guare, Lindsay A %A Hackinger, Sophie %A Hakaste, Liisa %A Han, Sohee %A Hattersley, Andrew T %A Herder, Christian %A Horikoshi, Momoko %A Howard, Annie-Green %A Hsueh, Willa %A Huang, Mengna %A Huang, Wei %A Hung, Yi-Jen %A Hwang, Mi Yeong %A Hwu, Chii-Min %A Ichihara, Sahoko %A Ikram, Mohammad Arfan %A Ingelsson, Martin %A Islam, Md Tariqul %A Isono, Masato %A Jang, Hye-Mi %A Jasmine, Farzana %A Jiang, Guozhi %A Jonas, Jost B %A Jørgensen, Torben %A Kamanu, Frederick K %A Kandeel, Fouad R %A Kasturiratne, Anuradhani %A Katsuya, Tomohiro %A Kaur, Varinderpal %A Kawaguchi, Takahisa %A Keaton, Jacob M %A Kho, Abel N %A Khor, Chiea-Chuen %A Kibriya, Muhammad G %A Kim, Duk-Hwan %A Kronenberg, Florian %A Kuusisto, Johanna %A Läll, Kristi %A Lange, Leslie A %A Lee, Kyung Min %A Lee, Myung-Shik %A Lee, Nanette R %A Leong, Aaron %A Li, Liming %A Li, Yun %A Li-Gao, Ruifang %A Ligthart, Symen %A Lindgren, Cecilia M %A Linneberg, Allan %A Liu, Ching-Ti %A Liu, Jianjun %A Locke, Adam E %A Louie, Tin %A Luan, Jian'an %A Luk, Andrea O %A Luo, Xi %A Lv, Jun %A Lynch, Julie A %A Lyssenko, Valeriya %A Maeda, Shiro %A Mamakou, Vasiliki %A Mansuri, Sohail Rafik %A Matsuda, Koichi %A Meitinger, Thomas %A Melander, Olle %A Metspalu, Andres %A Mo, Huan %A Morris, Andrew D %A Moura, Filipe A %A Nadler, Jerry L %A Nalls, Michael A %A Nayak, Uma %A Ntalla, Ioanna %A Okada, Yukinori %A Orozco, Lorena %A Patel, Sanjay R %A Patil, Snehal %A Pei, Pei %A Pereira, Mark A %A Peters, Annette %A Pirie, Fraser J %A Polikowsky, Hannah G %A Porneala, Bianca %A Prasad, Gauri %A Rasmussen-Torvik, Laura J %A Reiner, Alexander P %A Roden, Michael %A Rohde, Rebecca %A Roll, Katheryn %A Sabanayagam, Charumathi %A Sandow, Kevin %A Sankareswaran, Alagu %A Sattar, Naveed %A Schönherr, Sebastian %A Shahriar, Mohammad %A Shen, Botong %A Shi, Jinxiu %A Shin, Dong Mun %A Shojima, Nobuhiro %A Smith, Jennifer A %A So, Wing Yee %A Stančáková, Alena %A Steinthorsdottir, Valgerdur %A Stilp, Adrienne M %A Strauch, Konstantin %A Taylor, Kent D %A Thorand, Barbara %A Thorsteinsdottir, Unnur %A Tomlinson, Brian %A Tran, Tam C %A Tsai, Fuu-Jen %A Tuomilehto, Jaakko %A Tusié-Luna, Teresa %A Udler, Miriam S %A Valladares-Salgado, Adan %A van Dam, Rob M %A van Klinken, Jan B %A Varma, Rohit %A Wacher-Rodarte, Niels %A Wheeler, Eleanor %A Wickremasinghe, Ananda R %A van Dijk, Ko Willems %A Witte, Daniel R %A Yajnik, Chittaranjan S %A Yamamoto, Ken %A Yamamoto, Kenichi %A Yoon, Kyungheon %A Yu, Canqing %A Yuan, Jian-Min %A Yusuf, Salim %A Zawistowski, Matthew %A Zhang, Liang %A Zheng, Wei %A Raffel, Leslie J %A Igase, Michiya %A Ipp, Eli %A Redline, Susan %A Cho, Yoon Shin %A Lind, Lars %A Province, Michael A %A Fornage, Myriam %A Hanis, Craig L %A Ingelsson, Erik %A Zonderman, Alan B %A Psaty, Bruce M %A Wang, Ya-Xing %A Rotimi, Charles N %A Becker, Diane M %A Matsuda, Fumihiko %A Liu, Yongmei %A Yokota, Mitsuhiro %A Kardia, Sharon L R %A Peyser, Patricia A %A Pankow, James S %A Engert, James C %A Bonnefond, Amélie %A Froguel, Philippe %A Wilson, James G %A Sheu, Wayne H H %A Wu, Jer-Yuarn %A Hayes, M Geoffrey %A Ma, Ronald C W %A Wong, Tien-Yin %A Mook-Kanamori, Dennis O %A Tuomi, Tiinamaija %A Chandak, Giriraj R %A Collins, Francis S %A Bharadwaj, Dwaipayan %A Paré, Guillaume %A Sale, Michèle M %A Ahsan, Habibul %A Motala, Ayesha A %A Shu, Xiao-Ou %A Park, Kyong-Soo %A Jukema, J Wouter %A Cruz, Miguel %A Chen, Yii-Der Ida %A Rich, Stephen S %A McKean-Cowdin, Roberta %A Grallert, Harald %A Cheng, Ching-Yu %A Ghanbari, Mohsen %A Tai, E-Shyong %A Dupuis, Josée %A Kato, Norihiro %A Laakso, Markku %A Köttgen, Anna %A Koh, Woon-Puay %A Bowden, Donald W %A Palmer, Colin N A %A Kooner, Jaspal S %A Kooperberg, Charles %A Liu, Simin %A North, Kari E %A Saleheen, Danish %A Hansen, Torben %A Pedersen, Oluf %A Wareham, Nicholas J %A Lee, Juyoung %A Kim, Bong-Jo %A Millwood, Iona Y %A Walters, Robin G %A Stefansson, Kari %A Ahlqvist, Emma %A Goodarzi, Mark O %A Mohlke, Karen L %A Langenberg, Claudia %A Haiman, Christopher A %A Loos, Ruth J F %A Florez, Jose C %A Rader, Daniel J %A Ritchie, Marylyn D %A Zöllner, Sebastian %A Mägi, Reedik %A Marston, Nicholas A %A Ruff, Christian T %A van Heel, David A %A Finer, Sarah %A Denny, Joshua C %A Yamauchi, Toshimasa %A Kadowaki, Takashi %A Chambers, John C %A Ng, Maggie C Y %A Sim, Xueling %A Below, Jennifer E %A Tsao, Philip S %A Chang, Kyong-Mi %A McCarthy, Mark I %A Meigs, James B %A Mahajan, Anubha %A Spracklen, Cassandra N %A Mercader, Josep M %A Boehnke, Michael %A Rotter, Jerome I %A Vujkovic, Marijana %A Voight, Benjamin F %A Morris, Andrew P %A Zeggini, Eleftheria %X

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes and molecular mechanisms that are often specific to cell type. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.

%B Nature %8 2024 Feb 19 %G eng %R 10.1038/s41586-024-07019-6 %0 Journal Article %J Eur Respir J %D 2024 %T {Genome-wide association study of preserved ratio impaired spirometry (PRISm) %A Higbee, D. H. %A Lirio, A. %A Hamilton, F. %A Granell, R. %A Wyss, A. B. %A London, S. J. %A Bartz, T. M. %A Gharib, S. A. %A Cho, M. H. %A Wan, E. %A Silverman, E. %A Crapo, J. D. %A Lominchar, J. V. T. %A Hansen, T. %A Grarup, N. %A Dantoft, T. %A rhus, L. %A Linneberg, A. %A O'Connor, G. T. %A Dupuis, J. %A Xu, H. %A De Vries, M. M. %A Hu, X. %A Rich, S. S. %A Barr, R. G. %A Manichaikul, A. %A Wijnant, S. R. A. %A Brusselle, G. G. %A Lahousse, L. %A Li, X. %A ndez Cordero, A. I. %A Obeidat, M. %A Sin, D. D. %A Harris, S. E. %A Redmond, P. %A Taylor, A. M. %A Cox, S. R. %A Williams, A. T. %A Shrine, N. %A John, C. %A Guyatt, A. L. %A Hall, I. P. %A Davey Smith, G. %A Tobin, M. D. %A Dodd, J. W. %X {0.70. PRISm is associated with respiratory symptoms and comorbidities. Our objective was to discover novel genetic signals for PRISm and see if they provide insight into the pathogenesis of PRISm and associated comorbidities.\ We undertook a genome-wide association study (GWAS) of PRISm in UK Biobank participants (Stage 1), and selected single nucleotide polymorphisms (SNPs) reaching genome-wide significance for replication in 13 cohorts (Stage 2). A combined meta-analysis of Stage 1 and Stage 2 was done to determine top SNPs. We used cross-trait linkage disequilibrium score regression to estimate genome-wide genetic correlation between PRISm and pulmonary and extrapulmonary traits. Phenome-wide association studies of top SNPs were performed.\ =0.12 %B Eur Respir J %V 63 %8 Jan %G eng %0 Journal Article %J Nat Commun %D 2024 %T Human whole-exome genotype data for Alzheimer's disease. %A Leung, Yuk Yee %A Naj, Adam C %A Chou, Yi-Fan %A Valladares, Otto %A Schmidt, Michael %A Hamilton-Nelson, Kara %A Wheeler, Nicholas %A Lin, Honghuang %A Gangadharan, Prabhakaran %A Qu, Liming %A Clark, Kaylyn %A Kuzma, Amanda B %A Lee, Wan-Ping %A Cantwell, Laura %A Nicaretta, Heather %A Haines, Jonathan %A Farrer, Lindsay %A Seshadri, Sudha %A Brkanac, Zoran %A Cruchaga, Carlos %A Pericak-Vance, Margaret %A Mayeux, Richard P %A Bush, William S %A DeStefano, Anita %A Martin, Eden %A Schellenberg, Gerard D %A Wang, Li-San %K Alzheimer Disease %K Computational Biology %K Data Accuracy %K Exome %K Genotype %K Humans %X

The heterogeneity of the whole-exome sequencing (WES) data generation methods present a challenge to a joint analysis. Here we present a bioinformatics strategy for joint-calling 20,504 WES samples collected across nine studies and sequenced using ten capture kits in fourteen sequencing centers in the Alzheimer's Disease Sequencing Project. The joint-genotype called variant-called format (VCF) file contains only positions within the union of capture kits. The VCF was then processed specifically to account for the batch effects arising from the use of different capture kits from different studies. We identified 8.2 million autosomal variants. 96.82% of the variants are high-quality, and are located in 28,579 Ensembl transcripts. 41% of the variants are intronic and 1.8% of the variants are with CADD > 30, indicating they are of high predicted pathogenicity. Here we show our new strategy can generate high-quality data from processing these diversely generated WES samples. The improved ability to combine data sequenced in different batches benefits the whole genomics research community.

%B Nat Commun %V 15 %P 684 %8 2024 Jan 23 %G eng %N 1 %R 10.1038/s41467-024-44781-7 %0 Journal Article %J ESC Heart Fail %D 2024 %T Iron Deficiency and Incident Heart Failure in Older Community-Dwelling Individuals. %A Sharma, Shilpa %A Katz, Ronit %A Chaves, Paulo H M %A Hoofnagle, Andrew N %A Kizer, Jorge R %A Bansal, Nisha %A Ganz, Tomas %A Ix, Joachim H %X

AIMS: Among persons with prevalent heart failure (HF), iron deficiency has been linked to HF admissions, and intravenous iron replacement improves HF outcomes. Recent studies in persons with chronic kidney disease (CKD) demonstrate that iron deficiency is associated with incident HF. This study aimed to determine the relationship of iron status with incident HF in community-dwelling older adults irrespective of their kidney function.

METHODS: In this case-cohort study, 1,006 Cardiovascular Health Study participants (785 from the random sub-cohort [including 193 HF cases] and 221 additional HF cases [N = 414 total HF cases]) aged ≥ 65 years without HF (41% with CKD), we used weighted Cox models to evaluate associations of iron status with incident HF. Participants were categorized based on quartiles of transferrin saturation and ferritin as "iron replete" (27.3%), "functional iron deficiency" (7.7%), "iron deficiency" (11.8%), "mixed iron deficiency" (5.6%), "high iron" (9.3%) and "non-classified" (38.1%), consistent with prior studies.

RESULTS: Compared to older persons who were iron replete, those with iron deficiency were at higher risk of incident HF (HR 1.47; 1.02-2.11) in models adjusting for demographics, HF risk factors, and estimated glomerular filtration rate. Other iron categories did not associate with incident HF. The relationship of iron deficiency with incident HF did not differ by CKD status (interaction P value 0.2).

CONCLUSIONS: Among community-dwelling elders, iron deficiency is independently associated with incident HF, an association that was similar irrespective of CKD status. Our findings support conduct of clinical trials of iron replacement for prevention of HF in older adults with iron deficiency.

%B ESC Heart Fail %8 2024 Feb 26 %G eng %R 10.1002/ehf2.14724 %0 Journal Article %J Thromb Res %D 2024 %T Levels of procoagulant factors and peak thrombin generation in relation to dementia risk in older adults: The Cardiovascular Health Study. %A Harrington, Laura B %A Ehlert, Alexa N %A Thacker, Evan L %A Jenny, Nancy S %A Lopez, Oscar %A Cushman, Mary %A Olson, Nels C %A Fitzpatrick, Annette %A Mukamal, Kenneth J %A Jensen, Majken K %K Aged %K Anticoagulants %K Antithrombin III %K Antithrombins %K Dementia %K Factor VIIa %K Fibrinogen %K Hemostatics %K Humans %K Prospective Studies %K Thrombin %X

INTRODUCTION: Markers of hemostasis such as procoagulant factors and peak thrombin generation are associated with cardiovascular outcomes, but their associations with dementia risk are unclear. We aimed to evaluate prospective associations of selected procoagulant factors and peak thrombin generation with dementia risk.

METHODS: We measured levels of 7 hemostatic factors (fibrinogen, factor VII coagulant activity [FVIIc], activated factor VII [FVIIa], factor VIIa-antithrombin [FVIIa-AT], factor XI antigen [FXI], peak thrombin generation, and platelet count) among participants in the Cardiovascular Health Study, a cohort of older adults free of dementia in 1992/1993 (n = 3185). Dementia was adjudicated and classified by DSM-IV criteria through 1998/1999. Cox proportional hazards models estimated hazard ratios (HRs) for any dementia associated with 1-standard deviation (SD) differences, adjusting for sociodemographic and clinical factors and APOE genotype. Secondary analyses separately evaluated the risk of vascular dementia, Alzheimer's disease, and mixed dementia.

RESULTS: At baseline, participants had a median age of 73 years. Over 5.4 years of follow-up, we identified 448 dementia cases. There was no evidence of linear associations between levels of these hemostatic factors with any dementia risk (HRs per 1-SD difference ranged from 1.0 to 1.1; 95 % confidence intervals included 1.0). Results of secondary analyses by dementia subtype were similar.

CONCLUSIONS: In this prospective study, there was no strong evidence of linear associations between levels of fibrinogen, FVIIc, FVIIa, FVIIa-AT, FXI, peak thrombin generation, or platelet count with dementia risk. Despite their associations with cardiovascular disease, higher levels of these biomarkers measured among older adults may not reflect dementia risk.

%B Thromb Res %V 235 %P 148-154 %8 2024 Mar %G eng %R 10.1016/j.thromres.2024.01.024 %0 Journal Article %J Alzheimers Res Ther %D 2024 %T Multi-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance. %A Mei, Hao %A Simino, Jeannette %A Li, Lianna %A Jiang, Fan %A Bis, Joshua C %A Davies, Gail %A Hill, W David %A Xia, Charley %A Gudnason, Vilmundur %A Yang, Qiong %A Lahti, Jari %A Smith, Jennifer A %A Kirin, Mirna %A De Jager, Philip %A Armstrong, Nicola J %A Ghanbari, Mohsen %A Kolcic, Ivana %A Moran, Christopher %A Teumer, Alexander %A Sargurupremraj, Murali %A Mahmud, Shamsed %A Fornage, Myriam %A Zhao, Wei %A Satizabal, Claudia L %A Polasek, Ozren %A Räikkönen, Katri %A Liewald, David C %A Homuth, Georg %A Callisaya, Michele %A Mather, Karen A %A Windham, B Gwen %A Zemunik, Tatijana %A Palotie, Aarno %A Pattie, Alison %A van der Auwera, Sandra %A Thalamuthu, Anbupalam %A Knopman, David S %A Rudan, Igor %A Starr, John M %A Wittfeld, Katharina %A Kochan, Nicole A %A Griswold, Michael E %A Vitart, Veronique %A Brodaty, Henry %A Gottesman, Rebecca %A Cox, Simon R %A Psaty, Bruce M %A Boerwinkle, Eric %A Chasman, Daniel I %A Grodstein, Francine %A Sachdev, Perminder S %A Srikanth, Velandai %A Hayward, Caroline %A Wilson, James F %A Eriksson, Johan G %A Kardia, Sharon L R %A Grabe, Hans J %A Bennett, David A %A Ikram, M Arfan %A Deary, Ian J %A van Duijn, Cornelia M %A Launer, Lenore %A Fitzpatrick, Annette L %A Seshadri, Sudha %A Bressler, Jan %A Debette, Stephanie %A Mosley, Thomas H %K Aged %K Cognition %K Genome-Wide Association Study %K Humans %K Memory %K MicroRNAs %K Multiomics %K Polymorphism, Single Nucleotide %X

BACKGROUND: Uncovering the functional relevance underlying verbal declarative memory (VDM) genome-wide association study (GWAS) results may facilitate the development of interventions to reduce age-related memory decline and dementia.

METHODS: We performed multi-omics and pathway enrichment analyses of paragraph (PAR-dr) and word list (WL-dr) delayed recall GWAS from 29,076 older non-demented individuals of European descent. We assessed the relationship between single-variant associations and expression quantitative trait loci (eQTLs) in 44 tissues and methylation quantitative trait loci (meQTLs) in the hippocampus. We determined the relationship between gene associations and transcript levels in 53 tissues, annotation as immune genes, and regulation by transcription factors (TFs) and microRNAs. To identify significant pathways, gene set enrichment was tested in each cohort and meta-analyzed across cohorts. Analyses of differential expression in brain tissues were conducted for pathway component genes.

RESULTS: The single-variant associations of VDM showed significant linkage disequilibrium (LD) with eQTLs across all tissues and meQTLs within the hippocampus. Stronger WL-dr gene associations correlated with reduced expression in four brain tissues, including the hippocampus. More robust PAR-dr and/or WL-dr gene associations were intricately linked with immunity and were influenced by 31 TFs and 2 microRNAs. Six pathways, including type I diabetes, exhibited significant associations with both PAR-dr and WL-dr. These pathways included fifteen MHC genes intricately linked to VDM performance, showing diverse expression patterns based on cognitive status in brain tissues.

CONCLUSIONS: VDM genetic associations influence expression regulation via eQTLs and meQTLs. The involvement of TFs, microRNAs, MHC genes, and immune-related pathways contributes to VDM performance in older individuals.

%B Alzheimers Res Ther %V 16 %P 14 %8 2024 Jan 20 %G eng %N 1 %R 10.1186/s13195-023-01376-6 %0 Journal Article %J Nat Commun %D 2024 %T {Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications %A Sterenborg, R. B. T. M. %A Steinbrenner, I. %A Li, Y. %A Bujnis, M. N. %A Naito, T. %A Marouli, E. %A Galesloot, T. E. %A Babajide, O. %A Andreasen, L. %A Astrup, A. %A svold, B. O. %A Bandinelli, S. %A Beekman, M. %A Beilby, J. P. %A Bork-Jensen, J. %A Boutin, T. %A Brody, J. A. %A Brown, S. J. %A Brumpton, B. %A Campbell, P. J. %A Cappola, A. R. %A Ceresini, G. %A Chaker, L. %A Chasman, D. I. %A Concas, M. P. %A Coutinho de Almeida, R. %A Cross, S. M. %A Cucca, F. %A Deary, I. J. %A Kjaergaard, A. D. %A Echouffo Tcheugui, J. B. %A Ellervik, C. %A Eriksson, J. G. %A Ferrucci, L. %A Freudenberg, J. %A Fuchsberger, C. %A Gieger, C. %A Giulianini, F. %A gele, M. %A Graham, S. E. %A Grarup, N. %A ä, I. %A Hansen, T. %A Harding, B. N. %A Harris, S. E. %A ø, S. %A Hayward, C. %A Hui, J. %A Ittermann, T. %A Jukema, J. W. %A Kajantie, E. %A Kanters, J. K. %A rhus, L. L. %A Kiemeney, L. A. L. M. %A Kloppenburg, M. %A hnel, B. %A Lahti, J. %A Langenberg, C. %A Lapauw, B. %A Leese, G. %A Li, S. %A Liewald, D. C. M. %A Linneberg, A. %A Lominchar, J. V. T. %A Luan, J. %A Martin, N. G. %A Matana, A. %A Meima, M. E. %A Meitinger, T. %A Meulenbelt, I. %A Mitchell, B. D. %A llehave, L. T. %A Mora, S. %A Naitza, S. %A Nauck, M. %A Netea-Maier, R. T. %A Noordam, R. %A Nursyifa, C. %A Okada, Y. %A Onano, S. %A Papadopoulou, A. %A Palmer, C. N. A. %A Pattaro, C. %A Pedersen, O. %A Peters, A. %A Pietzner, M. %A ek, O. %A Pramstaller, P. P. %A Psaty, B. M. %A Punda, A. %A Ray, D. %A Redmond, P. %A Richards, J. B. %A Ridker, P. M. %A Russ, T. C. %A Ryan, K. A. %A Olesen, M. S. %A Schultheiss, U. T. %A Selvin, E. %A Siddiqui, M. K. %A Sidore, C. %A Slagboom, P. E. %A rensen, T. I. A. %A Soto-Pedre, E. %A Spector, T. D. %A Spedicati, B. %A Srinivasan, S. %A Starr, J. M. %A Stott, D. J. %A Tanaka, T. %A Torlak, V. %A Trompet, S. %A Tuhkanen, J. %A Uitterlinden, A. G. %A van den Akker, E. B. %A van den Eynde, T. %A van der Klauw, M. M. %A van Heemst, D. %A Verroken, C. %A Visser, W. E. %A Vojinovic, D. %A lzke, H. %A Waldenberger, M. %A Walsh, J. P. %A Wareham, N. J. %A Weiss, S. %A Willer, C. J. %A Wilson, S. G. %A Wolffenbuttel, B. H. R. %A Wouters, H. J. C. M. %A Wright, M. J. %A Yang, Q. %A Zemunik, T. %A Zhou, W. %A Zhu, G. %A llner, S. %A Smit, J. W. A. %A Peeters, R. P. %A ttgen, A. %A Teumer, A. %A Medici, M. %X T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases. %B Nat Commun %V 15 %P 888 %8 Jan %G eng %0 Journal Article %J ESC Heart Fail %D 2024 %T A polygenic risk score of atrial fibrillation improves prediction of lifetime risk for heart failure. %A Alkis, Taryn %A Luo, Xi %A Wall, Katherine %A Brody, Jennifer %A Bartz, Traci %A Chang, Patricia P %A Norby, Faye L %A Hoogeveen, Ron C %A Morrison, Alanna C %A Ballantyne, Christie M %A Coresh, Josef %A Boerwinkle, Eric %A Psaty, Bruce M %A Shah, Amil M %A Yu, Bing %X

AIMS: Heart failure (HF) has shared genetic architecture with its risk factors: atrial fibrillation (AF), body mass index (BMI), coronary heart disease (CHD), systolic blood pressure (SBP), and type 2 diabetes (T2D). We aim to assess the association and risk prediction performance of risk-factor polygenic risk scores (PRSs) for incident HF and its subtypes in bi-racial populations.

METHODS AND RESULTS: Five PRSs were constructed for AF, BMI, CHD, SBP, and T2D in White participants of the Atherosclerosis Risk in Communities (ARIC) study. The associations between PRSs and incident HF and its subtypes were assessed using Cox models, and the risk prediction performance of PRSs was assessed using C statistics. Replication was performed in the ARIC study Black and Cardiovascular Health Study (CHS) White participants. In 8624 ARIC study Whites, 1922 (31% cumulative incidence) HF cases developed over 30 years of follow-up. PRSs of AF, BMI, and CHD were associated with incident HF (P < 0.001), where PRS showed the strongest association [hazard ratio (HR): 1.47, 95% confidence interval (CI): 1.41-1.53]. Only the addition of PRS to the ARIC study HF risk equation improved C statistics for 10 year risk prediction from 0.812 to 0.829 (∆C: 0.017, 95% CI: 0.009-0.026). The PRS was associated with both incident HF with reduced ejection fraction (HR: 1.43, 95% CI: 1.27-1.60) and incident HF with preserved ejection fraction (HR: 1.46, 95% CI: 1.33-1.62). The associations between PRS and incident HF and its subtypes, as well as the improved risk prediction, were replicated in the ARIC study Blacks and the CHS Whites (P < 0.050). Protein analyses revealed that N-terminal pro-brain natriuretic peptide and other 98 proteins were associated with PRS .

CONCLUSIONS: The PRS was associated with incident HF and its subtypes and had significant incremental value over an established HF risk prediction equation.

%B ESC Heart Fail %8 2024 Jan 22 %G eng %R 10.1002/ehf2.14665 %0 Journal Article %J Circulation %D 2024 %T Role of Polyunsaturated Fat in Modifying Cardiovascular Risk Associated With Family History of Cardiovascular Disease: Pooled De Novo Results From 15 Observational Studies. %A Laguzzi, Federica %A Åkesson, Agneta %A Marklund, Matti %A Qian, Frank %A Gigante, Bruna %A Bartz, Traci M %A Bassett, Julie K %A Birukov, Anna %A Campos, Hannia %A Hirakawa, Yoichiro %A Imamura, Fumiaki %A Jäger, Susanne %A Lankinen, Maria %A Murphy, Rachel A %A Senn, Mackenzie %A Tanaka, Toshiko %A Tintle, Nathan %A Virtanen, Jyrki K %A Yamagishi, Kazumasa %A Allison, Matthew %A Brouwer, Ingeborg A %A de Faire, Ulf %A Eiriksdottir, Gudny %A Ferrucci, Luigi %A Forouhi, Nita G %A Geleijnse, Johanna M %A Hodge, Allison M %A Kimura, Hitomi %A Laakso, Markku %A Riserus, Ulf %A van Westing, Anniek C %A Bandinelli, Stefania %A Baylin, Ana %A Giles, Graham G %A Gudnason, Vilmundur %A Iso, Hiroyasu %A Lemaitre, Rozenn N %A Ninomiya, Toshiharu %A Post, Wendy S %A Psaty, Bruce M %A Salonen, Jukka T %A Schulze, Matthias B %A Tsai, Michael Y %A Uusitupa, Matti %A Wareham, Nicholas J %A Oh, Seung-Won %A Wood, Alexis C %A Harris, William S %A Siscovick, David %A Mozaffarian, Dariush %A Leander, Karin %K Animals %K Biomarkers %K Cardiovascular Diseases %K Docosahexaenoic Acids %K Fatty Acids, Omega-3 %K Risk Factors %X

BACKGROUND: It is unknown whether dietary intake of polyunsaturated fatty acids (PUFA) modifies the cardiovascular disease (CVD) risk associated with a family history of CVD. We assessed interactions between biomarkers of low PUFA intake and a family history in relation to long-term CVD risk in a large consortium.

METHODS: Blood and tissue PUFA data from 40 885 CVD-free adults were assessed. PUFA levels ≤25th percentile were considered to reflect low intake of linoleic, alpha-linolenic, and eicosapentaenoic/docosahexaenoic acids (EPA/DHA). Family history was defined as having ≥1 first-degree relative who experienced a CVD event. Relative risks with 95% CI of CVD were estimated using Cox regression and meta-analyzed. Interactions were assessed by analyzing product terms and calculating relative excess risk due to interaction.

RESULTS: After multivariable adjustments, a significant interaction between low EPA/DHA and family history was observed (product term pooled RR, 1.09 [95% CI, 1.02-1.16]; =0.01). The pooled relative risk of CVD associated with the combined exposure to low EPA/DHA, and family history was 1.41 (95% CI, 1.30-1.54), whereas it was 1.25 (95% CI, 1.16-1.33) for family history alone and 1.06 (95% CI, 0.98-1.14) for EPA/DHA alone, compared with those with neither exposure. The relative excess risk due to interaction results indicated no interactions.

CONCLUSIONS: A significant interaction between biomarkers of low EPA/DHA intake, but not the other PUFA, and a family history was observed. This novel finding might suggest a need to emphasize the benefit of consuming oily fish for individuals with a family history of CVD.

%B Circulation %V 149 %P 305-316 %8 2024 Jan 23 %G eng %N 4 %R 10.1161/CIRCULATIONAHA.123.065530 %0 Journal Article %J Nat Commun %D 2024 %T X-chromosome and kidney function: evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements. %A Scholz, Markus %A Horn, Katrin %A Pott, Janne %A Wuttke, Matthias %A Kühnapfel, Andreas %A Nasr, M Kamal %A Kirsten, Holger %A Li, Yong %A Hoppmann, Anselm %A Gorski, Mathias %A Ghasemi, Sahar %A Li, Man %A Tin, Adrienne %A Chai, Jin-Fang %A Cocca, Massimiliano %A Wang, Judy %A Nutile, Teresa %A Akiyama, Masato %A Åsvold, Bjørn Olav %A Bansal, Nisha %A Biggs, Mary L %A Boutin, Thibaud %A Brenner, Hermann %A Brumpton, Ben %A Burkhardt, Ralph %A Cai, Jianwen %A Campbell, Archie %A Campbell, Harry %A Chalmers, John %A Chasman, Daniel I %A Chee, Miao Ling %A Chee, Miao Li %A Chen, Xu %A Cheng, Ching-Yu %A Cifkova, Renata %A Daviglus, Martha %A Delgado, Graciela %A Dittrich, Katalin %A Edwards, Todd L %A Endlich, Karlhans %A Michael Gaziano, J %A Giri, Ayush %A Giulianini, Franco %A Gordon, Scott D %A Gudbjartsson, Daniel F %A Hallan, Stein %A Hamet, Pavel %A Hartman, Catharina A %A Hayward, Caroline %A Heid, Iris M %A Hellwege, Jacklyn N %A Holleczek, Bernd %A Holm, Hilma %A Hutri-Kähönen, Nina %A Hveem, Kristian %A Isermann, Berend %A Jonas, Jost B %A Joshi, Peter K %A Kamatani, Yoichiro %A Kanai, Masahiro %A Kastarinen, Mika %A Khor, Chiea Chuen %A Kiess, Wieland %A Kleber, Marcus E %A Körner, Antje %A Kovacs, Peter %A Krajcoviechova, Alena %A Kramer, Holly %A Krämer, Bernhard K %A Kuokkanen, Mikko %A Kähönen, Mika %A Lange, Leslie A %A Lash, James P %A Lehtimäki, Terho %A Li, Hengtong %A Lin, Bridget M %A Liu, Jianjun %A Loeffler, Markus %A Lyytikäinen, Leo-Pekka %A Magnusson, Patrik K E %A Martin, Nicholas G %A Matsuda, Koichi %A Milaneschi, Yuri %A Mishra, Pashupati P %A Mononen, Nina %A Montgomery, Grant W %A Mook-Kanamori, Dennis O %A Mychaleckyj, Josyf C %A März, Winfried %A Nauck, Matthias %A Nikus, Kjell %A Nolte, Ilja M %A Noordam, Raymond %A Okada, Yukinori %A Olafsson, Isleifur %A Oldehinkel, Albertine J %A Penninx, Brenda W J H %A Perola, Markus %A Pirastu, Nicola %A Polasek, Ozren %A Porteous, David J %A Poulain, Tanja %A Psaty, Bruce M %A Rabelink, Ton J %A Raffield, Laura M %A Raitakari, Olli T %A Rasheed, Humaira %A Reilly, Dermot F %A Rice, Kenneth M %A Richmond, Anne %A Ridker, Paul M %A Rotter, Jerome I %A Rudan, Igor %A Sabanayagam, Charumathi %A Salomaa, Veikko %A Schneiderman, Neil %A Schöttker, Ben %A Sims, Mario %A Snieder, Harold %A Stark, Klaus J %A Stefansson, Kari %A Stocker, Hannah %A Stumvoll, Michael %A Sulem, Patrick %A Sveinbjornsson, Gardar %A Svensson, Per O %A Tai, E-Shyong %A Taylor, Kent D %A Tayo, Bamidele O %A Teren, Andrej %A Tham, Yih-Chung %A Thiery, Joachim %A Thio, Chris H L %A Thomas, Laurent F %A Tremblay, Johanne %A Tönjes, Anke %A van der Most, Peter J %A Vitart, Veronique %A Völker, Uwe %A Wang, Ya Xing %A Wang, Chaolong %A Wei, Wen Bin %A Whitfield, John B %A Wild, Sarah H %A Wilson, James F %A Winkler, Thomas W %A Wong, Tien-Yin %A Woodward, Mark %A Sim, Xueling %A Chu, Audrey Y %A Feitosa, Mary F %A Thorsteinsdottir, Unnur %A Hung, Adriana M %A Teumer, Alexander %A Franceschini, Nora %A Parsa, Afshin %A Köttgen, Anna %A Schlosser, Pascal %A Pattaro, Cristian %K Androgens %K Chromosomes, Human, X %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Kidney %K Male %K Polymorphism, Single Nucleotide %K Response Elements %K Tetraspanins %X

X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.

%B Nat Commun %V 15 %P 586 %8 2024 Jan 18 %G eng %N 1 %R 10.1038/s41467-024-44709-1