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

Plasmin-alpha2-antiplasmin complex (PAP) marks plasmin generation and fibrinolytic balance. We recently observed that elevated levels of PAP predict acute myocardial infarction in the elderly, yet little is known about the correlates of PAP. We measured PAP in 800 elderly subjects who were free of clinical cardiovascular disease in 2 cohort studies: the Cardiovascular Health Study and the Honolulu Heart Program. Median PAP levels did not differ between the Cardiovascular Health Study (6.05+/-1.46 nmol/L) and the Honolulu Heart Program (6.11+/-1.44 nmol/L), and correlates of PAP were similar in both cohorts. In CHS, PAP levels increased with age (r=0. 30), procoagulant factors (eg, factor VIIc, r=0.15), thrombin activity (prothrombin fragment F1+2, r=0.29), and inflammation-sensitive proteins (eg, fibrinogen, r=0.44; factor VIIIc, r=0.37). PAP was associated with increased atherosclerosis as measured by the ankle-arm index (AAI) (P for trend, VL - 19 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/10073949?dopt=Abstract ER - TY - JOUR T1 - Diabetes mellitus: subclinical cardiovascular disease and risk of incident cardiovascular disease and all-cause mortality. JF - Arterioscler Thromb Vasc Biol Y1 - 2000 A1 - Kuller, L H A1 - Velentgas, P A1 - Barzilay, J A1 - Beauchamp, N J A1 - O'Leary, D H A1 - Savage, P J KW - Aged KW - Arteriosclerosis KW - Coronary Disease KW - Diabetes Mellitus, Type 1 KW - Diabetes Mellitus, Type 2 KW - Diabetic Angiopathies KW - Female KW - Humans KW - Incidence KW - Male KW - Multivariate Analysis KW - Myocardial Infarction KW - Prevalence KW - Proportional Hazards Models KW - Risk Factors KW - Sex Distribution KW - Stroke AB -

Previously diagnosed diabetes mellitus, newly diagnosed diabetes mellitus, and impaired glucose tolerance are important determinants of the risk of clinical cardiovascular disease (CVD). We have evaluated the relation of patients with subclinical CVD, diabetes, and impaired glucose tolerance and "normal" subjects and the risk of clinical CVD in the Cardiovascular Health Study. Diabetes (1343), impaired glucose tolerance (1433), and normal (2421) were defined by World Health Organization criteria at baseline in 1989 to 1990. The average follow-up was 6.4 years (mean age 73 years). Diabetics had a higher prevalence of clinical and subclinical CVD at baseline. Compared with diabetes in the absence of subclinical disease, the presence of subclinical CVD and diabetes was associated with significant increased adjusted relative risk of death (1.5, CI 0.93 to 2.41), relative risk of incident coronary heart disease (1.99, CI 1.25 to 3.19), and incident myocardial infarction (1.93, CI 0.96 to 3.91). The risk of clinical events was greater for participants with a history of diabetes compared with newly diagnosed diabetics at baseline. Compared with nondiabetic nonhypertensive subjects without subclinical disease, patients with a combination of diabetes, hypertension, and subclinical disease had a 12-fold increased risk of stroke. Fasting blood glucose levels were a weak predictor of incident coronary heart disease as were most other risk factors. Subclinical CVD was the primary determinant of clinical CVD among diabetics in the Cardiovascular Health Study.

VL - 20 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/10712409?dopt=Abstract ER - TY - JOUR T1 - Evidence of islet cell autoimmunity in elderly patients with type 2 diabetes. JF - Diabetes Y1 - 2000 A1 - Pietropaolo, M A1 - Barinas-Mitchell, E A1 - Pietropaolo, S L A1 - Kuller, L H A1 - Trucco, M KW - Aged KW - Aged, 80 and over KW - Aging KW - Autoantibodies KW - Autoantigens KW - Autoimmunity KW - Blood Glucose KW - C-Reactive Protein KW - Diabetes Mellitus, Type 2 KW - Female KW - Fibrinogen KW - Glucose Tolerance Test KW - Glutamate Decarboxylase KW - Humans KW - Islets of Langerhans KW - Male KW - Membrane Proteins KW - Protein Tyrosine Phosphatases KW - Receptor-Like Protein Tyrosine Phosphatases, Class 8 AB -

In light of an occurring growth of elderly people affected by type 2 diabetes and recent observations indicating that type 2 diabetes may be a disease of the innate immune system, we evaluated whether signs of islet cell autoimmunity are associated with an abnormal glucose control, the presence of insulin requirement, or an activation of the acute-phase response in older individuals with type 2 diabetes. GAD65 and IA-2 autoantibodies along with the acute-phase response markers fibrinogen and C-reactive protein were tested in 196 serum samples from patients with type 2 diabetes and in 94 nondiabetic control subjects over the age of 65 years from the Pittsburgh cohort of the Cardiovascular Health Study. Of the diabetic patients, 12% (24 of 196) had autoantibodies against GAD65 and/or IA-2, a prevalence significantly higher than that found in nondiabetic individuals (1 of 94, 1.1%; P = 0.001). Type 2 diabetic patients who were positive for GAD65 and/or IA-2 autoantibodies (Ab+), as compared with those negative for these autoantibodies (Ab-), had an abnormal oral glucose tolerance test (OGTT) (P = 0.03) before and a higher frequency of oral hypoglycemic treatment (P = 0.003) at the time of autoantibody testing. No differences were seen in the percentage of insulin requirement in the two groups. Moreover, a statistically significant increase in fibrinogen (P = 0.005) and C-reactive protein levels (P = 0.025) was found in type 2 diabetic patients with high levels of GAD65 and/or IA-2 autoantibodies as compared with Ab-patients and control subjects. In conclusion, in type 2 diabetic subjects > or =65 years old, the presence of islet cell autoimmunity is associated with an impairment of the acute-phase insulin secretion, as revealed by an OGTT. A pronounced activation of the acute-phase response, found to be associated with islet cell autoimmunity, may in part explain this defect in insulin secretion. These findings not only have direct implications for adequate classification and treatment of diabetes in the elderly, but also for understanding the autoimmune/inflammatory mechanisms involved in the pathogenesis of hyperglycemia.

VL - 49 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/10615947?dopt=Abstract ER - TY - JOUR T1 - Prevalence of clinical and isolated subclinical cardiovascular disease in older adults with glucose disorders: the Cardiovascular Health Study. JF - Diabetes Care Y1 - 2001 A1 - Barzilay, J I A1 - Spiekerman, C F A1 - Kuller, L H A1 - Burke, G L A1 - Bittner, V A1 - Gottdiener, J S A1 - Brancati, F L A1 - Orchard, T J A1 - O'Leary, D H A1 - Savage, P J KW - Aged KW - Angina Pectoris KW - Cardiovascular Diseases KW - Cerebrovascular Disorders KW - Cohort Studies KW - Diabetes Mellitus KW - Diabetes Mellitus, Type 1 KW - Diabetes Mellitus, Type 2 KW - Electrocardiography KW - Female KW - Glucose Intolerance KW - Heart Diseases KW - Humans KW - Male KW - Peripheral Vascular Diseases KW - Prevalence KW - United States AB -

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.

VL - 24 IS - 7 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11423508?dopt=Abstract ER - TY - JOUR T1 - The relation of atherosclerotic cardiovascular disease to retinopathy in people with diabetes in the Cardiovascular Health Study. JF - Br J Ophthalmol Y1 - 2002 A1 - Klein, Ronald A1 - Marino, Emily K A1 - Kuller, Lewis H A1 - Polak, Joseph F A1 - Tracy, Russell P A1 - Gottdiener, John S A1 - Burke, Gregory L A1 - Hubbard, Larry D A1 - Boineau, Robin KW - Age of Onset KW - Aged KW - Aged, 80 and over KW - Arteriosclerosis KW - Black People KW - Blood Pressure KW - Cohort Studies KW - Diabetes Mellitus, Type 2 KW - Diabetic Retinopathy KW - Female KW - Humans KW - Longitudinal Studies KW - Male KW - Odds Ratio KW - Prospective Studies KW - Regression Analysis KW - Risk Factors KW - Time Factors KW - White People AB -

AIMS: To describe the association of retinopathy with atherosclerosis and atherosclerotic risk factors in people with diabetes.

METHODS: 296 of the 558 people classified as having diabetes by the American Diabetes Association criteria, from a population based cohort of adults (ranging in age from 69 to 102 years) living in four United States communities (Allegheny County, Pennsylvania; Forsyth County, North Carolina; Sacramento County, California; and Washington County, Maryland) were studied from 1997 to 1998. Lesions typical of diabetic retinopathy were determined by grading a 45 degrees colour fundus photograph of one eye of each participant, using a modification of the Airlie House classification system.

RESULTS: Retinopathy was present in 20% of the diabetic cohort, with the lowest prevalence (16%), in those 80 years of age or older. Retinopathy was detected in 20.3% of the 296 people with diabetes; 2.7% of the 296 had signs of proliferative retinopathy and 2.1% had signs of macular oedema. The prevalence of diabetic retinopathy was higher in black people (35.4%) than white (16.0%). Controlling for age, sex, and blood glucose, retinopathy was more frequent in black people than white (odds ratio (OR) 2.26, 95% confidence interval (CI) 1.01, 5.05), in those with longer duration of diabetes (OR (per 5 years of diabetes) 1.42, 95% CI 1.18, 1.70), in those with subclinical cardiovascular disease (OR 1.49, 95% CI 0.51, 4.31), or coronary heart disease or stroke (OR 3.23, 95% CI 1.09, 9.56) than those without those diseases, in those with higher plasma low density lipoprotein (LDL) cholesterol (OR (per 10 mg/dl of LDL cholesterol) 1.12, 95% CI 1.02, 1.23), and in those with gross proteinuria (OR 4.76, 95% CI 1.53, 14.86).

CONCLUSION: Data from this population based study suggest a higher prevalence of retinopathy in black people than white people with diabetes and the association of cardiovascular disease, elevated plasma LDL cholesterol, and gross proteinuria with diabetic retinopathy. However, any conclusions or explanations regarding associations described here must be made with caution because only about one half of those with diabetes mellitus were evaluated.

VL - 86 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11801510?dopt=Abstract ER - TY - JOUR T1 - The 6-min walk test: a quick measure of functional status in elderly adults. JF - Chest Y1 - 2003 A1 - Enright, Paul L A1 - McBurnie, Mary Ann A1 - Bittner, Vera A1 - Tracy, Russell P A1 - McNamara, Robert A1 - Arnold, Alice A1 - Newman, Anne B KW - Activities of Daily Living KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Cohort Studies KW - Coronary Disease KW - Cross-Sectional Studies KW - Diabetes Mellitus, Type 2 KW - Exercise Test KW - Female KW - Humans KW - Ischemic Attack, Transient KW - Linear Models KW - Male KW - Mass Screening KW - Sensitivity and Specificity KW - Stroke KW - United States KW - Walking AB -

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.

VL - 123 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12576356?dopt=Abstract ER - TY - JOUR T1 - Sleep-disordered breathing, glucose intolerance, and insulin resistance: the Sleep Heart Health Study. JF - Am J Epidemiol Y1 - 2004 A1 - Punjabi, Naresh M A1 - Shahar, Eyal A1 - Redline, Susan A1 - Gottlieb, Daniel J A1 - Givelber, Rachel A1 - Resnick, Helaine E KW - Aged KW - Blood Gas Analysis KW - Body Constitution KW - Body Mass Index KW - Cohort Studies KW - Confounding Factors, Epidemiologic KW - Cross-Sectional Studies KW - Diabetes Mellitus, Type 2 KW - Fasting KW - Female KW - Glucose Intolerance KW - Glucose Tolerance Test KW - Humans KW - Insulin Resistance KW - Linear Models KW - Male KW - Middle Aged KW - Multivariate Analysis KW - Oxyhemoglobins KW - Polysomnography KW - Research Design KW - Risk Factors KW - Severity of Illness Index KW - Sleep Apnea Syndromes AB -

Clinic-based studies suggest that sleep-disordered breathing (SDB) is associated with glucose intolerance and insulin resistance. However, in the available studies, researchers have not rigorously controlled for confounding variables to assess the independent relation between SDB and impaired glucose metabolism. The objective of this study was to determine whether SDB was associated with glucose intolerance and insulin resistance among community-dwelling subjects (n=2,656) participating in the Sleep Heart Health Study (1994-1999). SDB was characterized with the respiratory disturbance index and measurements of oxygen saturation during sleep. Fasting and 2-hour glucose levels measured during an oral glucose tolerance test were used to assess glycemic status. Relative to subjects with a respiratory disturbance index of less than 5.0 events/hour (the reference category), subjects with mild SDB (5.0-14.9 events/hour) and moderate to severe SDB (> or =15 events/hour) had adjusted odds ratios of 1.27 (95% confidence interval: 0.98, 1.64) and 1.46 (95% confidence interval: 1.09, 1.97), respectively, for fasting glucose intolerance (p for trend < 0.01). Sleep-related hypoxemia was also associated with glucose intolerance independently of age, gender, body mass index, and waist circumference. The results of this study suggest that SDB is independently associated with glucose intolerance and insulin resistance and may lead to type 2 diabetes mellitus.

VL - 160 IS - 6 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15353412?dopt=Abstract ER - TY - JOUR T1 - The prevalence of the 65-kilodalton isoform of glutamic acid decarboxylase autoantibodies by glucose tolerance status in elderly patients from the cardiovascular health study. JF - J Clin Endocrinol Metab Y1 - 2006 A1 - Barinas-Mitchell, Emma A1 - Kuller, Lewis H A1 - Pietropaolo, Susan A1 - Zhang, Ying-Jian A1 - Henderson, Tyona A1 - Pietropaolo, Massimo KW - Aged KW - Aging KW - Autoantibodies KW - Blood Glucose KW - Blood Pressure KW - Cardiovascular Diseases KW - Cohort Studies KW - Diabetes Mellitus, Type 2 KW - Fasting KW - Female KW - Glucose Intolerance KW - Glutamate Decarboxylase KW - Humans KW - Insulin KW - Isoenzymes KW - Lipids KW - Logistic Models KW - Male KW - Nutrition Surveys AB -

CONTEXT: Autoantibodies (AA) to glutamic acid decarboxylase (GAD65), a determinant of risk for autoimmune diabetes, have been found in up to 10% of patients with type 2 diabetes. In older adults, this marker may also serve as a determinant of risk for autoimmune diabetes and enhance diabetes classification.

OBJECTIVE: The objective of this study was to evaluate the relationship between GAD65AA and glucose tolerance status, current diabetes treatment, and clinical measures in older adults.

DESIGN: GAD65AA were measured at baseline in 3318 participants from the Cardiovascular Health Study, a cohort study of 5888 individuals 65 or older.

SETTING: The population-based cohort was recruited from four U.S. sites.

PATIENTS: Patients included all Cardiovascular Health Study participants with known diabetes, newly diagnosed diabetes, impaired fasting glucose, impaired glucose tolerance, and a sample of normal glucose-tolerant participants.

MAIN OUTCOME MEASURES: GAD65AA, body mass index, fasting glucose and insulin levels, blood pressure, lipid levels, and diabetes treatment at baseline were measured.

RESULTS: The prevalence of GAD65AA increased with decreasing glucose tolerance in both Blacks (n = 560) and Whites (n = 2730), being more pronounced in known diabetic individuals. GAD65AA were found in 2.3, 5.8, 7.8, and 8.3% of diabetic participants, reporting use of no diabetes medication, oral hypoglycemic agents, insulin only, and both oral hypoglycemic agents and insulin, respectively (P = 0.02, linear trend). Among diabetic participants, GAD65AA positivity was associated with diabetes treatment, higher fasting glucose, and lower body mass index.

CONCLUSIONS: Even among older individuals with diabetes, GAD65AA may be a useful marker in identifying a subgroup of autoimmune diabetes, serve as a marker of insulin requirement, and remain stable over years.

VL - 91 IS - 8 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16720660?dopt=Abstract ER - TY - JOUR T1 - Alcohol consumption and type 2 diabetes among older adults: the Cardiovascular Health Study. JF - Obesity (Silver Spring) Y1 - 2007 A1 - Djoussé, Luc A1 - Biggs, Mary L A1 - Mukamal, Kenneth J A1 - Siscovick, David S KW - Aged KW - Aged, 80 and over KW - Alcohol Drinking KW - Diabetes Mellitus, Type 2 KW - Female KW - Follow-Up Studies KW - Humans KW - Incidence KW - Longitudinal Studies KW - Male KW - Medicare KW - Middle Aged KW - Risk KW - Smoking KW - Temperance KW - United States AB -

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

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

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

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

VL - 15 IS - 7 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17636094?dopt=Abstract ER - TY - JOUR T1 - Longitudinal association between depressive symptoms and incident type 2 diabetes mellitus in older adults: the cardiovascular health study. JF - Arch Intern Med Y1 - 2007 A1 - Carnethon, Mercedes R A1 - Biggs, Mary L A1 - Barzilay, Joshua I A1 - Smith, Nicholas L A1 - Vaccarino, Viola A1 - Bertoni, Alain G A1 - Arnold, Alice A1 - Siscovick, David KW - Aged KW - Body Mass Index KW - C-Reactive Protein KW - Depression KW - Diabetes Mellitus, Type 2 KW - Drinking KW - Female KW - Humans KW - Longitudinal Studies KW - Male KW - Smoking AB -

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.

VL - 167 IS - 8 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17452543?dopt=Abstract ER - TY - JOUR T1 - Enhanced risk for Alzheimer disease in persons with type 2 diabetes and APOE epsilon4: the Cardiovascular Health Study Cognition Study. JF - Arch Neurol Y1 - 2008 A1 - Irie, Fumiko A1 - Fitzpatrick, Annette L A1 - Lopez, Oscar L A1 - Kuller, Lewis H A1 - Peila, Rita A1 - Newman, Anne B A1 - Launer, Lenore J KW - African Americans KW - Age Factors KW - Aged KW - Alzheimer Disease KW - Apolipoprotein E4 KW - Cognition KW - Cohort Studies KW - Confidence Intervals KW - Dementia, Vascular KW - Diabetes Mellitus, Type 2 KW - European Continental Ancestry Group KW - Female KW - Genotype KW - Humans KW - Longitudinal Studies KW - Male KW - Neuropsychological Tests KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Factors KW - Sex Factors AB -

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

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

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

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

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

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

STUDY OBJECTIVES: Commonly used definitions of sleep-disordered breathing (SDB) are based on identifying discrete events of breathing abnormalities during sleep that are accompanied by an oxyhemoglobin desaturation (delta SaO2) of at least 4%. However, it is not known whether disordered breathing events with oxyhemoglobin desaturation less than 4% are associated with clinical sequelae such as abnormalities in fasting glycemia.

DESIGN: Cross-sectional study.

SUBJECTS AND SETTING: Participants from the Sleep Heart Health Study (SHHS) with a fasting glucose measurement made within a year of the baseline polysomnogram.

MEASUREMENTS AND RESULTS: SDB severity was defined using the apnea-hypopnea index (AHI) and the hypopnea index (HI) by counting events with different levels of oxyhemoglobin desaturation (0.0%-1.9%, 2.0%-2.9%, 3.0%-3.9%, > or = 4.0%). Fasting glucose levels were used to classify individuals into normal (<100 mg/dL), impaired (100-125 mg/dL), and diabetic (> or = 126 mg/dL) groups. Ordinal logistic regression was used to determine the adjusted relative odds of an abnormal glucose value across quartiles of the hypopnea index, independent of factors such as age, body mass index, waist circumference, and usual sleep duration. The prevalence of impaired and diabetic fasting glucose in the analytical sample was 32.9% and 5.8%, respectively. The covariate-adjusted relative odds of impaired or diabetic fasting glucose in the highest versus the lowest AHI quartile was 1.35 (95% CI: 1.04-1.76) for events with a delta SaO2 > or = 4.0%, 1.72 (95% CI: 1.20-2.48) for events with a delta SaO2 between 3.0%-3.9%, 1.41 (95% CI: 1.07-1.86) for events with a delta SaO2 between 2.0%-2.9%, and 1.07 (95% CI: 0.84-1.37) for events with a delta SaO2 between 0.0%-1.9%. The corresponding odds ratios for the HI were 1.47 (95% CI: 1.13-1.92), 2.25 (95% CI: 1.59-3.19), 1.44 (95% CI: 1.09-1.90), and 1.15 (95% CI: 0.90-1.47), respectively.

CONCLUSIONS: The results of this study indicate that SDB events accompanied by oxyhemoglobin desaturation of between 2% to 4% are associated with fasting hyperglycemia. These findings suggest that milder degrees of SDB may predispose to adverse metabolic outcomes.

VL - 31 IS - 7 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18652097?dopt=Abstract ER - TY - JOUR T1 - Lifestyle risk factors and new-onset diabetes mellitus in older adults: the cardiovascular health study. JF - Arch Intern Med Y1 - 2009 A1 - Mozaffarian, Dariush A1 - Kamineni, Aruna A1 - Carnethon, Mercedes A1 - Djoussé, Luc A1 - Mukamal, Kenneth J A1 - Siscovick, David KW - Age of Onset KW - Aged KW - Aged, 80 and over KW - Diabetes Mellitus, Type 2 KW - Female KW - Humans KW - Incidence KW - Life Style KW - Male KW - National Heart, Lung, and Blood Institute (U.S.) KW - Prospective Studies KW - Risk Factors KW - United States AB -

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.

VL - 169 IS - 8 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19398692?dopt=Abstract ER - TY - JOUR T1 - Association between adiposity in midlife and older age and risk of diabetes in older adults. JF - JAMA Y1 - 2010 A1 - Biggs, Mary L A1 - Mukamal, Kenneth J A1 - Luchsinger, José A A1 - Ix, Joachim H A1 - Carnethon, Mercedes R A1 - Newman, Anne B A1 - de Boer, Ian H A1 - Strotmeyer, Elsa S A1 - Mozaffarian, Dariush A1 - Siscovick, David S KW - Adiposity KW - Age Factors KW - Aged KW - Body Mass Index KW - Diabetes Mellitus, Type 2 KW - Female KW - Humans KW - Incidence KW - Male KW - Prospective Studies KW - Risk Factors KW - United States KW - Weight Gain AB -

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.

VL - 303 IS - 24 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20571017?dopt=Abstract ER - TY - JOUR T1 - Brain structure and obesity. JF - Hum Brain Mapp Y1 - 2010 A1 - Raji, Cyrus A A1 - Ho, April J A1 - Parikshak, Neelroop N A1 - Becker, James T A1 - Lopez, Oscar L A1 - Kuller, Lewis H A1 - Hua, Xue A1 - Leow, Alex D A1 - Toga, Arthur W A1 - Thompson, Paul M KW - Age Factors KW - Aged KW - Analysis of Variance KW - Body Mass Index KW - Brain KW - Continental Population Groups KW - Diabetes Mellitus, Type 2 KW - Fasting KW - Female KW - Humans KW - Insulin KW - Magnetic Resonance Imaging KW - Male KW - Nerve Fibers, Myelinated KW - Nerve Fibers, Unmyelinated KW - Obesity KW - Organ Size KW - Regression Analysis KW - Sex Factors AB -

Obesity is associated with increased risk for cardiovascular health problems including diabetes, hypertension, and stroke. These cardiovascular afflictions increase risk for cognitive decline and dementia, but it is unknown whether these factors, specifically obesity and Type II diabetes, are associated with specific patterns of brain atrophy. We used tensor-based morphometry (TBM) to examine gray matter (GM) and white matter (WM) volume differences in 94 elderly subjects who remained cognitively normal for at least 5 years after their scan. Bivariate analyses with corrections for multiple comparisons strongly linked body mass index (BMI), fasting plasma insulin (FPI) levels, and Type II Diabetes Mellitus (DM2) with atrophy in frontal, temporal, and subcortical brain regions. A multiple regression model, also correcting for multiple comparisons, revealed that BMI was still negatively correlated with brain atrophy (FDR <5%), while DM2 and FPI were no longer associated with any volume differences. In an Analysis of Covariance (ANCOVA) model controlling for age, gender, and race, obese subjects with a high BMI (BMI > 30) showed atrophy in the frontal lobes, anterior cingulate gyrus, hippocampus, and thalamus compared with individuals with a normal BMI (18.5-25). Overweight subjects (BMI: 25-30) had atrophy in the basal ganglia and corona radiata of the WM. Overall brain volume did not differ between overweight and obese persons. Higher BMI was associated with lower brain volumes in overweight and obese elderly subjects. Obesity is therefore associated with detectable brain volume deficits in cognitively normal elderly subjects.

VL - 31 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19662657?dopt=Abstract ER - TY - JOUR T1 - Diabetes and coronary heart disease as risk factors for mortality in older adults. JF - Am J Med Y1 - 2010 A1 - Carnethon, Mercedes R A1 - Biggs, Mary L A1 - Barzilay, Joshua A1 - Kuller, Lewis H A1 - Mozaffarian, Dariush A1 - Mukamal, Kenneth A1 - Smith, Nicholas L A1 - Siscovick, David KW - Aged KW - Coronary Disease KW - Diabetes Mellitus, Type 2 KW - Female KW - Follow-Up Studies KW - Humans KW - Male KW - Prevalence KW - Risk Factors KW - Sex Distribution KW - Survival Rate KW - Time Factors KW - United States AB -

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.

VL - 123 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20569763?dopt=Abstract ER - TY - JOUR T1 - Differential white blood cell count and type 2 diabetes: systematic review and meta-analysis of cross-sectional and prospective studies. JF - PLoS One Y1 - 2010 A1 - Gkrania-Klotsas, Effrossyni A1 - Ye, Zheng A1 - Cooper, Andrew J A1 - Sharp, Stephen J A1 - Luben, Robert A1 - Biggs, Mary L A1 - Chen, Liang-Kung A1 - Gokulakrishnan, Kuppan A1 - Hanefeld, Markolf A1 - Ingelsson, Erik A1 - Lai, Wen-An A1 - Lin, Shih-Yi A1 - Lind, Lars A1 - Lohsoonthorn, Vitool A1 - Mohan, Viswanathan A1 - Muscari, Antonio A1 - Nilsson, Goran A1 - Ohrvik, John A1 - Chao Qiang, Jiang A1 - Jenny, Nancy Swords A1 - Tamakoshi, Koji A1 - Temelkova-Kurktschiev, Theodora A1 - Wang, Ya-Yu A1 - Yajnik, Chittaranjan Sakerlal A1 - Zoli, Marco A1 - Khaw, Kay-Tee A1 - Forouhi, Nita G A1 - Wareham, Nicholas J A1 - Langenberg, Claudia KW - Adult KW - Aged KW - Cross-Sectional Studies KW - Diabetes Mellitus, Type 2 KW - Female KW - Humans KW - Leukocyte Count KW - Male KW - Middle Aged KW - Prospective Studies AB -

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.

VL - 5 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20976133?dopt=Abstract ER - TY - JOUR T1 - Egg consumption and risk of type 2 diabetes in older adults. JF - Am J Clin Nutr Y1 - 2010 A1 - Djoussé, Luc A1 - Kamineni, Aruna A1 - Nelson, Tracy L A1 - Carnethon, Mercedes A1 - Mozaffarian, Dariush A1 - Siscovick, David A1 - Mukamal, Kenneth J KW - Aged KW - Blood Glucose KW - Cholesterol, Dietary KW - Diabetes Mellitus, Type 2 KW - Diet KW - Diet Surveys KW - Eggs KW - Feeding Behavior KW - Female KW - Humans KW - Insulin KW - Insulin Resistance KW - Male KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Factors KW - Surveys and Questionnaires AB -

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.

VL - 92 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20534749?dopt=Abstract ER - TY - JOUR T1 - New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. JF - Nat Genet Y1 - 2010 A1 - Dupuis, Josée A1 - Langenberg, Claudia A1 - Prokopenko, Inga A1 - Saxena, Richa A1 - Soranzo, Nicole A1 - Jackson, Anne U A1 - Wheeler, Eleanor A1 - Glazer, Nicole L A1 - Bouatia-Naji, Nabila A1 - Gloyn, Anna L A1 - Lindgren, Cecilia M A1 - Mägi, Reedik A1 - Morris, Andrew P A1 - Randall, Joshua A1 - Johnson, Toby A1 - Elliott, Paul A1 - Rybin, Denis A1 - Thorleifsson, Gudmar A1 - Steinthorsdottir, Valgerdur A1 - Henneman, Peter A1 - Grallert, Harald A1 - Dehghan, Abbas A1 - Hottenga, Jouke Jan A1 - Franklin, Christopher S A1 - Navarro, Pau A1 - Song, Kijoung A1 - Goel, Anuj A1 - Perry, John R B A1 - Egan, Josephine M A1 - Lajunen, Taina A1 - Grarup, Niels A1 - Sparsø, Thomas A1 - Doney, Alex A1 - Voight, Benjamin F A1 - Stringham, Heather M A1 - Li, Man A1 - Kanoni, Stavroula A1 - Shrader, Peter A1 - Cavalcanti-Proença, Christine A1 - Kumari, Meena A1 - Qi, Lu A1 - Timpson, Nicholas J A1 - Gieger, Christian A1 - Zabena, Carina A1 - Rocheleau, Ghislain A1 - Ingelsson, Erik A1 - An, Ping A1 - O'Connell, Jeffrey A1 - Luan, Jian'an A1 - Elliott, Amanda A1 - McCarroll, Steven A A1 - Payne, Felicity A1 - Roccasecca, Rosa Maria A1 - Pattou, François A1 - Sethupathy, Praveen A1 - Ardlie, Kristin A1 - Ariyurek, Yavuz A1 - Balkau, Beverley A1 - Barter, Philip A1 - Beilby, John P A1 - Ben-Shlomo, Yoav A1 - Benediktsson, Rafn A1 - Bennett, Amanda J A1 - Bergmann, Sven A1 - Bochud, Murielle A1 - Boerwinkle, Eric A1 - Bonnefond, Amélie A1 - Bonnycastle, Lori L A1 - Borch-Johnsen, Knut A1 - Böttcher, Yvonne A1 - Brunner, Eric A1 - Bumpstead, Suzannah J A1 - Charpentier, Guillaume A1 - Chen, Yii-Der Ida A1 - Chines, Peter A1 - Clarke, Robert A1 - Coin, Lachlan J M A1 - Cooper, Matthew N A1 - Cornelis, Marilyn A1 - Crawford, Gabe A1 - Crisponi, Laura A1 - Day, Ian N M A1 - de Geus, Eco J C A1 - Delplanque, Jerome A1 - Dina, Christian A1 - Erdos, Michael R A1 - Fedson, Annette C A1 - Fischer-Rosinsky, Antje A1 - Forouhi, Nita G A1 - Fox, Caroline S A1 - Frants, Rune A1 - Franzosi, Maria Grazia A1 - Galan, Pilar A1 - Goodarzi, Mark O A1 - Graessler, Jürgen A1 - Groves, Christopher J A1 - Grundy, Scott A1 - Gwilliam, Rhian A1 - Gyllensten, Ulf A1 - Hadjadj, Samy A1 - Hallmans, Göran A1 - Hammond, Naomi A1 - Han, Xijing A1 - Hartikainen, Anna-Liisa A1 - Hassanali, Neelam A1 - Hayward, Caroline A1 - Heath, Simon C A1 - Hercberg, Serge A1 - Herder, Christian A1 - Hicks, Andrew A A1 - Hillman, David R A1 - Hingorani, Aroon D A1 - Hofman, Albert A1 - Hui, Jennie A1 - Hung, Joe A1 - Isomaa, Bo A1 - Johnson, Paul R V A1 - Jørgensen, Torben A1 - Jula, Antti A1 - Kaakinen, Marika A1 - Kaprio, Jaakko A1 - Kesaniemi, Y Antero A1 - Kivimaki, Mika A1 - Knight, Beatrice A1 - Koskinen, Seppo A1 - Kovacs, Peter A1 - Kyvik, Kirsten Ohm A1 - Lathrop, G Mark A1 - Lawlor, Debbie A A1 - Le Bacquer, Olivier A1 - Lecoeur, Cécile A1 - Li, Yun A1 - Lyssenko, Valeriya A1 - Mahley, Robert A1 - Mangino, Massimo A1 - Manning, Alisa K A1 - Martínez-Larrad, María Teresa A1 - McAteer, Jarred B A1 - McCulloch, Laura J A1 - McPherson, Ruth A1 - Meisinger, Christa A1 - Melzer, David A1 - Meyre, David A1 - Mitchell, Braxton D A1 - Morken, Mario A A1 - Mukherjee, Sutapa A1 - Naitza, Silvia A1 - Narisu, Narisu A1 - Neville, Matthew J A1 - Oostra, Ben A A1 - Orrù, Marco A1 - Pakyz, Ruth A1 - Palmer, Colin N A A1 - Paolisso, Giuseppe A1 - Pattaro, Cristian A1 - Pearson, Daniel A1 - Peden, John F A1 - Pedersen, Nancy L A1 - Perola, Markus A1 - Pfeiffer, Andreas F H A1 - Pichler, Irene A1 - Polasek, Ozren A1 - Posthuma, Danielle A1 - Potter, Simon C A1 - Pouta, Anneli A1 - Province, Michael A A1 - Psaty, Bruce M A1 - Rathmann, Wolfgang A1 - Rayner, Nigel W A1 - Rice, Kenneth A1 - Ripatti, Samuli A1 - Rivadeneira, Fernando A1 - Roden, Michael A1 - Rolandsson, Olov A1 - Sandbaek, Annelli A1 - Sandhu, Manjinder A1 - Sanna, Serena A1 - Sayer, Avan Aihie A1 - Scheet, Paul A1 - Scott, Laura J A1 - Seedorf, Udo A1 - Sharp, Stephen J A1 - Shields, Beverley A1 - Sigurethsson, Gunnar A1 - Sijbrands, Eric J G A1 - Silveira, Angela A1 - Simpson, Laila A1 - Singleton, Andrew A1 - Smith, Nicholas L A1 - Sovio, Ulla A1 - Swift, Amy A1 - Syddall, Holly A1 - Syvänen, Ann-Christine A1 - Tanaka, Toshiko A1 - Thorand, Barbara A1 - Tichet, Jean A1 - Tönjes, Anke A1 - Tuomi, Tiinamaija A1 - Uitterlinden, André G A1 - van Dijk, Ko Willems A1 - van Hoek, Mandy A1 - Varma, Dhiraj A1 - Visvikis-Siest, Sophie A1 - Vitart, Veronique A1 - Vogelzangs, Nicole A1 - Waeber, Gérard A1 - Wagner, Peter J A1 - Walley, Andrew A1 - Walters, G Bragi A1 - Ward, Kim L A1 - Watkins, Hugh A1 - Weedon, Michael N A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Witteman, Jaqueline C M A1 - Yarnell, John W G A1 - Zeggini, Eleftheria A1 - Zelenika, Diana A1 - Zethelius, Björn A1 - Zhai, Guangju A1 - Zhao, Jing Hua A1 - Zillikens, M Carola A1 - Borecki, Ingrid B A1 - Loos, Ruth J F A1 - Meneton, Pierre A1 - Magnusson, Patrik K E A1 - Nathan, David M A1 - Williams, Gordon H A1 - Hattersley, Andrew T A1 - Silander, Kaisa A1 - Salomaa, Veikko A1 - Smith, George Davey A1 - Bornstein, Stefan R A1 - Schwarz, Peter A1 - Spranger, Joachim A1 - Karpe, Fredrik A1 - Shuldiner, Alan R A1 - Cooper, Cyrus A1 - Dedoussis, George V A1 - Serrano-Ríos, Manuel A1 - Morris, Andrew D A1 - Lind, Lars A1 - Palmer, Lyle J A1 - Hu, Frank B A1 - Franks, Paul W A1 - Ebrahim, Shah A1 - Marmot, Michael A1 - Kao, W H Linda A1 - Pankow, James S A1 - Sampson, Michael J A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Hansen, Torben A1 - Pedersen, Oluf A1 - Pramstaller, Peter Paul A1 - Wichmann, H Erich A1 - Illig, Thomas A1 - Rudan, Igor A1 - Wright, Alan F A1 - Stumvoll, Michael A1 - Campbell, Harry A1 - Wilson, James F A1 - Bergman, Richard N A1 - Buchanan, Thomas A A1 - Collins, Francis S A1 - Mohlke, Karen L A1 - Tuomilehto, Jaakko A1 - Valle, Timo T A1 - Altshuler, David A1 - Rotter, Jerome I A1 - Siscovick, David S A1 - Penninx, Brenda W J H A1 - Boomsma, Dorret I A1 - Deloukas, Panos A1 - Spector, Timothy D A1 - Frayling, Timothy M A1 - Ferrucci, Luigi A1 - Kong, Augustine A1 - Thorsteinsdottir, Unnur A1 - Stefansson, Kari A1 - van Duijn, Cornelia M A1 - Aulchenko, Yurii S A1 - Cao, Antonio A1 - Scuteri, Angelo A1 - Schlessinger, David A1 - Uda, Manuela A1 - Ruokonen, Aimo A1 - Jarvelin, Marjo-Riitta A1 - Waterworth, Dawn M A1 - Vollenweider, Peter A1 - Peltonen, Leena A1 - Mooser, Vincent A1 - Abecasis, Goncalo R A1 - Wareham, Nicholas J A1 - Sladek, Robert A1 - Froguel, Philippe A1 - Watanabe, Richard M A1 - Meigs, James B A1 - Groop, Leif A1 - Boehnke, Michael A1 - McCarthy, Mark I A1 - Florez, Jose C A1 - Barroso, Inês KW - Adolescent KW - Adult KW - Alleles KW - Blood Glucose KW - Child KW - Databases, Genetic KW - Diabetes Mellitus, Type 2 KW - DNA Copy Number Variations KW - Fasting KW - Gene Expression Regulation KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Homeostasis KW - Humans KW - Meta-Analysis as Topic KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Quantitative Trait, Heritable KW - Reproducibility of Results AB -

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

VL - 42 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20081858?dopt=Abstract ER - TY - JOUR T1 - Trans-palmitoleic acid, metabolic risk factors, and new-onset diabetes in U.S. adults: a cohort study. JF - Ann Intern Med Y1 - 2010 A1 - Mozaffarian, Dariush A1 - Cao, Haiming A1 - King, Irena B A1 - Lemaitre, Rozenn N A1 - Song, Xiaoling A1 - Siscovick, David S A1 - Hotamisligil, Gökhan S KW - Adiposity KW - Aged KW - C-Reactive Protein KW - Cholesterol KW - Cholesterol, HDL KW - Dairy Products KW - Diabetes Mellitus, Type 2 KW - Fatty Acids, Monounsaturated KW - Feeding Behavior KW - Female KW - Humans KW - Incidence KW - Insulin Resistance KW - Male KW - Prospective Studies KW - Risk Factors KW - Triglycerides KW - United States AB -

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.

VL - 153 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21173413?dopt=Abstract ER - TY - JOUR T1 - Candidate gene association study for diabetic retinopathy in persons with type 2 diabetes: the Candidate gene Association Resource (CARe). JF - Invest Ophthalmol Vis Sci Y1 - 2011 A1 - Sobrin, Lucia A1 - Green, Todd A1 - Sim, Xueling A1 - Jensen, Richard A A1 - Tai, E Shyong A1 - Tay, Wan Ting A1 - Wang, Jie Jin A1 - Mitchell, Paul A1 - Sandholm, Niina A1 - Liu, Yiyuan A1 - Hietala, Kustaa A1 - Iyengar, Sudha K A1 - Brooks, Matthew A1 - Buraczynska, Monika A1 - Van Zuydam, Natalie A1 - Smith, Albert V A1 - Gudnason, Vilmundur A1 - Doney, Alex S F A1 - Morris, Andrew D A1 - Leese, Graham P A1 - Palmer, Colin N A A1 - Swaroop, Anand A1 - Taylor, Herman A A1 - Wilson, James G A1 - Penman, Alan A1 - Chen, Ching J A1 - Groop, Per-Henrik A1 - Saw, Seang-Mei A1 - Aung, Tin A1 - Klein, Barbara E A1 - Rotter, Jerome I A1 - Siscovick, David S A1 - Cotch, Mary Frances A1 - Klein, Ronald A1 - Daly, Mark J A1 - Wong, Tien Y KW - Cardiovascular Diseases KW - Diabetes Mellitus, Type 2 KW - Diabetic Nephropathies KW - Diabetic Retinopathy KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Iduronidase KW - Odds Ratio KW - P-Selectin KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

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

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

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

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

VL - 52 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21873659?dopt=Abstract ER - TY - JOUR T1 - Enhanced statistical tests for GWAS in admixed populations: assessment using African Americans from CARe and a Breast Cancer Consortium. JF - PLoS Genet Y1 - 2011 A1 - Pasaniuc, Bogdan A1 - Zaitlen, Noah A1 - Lettre, Guillaume A1 - Chen, Gary K A1 - Tandon, Arti A1 - Kao, W H Linda A1 - Ruczinski, Ingo A1 - Fornage, Myriam A1 - Siscovick, David S A1 - Zhu, Xiaofeng A1 - Larkin, Emma A1 - Lange, Leslie A A1 - Cupples, L Adrienne A1 - Yang, Qiong A1 - Akylbekova, Ermeg L A1 - Musani, Solomon K A1 - Divers, Jasmin A1 - Mychaleckyj, Joe A1 - Li, Mingyao A1 - Papanicolaou, George J A1 - Millikan, Robert C A1 - Ambrosone, Christine B A1 - John, Esther M A1 - Bernstein, Leslie A1 - Zheng, Wei A1 - Hu, Jennifer J A1 - Ziegler, Regina G A1 - Nyante, Sarah J A1 - Bandera, Elisa V A1 - Ingles, Sue A A1 - Press, Michael F A1 - Chanock, Stephen J A1 - Deming, Sandra L A1 - Rodriguez-Gil, Jorge L A1 - Palmer, Cameron D A1 - Buxbaum, Sarah A1 - Ekunwe, Lynette A1 - Hirschhorn, Joel N A1 - Henderson, Brian E A1 - Myers, Simon A1 - Haiman, Christopher A A1 - Reich, David A1 - Patterson, Nick A1 - Wilson, James G A1 - Price, Alkes L KW - African Americans KW - Algorithms KW - Breast Neoplasms KW - Chromosome Mapping KW - Coronary Disease KW - Diabetes Mellitus, Type 2 KW - Female KW - Gene Frequency KW - Genetic Variation KW - Genetics, Population KW - Genome, Human KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Linkage Disequilibrium KW - Male KW - Odds Ratio KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Principal Component Analysis KW - Receptor, Fibroblast Growth Factor, Type 2 KW - Software AB -

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

VL - 7 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21541012?dopt=Abstract ER - TY - JOUR T1 - Lipoprotein-associated phospholipase A(2) and future risk of subclinical disease and cardiovascular events in individuals with type 2 diabetes: the Cardiovascular Health Study. JF - Diabetologia Y1 - 2011 A1 - Nelson, T L A1 - Kamineni, A A1 - Psaty, B A1 - Cushman, M A1 - Jenny, N S A1 - Hokanson, J A1 - Furberg, C A1 - Mukamal, K J KW - 1-Alkyl-2-acetylglycerophosphocholine Esterase KW - Aged KW - Cardiovascular Diseases KW - Cross-Sectional Studies KW - Diabetes Mellitus, Type 2 KW - Female KW - Humans KW - Male KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Factors AB -

AIMS/HYPOTHESIS: Type 2 diabetes is an established risk factor for cardiovascular disease (CVD). This increased risk may be due in part to the increased levels of inflammatory factors associated with diabetes. Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is a risk marker for CVD and has pro-inflammatory effects in atherosclerotic plaques. We therefore sought to determine whether Lp-PLA(2) levels partially explain the greater prevalence of subclinical CVD and greater incidence of CVD outcomes associated with type 2 diabetes in the Cardiovascular Health Study.

METHODS: We conducted a cross-sectional and prospective study of 4,062 men and women without previous CVD from the Cardiovascular Health Study (1989 to 2007). Lp-PLA(2) mass and activity were measured in baseline plasma. Subclinical disease was determined at baseline and incident CVD was ascertained annually. We used logistic regression for cross-sectional analyses and Cox proportional hazards models for incident analyses.

RESULTS: At baseline, Lp-PLA(2) mass did not differ significantly by type 2 diabetes status; however, Lp-PLA(2) activity was significantly higher among type 2 diabetic individuals. Baseline subclinical disease was significantly associated with baseline diabetes and this association was similar in models unadjusted or adjusted for Lp-PLA(2) (OR 1.68 [95% CI 1.31-2.15] vs OR 1.67 [95% CI 1.30-2.13]). Baseline type 2 diabetes was also significantly associated with incident CVD events, including fatal CHD, fatal myocardial infarction (MI) and non-fatal MI in multivariable analyses. There were no differences in these estimates after further adjustment for Lp-PLA(2) activity.

CONCLUSIONS/INTERPRETATION: In this older cohort, differences in Lp-PLA(2) activity did not explain any of the excess risk for subclinical disease or CVD outcomes related to diabetes.

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

INTRODUCTION: Genetic discoveries are validated through the meta-analysis of genome-wide association scans in large international consortia. Because environmental variables may interact with genetic factors, investigation of differing genetic effects for distinct levels of an environmental exposure in these large consortia may yield additional susceptibility loci undetected by main effects analysis. We describe a method of joint meta-analysis (JMA) of SNP and SNP by Environment (SNP × E) regression coefficients for use in gene-environment interaction studies.

METHODS: In testing SNP × E interactions, one approach uses a two degree of freedom test to identify genetic variants that influence the trait of interest. This approach detects both main and interaction effects between the trait and the SNP. We propose a method to jointly meta-analyze the SNP and SNP × E coefficients using multivariate generalized least squares. This approach provides confidence intervals of the two estimates, a joint significance test for SNP and SNP × E terms, and a test of homogeneity across samples.

RESULTS: We present a simulation study comparing this method to four other methods of meta-analysis and demonstrate that the JMA performs better than the others when both main and interaction effects are present. Additionally, we implemented our methods in a meta-analysis of the association between SNPs from the type 2 diabetes-associated gene PPARG and log-transformed fasting insulin levels and interaction by body mass index in a combined sample of 19,466 individuals from five cohorts.

VL - 35 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21181894?dopt=Abstract ER - TY - JOUR T1 - Association of fetuin-a with incident diabetes mellitus in community-living older adults: the cardiovascular health study. JF - Circulation Y1 - 2012 A1 - Ix, Joachim H A1 - Biggs, Mary L A1 - Mukamal, Kenneth J A1 - Kizer, Jorge R A1 - Zieman, Susan J A1 - Siscovick, David S A1 - Mozzaffarian, Dariush A1 - Jensen, Majken K A1 - Nelson, Lauren A1 - Ruderman, Neil A1 - Djoussé, Luc KW - African Continental Ancestry Group KW - Age Distribution KW - Aged KW - Aged, 80 and over KW - alpha-2-HS-Glycoprotein KW - Body Mass Index KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Diabetes Mellitus, Type 2 KW - European Continental Ancestry Group KW - Female KW - Humans KW - Incidence KW - Life Style KW - Lipids KW - Male KW - Pilot Projects KW - Prevalence KW - Proportional Hazards Models KW - Residence Characteristics KW - Risk Factors KW - Sex Distribution AB -

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

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

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

VL - 125 IS - 19 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22511752?dopt=Abstract ER - TY - JOUR T1 - Association of weight status with mortality in adults with incident diabetes. JF - JAMA Y1 - 2012 A1 - Carnethon, Mercedes R A1 - De Chavez, Peter John D A1 - Biggs, Mary L A1 - Lewis, Cora E A1 - Pankow, James S A1 - Bertoni, Alain G A1 - Golden, Sherita H A1 - Liu, Kiang A1 - Mukamal, Kenneth J A1 - Campbell-Jenkins, Brenda A1 - Dyer, Alan R KW - Adult KW - Aged KW - Aged, 80 and over KW - Body Mass Index KW - Body Weight KW - Cardiovascular Diseases KW - Cause of Death KW - Diabetes Mellitus, Type 2 KW - Female KW - Humans KW - Longitudinal Studies KW - Male KW - Middle Aged KW - Obesity KW - Overweight KW - United States AB -

CONTEXT: Type 2 diabetes in normal-weight adults (body mass index [BMI] <25) is a representation of the metabolically obese normal-weight phenotype with unknown mortality consequences.

OBJECTIVE: To test the association of weight status with mortality in adults with new-onset diabetes in order to minimize the influence of diabetes duration and voluntary weight loss on mortality.

DESIGN, SETTING, AND PARTICIPANTS: Pooled analysis of 5 longitudinal cohort studies: Atherosclerosis Risk in Communities study, 1990-2006; Cardiovascular Health Study, 1992-2008; Coronary Artery Risk Development in Young Adults, 1987-2011; Framingham Offspring Study, 1979-2007; and Multi-Ethnic Study of Atherosclerosis, 2002-2011. A total of 2625 participants with incident diabetes contributed 27,125 person-years of follow-up. Included were men and women (age >40 years) who developed incident diabetes based on fasting glucose 126 mg/dL or greater or newly initiated diabetes medication and who had concurrent measurements of BMI. Participants were classified as normal weight if their BMI was 18.5 to 24.99 or overweight/obese if BMI was 25 or greater.

MAIN OUTCOME MEASURES: Total, cardiovascular, and noncardiovascular mortality.

RESULTS: The proportion of adults who were normal weight at the time of incident diabetes ranged from 9% to 21% (overall 12%). During follow-up, 449 participants died: 178 from cardiovascular causes and 253 from noncardiovascular causes (18 were not classified). The rates of total, cardiovascular, and noncardiovascular mortality were higher in normal-weight participants (284.8, 99.8, and 198.1 per 10,000 person-years, respectively) than in overweight/obese participants (152.1, 67.8, and 87.9 per 10,000 person-years, respectively). After adjustment for demographic characteristics and blood pressure, lipid levels, waist circumference, and smoking status, hazard ratios comparing normal-weight participants with overweight/obese participants for total, cardiovascular, and noncardiovascular mortality were 2.08 (95% CI, 1.52-2.85), 1.52 (95% CI, 0.89-2.58), and 2.32 (95% CI, 1.55-3.48), respectively.

CONCLUSION: Adults who were normal weight at the time of incident diabetes had higher mortality than adults who are overweight or obese.

VL - 308 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22871870?dopt=Abstract ER - TY - JOUR T1 - Common genetic variants differentially influence the transition from clinically defined states of fasting glucose metabolism. JF - Diabetologia Y1 - 2012 A1 - Walford, G A A1 - Green, T A1 - Neale, B A1 - Isakova, T A1 - Rotter, J I A1 - Grant, S F A A1 - Fox, C S A1 - Pankow, J S A1 - Wilson, J G A1 - Meigs, J B A1 - Siscovick, D S A1 - Bowden, D W A1 - Daly, M J A1 - Florez, J C KW - Adult KW - Aged KW - Blood Glucose KW - Cohort Studies KW - Diabetes Mellitus, Type 2 KW - Disease Progression KW - Fasting KW - Female KW - Genetic Variation KW - Genotype KW - Humans KW - Male KW - Middle Aged KW - Models, Genetic KW - Polymorphism, Single Nucleotide KW - Proportional Hazards Models KW - Regression Analysis KW - Risk AB -

AIMS/HYPOTHESIS: Common genetic variants have been associated with type 2 diabetes. We hypothesised that a subset of these variants may have different effects on the transition from normal fasting glucose (NFG) to impaired fasting glucose (IFG) than on that from IFG to diabetes.

METHODS: We identified 16 type 2 diabetes risk variants from the Illumina Broad Candidate-gene Association Resource (CARe) array genotyped in 26,576 CARe participants. Participants were categorised at baseline as NFG, IFG or type 2 diabetic (n = 16,465, 8,017 or 2,291, respectively). Using Cox proportional hazards and likelihood ratio tests (LRTs), we compared rates of progression by genotype for 4,909 (NFG to IFG) and 1,518 (IFG to type 2 diabetes) individuals, respectively. We then performed multinomial regression analyses at baseline, comparing the risk of assignment to the NFG, IFG or diabetes groups by genotype.

RESULTS: The rate of progression from NFG to IFG was significantly greater in participants carrying the risk allele at MTNR1B (p = 1 × 10(-4)), nominally greater at GCK and SLC30A8 (p < 0.05) and nominally smaller at IGF2BP2 (p = 0.01) than the rate of progression from IFG to diabetes by the LRT. Results of the baseline, multinomial regression model were consistent with these findings.

CONCLUSIONS/INTERPRETATION: Common genetic risk variants at GCK, SLC30A8, IGF2BP2 and MTNR1B influence to different extents the development of IFG and the transition from IFG to type 2 diabetes. Our findings may have implications for understanding the genetic contribution of these variants to the development of IFG and type 2 diabetes.

VL - 55 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22038522?dopt=Abstract ER - TY - JOUR T1 - Consistent directions of effect for established type 2 diabetes risk variants across populations: the population architecture using Genomics and Epidemiology (PAGE) Consortium. JF - Diabetes Y1 - 2012 A1 - Haiman, Christopher A A1 - Fesinmeyer, Megan D A1 - Spencer, Kylee L A1 - Bůzková, Petra A1 - Voruganti, V Saroja A1 - Wan, Peggy A1 - Haessler, Jeff A1 - Franceschini, Nora A1 - Monroe, Kristine R A1 - Howard, Barbara V A1 - Jackson, Rebecca D A1 - Florez, Jose C A1 - Kolonel, Laurence N A1 - Buyske, Steven A1 - Goodloe, Robert J A1 - Liu, Simin A1 - Manson, JoAnn E A1 - Meigs, James B A1 - Waters, Kevin A1 - Mukamal, Kenneth J A1 - Pendergrass, Sarah A A1 - Shrader, Peter A1 - Wilkens, Lynne R A1 - Hindorff, Lucia A A1 - Ambite, Jose Luis A1 - North, Kari E A1 - Peters, Ulrike A1 - Crawford, Dana C A1 - Le Marchand, Loïc A1 - Pankow, James S KW - Adult KW - Aged KW - Aged, 80 and over KW - Alleles KW - Diabetes Mellitus, Type 2 KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Male KW - Metagenomics KW - Middle Aged KW - Population Groups KW - Risk KW - Risk Factors AB -

Common genetic risk variants for type 2 diabetes (T2D) have primarily been identified in populations of European and Asian ancestry. We tested whether the direction of association with 20 T2D risk variants generalizes across six major racial/ethnic groups in the U.S. as part of the Population Architecture using Genomics and Epidemiology Consortium (16,235 diabetes case and 46,122 control subjects of European American, African American, Hispanic, East Asian, American Indian, and Native Hawaiian ancestry). The percentage of positive (odds ratio [OR] >1 for putative risk allele) associations ranged from 69% in American Indians to 100% in European Americans. Of the nine variants where we observed significant heterogeneity of effect by racial/ethnic group (P(heterogeneity) < 0.05), eight were positively associated with risk (OR >1) in at least five groups. The marked directional consistency of association observed for most genetic variants across populations implies a shared functional common variant in each region. Fine-mapping of all loci will be required to reveal markers of risk that are important within and across populations.

VL - 61 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22474029?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation. JF - Blood Y1 - 2012 A1 - Huang, Jie A1 - Sabater-Lleal, Maria A1 - Asselbergs, Folkert W A1 - Tregouet, David A1 - Shin, So-Youn A1 - Ding, Jingzhong A1 - Baumert, Jens A1 - Oudot-Mellakh, Tiphaine A1 - Folkersen, Lasse A1 - Johnson, Andrew D A1 - Smith, Nicholas L A1 - Williams, Scott M A1 - Ikram, Mohammad A A1 - Kleber, Marcus E A1 - Becker, Diane M A1 - Truong, Vinh A1 - Mychaleckyj, Josyf C A1 - Tang, Weihong A1 - Yang, Qiong A1 - Sennblad, Bengt A1 - Moore, Jason H A1 - Williams, Frances M K A1 - Dehghan, Abbas A1 - Silbernagel, Günther A1 - Schrijvers, Elisabeth M C A1 - Smith, Shelly A1 - Karakas, Mahir A1 - Tofler, Geoffrey H A1 - Silveira, Angela A1 - Navis, Gerjan J A1 - Lohman, Kurt A1 - Chen, Ming-Huei A1 - Peters, Annette A1 - Goel, Anuj A1 - Hopewell, Jemma C A1 - Chambers, John C A1 - Saleheen, Danish A1 - Lundmark, Per A1 - Psaty, Bruce M A1 - Strawbridge, Rona J A1 - Boehm, Bernhard O A1 - Carter, Angela M A1 - Meisinger, Christa A1 - Peden, John F A1 - Bis, Joshua C A1 - McKnight, Barbara A1 - Ohrvik, John A1 - Taylor, Kent A1 - Franzosi, Maria Grazia A1 - Seedorf, Udo A1 - Collins, Rory A1 - Franco-Cereceda, Anders A1 - Syvänen, Ann-Christine A1 - Goodall, Alison H A1 - Yanek, Lisa R A1 - Cushman, Mary A1 - Müller-Nurasyid, Martina A1 - Folsom, Aaron R A1 - Basu, Saonli A1 - Matijevic, Nena A1 - van Gilst, Wiek H A1 - Kooner, Jaspal S A1 - Hofman, Albert A1 - Danesh, John A1 - Clarke, Robert A1 - Meigs, James B A1 - Kathiresan, Sekar A1 - Reilly, Muredach P A1 - Klopp, Norman A1 - Harris, Tamara B A1 - Winkelmann, Bernhard R A1 - Grant, Peter J A1 - Hillege, Hans L A1 - Watkins, Hugh A1 - Spector, Timothy D A1 - Becker, Lewis C A1 - Tracy, Russell P A1 - März, Winfried A1 - Uitterlinden, André G A1 - Eriksson, Per A1 - Cambien, Francois A1 - Morange, Pierre-Emmanuel A1 - Koenig, Wolfgang A1 - Soranzo, Nicole A1 - van der Harst, Pim A1 - Liu, Yongmei A1 - O'Donnell, Christopher J A1 - Hamsten, Anders KW - Adaptor Proteins, Signal Transducing KW - ARNTL Transcription Factors KW - ATPases Associated with Diverse Cellular Activities KW - Cell Line KW - Cell Line, Tumor KW - Cohort Studies KW - Coronary Artery Disease KW - Diabetes Mellitus, Type 2 KW - Gene Expression Profiling KW - Gene Expression Regulation KW - Gene Frequency KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - LIM Domain Proteins KW - Meta-Analysis as Topic KW - Monocytes KW - Mucin-3 KW - Plasminogen Activator Inhibitor 1 KW - Polymorphism, Single Nucleotide KW - PPAR gamma KW - Proteasome Endopeptidase Complex KW - RNA Interference KW - Transcription Factors AB -

We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery meta-analysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P < 5 × 10(-8)) single nucleotide polymorphisms (SNPs) in 10 796 independent samples. We further examined associations with type 2 diabetes and coronary artery disease, assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA-silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1 (7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1 (rs6976053, discovery P = 3.4 × 10(-10)); chromosome 11p15.2 within ARNTL (rs6486122, discovery P = 3.0 × 10(-8)); and chromosome 3p25.2 within PPARG (rs11128603, discovery P = 2.9 × 10(-8)). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with type 2 diabetes and coronary artery disease at ARNTL (P < .05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL and an SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1.

VL - 120 IS - 24 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22990020?dopt=Abstract ER - TY - JOUR T1 - Insulin resistance and incident peripheral artery disease in the Cardiovascular Health Study. JF - Vasc Med Y1 - 2012 A1 - Britton, Kathryn A A1 - Mukamal, Kenneth J A1 - Ix, Joachim H A1 - Siscovick, David S A1 - Newman, Anne B A1 - de Boer, Ian H A1 - Thacker, Evan L A1 - Biggs, Mary L A1 - Gaziano, J Michael A1 - Djoussé, Luc KW - Aged KW - Ankle Brachial Index KW - Biomarkers KW - Blood Glucose KW - Diabetes Mellitus, Type 2 KW - Diabetic Angiopathies KW - Fasting KW - Female KW - Health Surveys KW - Humans KW - Incidence KW - Insulin KW - Insulin Resistance KW - Logistic Models KW - Longitudinal Studies KW - Male KW - Odds Ratio KW - Peripheral Arterial Disease KW - Predictive Value of Tests KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Assessment KW - Risk Factors KW - Time Factors KW - United States AB -

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

VL - 17 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22402937?dopt=Abstract ER - TY - JOUR T1 - Lipoprotein-associated phospholipase A2 (Lp-PLA2) and future risk of type 2 diabetes: results from the Cardiovascular Health Study. JF - J Clin Endocrinol Metab Y1 - 2012 A1 - Nelson, T L A1 - Biggs, M L A1 - Kizer, J R A1 - Cushman, M A1 - Hokanson, J E A1 - Furberg, C D A1 - Mukamal, K J KW - 1-Alkyl-2-acetylglycerophosphocholine Esterase KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Diabetes Mellitus, Type 2 KW - Female KW - Humans KW - Incidence KW - Insulin Resistance KW - Male KW - Middle Aged KW - Predictive Value of Tests KW - Prevalence KW - Prospective Studies KW - Risk KW - Risk Factors AB -

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.

VL - 97 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22399516?dopt=Abstract ER - TY - JOUR T1 - Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals. JF - PLoS Genet Y1 - 2012 A1 - Dastani, Zari A1 - Hivert, Marie-France A1 - Timpson, Nicholas A1 - Perry, John R B A1 - Yuan, Xin A1 - Scott, Robert A A1 - Henneman, Peter A1 - Heid, Iris M A1 - Kizer, Jorge R A1 - Lyytikäinen, Leo-Pekka A1 - Fuchsberger, Christian A1 - Tanaka, Toshiko A1 - Morris, Andrew P A1 - Small, Kerrin A1 - Isaacs, Aaron A1 - Beekman, Marian A1 - Coassin, Stefan A1 - Lohman, Kurt A1 - Qi, Lu A1 - Kanoni, Stavroula A1 - Pankow, James S A1 - Uh, Hae-Won A1 - Wu, Ying A1 - Bidulescu, Aurelian A1 - Rasmussen-Torvik, Laura J A1 - Greenwood, Celia M T A1 - Ladouceur, Martin A1 - Grimsby, Jonna A1 - Manning, Alisa K A1 - Liu, Ching-Ti A1 - Kooner, Jaspal A1 - Mooser, Vincent E A1 - Vollenweider, Peter A1 - Kapur, Karen A A1 - Chambers, John A1 - Wareham, Nicholas J A1 - Langenberg, Claudia A1 - Frants, Rune A1 - Willems-Vandijk, Ko A1 - Oostra, Ben A A1 - Willems, Sara M A1 - Lamina, Claudia A1 - Winkler, Thomas W A1 - Psaty, Bruce M A1 - Tracy, Russell P A1 - Brody, Jennifer A1 - Chen, Ida A1 - Viikari, Jorma A1 - Kähönen, Mika A1 - Pramstaller, Peter P A1 - Evans, David M A1 - St Pourcain, Beate A1 - Sattar, Naveed A1 - Wood, Andrew R A1 - Bandinelli, Stefania A1 - Carlson, Olga D A1 - Egan, Josephine M A1 - Böhringer, Stefan A1 - van Heemst, Diana A1 - Kedenko, Lyudmyla A1 - Kristiansson, Kati A1 - Nuotio, Marja-Liisa A1 - Loo, Britt-Marie A1 - Harris, Tamara A1 - Garcia, Melissa A1 - Kanaya, Alka A1 - Haun, Margot A1 - Klopp, Norman A1 - Wichmann, H-Erich A1 - Deloukas, Panos A1 - Katsareli, Efi A1 - Couper, David J A1 - Duncan, Bruce B A1 - Kloppenburg, Margreet A1 - Adair, Linda S A1 - Borja, Judith B A1 - Wilson, James G A1 - Musani, Solomon A1 - Guo, Xiuqing A1 - Johnson, Toby A1 - Semple, Robert A1 - Teslovich, Tanya M A1 - Allison, Matthew A A1 - Redline, Susan A1 - Buxbaum, Sarah G A1 - Mohlke, Karen L A1 - Meulenbelt, Ingrid A1 - Ballantyne, Christie M A1 - Dedoussis, George V A1 - Hu, Frank B A1 - Liu, Yongmei A1 - Paulweber, Bernhard A1 - Spector, Timothy D A1 - Slagboom, P Eline A1 - Ferrucci, Luigi A1 - Jula, Antti A1 - Perola, Markus A1 - Raitakari, Olli A1 - Florez, Jose C A1 - Salomaa, Veikko A1 - Eriksson, Johan G A1 - Frayling, Timothy M A1 - Hicks, Andrew A A1 - Lehtimäki, Terho A1 - Smith, George Davey A1 - Siscovick, David S A1 - Kronenberg, Florian A1 - van Duijn, Cornelia A1 - Loos, Ruth J F A1 - Waterworth, Dawn M A1 - Meigs, James B A1 - Dupuis, Josée A1 - Richards, J Brent A1 - Voight, Benjamin F A1 - Scott, Laura J A1 - Steinthorsdottir, Valgerdur A1 - Dina, Christian A1 - Welch, Ryan P A1 - Zeggini, Eleftheria A1 - Huth, Cornelia A1 - Aulchenko, Yurii S A1 - Thorleifsson, Gudmar A1 - McCulloch, Laura J A1 - Ferreira, Teresa A1 - Grallert, Harald A1 - Amin, Najaf A1 - Wu, Guanming A1 - Willer, Cristen J A1 - Raychaudhuri, Soumya A1 - McCarroll, Steve A A1 - Hofmann, Oliver M A1 - Segrè, Ayellet V A1 - van Hoek, Mandy A1 - Navarro, Pau A1 - Ardlie, Kristin A1 - Balkau, Beverley A1 - Benediktsson, Rafn A1 - Bennett, Amanda J A1 - Blagieva, Roza A1 - Boerwinkle, Eric A1 - Bonnycastle, Lori L A1 - Boström, Kristina Bengtsson A1 - Bravenboer, Bert A1 - Bumpstead, Suzannah A1 - Burtt, Noel P A1 - Charpentier, Guillaume A1 - Chines, Peter S A1 - Cornelis, Marilyn A1 - Crawford, Gabe A1 - Doney, Alex S F A1 - Elliott, Katherine S A1 - Elliott, Amanda L A1 - Erdos, Michael R A1 - Fox, Caroline S A1 - Franklin, Christopher S A1 - Ganser, Martha A1 - Gieger, Christian A1 - Grarup, Niels A1 - Green, Todd A1 - Griffin, Simon A1 - Groves, Christopher J A1 - Guiducci, Candace A1 - Hadjadj, Samy A1 - Hassanali, Neelam A1 - Herder, Christian A1 - Isomaa, Bo A1 - Jackson, Anne U A1 - Johnson, Paul R V A1 - Jørgensen, Torben A1 - Kao, Wen H L A1 - Kong, Augustine A1 - Kraft, Peter A1 - Kuusisto, Johanna A1 - Lauritzen, Torsten A1 - Li, Man A1 - Lieverse, Aloysius A1 - Lindgren, Cecilia M A1 - Lyssenko, Valeriya A1 - Marre, Michel A1 - Meitinger, Thomas A1 - Midthjell, Kristian A1 - Morken, Mario A A1 - Narisu, Narisu A1 - Nilsson, Peter A1 - Owen, Katharine R A1 - Payne, Felicity A1 - Petersen, Ann-Kristin A1 - Platou, Carl A1 - Proença, Christine A1 - Prokopenko, Inga A1 - Rathmann, Wolfgang A1 - Rayner, N William A1 - Robertson, Neil R A1 - Rocheleau, Ghislain A1 - Roden, Michael A1 - Sampson, Michael J A1 - Saxena, Richa A1 - Shields, Beverley M A1 - Shrader, Peter A1 - Sigurdsson, Gunnar A1 - Sparsø, Thomas A1 - Strassburger, Klaus A1 - Stringham, Heather M A1 - Sun, Qi A1 - Swift, Amy J A1 - Thorand, Barbara A1 - Tichet, Jean A1 - Tuomi, Tiinamaija A1 - van Dam, Rob M A1 - van Haeften, Timon W A1 - van Herpt, Thijs A1 - van Vliet-Ostaptchouk, Jana V A1 - Walters, G Bragi A1 - Weedon, Michael N A1 - Wijmenga, Cisca A1 - Witteman, Jacqueline A1 - Bergman, Richard N A1 - Cauchi, Stephane A1 - Collins, Francis S A1 - Gloyn, Anna L A1 - Gyllensten, Ulf A1 - Hansen, Torben A1 - Hide, Winston A A1 - Hitman, Graham A A1 - Hofman, Albert A1 - Hunter, David J A1 - Hveem, Kristian A1 - Laakso, Markku A1 - Morris, Andrew D A1 - Palmer, Colin N A A1 - Rudan, Igor A1 - Sijbrands, Eric A1 - Stein, Lincoln D A1 - Tuomilehto, Jaakko A1 - Uitterlinden, Andre A1 - Walker, Mark A1 - Watanabe, Richard M A1 - Abecasis, Goncalo R A1 - Boehm, Bernhard O A1 - Campbell, Harry A1 - Daly, Mark J A1 - Hattersley, Andrew T A1 - Pedersen, Oluf A1 - Barroso, Inês A1 - Groop, Leif A1 - Sladek, Rob A1 - Thorsteinsdottir, Unnur A1 - Wilson, James F A1 - Illig, Thomas A1 - Froguel, Philippe A1 - van Duijn, Cornelia M A1 - Stefansson, Kari A1 - Altshuler, David A1 - Boehnke, Michael A1 - McCarthy, Mark I A1 - Soranzo, Nicole A1 - Wheeler, Eleanor A1 - Glazer, Nicole L A1 - Bouatia-Naji, Nabila A1 - Mägi, Reedik A1 - Randall, Joshua A1 - Elliott, Paul A1 - Rybin, Denis A1 - Dehghan, Abbas A1 - Hottenga, Jouke Jan A1 - Song, Kijoung A1 - Goel, Anuj A1 - Lajunen, Taina A1 - Doney, Alex A1 - Cavalcanti-Proença, Christine A1 - Kumari, Meena A1 - Timpson, Nicholas J A1 - Zabena, Carina A1 - Ingelsson, Erik A1 - An, Ping A1 - O'Connell, Jeffrey A1 - Luan, Jian'an A1 - Elliott, Amanda A1 - McCarroll, Steven A A1 - Roccasecca, Rosa Maria A1 - Pattou, François A1 - Sethupathy, Praveen A1 - Ariyurek, Yavuz A1 - Barter, Philip A1 - Beilby, John P A1 - Ben-Shlomo, Yoav A1 - Bergmann, Sven A1 - Bochud, Murielle A1 - Bonnefond, Amélie A1 - Borch-Johnsen, Knut A1 - Böttcher, Yvonne A1 - Brunner, Eric A1 - Bumpstead, Suzannah J A1 - Chen, Yii-Der Ida A1 - Chines, Peter A1 - Clarke, Robert A1 - Coin, Lachlan J M A1 - Cooper, Matthew N A1 - Crisponi, Laura A1 - Day, Ian N M A1 - de Geus, Eco J C A1 - Delplanque, Jerome A1 - Fedson, Annette C A1 - Fischer-Rosinsky, Antje A1 - Forouhi, Nita G A1 - Franzosi, Maria Grazia A1 - Galan, Pilar A1 - Goodarzi, Mark O A1 - Graessler, Jürgen A1 - Grundy, Scott A1 - Gwilliam, Rhian A1 - Hallmans, Göran A1 - Hammond, Naomi A1 - Han, Xijing A1 - Hartikainen, Anna-Liisa A1 - Hayward, Caroline A1 - Heath, Simon C A1 - Hercberg, Serge A1 - Hillman, David R A1 - Hingorani, Aroon D A1 - Hui, Jennie A1 - Hung, Joe A1 - Kaakinen, Marika A1 - Kaprio, Jaakko A1 - Kesaniemi, Y Antero A1 - Kivimaki, Mika A1 - Knight, Beatrice A1 - Koskinen, Seppo A1 - Kovacs, Peter A1 - Kyvik, Kirsten Ohm A1 - Lathrop, G Mark A1 - Lawlor, Debbie A A1 - Le Bacquer, Olivier A1 - Lecoeur, Cécile A1 - Li, Yun A1 - Mahley, Robert A1 - Mangino, Massimo A1 - Martínez-Larrad, María Teresa A1 - McAteer, Jarred B A1 - McPherson, Ruth A1 - Meisinger, Christa A1 - Melzer, David A1 - Meyre, David A1 - Mitchell, Braxton D A1 - Mukherjee, Sutapa A1 - Naitza, Silvia A1 - Neville, Matthew J A1 - Orrù, Marco A1 - Pakyz, Ruth A1 - Paolisso, Giuseppe A1 - Pattaro, Cristian A1 - Pearson, Daniel A1 - Peden, John F A1 - Pedersen, Nancy L A1 - Pfeiffer, Andreas F H A1 - Pichler, Irene A1 - Polasek, Ozren A1 - Posthuma, Danielle A1 - Potter, Simon C A1 - Pouta, Anneli A1 - Province, Michael A A1 - Rayner, Nigel W A1 - Rice, Kenneth A1 - Ripatti, Samuli A1 - Rivadeneira, Fernando A1 - Rolandsson, Olov A1 - Sandbaek, Annelli A1 - Sandhu, Manjinder A1 - Sanna, Serena A1 - Sayer, Avan Aihie A1 - Scheet, Paul A1 - Seedorf, Udo A1 - Sharp, Stephen J A1 - Shields, Beverley A1 - Sigurðsson, Gunnar A1 - Sijbrands, Eric J G A1 - Silveira, Angela A1 - Simpson, Laila A1 - Singleton, Andrew A1 - Smith, Nicholas L A1 - Sovio, Ulla A1 - Swift, Amy A1 - Syddall, Holly A1 - Syvänen, Ann-Christine A1 - Tönjes, Anke A1 - Uitterlinden, André G A1 - van Dijk, Ko Willems A1 - Varma, Dhiraj A1 - Visvikis-Siest, Sophie A1 - Vitart, Veronique A1 - Vogelzangs, Nicole A1 - Waeber, Gérard A1 - Wagner, Peter J A1 - Walley, Andrew A1 - Ward, Kim L A1 - Watkins, Hugh A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Witteman, Jaqueline C M A1 - Yarnell, John W G A1 - Zelenika, Diana A1 - Zethelius, Björn A1 - Zhai, Guangju A1 - Zhao, Jing Hua A1 - Zillikens, M Carola A1 - Borecki, Ingrid B A1 - Meneton, Pierre A1 - Magnusson, Patrik K E A1 - Nathan, David M A1 - Williams, Gordon H A1 - Silander, Kaisa A1 - Bornstein, Stefan R A1 - Schwarz, Peter A1 - Spranger, Joachim A1 - Karpe, Fredrik A1 - Shuldiner, Alan R A1 - Cooper, Cyrus A1 - Serrano-Ríos, Manuel A1 - Lind, Lars A1 - Palmer, Lyle J A1 - Hu, Frank B A1 - Franks, Paul W A1 - Ebrahim, Shah A1 - Marmot, Michael A1 - Kao, W H Linda A1 - Pramstaller, Peter Paul A1 - Wright, Alan F A1 - Stumvoll, Michael A1 - Hamsten, Anders A1 - Buchanan, Thomas A A1 - Valle, Timo T A1 - Rotter, Jerome I A1 - Penninx, Brenda W J H A1 - Boomsma, Dorret I A1 - Cao, Antonio A1 - Scuteri, Angelo A1 - Schlessinger, David A1 - Uda, Manuela A1 - Ruokonen, Aimo A1 - Jarvelin, Marjo-Riitta A1 - Peltonen, Leena A1 - Mooser, Vincent A1 - Sladek, Robert A1 - Musunuru, Kiran A1 - Smith, Albert V A1 - Edmondson, Andrew C A1 - Stylianou, Ioannis M A1 - Koseki, Masahiro A1 - Pirruccello, James P A1 - Chasman, Daniel I A1 - Johansen, Christopher T A1 - Fouchier, Sigrid W A1 - Peloso, Gina M A1 - Barbalic, Maja A1 - Ricketts, Sally L A1 - Bis, Joshua C A1 - Feitosa, Mary F A1 - Orho-Melander, Marju A1 - Melander, Olle A1 - Li, Xiaohui A1 - Li, Mingyao A1 - Cho, Yoon Shin A1 - Go, Min Jin A1 - Kim, Young Jin A1 - Lee, Jong-Young A1 - Park, Taesung A1 - Kim, Kyunga A1 - Sim, Xueling A1 - Ong, Rick Twee-Hee A1 - Croteau-Chonka, Damien C A1 - Lange, Leslie A A1 - Smith, Joshua D A1 - Ziegler, Andreas A1 - Zhang, Weihua A1 - Zee, Robert Y L A1 - Whitfield, John B A1 - Thompson, John R A1 - Surakka, Ida A1 - Spector, Tim D A1 - Smit, Johannes H A1 - Sinisalo, Juha A1 - Scott, James A1 - Saharinen, Juha A1 - Sabatti, Chiara A1 - Rose, Lynda M A1 - Roberts, Robert A1 - Rieder, Mark A1 - Parker, Alex N A1 - Paré, Guillaume A1 - O'Donnell, Christopher J A1 - Nieminen, Markku S A1 - Nickerson, Deborah A A1 - Montgomery, Grant W A1 - McArdle, Wendy A1 - Masson, David A1 - Martin, Nicholas G A1 - Marroni, Fabio A1 - Lucas, Gavin A1 - Luben, Robert A1 - Lokki, Marja-Liisa A1 - Lettre, Guillaume A1 - Launer, Lenore J A1 - Lakatta, Edward G A1 - Laaksonen, Reijo A1 - Kyvik, Kirsten O A1 - König, Inke R A1 - Khaw, Kay-Tee A1 - Kaplan, Lee M A1 - Johansson, Asa A1 - Janssens, A Cecile J W A1 - Igl, Wilmar A1 - Hovingh, G Kees A1 - Hengstenberg, Christian A1 - Havulinna, Aki S A1 - Hastie, Nicholas D A1 - Harris, Tamara B A1 - Haritunians, Talin A1 - Hall, Alistair S A1 - Groop, Leif C A1 - Gonzalez, Elena A1 - Freimer, Nelson B A1 - Erdmann, Jeanette A1 - Ejebe, Kenechi G A1 - Döring, Angela A1 - Dominiczak, Anna F A1 - Demissie, Serkalem A1 - Deloukas, Panagiotis A1 - de Faire, Ulf A1 - Crawford, Gabriel A1 - Chen, Yii-der I A1 - Caulfield, Mark J A1 - Boekholdt, S Matthijs A1 - Assimes, Themistocles L A1 - Quertermous, Thomas A1 - Seielstad, Mark A1 - Wong, Tien Y A1 - Tai, E-Shyong A1 - Feranil, Alan B A1 - Kuzawa, Christopher W A1 - Taylor, Herman A A1 - Gabriel, Stacey B A1 - Holm, Hilma A1 - Gudnason, Vilmundur A1 - Krauss, Ronald M A1 - Ordovas, Jose M A1 - Munroe, Patricia B A1 - Kooner, Jaspal S A1 - Tall, Alan R A1 - Hegele, Robert A A1 - Kastelein, John J P A1 - Schadt, Eric E A1 - Strachan, David P A1 - Reilly, Muredach P A1 - Samani, Nilesh J A1 - Schunkert, Heribert A1 - Cupples, L Adrienne A1 - Sandhu, Manjinder S A1 - Ridker, Paul M A1 - Rader, Daniel J A1 - Kathiresan, Sekar KW - Adiponectin KW - African Americans KW - Asian Continental Ancestry Group KW - Cholesterol, HDL KW - Diabetes Mellitus, Type 2 KW - European Continental Ancestry Group KW - Female KW - Gene Expression KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Glucose Tolerance Test KW - Humans KW - Insulin Resistance KW - Male KW - Metabolic Networks and Pathways KW - Polymorphism, Single Nucleotide KW - Waist-Hip Ratio AB -

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

VL - 8 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22479202?dopt=Abstract ER - TY - JOUR T1 - Plasma free fatty acids and risk of atrial fibrillation (from the Cardiovascular Health Study). JF - Am J Cardiol Y1 - 2012 A1 - Khawaja, Owais A1 - Bartz, Traci M A1 - Ix, Joachim H A1 - Heckbert, Susan R A1 - Kizer, Jorge R A1 - Zieman, Susan J A1 - Mukamal, Kenneth J A1 - Tracy, Russell P A1 - Siscovick, David S A1 - Djoussé, Luc KW - Aged KW - Atrial Fibrillation KW - C-Reactive Protein KW - Diabetes Mellitus, Type 2 KW - Fatty Acids, Nonesterified KW - Female KW - Follow-Up Studies KW - Humans KW - Hypertension KW - Incidence KW - Lipoproteins, HDL KW - Lipoproteins, LDL KW - Male KW - Natriuretic Peptide, Brain KW - Obesity KW - Peptide Fragments KW - Prospective Studies KW - Sex Factors KW - Triglycerides KW - United States AB -

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

VL - 110 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22503582?dopt=Abstract ER - TY - JOUR T1 - Fetuin-A, type 2 diabetes, and risk of cardiovascular disease in older adults: the cardiovascular health study. JF - Diabetes Care Y1 - 2013 A1 - Jensen, Majken K A1 - Bartz, Traci M A1 - Mukamal, Kenneth J A1 - Djoussé, Luc A1 - Kizer, Jorge R A1 - Tracy, Russell P A1 - Zieman, Susan J A1 - Rimm, Eric B A1 - Siscovick, David S A1 - Shlipak, Michael A1 - Ix, Joachim H KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Diabetes Mellitus, Type 2 KW - Female KW - Fetuins KW - Humans KW - Incidence KW - Longitudinal Studies KW - Male KW - Risk Factors AB -

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

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

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

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

VL - 36 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23250801?dopt=Abstract ER - TY - JOUR T1 - Generalization and dilution of association results from European GWAS in populations of non-European ancestry: the PAGE study. JF - PLoS Biol Y1 - 2013 A1 - Carlson, Christopher S A1 - Matise, Tara C A1 - North, Kari E A1 - Haiman, Christopher A A1 - Fesinmeyer, Megan D A1 - Buyske, Steven A1 - Schumacher, Fredrick R A1 - Peters, Ulrike A1 - Franceschini, Nora A1 - Ritchie, Marylyn D A1 - Duggan, David J A1 - Spencer, Kylee L A1 - Dumitrescu, Logan A1 - Eaton, Charles B A1 - Thomas, Fridtjof A1 - Young, Alicia A1 - Carty, Cara A1 - Heiss, Gerardo A1 - Le Marchand, Loïc A1 - Crawford, Dana C A1 - Hindorff, Lucia A A1 - Kooperberg, Charles L KW - African Americans KW - Asian Americans KW - Body Mass Index KW - Diabetes Mellitus, Type 2 KW - European Continental Ancestry Group KW - Gene Frequency KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genome-Wide Association Study KW - Hispanic Americans KW - Humans KW - Indians, North American KW - Lipids KW - Metagenomics KW - Oceanic Ancestry Group KW - Polymorphism, Single Nucleotide AB -

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

VL - 11 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24068893?dopt=Abstract ER - TY - JOUR T1 - Genetic variants associated with fasting glucose and insulin concentrations in an ethnically diverse population: results from the Population Architecture using Genomics and Epidemiology (PAGE) study. JF - BMC Med Genet Y1 - 2013 A1 - Fesinmeyer, Megan D A1 - Meigs, James B A1 - North, Kari E A1 - Schumacher, Fredrick R A1 - Bůzková, Petra A1 - Franceschini, Nora A1 - Haessler, Jeffrey A1 - Goodloe, Robert A1 - Spencer, Kylee L A1 - Voruganti, Venkata Saroja A1 - Howard, Barbara V A1 - Jackson, Rebecca A1 - Kolonel, Laurence N A1 - Liu, Simin A1 - Manson, JoAnn E A1 - Monroe, Kristine R A1 - Mukamal, Kenneth A1 - Dilks, Holli H A1 - Pendergrass, Sarah A A1 - Nato, Andrew A1 - Wan, Peggy A1 - Wilkens, Lynne R A1 - Le Marchand, Loïc A1 - Ambite, Jose Luis A1 - Buyske, Steven A1 - Florez, Jose C A1 - Crawford, Dana C A1 - Hindorff, Lucia A A1 - Haiman, Christopher A A1 - Peters, Ulrike A1 - Pankow, James S KW - Adaptor Proteins, Signal Transducing KW - Adult KW - African Americans KW - Aged KW - Alleles KW - Asian Continental Ancestry Group KW - Blood Glucose KW - Diabetes Mellitus, Type 2 KW - European Continental Ancestry Group KW - Female KW - Gene Frequency KW - Genetic Loci KW - Genome-Wide Association Study KW - Genomics KW - Hispanic Americans KW - Humans KW - Indians, North American KW - Insulin KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Transcription Factor 7-Like 2 Protein AB -

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

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

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

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

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

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

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

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

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

VL - 36 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23801724?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association study identifies novel loci associated with concentrations of four plasma phospholipid fatty acids in the de novo lipogenesis pathway: results from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortiu JF - Circ Cardiovasc Genet Y1 - 2013 A1 - Wu, Jason H Y A1 - Lemaitre, Rozenn N A1 - Manichaikul, Ani A1 - Guan, Weihua A1 - Tanaka, Toshiko A1 - Foy, Millennia A1 - Kabagambe, Edmond K A1 - Djoussé, Luc A1 - Siscovick, David A1 - Fretts, Amanda M A1 - Johnson, Catherine A1 - King, Irena B A1 - Psaty, Bruce M A1 - McKnight, Barbara A1 - Rich, Stephen S A1 - Chen, Yii-der I A1 - Nettleton, Jennifer A A1 - Tang, Weihong A1 - Bandinelli, Stefania A1 - Jacobs, David R A1 - Browning, Brian L A1 - Laurie, Cathy C A1 - Gu, Xiangjun A1 - Tsai, Michael Y A1 - Steffen, Lyn M A1 - Ferrucci, Luigi A1 - Fornage, Myriam A1 - Mozaffarian, Dariush KW - Adult KW - Aged KW - Chromosomes, Human, Pair 2 KW - Cohort Studies KW - Coronary Disease KW - Diabetes Mellitus, Type 2 KW - Fatty Acids, Monounsaturated KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Linkage Disequilibrium KW - Lipogenesis KW - Male KW - Middle Aged KW - Oleic Acid KW - Palmitic Acid KW - Polymorphism, Single Nucleotide KW - Stearic Acids AB -

BACKGROUND- Palmitic acid (16:0), stearic acid (18:0), palmitoleic acid (16:1n-7), and oleic acid (18:1n-9) are major saturated and monounsaturated fatty acids that affect cellular signaling and metabolic pathways. They are synthesized via de novo lipogenesis and are the main saturated and monounsaturated fatty acids in the diet. Levels of these fatty acids have been linked to diseases including type 2 diabetes mellitus and coronary heart disease. METHODS AND RESULTS- Genome-wide association studies were conducted in 5 population-based cohorts comprising 8961 participants of European ancestry to investigate the association of common genetic variation with plasma levels of these 4 fatty acids. We identified polymorphisms in 7 novel loci associated with circulating levels of ≥1 of these fatty acids. ALG14 (asparagine-linked glycosylation 14 homolog) polymorphisms were associated with higher 16:0 (P=2.7×10(-11)) and lower 18:0 (P=2.2×10(-18)). FADS1 and FADS2 (desaturases) polymorphisms were associated with higher 16:1n-7 (P=6.6×10(-13)) and 18:1n-9 (P=2.2×10(-32)) and lower 18:0 (P=1.3×10(-20)). LPGAT1 (lysophosphatidylglycerol acyltransferase) polymorphisms were associated with lower 18:0 (P=2.8×10(-9)). GCKR (glucokinase regulator; P=9.8×10(-10)) and HIF1AN (factor inhibiting hypoxia-inducible factor-1; P=5.7×10(-9)) polymorphisms were associated with higher 16:1n-7, whereas PKD2L1 (polycystic kidney disease 2-like 1; P=5.7×10(-15)) and a locus on chromosome 2 (not near known genes) were associated with lower 16:1n-7 (P=4.1×10(-8)). CONCLUSIONS- Our findings provide novel evidence that common variations in genes with diverse functions, including protein-glycosylation, polyunsaturated fatty acid metabolism, phospholipid modeling, and glucose- and oxygen-sensing pathways, are associated with circulating levels of 4 fatty acids in the de novo lipogenesis pathway. These results expand our knowledge of genetic factors relevant to de novo lipogenesis and fatty acid biology.

VL - 6 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23362303?dopt=Abstract ER - TY - JOUR T1 - Risk factors for type 2 diabetes mellitus preceded by β-cell dysfunction, insulin resistance, or both in older adults: the Cardiovascular Health Study. JF - Am J Epidemiol Y1 - 2013 A1 - Imamura, Fumiaki A1 - Mukamal, Kenneth J A1 - Meigs, James B A1 - Luchsinger, José A A1 - Ix, Joachim H A1 - Siscovick, David S A1 - Mozaffarian, Dariush KW - Adiposity KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Aging KW - Alcohol Drinking KW - Blood Pressure KW - Cross-Sectional Studies KW - Diabetes Mellitus, Type 2 KW - Female KW - Humans KW - Incidence KW - Insulin Resistance KW - Insulin-Secreting Cells KW - Lipids KW - Male KW - Prospective Studies KW - Risk Factors KW - Socioeconomic Factors KW - United States AB -

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

VL - 177 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23707958?dopt=Abstract ER - TY - JOUR T1 - Association of levels of fasting glucose and insulin with rare variants at the chromosome 11p11.2-MADD locus: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. JF - Circ Cardiovasc Genet Y1 - 2014 A1 - Cornes, Belinda K A1 - Brody, Jennifer A A1 - Nikpoor, Naghmeh A1 - Morrison, Alanna C A1 - Chu, Huan A1 - Ahn, Byung Soo A1 - Wang, Shuai A1 - Dauriz, Marco A1 - Barzilay, Joshua I A1 - Dupuis, Josée A1 - Florez, Jose C A1 - Coresh, Josef A1 - Gibbs, Richard A A1 - Kao, W H Linda A1 - Liu, Ching-Ti A1 - McKnight, Barbara A1 - Muzny, Donna A1 - Pankow, James S A1 - Reid, Jeffrey G A1 - White, Charles C A1 - Johnson, Andrew D A1 - Wong, Tien Y A1 - Psaty, Bruce M A1 - Boerwinkle, Eric A1 - Rotter, Jerome I A1 - Siscovick, David S A1 - Sladek, Robert A1 - Meigs, James B KW - Aged KW - Aged, 80 and over KW - Aging KW - Blood Glucose KW - Chromosomes, Human, Pair 11 KW - Cohort Studies KW - Death Domain Receptor Signaling Adaptor Proteins KW - Diabetes Mellitus, Type 2 KW - Fasting KW - Female KW - Gene Frequency KW - Genetic Variation KW - Genome-Wide Association Study KW - Genomics KW - Guanine Nucleotide Exchange Factors KW - Heart Diseases KW - Humans KW - Insulin KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Sequence Analysis, DNA AB -

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

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

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

VL - 7 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24951664?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis of genome-wide association studies in African Americans provides insights into the genetic architecture of type 2 diabetes. JF - PLoS Genet Y1 - 2014 A1 - Ng, Maggie C Y A1 - Shriner, Daniel A1 - Chen, Brian H A1 - Li, Jiang A1 - Chen, Wei-Min A1 - Guo, Xiuqing A1 - Liu, Jiankang A1 - Bielinski, Suzette J A1 - Yanek, Lisa R A1 - Nalls, Michael A A1 - Comeau, Mary E A1 - Rasmussen-Torvik, Laura J A1 - Jensen, Richard A A1 - Evans, Daniel S A1 - Sun, Yan V A1 - An, Ping A1 - Patel, Sanjay R A1 - Lu, Yingchang A1 - Long, Jirong A1 - Armstrong, Loren L A1 - Wagenknecht, Lynne A1 - Yang, Lingyao A1 - Snively, Beverly M A1 - Palmer, Nicholette D A1 - Mudgal, Poorva A1 - Langefeld, Carl D A1 - Keene, Keith L A1 - Freedman, Barry I A1 - Mychaleckyj, Josyf C A1 - Nayak, Uma A1 - Raffel, Leslie J A1 - Goodarzi, Mark O A1 - Chen, Y-D Ida A1 - Taylor, Herman A A1 - Correa, Adolfo A1 - Sims, Mario A1 - Couper, David A1 - Pankow, James S A1 - Boerwinkle, Eric A1 - Adeyemo, Adebowale A1 - Doumatey, Ayo A1 - Chen, Guanjie A1 - Mathias, Rasika A A1 - Vaidya, Dhananjay A1 - Singleton, Andrew B A1 - Zonderman, Alan B A1 - Igo, Robert P A1 - Sedor, John R A1 - Kabagambe, Edmond K A1 - Siscovick, David S A1 - McKnight, Barbara A1 - Rice, Kenneth A1 - Liu, Yongmei A1 - Hsueh, Wen-Chi A1 - Zhao, Wei A1 - Bielak, Lawrence F A1 - Kraja, Aldi A1 - Province, Michael A A1 - Bottinger, Erwin P A1 - Gottesman, Omri A1 - Cai, Qiuyin A1 - Zheng, Wei A1 - Blot, William J A1 - Lowe, William L A1 - Pacheco, Jennifer A A1 - Crawford, Dana C A1 - Grundberg, Elin A1 - Rich, Stephen S A1 - Hayes, M Geoffrey A1 - Shu, Xiao-Ou A1 - Loos, Ruth J F A1 - Borecki, Ingrid B A1 - Peyser, Patricia A A1 - Cummings, Steven R A1 - Psaty, Bruce M A1 - Fornage, Myriam A1 - Iyengar, Sudha K A1 - Evans, Michele K A1 - Becker, Diane M A1 - Kao, W H Linda A1 - Wilson, James G A1 - Rotter, Jerome I A1 - Sale, Michèle M A1 - Liu, Simin A1 - Rotimi, Charles N A1 - Bowden, Donald W KW - African Americans KW - Diabetes Mellitus, Type 2 KW - Genome-Wide Association Study KW - HLA-B27 Antigen KW - HMGA2 Protein KW - Humans KW - KCNQ1 Potassium Channel KW - Mutant Chimeric Proteins KW - Polymorphism, Single Nucleotide KW - Transcription Factor 7-Like 2 Protein AB -

Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 × 10(-94) VL - 10 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25102180?dopt=Abstract ER - TY - JOUR T1 - Sleep duration does not mediate or modify association of common genetic variants with type 2 diabetes. JF - Diabetologia Y1 - 2014 A1 - Tare, Archana A1 - Lane, Jacqueline M A1 - Cade, Brian E A1 - Grant, Struan F A A1 - Chen, Ting-Hsu A1 - Punjabi, Naresh M A1 - Lauderdale, Diane S A1 - Zee, Phyllis C A1 - Gharib, Sina A A1 - Gottlieb, Daniel J A1 - Scheer, Frank A J L A1 - Redline, Susan A1 - Saxena, Richa KW - Blood Glucose KW - Body Composition KW - Body Mass Index KW - Cross-Sectional Studies KW - Diabetes Mellitus, Type 2 KW - European Continental Ancestry Group KW - Fasting KW - Female KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genotype KW - Glucose Intolerance KW - Glycated Hemoglobin A KW - Humans KW - Insulin Resistance KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Risk Factors KW - Sleep KW - Surveys and Questionnaires KW - Time Factors KW - United States AB -

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

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

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

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

VL - 57 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24280871?dopt=Abstract ER - TY - JOUR T1 - Atherosclerotic cardiovascular disease in older adults with diabetes mellitus. JF - Clin Geriatr Med Y1 - 2015 A1 - Barzilay, Joshua I A1 - Mukamal, Kenneth J A1 - Kizer, Jorge R KW - Age Factors KW - Aged KW - Coronary Artery Disease KW - Diabetes Mellitus, Type 2 KW - Female KW - Humans KW - Male KW - Risk Factors KW - Survival Rate AB -

Diabetes mellitus exerts a strong effect on atherosclerotic cardiovascular disease risk into older age (beyond ages 70-74 years). This effect is particularly noticeable with regard to coronary artery disease and cerebral microvascular disease. Thus, diabetes mellitus in older adults deserves the same careful medical attention as it does in middle age.

VL - 31 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25453299?dopt=Abstract ER - TY - JOUR T1 - Changes in insulin-like growth factor-I and its binding proteins are associated with diabetes mellitus in older adults. JF - J Am Geriatr Soc Y1 - 2015 A1 - Aneke-Nash, Chino S A1 - Parrinello, Christina M A1 - Rajpathak, Swapnil N A1 - Rohan, Thomas E A1 - Strotmeyer, Elsa S A1 - Kritchevsky, Stephen B A1 - Psaty, Bruce M A1 - Bůzková, Petra A1 - Kizer, Jorge R A1 - Newman, Anne B A1 - Strickler, Howard D A1 - Kaplan, Robert C KW - Aged KW - Blood Glucose KW - Cohort Studies KW - Diabetes Mellitus, Type 2 KW - Female KW - Humans KW - Insulin-Like Growth Factor Binding Protein 1 KW - Insulin-Like Growth Factor Binding Protein 3 KW - Insulin-Like Growth Factor I KW - Male KW - Retrospective Studies AB -

OBJECTIVES: To determine whether changes in insulin-like growth factor (IGF) protein levels are greater in participants with type 2 diabetes mellitus or worsening glycemia than in normoglycemic individuals over a 9-year follow-up period.

DESIGN: Retrospective analysis of a cohort study.

SETTING: Participants were recruited from North Carolina, California, Maryland, and Pennsylvania.

PARTICIPANTS: Cardiovascular Health Study All Stars participants, a cohort study of community-dwelling adults aged 65 and older (N=897).

MEASUREMENTS: Plasma IGF-I, IGF binding protein (IGFBP)-1, and IGFBP-3 levels were assessed and American Diabetes Association cut-points for impaired glucose tolerance (IGT), impaired fasting glucose (IFG), and diabetes mellitus were used to classify participants at baseline (1996-97) and follow-up (2005-06).

RESULTS: At baseline, mean age was 76.3±3.6, and 18.5% had diabetes mellitus. Participants with IFG alone and IGT plus IFG had higher IGF-I levels and lower IGFBP-1 levels than those with normoglycemia or diabetes mellitus. The greatest percentage change in IGF levels occurred in those who had diabetes mellitus at baseline (9-year changes: -9.3% for IGF-I, 59.7% for IGFBP-1, -13.4% for IGFBP-3), the smallest in individuals who remained normoglycemic at follow-up (9-year changes: -3.7% for IGF-I, 25.6% for IGFBP-1, -6.4% for IGFBP-3), and intermediate in those who were normoglycemic but developed IFG at follow-up.

CONCLUSION: Degrees of glycemic impairment are associated with varying degrees of change in IGF protein levels. The changes observed in the diabetes mellitus group have been previously shown to be associated with heart failure, cancer, and noncancer mortality.

VL - 63 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25989565?dopt=Abstract ER - TY - JOUR T1 - Circulating and dietary trans fatty acids and incident type 2 diabetes in older adults: the Cardiovascular Health Study. JF - Diabetes Care Y1 - 2015 A1 - Wang, Qianyi A1 - Imamura, Fumiaki A1 - Ma, Wenjie A1 - Wang, Molin A1 - Lemaitre, Rozenn N A1 - King, Irena B A1 - Song, Xiaoling A1 - Biggs, Mary L A1 - Delaney, Joseph A A1 - Mukamal, Kenneth J A1 - Djoussé, Luc A1 - Siscovick, David S A1 - Mozaffarian, Dariush KW - Aged KW - Biomarkers KW - Diabetes Mellitus, Type 2 KW - Diabetic Angiopathies KW - Dietary Fats, Unsaturated KW - Epidemiologic Methods KW - Female KW - Food Habits KW - Humans KW - Male KW - Phospholipids KW - Trans Fatty Acids AB -

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

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

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

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

VL - 38 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25784660?dopt=Abstract ER - TY - JOUR T1 - Gene-Environment Interactions of Circadian-Related Genes for Cardiometabolic Traits. JF - Diabetes Care Y1 - 2015 A1 - Dashti, Hassan S A1 - Follis, Jack L A1 - Smith, Caren E A1 - Tanaka, Toshiko A1 - Garaulet, Marta A1 - Gottlieb, Daniel J A1 - Hruby, Adela A1 - Jacques, Paul F A1 - Kiefte-de Jong, Jessica C A1 - Lamon-Fava, Stefania A1 - Scheer, Frank A J L A1 - Bartz, Traci M A1 - Kovanen, Leena A1 - Wojczynski, Mary K A1 - Frazier-Wood, Alexis C A1 - Ahluwalia, Tarunveer S A1 - Perälä, Mia-Maria A1 - Jonsson, Anna A1 - Muka, Taulant A1 - Kalafati, Ioanna P A1 - Mikkilä, Vera A1 - Ordovas, Jose M KW - Adult KW - Alleles KW - Blood Glucose KW - Circadian Rhythm Signaling Peptides and Proteins KW - Cohort Studies KW - Diabetes Mellitus, Type 2 KW - Diet, Fat-Restricted KW - European Continental Ancestry Group KW - Fasting KW - Female KW - Gene-Environment Interaction KW - Humans KW - Insulin Resistance KW - Male KW - Middle Aged KW - Multicenter Studies as Topic KW - Observational Studies as Topic KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Sleep KW - Waist Circumference AB -

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

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

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

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

VL - 38 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26084345?dopt=Abstract ER - TY - JOUR T1 - HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. JF - Lancet Y1 - 2015 A1 - Swerdlow, Daniel I A1 - Preiss, David A1 - Kuchenbaecker, Karoline B A1 - Holmes, Michael V A1 - Engmann, Jorgen E L A1 - Shah, Tina A1 - Sofat, Reecha A1 - Stender, Stefan A1 - Johnson, Paul C D A1 - Scott, Robert A A1 - Leusink, Maarten A1 - Verweij, Niek A1 - Sharp, Stephen J A1 - Guo, Yiran A1 - Giambartolomei, Claudia A1 - Chung, Christina A1 - Peasey, Anne A1 - Amuzu, Antoinette A1 - Li, KaWah A1 - Palmen, Jutta A1 - Howard, Philip A1 - Cooper, Jackie A A1 - Drenos, Fotios A1 - Li, Yun R A1 - Lowe, Gordon A1 - Gallacher, John A1 - Stewart, Marlene C W A1 - Tzoulaki, Ioanna A1 - Buxbaum, Sarah G A1 - van der A, Daphne L A1 - Forouhi, Nita G A1 - Onland-Moret, N Charlotte A1 - van der Schouw, Yvonne T A1 - Schnabel, Renate B A1 - Hubacek, Jaroslav A A1 - Kubinova, Ruzena A1 - Baceviciene, Migle A1 - Tamosiunas, Abdonas A1 - Pajak, Andrzej A1 - Topor-Madry, Roman A1 - Stepaniak, Urszula A1 - Malyutina, Sofia A1 - Baldassarre, Damiano A1 - Sennblad, Bengt A1 - Tremoli, Elena A1 - de Faire, Ulf A1 - Veglia, Fabrizio A1 - Ford, Ian A1 - Jukema, J Wouter A1 - Westendorp, Rudi G J A1 - de Borst, Gert Jan A1 - de Jong, Pim A A1 - Algra, Ale A1 - Spiering, Wilko A1 - Maitland-van der Zee, Anke H A1 - Klungel, Olaf H A1 - de Boer, Anthonius A1 - Doevendans, Pieter A A1 - Eaton, Charles B A1 - Robinson, Jennifer G A1 - Duggan, David A1 - Kjekshus, John A1 - Downs, John R A1 - Gotto, Antonio M A1 - Keech, Anthony C A1 - Marchioli, Roberto A1 - Tognoni, Gianni A1 - Sever, Peter S A1 - Poulter, Neil R A1 - Waters, David D A1 - Pedersen, Terje R A1 - Amarenco, Pierre A1 - Nakamura, Haruo A1 - McMurray, John J V A1 - Lewsey, James D A1 - Chasman, Daniel I A1 - Ridker, Paul M A1 - Maggioni, Aldo P A1 - Tavazzi, Luigi A1 - Ray, Kausik K A1 - Seshasai, Sreenivasa Rao Kondapally A1 - Manson, JoAnn E A1 - Price, Jackie F A1 - Whincup, Peter H A1 - Morris, Richard W A1 - Lawlor, Debbie A A1 - Smith, George Davey A1 - Ben-Shlomo, Yoav A1 - Schreiner, Pamela J A1 - Fornage, Myriam A1 - Siscovick, David S A1 - Cushman, Mary A1 - Kumari, Meena A1 - Wareham, Nick J A1 - Verschuren, W M Monique A1 - Redline, Susan A1 - Patel, Sanjay R A1 - Whittaker, John C A1 - Hamsten, Anders A1 - Delaney, Joseph A A1 - Dale, Caroline A1 - Gaunt, Tom R A1 - Wong, Andrew A1 - Kuh, Diana A1 - Hardy, Rebecca A1 - Kathiresan, Sekar A1 - Castillo, Berta A A1 - van der Harst, Pim A1 - Brunner, Eric J A1 - Tybjaerg-Hansen, Anne A1 - Marmot, Michael G A1 - Krauss, Ronald M A1 - Tsai, Michael A1 - Coresh, Josef A1 - Hoogeveen, Ronald C A1 - Psaty, Bruce M A1 - Lange, Leslie A A1 - Hakonarson, Hakon A1 - Dudbridge, Frank A1 - Humphries, Steve E A1 - Talmud, Philippa J A1 - Kivimaki, Mika A1 - Timpson, Nicholas J A1 - Langenberg, Claudia A1 - Asselbergs, Folkert W A1 - Voevoda, Mikhail A1 - Bobak, Martin A1 - Pikhart, Hynek A1 - Wilson, James G A1 - Reiner, Alex P A1 - Keating, Brendan J A1 - Hingorani, Aroon D A1 - Sattar, Naveed KW - Aged KW - Body Mass Index KW - Body Weight KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Diabetes Mellitus, Type 2 KW - Female KW - Genetic Testing KW - Humans KW - Hydroxymethylglutaryl CoA Reductases KW - Hydroxymethylglutaryl-CoA Reductase Inhibitors KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Randomized Controlled Trials as Topic KW - Risk Factors AB -

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

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

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

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

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

VL - 385 IS - 9965 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25262344?dopt=Abstract ER - TY - JOUR T1 - Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility. JF - Nat Commun Y1 - 2015 A1 - Wessel, Jennifer A1 - Chu, Audrey Y A1 - Willems, Sara M A1 - Wang, Shuai A1 - Yaghootkar, Hanieh A1 - Brody, Jennifer A A1 - Dauriz, Marco A1 - Hivert, Marie-France A1 - Raghavan, Sridharan A1 - Lipovich, Leonard A1 - Hidalgo, Bertha A1 - Fox, Keolu A1 - Huffman, Jennifer E A1 - An, Ping A1 - Lu, Yingchang A1 - Rasmussen-Torvik, Laura J A1 - Grarup, Niels A1 - Ehm, Margaret G A1 - Li, Li A1 - Baldridge, Abigail S A1 - Stančáková, Alena A1 - Abrol, Ravinder A1 - Besse, Céline A1 - Boland, Anne A1 - Bork-Jensen, Jette A1 - Fornage, Myriam A1 - Freitag, Daniel F A1 - Garcia, Melissa E A1 - Guo, Xiuqing A1 - Hara, Kazuo A1 - Isaacs, Aaron A1 - Jakobsdottir, Johanna A1 - Lange, Leslie A A1 - Layton, Jill C A1 - Li, Man A1 - Hua Zhao, Jing A1 - Meidtner, Karina A1 - Morrison, Alanna C A1 - Nalls, Mike A A1 - Peters, Marjolein J A1 - Sabater-Lleal, Maria A1 - Schurmann, Claudia A1 - Silveira, Angela A1 - Smith, Albert V A1 - Southam, Lorraine A1 - Stoiber, Marcus H A1 - Strawbridge, Rona J A1 - Taylor, Kent D A1 - Varga, Tibor V A1 - Allin, Kristine H A1 - Amin, Najaf A1 - Aponte, Jennifer L A1 - Aung, Tin A1 - Barbieri, Caterina A1 - Bihlmeyer, Nathan A A1 - Boehnke, Michael A1 - Bombieri, Cristina A1 - Bowden, Donald W A1 - Burns, Sean M A1 - Chen, Yuning A1 - Chen, Yii-DerI A1 - Cheng, Ching-Yu A1 - Correa, Adolfo A1 - Czajkowski, Jacek A1 - Dehghan, Abbas A1 - Ehret, Georg B A1 - Eiriksdottir, Gudny A1 - Escher, Stefan A A1 - Farmaki, Aliki-Eleni A1 - Frånberg, Mattias A1 - Gambaro, Giovanni A1 - Giulianini, Franco A1 - Goddard, William A A1 - Goel, Anuj A1 - Gottesman, Omri A1 - Grove, Megan L A1 - Gustafsson, Stefan A1 - Hai, Yang A1 - Hallmans, Göran A1 - Heo, Jiyoung A1 - Hoffmann, Per A1 - Ikram, Mohammad K A1 - Jensen, Richard A A1 - Jørgensen, Marit E A1 - Jørgensen, Torben A1 - Karaleftheri, Maria A1 - Khor, Chiea C A1 - Kirkpatrick, Andrea A1 - Kraja, Aldi T A1 - Kuusisto, Johanna A1 - Lange, Ethan M A1 - Lee, I T A1 - Lee, Wen-Jane A1 - Leong, Aaron A1 - Liao, Jiemin A1 - Liu, Chunyu A1 - Liu, Yongmei A1 - Lindgren, Cecilia M A1 - Linneberg, Allan A1 - Malerba, Giovanni A1 - Mamakou, Vasiliki A1 - Marouli, Eirini A1 - Maruthur, Nisa M A1 - Matchan, Angela A1 - McKean-Cowdin, Roberta A1 - McLeod, Olga A1 - Metcalf, Ginger A A1 - Mohlke, Karen L A1 - Muzny, Donna M A1 - Ntalla, Ioanna A1 - Palmer, Nicholette D A1 - Pasko, Dorota A1 - Peter, Andreas A1 - Rayner, Nigel W A1 - Renstrom, Frida A1 - Rice, Ken A1 - Sala, Cinzia F A1 - Sennblad, Bengt A1 - Serafetinidis, Ioannis A1 - Smith, Jennifer A A1 - Soranzo, Nicole A1 - Speliotes, Elizabeth K A1 - Stahl, Eli A A1 - Stirrups, Kathleen A1 - Tentolouris, Nikos A1 - Thanopoulou, Anastasia A1 - Torres, Mina A1 - Traglia, Michela A1 - Tsafantakis, Emmanouil A1 - Javad, Sundas A1 - Yanek, Lisa R A1 - Zengini, Eleni A1 - Becker, Diane M A1 - Bis, Joshua C A1 - Brown, James B A1 - Cupples, L Adrienne A1 - Hansen, Torben A1 - Ingelsson, Erik A1 - Karter, Andrew J A1 - Lorenzo, Carlos A1 - Mathias, Rasika A A1 - Norris, Jill M A1 - Peloso, Gina M A1 - Sheu, Wayne H-H A1 - Toniolo, Daniela A1 - Vaidya, Dhananjay A1 - Varma, Rohit A1 - Wagenknecht, Lynne E A1 - Boeing, Heiner A1 - Bottinger, Erwin P A1 - Dedoussis, George A1 - Deloukas, Panos A1 - Ferrannini, Ele A1 - Franco, Oscar H A1 - Franks, Paul W A1 - Gibbs, Richard A A1 - Gudnason, Vilmundur A1 - Hamsten, Anders A1 - Harris, Tamara B A1 - Hattersley, Andrew T A1 - Hayward, Caroline A1 - Hofman, Albert A1 - Jansson, Jan-Håkan A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Levy, Daniel A1 - Oostra, Ben A A1 - O'Donnell, Christopher J A1 - O'Rahilly, Stephen A1 - Padmanabhan, Sandosh A1 - Pankow, James S A1 - Polasek, Ozren A1 - Province, Michael A A1 - Rich, Stephen S A1 - Ridker, Paul M A1 - Rudan, Igor A1 - Schulze, Matthias B A1 - Smith, Blair H A1 - Uitterlinden, André G A1 - Walker, Mark A1 - Watkins, Hugh A1 - Wong, Tien Y A1 - Zeggini, Eleftheria A1 - Laakso, Markku A1 - Borecki, Ingrid B A1 - Chasman, Daniel I A1 - Pedersen, Oluf A1 - Psaty, Bruce M A1 - Tai, E Shyong A1 - van Duijn, Cornelia M A1 - Wareham, Nicholas J A1 - Waterworth, Dawn M A1 - Boerwinkle, Eric A1 - Kao, W H Linda A1 - Florez, Jose C A1 - Loos, Ruth J F A1 - Wilson, James G A1 - Frayling, Timothy M A1 - Siscovick, David S A1 - Dupuis, Josée A1 - Rotter, Jerome I A1 - Meigs, James B A1 - Scott, Robert A A1 - Goodarzi, Mark O KW - African Continental Ancestry Group KW - Blood Glucose KW - Diabetes Mellitus, Type 2 KW - European Continental Ancestry Group KW - Exome KW - Fasting KW - Genetic Association Studies KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Glucagon-Like Peptide-1 Receptor KW - Glucose-6-Phosphatase KW - Humans KW - Insulin KW - Mutation Rate KW - Oligonucleotide Array Sequence Analysis KW - Polymorphism, Single Nucleotide AB -

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

VL - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25631608?dopt=Abstract ER - TY - JOUR T1 - Prospective association of fatty acids in the de novo lipogenesis pathway with risk of type 2 diabetes: the Cardiovascular Health Study. JF - Am J Clin Nutr Y1 - 2015 A1 - Ma, Wenjie A1 - Wu, Jason H Y A1 - Wang, Qianyi A1 - Lemaitre, Rozenn N A1 - Mukamal, Kenneth J A1 - Djoussé, Luc A1 - King, Irena B A1 - Song, Xiaoling A1 - Biggs, Mary L A1 - Delaney, Joseph A A1 - Kizer, Jorge R A1 - Siscovick, David S A1 - Mozaffarian, Dariush KW - Aged KW - Biomarkers KW - Cohort Studies KW - Cross-Sectional Studies KW - Diabetes Mellitus, Type 2 KW - Female KW - Follow-Up Studies KW - Humans KW - Incidence KW - Lipogenesis KW - Liver KW - Male KW - Palmitic Acid KW - Phospholipids KW - Prevalence KW - Proportional Hazards Models KW - Risk Factors KW - Stearic Acids KW - United States KW - Up-Regulation AB -

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

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

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

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

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

VL - 101 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25527759?dopt=Abstract ER - TY - JOUR T1 - Sleep Disturbances and Glucose Metabolism in Older Adults: The Cardiovascular Health Study. JF - Diabetes Care Y1 - 2015 A1 - Strand, Linn Beate A1 - Carnethon, Mercedes A1 - Biggs, Mary Lou A1 - Djoussé, Luc A1 - Kaplan, Robert C A1 - Siscovick, David S A1 - Robbins, John A A1 - Redline, Susan A1 - Patel, Sanjay R A1 - Janszky, Imre A1 - Mukamal, Kenneth J KW - Adult KW - Aged KW - Blood Glucose KW - Cardiovascular System KW - Cross-Sectional Studies KW - Diabetes Mellitus, Type 2 KW - Fasting KW - Female KW - Glucose Tolerance Test KW - Humans KW - Incidence KW - Insulin KW - Insulin Resistance KW - Male KW - Middle Aged KW - Sleep Apnea Syndromes KW - Sleep Initiation and Maintenance Disorders KW - Snoring KW - United States AB -

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

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

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

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

VL - 38 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26384390?dopt=Abstract ER - TY - JOUR T1 - Exome-wide association study of plasma lipids in >300,000 individuals. JF - Nat Genet Y1 - 2017 A1 - Liu, Dajiang J A1 - Peloso, Gina M A1 - Yu, Haojie A1 - Butterworth, Adam S A1 - Wang, Xiao A1 - Mahajan, Anubha A1 - Saleheen, Danish A1 - Emdin, Connor A1 - Alam, Dewan A1 - Alves, Alexessander Couto A1 - Amouyel, Philippe A1 - Di Angelantonio, Emanuele A1 - Arveiler, Dominique A1 - Assimes, Themistocles L A1 - Auer, Paul L A1 - Baber, Usman A1 - Ballantyne, Christie M A1 - Bang, Lia E A1 - Benn, Marianne A1 - Bis, Joshua C A1 - Boehnke, Michael A1 - Boerwinkle, Eric A1 - Bork-Jensen, Jette A1 - Bottinger, Erwin P A1 - Brandslund, Ivan A1 - Brown, Morris A1 - Busonero, Fabio A1 - Caulfield, Mark J A1 - Chambers, John C A1 - Chasman, Daniel I A1 - Chen, Y Eugene A1 - Chen, Yii-Der Ida A1 - Chowdhury, Rajiv A1 - Christensen, Cramer A1 - Chu, Audrey Y A1 - Connell, John M A1 - Cucca, Francesco A1 - Cupples, L Adrienne A1 - Damrauer, Scott M A1 - Davies, Gail A1 - Deary, Ian J A1 - Dedoussis, George A1 - Denny, Joshua C A1 - Dominiczak, Anna A1 - Dubé, Marie-Pierre A1 - Ebeling, Tapani A1 - Eiriksdottir, Gudny A1 - Esko, Tõnu A1 - Farmaki, Aliki-Eleni A1 - Feitosa, Mary F A1 - Ferrario, Marco A1 - Ferrieres, Jean A1 - Ford, Ian A1 - Fornage, Myriam A1 - Franks, Paul W A1 - Frayling, Timothy M A1 - Frikke-Schmidt, Ruth A1 - Fritsche, Lars G A1 - Frossard, Philippe A1 - Fuster, Valentin A1 - Ganesh, Santhi K A1 - Gao, Wei A1 - Garcia, Melissa E A1 - Gieger, Christian A1 - Giulianini, Franco A1 - Goodarzi, Mark O A1 - Grallert, Harald A1 - Grarup, Niels A1 - Groop, Leif A1 - Grove, Megan L A1 - Gudnason, Vilmundur A1 - Hansen, Torben A1 - Harris, Tamara B A1 - Hayward, Caroline A1 - Hirschhorn, Joel N A1 - Holmen, Oddgeir L A1 - Huffman, Jennifer A1 - Huo, Yong A1 - Hveem, Kristian A1 - Jabeen, Sehrish A1 - Jackson, Anne U A1 - Jakobsdottir, Johanna A1 - Jarvelin, Marjo-Riitta A1 - Jensen, Gorm B A1 - Jørgensen, Marit E A1 - Jukema, J Wouter A1 - Justesen, Johanne M A1 - Kamstrup, Pia R A1 - Kanoni, Stavroula A1 - Karpe, Fredrik A1 - Kee, Frank A1 - Khera, Amit V A1 - Klarin, Derek A1 - Koistinen, Heikki A A1 - Kooner, Jaspal S A1 - Kooperberg, Charles A1 - Kuulasmaa, Kari A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Lakka, Timo A1 - Langenberg, Claudia A1 - Langsted, Anne A1 - Launer, Lenore J A1 - Lauritzen, Torsten A1 - Liewald, David C M A1 - Lin, Li An A1 - Linneberg, Allan A1 - Loos, Ruth J F A1 - Lu, Yingchang A1 - Lu, Xiangfeng A1 - Mägi, Reedik A1 - Mälarstig, Anders A1 - Manichaikul, Ani A1 - Manning, Alisa K A1 - Mäntyselkä, Pekka A1 - Marouli, Eirini A1 - Masca, Nicholas G D A1 - Maschio, Andrea A1 - Meigs, James B A1 - Melander, Olle A1 - Metspalu, Andres A1 - Morris, Andrew P A1 - Morrison, Alanna C A1 - Mulas, Antonella A1 - Müller-Nurasyid, Martina A1 - Munroe, Patricia B A1 - Neville, Matt J A1 - Nielsen, Jonas B A1 - Nielsen, Sune F A1 - Nordestgaard, Børge G A1 - Ordovas, Jose M A1 - Mehran, Roxana A1 - O'Donnell, Christoper J A1 - Orho-Melander, Marju A1 - Molony, Cliona M A1 - Muntendam, Pieter A1 - Padmanabhan, Sandosh A1 - Palmer, Colin N A A1 - Pasko, Dorota A1 - Patel, Aniruddh P A1 - Pedersen, Oluf A1 - Perola, Markus A1 - Peters, Annette A1 - Pisinger, Charlotta A1 - Pistis, Giorgio A1 - Polasek, Ozren A1 - Poulter, Neil A1 - Psaty, Bruce M A1 - Rader, Daniel J A1 - Rasheed, Asif A1 - Rauramaa, Rainer A1 - Reilly, Dermot F A1 - Reiner, Alex P A1 - Renstrom, Frida A1 - Rich, Stephen S A1 - Ridker, Paul M A1 - Rioux, John D A1 - Robertson, Neil R A1 - Roden, Dan M A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Salomaa, Veikko A1 - Samani, Nilesh J A1 - Sanna, Serena A1 - Sattar, Naveed A1 - Schmidt, Ellen M A1 - Scott, Robert A A1 - Sever, Peter A1 - Sevilla, Raquel S A1 - Shaffer, Christian M A1 - Sim, Xueling A1 - Sivapalaratnam, Suthesh A1 - Small, Kerrin S A1 - Smith, Albert V A1 - Smith, Blair H A1 - Somayajula, Sangeetha A1 - Southam, Lorraine A1 - Spector, Timothy D A1 - Speliotes, Elizabeth K A1 - Starr, John M A1 - Stirrups, Kathleen E A1 - Stitziel, Nathan A1 - Strauch, Konstantin A1 - Stringham, Heather M A1 - Surendran, Praveen A1 - Tada, Hayato A1 - Tall, Alan R A1 - Tang, Hua A1 - Tardif, Jean-Claude A1 - Taylor, Kent D A1 - Trompet, Stella A1 - Tsao, Philip S A1 - Tuomilehto, Jaakko A1 - Tybjaerg-Hansen, Anne A1 - van Zuydam, Natalie R A1 - Varbo, Anette A1 - Varga, Tibor V A1 - Virtamo, Jarmo A1 - Waldenberger, Melanie A1 - Wang, Nan A1 - Wareham, Nick J A1 - Warren, Helen R A1 - Weeke, Peter E A1 - Weinstock, Joshua A1 - Wessel, Jennifer A1 - Wilson, James G A1 - Wilson, Peter W F A1 - Xu, Ming A1 - Yaghootkar, Hanieh A1 - Young, Robin A1 - Zeggini, Eleftheria A1 - Zhang, He A1 - Zheng, Neil S A1 - Zhang, Weihua A1 - Zhang, Yan A1 - Zhou, Wei A1 - Zhou, Yanhua A1 - Zoledziewska, Magdalena A1 - Howson, Joanna M M A1 - Danesh, John A1 - McCarthy, Mark I A1 - Cowan, Chad A A1 - Abecasis, Goncalo A1 - Deloukas, Panos A1 - Musunuru, Kiran A1 - Willer, Cristen J A1 - Kathiresan, Sekar KW - Coronary Artery Disease KW - Diabetes Mellitus, Type 2 KW - Exome KW - Genetic Association Studies KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genotype KW - Humans KW - Lipids KW - Macular Degeneration KW - Phenotype KW - Risk Factors AB -

We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.

VL - 49 IS - 12 ER - TY - JOUR T1 - Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis. JF - PLoS Med Y1 - 2017 A1 - Wheeler, Eleanor A1 - Leong, Aaron A1 - Liu, Ching-Ti A1 - Hivert, Marie-France A1 - Strawbridge, Rona J A1 - Podmore, Clara A1 - Li, Man A1 - Yao, Jie A1 - Sim, Xueling A1 - Hong, Jaeyoung A1 - Chu, Audrey Y A1 - Zhang, Weihua A1 - Wang, Xu A1 - Chen, Peng A1 - Maruthur, Nisa M A1 - Porneala, Bianca C A1 - Sharp, Stephen J A1 - Jia, Yucheng A1 - Kabagambe, Edmond K A1 - Chang, Li-Ching A1 - Chen, Wei-Min A1 - Elks, Cathy E A1 - Evans, Daniel S A1 - Fan, Qiao A1 - Giulianini, Franco A1 - Go, Min Jin A1 - Hottenga, Jouke-Jan A1 - Hu, Yao A1 - Jackson, Anne U A1 - Kanoni, Stavroula A1 - Kim, Young Jin A1 - Kleber, Marcus E A1 - Ladenvall, Claes A1 - Lecoeur, Cécile A1 - Lim, Sing-Hui A1 - Lu, Yingchang A1 - Mahajan, Anubha A1 - Marzi, Carola A1 - Nalls, Mike A A1 - Navarro, Pau A1 - Nolte, Ilja M A1 - Rose, Lynda M A1 - Rybin, Denis V A1 - Sanna, Serena A1 - Shi, Yuan A1 - Stram, Daniel O A1 - Takeuchi, Fumihiko A1 - Tan, Shu Pei A1 - van der Most, Peter J A1 - van Vliet-Ostaptchouk, Jana V A1 - Wong, Andrew A1 - Yengo, Loic A1 - Zhao, Wanting A1 - Goel, Anuj A1 - Martinez Larrad, Maria Teresa A1 - Radke, Dörte A1 - Salo, Perttu A1 - Tanaka, Toshiko A1 - van Iperen, Erik P A A1 - Abecasis, Goncalo A1 - Afaq, Saima A1 - Alizadeh, Behrooz Z A1 - Bertoni, Alain G A1 - Bonnefond, Amélie A1 - Böttcher, Yvonne A1 - Bottinger, Erwin P A1 - Campbell, Harry A1 - Carlson, Olga D A1 - Chen, Chien-Hsiun A1 - Cho, Yoon Shin A1 - Garvey, W Timothy A1 - Gieger, Christian A1 - Goodarzi, Mark O A1 - Grallert, Harald A1 - Hamsten, Anders A1 - Hartman, Catharina A A1 - Herder, Christian A1 - Hsiung, Chao Agnes A1 - Huang, Jie A1 - Igase, Michiya A1 - Isono, Masato A1 - Katsuya, Tomohiro A1 - Khor, Chiea-Chuen A1 - Kiess, Wieland A1 - Kohara, Katsuhiko A1 - Kovacs, Peter A1 - Lee, Juyoung A1 - Lee, Wen-Jane A1 - Lehne, Benjamin A1 - Li, Huaixing A1 - Liu, Jianjun A1 - Lobbens, Stephane A1 - Luan, Jian'an A1 - Lyssenko, Valeriya A1 - Meitinger, Thomas A1 - Miki, Tetsuro A1 - Miljkovic, Iva A1 - Moon, Sanghoon A1 - Mulas, Antonella A1 - Müller, Gabriele A1 - Müller-Nurasyid, Martina A1 - Nagaraja, Ramaiah A1 - Nauck, Matthias A1 - Pankow, James S A1 - Polasek, Ozren A1 - Prokopenko, Inga A1 - Ramos, Paula S A1 - Rasmussen-Torvik, Laura A1 - Rathmann, Wolfgang A1 - Rich, Stephen S A1 - Robertson, Neil R A1 - Roden, Michael A1 - Roussel, Ronan A1 - Rudan, Igor A1 - Scott, Robert A A1 - Scott, William R A1 - Sennblad, Bengt A1 - Siscovick, David S A1 - Strauch, Konstantin A1 - Sun, Liang A1 - Swertz, Morris A1 - Tajuddin, Salman M A1 - Taylor, Kent D A1 - Teo, Yik-Ying A1 - Tham, Yih Chung A1 - Tönjes, Anke A1 - Wareham, Nicholas J A1 - Willemsen, Gonneke A1 - Wilsgaard, Tom A1 - Hingorani, Aroon D A1 - Egan, Josephine A1 - Ferrucci, Luigi A1 - Hovingh, G Kees A1 - Jula, Antti A1 - Kivimaki, Mika A1 - Kumari, Meena A1 - Njølstad, Inger A1 - Palmer, Colin N A A1 - Serrano Ríos, Manuel A1 - Stumvoll, Michael A1 - Watkins, Hugh A1 - Aung, Tin A1 - Blüher, Matthias A1 - Boehnke, Michael A1 - Boomsma, Dorret I A1 - Bornstein, Stefan R A1 - Chambers, John C A1 - Chasman, Daniel I A1 - Chen, Yii-Der Ida A1 - Chen, Yduan-Tsong A1 - Cheng, Ching-Yu A1 - Cucca, Francesco A1 - de Geus, Eco J C A1 - Deloukas, Panos A1 - Evans, Michele K A1 - Fornage, Myriam A1 - Friedlander, Yechiel A1 - Froguel, Philippe A1 - Groop, Leif A1 - Gross, Myron D A1 - Harris, Tamara B A1 - Hayward, Caroline A1 - Heng, Chew-Kiat A1 - Ingelsson, Erik A1 - Kato, Norihiro A1 - Kim, Bong-Jo A1 - Koh, Woon-Puay A1 - Kooner, Jaspal S A1 - Körner, Antje A1 - Kuh, Diana A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Lin, Xu A1 - Liu, Yongmei A1 - Loos, Ruth J F A1 - Magnusson, Patrik K E A1 - März, Winfried A1 - McCarthy, Mark I A1 - Oldehinkel, Albertine J A1 - Ong, Ken K A1 - Pedersen, Nancy L A1 - Pereira, Mark A A1 - Peters, Annette A1 - Ridker, Paul M A1 - Sabanayagam, Charumathi A1 - Sale, Michele A1 - Saleheen, Danish A1 - Saltevo, Juha A1 - Schwarz, Peter Eh A1 - Sheu, Wayne H H A1 - Snieder, Harold A1 - Spector, Timothy D A1 - Tabara, Yasuharu A1 - Tuomilehto, Jaakko A1 - van Dam, Rob M A1 - Wilson, James G A1 - Wilson, James F A1 - Wolffenbuttel, Bruce H R A1 - Wong, Tien Yin A1 - Wu, Jer-Yuarn A1 - Yuan, Jian-Min A1 - Zonderman, Alan B A1 - Soranzo, Nicole A1 - Guo, Xiuqing A1 - Roberts, David J A1 - Florez, Jose C A1 - Sladek, Robert A1 - Dupuis, Josée A1 - Morris, Andrew P A1 - Tai, E-Shyong A1 - Selvin, Elizabeth A1 - Rotter, Jerome I A1 - Langenberg, Claudia A1 - Barroso, Inês A1 - Meigs, James B KW - Diabetes Mellitus, Type 2 KW - Genetic Variation KW - Genome-Wide Association Study KW - Glycated Hemoglobin A KW - Humans KW - Phenotype KW - Risk AB -

BACKGROUND: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.

METHODS & FINDINGS: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 × 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.

CONCLUSIONS: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.

VL - 14 IS - 9 ER - TY - JOUR T1 - Fatty acid biomarkers of dairy fat consumption and incidence of type 2 diabetes: A pooled analysis of prospective cohort studies. JF - PLoS Med Y1 - 2018 A1 - Imamura, Fumiaki A1 - Fretts, Amanda A1 - Marklund, Matti A1 - Ardisson Korat, Andres V A1 - Yang, Wei-Sin A1 - Lankinen, Maria A1 - Qureshi, Waqas A1 - Helmer, Catherine A1 - Chen, Tzu-An A1 - Wong, Kerry A1 - Bassett, Julie K A1 - Murphy, Rachel A1 - Tintle, Nathan A1 - Yu, Chaoyu Ian A1 - Brouwer, Ingeborg A A1 - Chien, Kuo-Liong A1 - Frazier-Wood, Alexis C A1 - Del Gobbo, Liana C A1 - Djoussé, Luc A1 - Geleijnse, Johanna M A1 - Giles, Graham G A1 - de Goede, Janette A1 - Gudnason, Vilmundur A1 - Harris, William S A1 - Hodge, Allison A1 - Hu, Frank A1 - Koulman, Albert A1 - Laakso, Markku A1 - Lind, Lars A1 - Lin, Hung-Ju A1 - McKnight, Barbara A1 - Rajaobelina, Kalina A1 - Riserus, Ulf A1 - Robinson, Jennifer G A1 - Samieri, Cecilia A1 - Siscovick, David S A1 - Soedamah-Muthu, Sabita S A1 - Sotoodehnia, Nona A1 - Sun, Qi A1 - Tsai, Michael Y A1 - Uusitupa, Matti A1 - Wagenknecht, Lynne E A1 - Wareham, Nick J A1 - Wu, Jason HY A1 - Micha, Renata A1 - Forouhi, Nita G A1 - Lemaitre, Rozenn N A1 - Mozaffarian, Dariush KW - Aged KW - Australia KW - Biomarkers KW - Dairy Products KW - Diabetes Mellitus, Type 2 KW - Dietary Fats KW - Europe KW - Fatty Acids KW - Fatty Acids, Monounsaturated KW - Female KW - Humans KW - Incidence KW - Male KW - Middle Aged KW - Prospective Studies KW - Sex Factors KW - Taiwan KW - United States AB -

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.

VL - 15 IS - 10 ER - TY - JOUR T1 - Comment on Davis et al. Development and Validation of a Simple Hip Fracture Risk Prediction Tool for Type 2 Diabetes: The Fremantle Diabetes Study Phase I. Diabetes Care 2018;42:102-109. JF - Diabetes Care Y1 - 2019 A1 - Bůzková, Petra A1 - Barzilay, Joshua I KW - Diabetes Mellitus, Type 2 KW - Hip Fractures KW - Humans VL - 42 IS - 6 ER - TY - JOUR T1 - Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes. JF - Nat Commun Y1 - 2021 A1 - Goodrich, Julia K A1 - Singer-Berk, Moriel A1 - Son, Rachel A1 - Sveden, Abigail A1 - Wood, Jordan A1 - England, Eleina A1 - Cole, Joanne B A1 - Weisburd, Ben A1 - Watts, Nick A1 - Caulkins, Lizz A1 - Dornbos, Peter A1 - Koesterer, Ryan A1 - Zappala, Zachary A1 - Zhang, Haichen A1 - Maloney, Kristin A A1 - Dahl, Andy A1 - Aguilar-Salinas, Carlos A A1 - Atzmon, Gil A1 - Barajas-Olmos, Francisco A1 - Barzilai, Nir A1 - Blangero, John A1 - Boerwinkle, Eric A1 - Bonnycastle, Lori L A1 - Bottinger, Erwin A1 - Bowden, Donald W A1 - Centeno-Cruz, Federico A1 - Chambers, John C A1 - Chami, Nathalie A1 - Chan, Edmund A1 - Chan, Juliana A1 - Cheng, Ching-Yu A1 - Cho, Yoon Shin A1 - Contreras-Cubas, Cecilia A1 - Córdova, Emilio A1 - Correa, Adolfo A1 - DeFronzo, Ralph A A1 - Duggirala, Ravindranath A1 - Dupuis, Josée A1 - Garay-Sevilla, Ma Eugenia A1 - García-Ortiz, Humberto A1 - Gieger, Christian A1 - Glaser, Benjamin A1 - González-Villalpando, Clicerio A1 - Gonzalez, Ma Elena A1 - Grarup, Niels A1 - Groop, Leif A1 - Gross, Myron A1 - Haiman, Christopher A1 - Han, Sohee A1 - Hanis, Craig L A1 - Hansen, Torben A1 - Heard-Costa, Nancy L A1 - Henderson, Brian E A1 - Hernandez, Juan Manuel Malacara A1 - Hwang, Mi Yeong A1 - Islas-Andrade, Sergio A1 - Jørgensen, Marit E A1 - Kang, Hyun Min A1 - Kim, Bong-Jo A1 - Kim, Young Jin A1 - Koistinen, Heikki A A1 - Kooner, Jaspal Singh A1 - Kuusisto, Johanna A1 - Kwak, Soo-Heon A1 - Laakso, Markku A1 - Lange, Leslie A1 - Lee, Jong-Young A1 - Lee, Juyoung A1 - Lehman, Donna M A1 - Linneberg, Allan A1 - Liu, Jianjun A1 - Loos, Ruth J F A1 - Lyssenko, Valeriya A1 - Ma, Ronald C W A1 - Martínez-Hernández, Angélica A1 - Meigs, James B A1 - Meitinger, Thomas A1 - Mendoza-Caamal, Elvia A1 - Mohlke, Karen L A1 - Morris, Andrew D A1 - Morrison, Alanna C A1 - Ng, Maggie C Y A1 - Nilsson, Peter M A1 - O'Donnell, Christopher J A1 - Orozco, Lorena A1 - Palmer, Colin N A A1 - Park, Kyong Soo A1 - Post, Wendy S A1 - Pedersen, Oluf A1 - Preuss, Michael A1 - Psaty, Bruce M A1 - Reiner, Alexander P A1 - Revilla-Monsalve, Cristina A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Saleheen, Danish A1 - Schurmann, Claudia A1 - Sim, Xueling A1 - Sladek, Rob A1 - Small, Kerrin S A1 - So, Wing Yee A1 - Spector, Timothy D A1 - Strauch, Konstantin A1 - Strom, Tim M A1 - Tai, E Shyong A1 - Tam, Claudia H T A1 - Teo, Yik Ying A1 - Thameem, Farook A1 - Tomlinson, Brian A1 - Tracy, Russell P A1 - Tuomi, Tiinamaija A1 - Tuomilehto, Jaakko A1 - Tusié-Luna, Teresa A1 - van Dam, Rob M A1 - Vasan, Ramachandran S A1 - Wilson, James G A1 - Witte, Daniel R A1 - Wong, Tien-Yin A1 - Burtt, Noel P A1 - Zaitlen, Noah A1 - McCarthy, Mark I A1 - Boehnke, Michael A1 - Pollin, Toni I A1 - Flannick, Jason A1 - Mercader, Josep M A1 - O'Donnell-Luria, Anne A1 - Baxter, Samantha A1 - Florez, Jose C A1 - MacArthur, Daniel G A1 - Udler, Miriam S KW - Adult KW - Biological Variation, Population KW - Biomarkers KW - Diabetes Mellitus, Type 2 KW - Dyslipidemias KW - Exome KW - Genetic Predisposition to Disease KW - Genotype KW - Humans KW - Multifactorial Inheritance KW - Penetrance KW - Risk Assessment AB -

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias.

VL - 12 IS - 1 ER - TY - JOUR T1 - Egg consumption, overall diet quality, and risk of type 2 diabetes and coronary heart disease: A pooling project of US prospective cohorts. JF - Clin Nutr Y1 - 2021 A1 - Djoussé, Luc A1 - Zhou, Guohai A1 - McClelland, Robyn L A1 - Ma, Nanxun A1 - Zhou, Xia A1 - Kabagambe, Edmond K A1 - Talegawkar, Sameera A A1 - Judd, Suzanne E A1 - Biggs, Mary L A1 - Fitzpatrick, Annette L A1 - Clark, Cheryl R A1 - Gagnon, David R A1 - Steffen, Lyn M A1 - Gaziano, J Michael A1 - Lee, I-Min A1 - Buring, Julie E A1 - Manson, JoAnn E KW - Adult KW - Aged KW - Cohort Studies KW - Coronary Disease KW - Diabetes Mellitus, Type 2 KW - Diet KW - Eggs KW - Humans KW - Middle Aged KW - Prospective Studies KW - Risk Factors KW - United States AB -

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.

VL - 40 IS - 5 ER - TY - JOUR T1 - Fasting and Postload Nonesterified Fatty Acids and Glucose Dysregulation in Older Adults. JF - Am J Epidemiol Y1 - 2022 A1 - Shitole, Sanyog G A1 - Biggs, Mary L A1 - Ix, Joachim H A1 - Fretts, Amanda M A1 - Tracy, Russell P A1 - Siscovick, David S A1 - Djoussé, Luc A1 - Mukamal, Kenneth J A1 - Kizer, Jorge R KW - Aged KW - Blood Glucose KW - Diabetes Mellitus, Type 2 KW - Fasting KW - Fatty Acids, Nonesterified KW - Female KW - Glucose KW - Humans KW - Insulin KW - Insulin Resistance KW - Male KW - Prospective Studies AB -

To evaluate the association of nonesterified fatty acids (NEFA) with dysglycemia in older adults, NEFA levels were measured among participants in the Cardiovascular Health Study (United States; enrolled 1989-1993). Associations with insulin sensitivity and pancreatic β-cell function, and with incident type 2 diabetes mellitus (DM), were examined. The sample comprised 2,144 participants (aged 77.9 (standard deviation, 4.5) years). Participant data from the Cardiovascular Health Study visit in 1996-1997 was used with prospective follow-up through 2010. Fasting and postload NEFA showed significant associations with lower insulin sensitivity and pancreatic β-cell function, individually and on concurrent adjustment. Over median follow-up of 9.7 years, 236 cases of DM occurred. Postload NEFA were associated with risk of DM (per standard deviation, hazard ratio = 1.18, 95% confidence interval: 1.08, 1.29), but fasting NEFA were not (hazard ratio = 1.12, 95% confidence interval: 0.97, 1.29). The association for postload NEFA persisted after adjustment for putative intermediates, and after adjustment for fasting NEFA. Sex and body mass index modified these associations, which were stronger for fasting NEFA with DM in men but were accentuated for postload NEFA in women and among leaner individuals. Fasting and postload NEFA were related to lower insulin sensitivity and pancreatic β-cell function, but only postload NEFA were associated with increased DM. Additional study into NEFA metabolism could uncover novel potential targets for diabetes prevention in elders.

VL - 191 IS - 7 ER - TY - JOUR T1 - Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation. JF - Nat Genet Y1 - 2022 A1 - Mahajan, Anubha A1 - Spracklen, Cassandra N A1 - Zhang, Weihua A1 - Ng, Maggie C Y A1 - Petty, Lauren E A1 - Kitajima, Hidetoshi A1 - Yu, Grace Z A1 - Rüeger, Sina A1 - Speidel, Leo A1 - Kim, Young Jin A1 - Horikoshi, Momoko A1 - Mercader, Josep M A1 - Taliun, Daniel A1 - Moon, Sanghoon A1 - Kwak, Soo-Heon A1 - Robertson, Neil R A1 - Rayner, Nigel W A1 - Loh, Marie A1 - Kim, Bong-Jo A1 - Chiou, Joshua A1 - Miguel-Escalada, Irene A1 - Della Briotta Parolo, Pietro A1 - Lin, Kuang A1 - Bragg, Fiona A1 - Preuss, Michael H A1 - Takeuchi, Fumihiko A1 - Nano, Jana A1 - Guo, Xiuqing A1 - Lamri, Amel A1 - Nakatochi, Masahiro A1 - Scott, Robert A A1 - Lee, Jung-Jin A1 - Huerta-Chagoya, Alicia A1 - Graff, Mariaelisa A1 - Chai, Jin-Fang A1 - Parra, Esteban J A1 - Yao, Jie A1 - Bielak, Lawrence F A1 - Tabara, Yasuharu A1 - Hai, Yang A1 - Steinthorsdottir, Valgerdur A1 - Cook, James P A1 - Kals, Mart A1 - Grarup, Niels A1 - Schmidt, Ellen M A1 - Pan, Ian A1 - Sofer, Tamar A1 - Wuttke, Matthias A1 - Sarnowski, Chloe A1 - Gieger, Christian A1 - Nousome, Darryl A1 - Trompet, Stella A1 - Long, Jirong A1 - Sun, Meng A1 - Tong, Lin A1 - Chen, Wei-Min A1 - Ahmad, Meraj A1 - Noordam, Raymond A1 - Lim, Victor J Y A1 - Tam, Claudia H T A1 - Joo, Yoonjung Yoonie A1 - Chen, Chien-Hsiun A1 - Raffield, Laura M A1 - Lecoeur, Cécile A1 - Prins, Bram Peter A1 - Nicolas, Aude A1 - Yanek, Lisa R A1 - Chen, Guanjie A1 - Jensen, Richard A A1 - Tajuddin, Salman A1 - Kabagambe, Edmond K A1 - An, Ping A1 - Xiang, Anny H A1 - Choi, Hyeok Sun A1 - Cade, Brian E A1 - Tan, Jingyi A1 - Flanagan, Jack A1 - Abaitua, Fernando A1 - Adair, Linda S A1 - Adeyemo, Adebowale A1 - Aguilar-Salinas, Carlos A A1 - Akiyama, Masato A1 - Anand, Sonia S A1 - Bertoni, Alain A1 - Bian, Zheng A1 - Bork-Jensen, Jette A1 - Brandslund, Ivan A1 - Brody, Jennifer A A1 - Brummett, Chad M A1 - Buchanan, Thomas A A1 - Canouil, Mickaël A1 - Chan, Juliana C N A1 - Chang, Li-Ching A1 - Chee, Miao-Li A1 - Chen, Ji A1 - Chen, Shyh-Huei A1 - Chen, Yuan-Tsong A1 - Chen, Zhengming A1 - Chuang, Lee-Ming A1 - Cushman, Mary A1 - Das, Swapan K A1 - de Silva, H Janaka A1 - Dedoussis, George A1 - Dimitrov, Latchezar A1 - Doumatey, Ayo P A1 - Du, Shufa A1 - Duan, Qing A1 - Eckardt, Kai-Uwe A1 - Emery, Leslie S A1 - Evans, Daniel S A1 - Evans, Michele K A1 - Fischer, Krista A1 - Floyd, James S A1 - Ford, Ian A1 - Fornage, Myriam A1 - Franco, Oscar H A1 - Frayling, Timothy M A1 - Freedman, Barry I A1 - Fuchsberger, Christian A1 - Genter, Pauline A1 - Gerstein, Hertzel C A1 - Giedraitis, Vilmantas A1 - González-Villalpando, Clicerio A1 - Gonzalez-Villalpando, Maria Elena A1 - Goodarzi, Mark O A1 - Gordon-Larsen, Penny A1 - Gorkin, David A1 - Gross, Myron A1 - Guo, Yu A1 - Hackinger, Sophie A1 - Han, Sohee A1 - Hattersley, Andrew T A1 - Herder, Christian A1 - Howard, Annie-Green A1 - Hsueh, Willa A1 - Huang, Mengna A1 - Huang, Wei A1 - Hung, Yi-Jen A1 - Hwang, Mi Yeong A1 - Hwu, Chii-Min A1 - Ichihara, Sahoko A1 - Ikram, Mohammad Arfan A1 - Ingelsson, Martin A1 - Islam, Md Tariqul A1 - Isono, Masato A1 - Jang, Hye-Mi A1 - Jasmine, Farzana A1 - Jiang, Guozhi A1 - Jonas, Jost B A1 - Jørgensen, Marit E A1 - Jørgensen, Torben A1 - Kamatani, Yoichiro A1 - Kandeel, Fouad R A1 - Kasturiratne, Anuradhani A1 - Katsuya, Tomohiro A1 - Kaur, Varinderpal A1 - Kawaguchi, Takahisa A1 - Keaton, Jacob M A1 - Kho, Abel N A1 - Khor, Chiea-Chuen A1 - Kibriya, Muhammad G A1 - Kim, Duk-Hwan A1 - Kohara, Katsuhiko A1 - Kriebel, Jennifer A1 - Kronenberg, Florian A1 - Kuusisto, Johanna A1 - Läll, Kristi A1 - Lange, Leslie A A1 - Lee, Myung-Shik A1 - Lee, Nanette R A1 - Leong, Aaron A1 - Li, Liming A1 - Li, Yun A1 - Li-Gao, Ruifang A1 - Ligthart, Symen A1 - Lindgren, Cecilia M A1 - Linneberg, Allan A1 - Liu, Ching-Ti A1 - Liu, Jianjun A1 - Locke, Adam E A1 - Louie, Tin A1 - Luan, Jian'an A1 - Luk, Andrea O A1 - Luo, Xi A1 - Lv, Jun A1 - Lyssenko, Valeriya A1 - Mamakou, Vasiliki A1 - Mani, K Radha A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Morris, Andrew D A1 - Nadkarni, Girish N A1 - Nadler, Jerry L A1 - Nalls, Michael A A1 - Nayak, Uma A1 - Nongmaithem, Suraj S A1 - Ntalla, Ioanna A1 - Okada, Yukinori A1 - Orozco, Lorena A1 - Patel, Sanjay R A1 - Pereira, Mark A A1 - Peters, Annette A1 - Pirie, Fraser J A1 - Porneala, Bianca A1 - Prasad, Gauri A1 - Preissl, Sebastian A1 - Rasmussen-Torvik, Laura J A1 - Reiner, Alexander P A1 - Roden, Michael A1 - Rohde, Rebecca A1 - Roll, Kathryn A1 - Sabanayagam, Charumathi A1 - Sander, Maike A1 - Sandow, Kevin A1 - Sattar, Naveed A1 - Schönherr, Sebastian A1 - Schurmann, Claudia A1 - Shahriar, Mohammad A1 - Shi, Jinxiu A1 - Shin, Dong Mun A1 - Shriner, Daniel A1 - Smith, Jennifer A A1 - So, Wing Yee A1 - Stančáková, Alena A1 - Stilp, Adrienne M A1 - Strauch, Konstantin A1 - Suzuki, Ken A1 - Takahashi, Atsushi A1 - Taylor, Kent D A1 - Thorand, Barbara A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Tomlinson, Brian A1 - Torres, Jason M A1 - Tsai, Fuu-Jen A1 - Tuomilehto, Jaakko A1 - Tusié-Luna, Teresa A1 - Udler, Miriam S A1 - Valladares-Salgado, Adan A1 - van Dam, Rob M A1 - van Klinken, Jan B A1 - Varma, Rohit A1 - Vujkovic, Marijana A1 - Wacher-Rodarte, Niels A1 - Wheeler, Eleanor A1 - Whitsel, Eric A A1 - Wickremasinghe, Ananda R A1 - van Dijk, Ko Willems A1 - Witte, Daniel R A1 - Yajnik, Chittaranjan S A1 - Yamamoto, Ken A1 - Yamauchi, Toshimasa A1 - Yengo, Loic A1 - Yoon, Kyungheon A1 - Yu, Canqing A1 - Yuan, Jian-Min A1 - Yusuf, Salim A1 - Zhang, Liang A1 - Zheng, Wei A1 - Raffel, Leslie J A1 - Igase, Michiya A1 - Ipp, Eli A1 - Redline, Susan A1 - Cho, Yoon Shin A1 - Lind, Lars A1 - Province, Michael A A1 - Hanis, Craig L A1 - Peyser, Patricia A A1 - Ingelsson, Erik A1 - Zonderman, Alan B A1 - Psaty, Bruce M A1 - Wang, Ya-Xing A1 - Rotimi, Charles N A1 - Becker, Diane M A1 - Matsuda, Fumihiko A1 - Liu, Yongmei A1 - Zeggini, Eleftheria A1 - Yokota, Mitsuhiro A1 - Rich, Stephen S A1 - Kooperberg, Charles A1 - Pankow, James S A1 - Engert, James C A1 - Chen, Yii-Der Ida A1 - Froguel, Philippe A1 - Wilson, James G A1 - Sheu, Wayne H H A1 - Kardia, Sharon L R A1 - Wu, Jer-Yuarn A1 - Hayes, M Geoffrey A1 - Ma, Ronald C W A1 - Wong, Tien-Yin A1 - Groop, Leif A1 - Mook-Kanamori, Dennis O A1 - Chandak, Giriraj R A1 - Collins, Francis S A1 - Bharadwaj, Dwaipayan A1 - Paré, Guillaume A1 - Sale, Michèle M A1 - Ahsan, Habibul A1 - Motala, Ayesha A A1 - Shu, Xiao-Ou A1 - Park, Kyong-Soo A1 - Jukema, J Wouter A1 - Cruz, Miguel A1 - McKean-Cowdin, Roberta A1 - Grallert, Harald A1 - Cheng, Ching-Yu A1 - Bottinger, Erwin P A1 - Dehghan, Abbas A1 - Tai, E-Shyong A1 - Dupuis, Josée A1 - Kato, Norihiro A1 - Laakso, Markku A1 - Köttgen, Anna A1 - Koh, Woon-Puay A1 - Palmer, Colin N A A1 - Liu, Simin A1 - Abecasis, Goncalo A1 - Kooner, Jaspal S A1 - Loos, Ruth J F A1 - North, Kari E A1 - Haiman, Christopher A A1 - Florez, Jose C A1 - Saleheen, Danish A1 - Hansen, Torben A1 - Pedersen, Oluf A1 - Mägi, Reedik A1 - Langenberg, Claudia A1 - Wareham, Nicholas J A1 - Maeda, Shiro A1 - Kadowaki, Takashi A1 - Lee, Juyoung A1 - Millwood, Iona Y A1 - Walters, Robin G A1 - Stefansson, Kari A1 - Myers, Simon R A1 - Ferrer, Jorge A1 - Gaulton, Kyle J A1 - Meigs, James B A1 - Mohlke, Karen L A1 - Gloyn, Anna L A1 - Bowden, Donald W A1 - Below, Jennifer E A1 - Chambers, John C A1 - Sim, Xueling A1 - Boehnke, Michael A1 - Rotter, Jerome I A1 - McCarthy, Mark I A1 - Morris, Andrew P KW - Diabetes Mellitus, Type 2 KW - Ethnicity KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 × 10), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background.

VL - 54 IS - 5 ER - TY - JOUR T1 - A multi-ethnic polygenic risk score is associated with hypertension prevalence and progression throughout adulthood. JF - Nat Commun Y1 - 2022 A1 - Kurniansyah, Nuzulul A1 - Goodman, Matthew O A1 - Kelly, Tanika N A1 - Elfassy, Tali A1 - Wiggins, Kerri L A1 - Bis, Joshua C A1 - Guo, Xiuqing A1 - Palmas, Walter A1 - Taylor, Kent D A1 - Lin, Henry J A1 - Haessler, Jeffrey A1 - Gao, Yan A1 - Shimbo, Daichi A1 - Smith, Jennifer A A1 - Yu, Bing A1 - Feofanova, Elena V A1 - Smit, Roelof A J A1 - Wang, Zhe A1 - Hwang, Shih-Jen A1 - Liu, Simin A1 - Wassertheil-Smoller, Sylvia A1 - Manson, JoAnn E A1 - Lloyd-Jones, Donald M A1 - Rich, Stephen S A1 - Loos, Ruth J F A1 - Redline, Susan A1 - Correa, Adolfo A1 - Kooperberg, Charles A1 - Fornage, Myriam A1 - Kaplan, Robert C A1 - Psaty, Bruce M A1 - Rotter, Jerome I A1 - Arnett, Donna K A1 - Morrison, Alanna C A1 - Franceschini, Nora A1 - Levy, Daniel A1 - Sofer, Tamar KW - Adult KW - Diabetes Mellitus, Type 2 KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Multifactorial Inheritance KW - Prevalence KW - Risk Factors AB -

In a multi-stage analysis of 52,436 individuals aged 17-90 across diverse cohorts and biobanks, we train, test, and evaluate a polygenic risk score (PRS) for hypertension risk and progression. The PRS is trained using genome-wide association studies (GWAS) for systolic, diastolic blood pressure, and hypertension, respectively. For each trait, PRS is selected by optimizing the coefficient of variation (CV) across estimated effect sizes from multiple potential PRS using the same GWAS, after which the 3 trait-specific PRSs are combined via an unweighted sum called "PRSsum", forming the HTN-PRS. The HTN-PRS is associated with both prevalent and incident hypertension at 4-6 years of follow up. This association is further confirmed in age-stratified analysis. In an independent biobank of 40,201 individuals, the HTN-PRS is confirmed to be predictive of increased risk for coronary artery disease, ischemic stroke, type 2 diabetes, and chronic kidney disease.

VL - 13 IS - 1 ER - TY - JOUR T1 - Plasma epoxyeicosatrienoic acids and diabetes-related cardiovascular disease: The cardiovascular health study. JF - EBioMedicine Y1 - 2022 A1 - Lemaitre, Rozenn N A1 - Jensen, Paul N A1 - Zeigler, Maxwell A1 - Fretts, Amanda M A1 - Umans, Jason G A1 - Howard, Barbara V A1 - Sitlani, Colleen M A1 - McKnight, Barbara A1 - Gharib, Sina A A1 - King, Irena B A1 - Siscovick, David S A1 - Psaty, Bruce M A1 - Sotoodehnia, Nona A1 - Totah, Rheem A KW - Animals KW - Arachidonic Acids KW - Cardiovascular Diseases KW - Diabetes Mellitus, Type 2 KW - Eicosanoids KW - Humans KW - Ischemic Stroke KW - Prospective Studies AB -

BACKGROUND: Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid that may impact atherosclerosis, and animal experimental studies suggest EETs protect cardiac function. Plasma EETs are mostly esterified to phospholipids and part of an active pool. To address the limited information about EETs and CVD in humans, we conducted a prospective study of total plasma EETs (free + esterified) and diabetes-related CVD in the Cardiovascular Health Study (CHS).

METHODS: We measured 4 EET species and their metabolites, dihydroxyepoxyeicosatrienoic acids (DHETs), in plasma samples from 892 CHS participants with type 2 diabetes. We determined the association of EETs and DHETs with incident myocardial infarction (MI) and ischemic stroke using Cox regression.

FINDINGS: During follow-up (median 7.5 years), we identified 150 MI and 134 ischemic strokes. In primary, multivariable analyses, elevated levels of each EET species were associated with non-significant lower risk of incident MI (for example, hazard ratio for 1 SD higher 14,15-EET: 0.86, 95% CI: 0.72-1.02; p=0.08). The EETs-MI associations became significant in analyses further adjusted for DHETs (hazard ratio for 1 SD higher 14,15-EET adjusted for 14,15-DHET: 0.76, 95% CI: 0.63-0.91; p=0.004). Elevated EET levels were associated with higher risk of ischemic stroke in primary but not secondary analyses. Three DHET species were associated with higher risk of ischemic stroke in all analyses.

INTERPRETATION: Findings from this prospective study complement the extensive studies in animal models showing EETs protect cardiac function and provide new information in humans. Replication is needed to confirm the associations.

FUNDING: US National Institutes of Health.

VL - 83 ER - TY - JOUR T1 - Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes. JF - Am J Hum Genet Y1 - 2022 A1 - Hindy, George A1 - Dornbos, Peter A1 - Chaffin, Mark D A1 - Liu, Dajiang J A1 - Wang, Minxian A1 - Selvaraj, Margaret Sunitha A1 - Zhang, David A1 - Park, Joseph A1 - Aguilar-Salinas, Carlos A A1 - Antonacci-Fulton, Lucinda A1 - Ardissino, Diego A1 - Arnett, Donna K A1 - Aslibekyan, Stella A1 - Atzmon, Gil A1 - Ballantyne, Christie M A1 - Barajas-Olmos, Francisco A1 - Barzilai, Nir A1 - Becker, Lewis C A1 - Bielak, Lawrence F A1 - Bis, Joshua C A1 - Blangero, John A1 - Boerwinkle, Eric A1 - Bonnycastle, Lori L A1 - Bottinger, Erwin A1 - Bowden, Donald W A1 - Bown, Matthew J A1 - Brody, Jennifer A A1 - Broome, Jai G A1 - Burtt, Noel P A1 - Cade, Brian E A1 - Centeno-Cruz, Federico A1 - Chan, Edmund A1 - Chang, Yi-Cheng A1 - Chen, Yii-der I A1 - Cheng, Ching-Yu A1 - Choi, Won Jung A1 - Chowdhury, Rajiv A1 - Contreras-Cubas, Cecilia A1 - Córdova, Emilio J A1 - Correa, Adolfo A1 - Cupples, L Adrienne A1 - Curran, Joanne E A1 - Danesh, John A1 - de Vries, Paul S A1 - DeFronzo, Ralph A A1 - Doddapaneni, Harsha A1 - Duggirala, Ravindranath A1 - Dutcher, Susan K A1 - Ellinor, Patrick T A1 - Emery, Leslie S A1 - Florez, Jose C A1 - Fornage, Myriam A1 - Freedman, Barry I A1 - Fuster, Valentin A1 - Garay-Sevilla, Ma Eugenia A1 - García-Ortiz, Humberto A1 - Germer, Soren A1 - Gibbs, Richard A A1 - Gieger, Christian A1 - Glaser, Benjamin A1 - Gonzalez, Clicerio A1 - Gonzalez-Villalpando, Maria Elena A1 - Graff, Mariaelisa A1 - Graham, Sarah E A1 - Grarup, Niels A1 - Groop, Leif C A1 - Guo, Xiuqing A1 - Gupta, Namrata A1 - Han, Sohee A1 - Hanis, Craig L A1 - Hansen, Torben A1 - He, Jiang A1 - Heard-Costa, Nancy L A1 - Hung, Yi-Jen A1 - Hwang, Mi Yeong A1 - Irvin, Marguerite R A1 - Islas-Andrade, Sergio A1 - Jarvik, Gail P A1 - Kang, Hyun Min A1 - Kardia, Sharon L R A1 - Kelly, Tanika A1 - Kenny, Eimear E A1 - Khan, Alyna T A1 - Kim, Bong-Jo A1 - Kim, Ryan W A1 - Kim, Young Jin A1 - Koistinen, Heikki A A1 - Kooperberg, Charles A1 - Kuusisto, Johanna A1 - Kwak, Soo Heon A1 - Laakso, Markku A1 - Lange, Leslie A A1 - Lee, Jiwon A1 - Lee, Juyoung A1 - Lee, Seonwook A1 - Lehman, Donna M A1 - Lemaitre, Rozenn N A1 - Linneberg, Allan A1 - Liu, Jianjun A1 - Loos, Ruth J F A1 - Lubitz, Steven A A1 - Lyssenko, Valeriya A1 - Ma, Ronald C W A1 - Martin, Lisa Warsinger A1 - Martínez-Hernández, Angélica A1 - Mathias, Rasika A A1 - McGarvey, Stephen T A1 - McPherson, Ruth A1 - Meigs, James B A1 - Meitinger, Thomas A1 - Melander, Olle A1 - Mendoza-Caamal, Elvia A1 - Metcalf, Ginger A A1 - Mi, Xuenan A1 - Mohlke, Karen L A1 - Montasser, May E A1 - Moon, Jee-Young A1 - Moreno-Macias, Hortensia A1 - Morrison, Alanna C A1 - Muzny, Donna M A1 - Nelson, Sarah C A1 - Nilsson, Peter M A1 - O'Connell, Jeffrey R A1 - Orho-Melander, Marju A1 - Orozco, Lorena A1 - Palmer, Colin N A A1 - Palmer, Nicholette D A1 - Park, Cheol Joo A1 - Park, Kyong Soo A1 - Pedersen, Oluf A1 - Peralta, Juan M A1 - Peyser, Patricia A A1 - Post, Wendy S A1 - Preuss, Michael A1 - Psaty, Bruce M A1 - Qi, Qibin A1 - Rao, D C A1 - Redline, Susan A1 - Reiner, Alexander P A1 - Revilla-Monsalve, Cristina A1 - Rich, Stephen S A1 - Samani, Nilesh A1 - Schunkert, Heribert A1 - Schurmann, Claudia A1 - Seo, Daekwan A1 - Seo, Jeong-Sun A1 - Sim, Xueling A1 - Sladek, Rob A1 - Small, Kerrin S A1 - So, Wing Yee A1 - Stilp, Adrienne M A1 - Tai, E Shyong A1 - Tam, Claudia H T A1 - Taylor, Kent D A1 - Teo, Yik Ying A1 - Thameem, Farook A1 - Tomlinson, Brian A1 - Tsai, Michael Y A1 - Tuomi, Tiinamaija A1 - Tuomilehto, Jaakko A1 - Tusié-Luna, Teresa A1 - Udler, Miriam S A1 - van Dam, Rob M A1 - Vasan, Ramachandran S A1 - Viaud Martinez, Karine A A1 - Wang, Fei Fei A1 - Wang, Xuzhi A1 - Watkins, Hugh A1 - Weeks, Daniel E A1 - Wilson, James G A1 - Witte, Daniel R A1 - Wong, Tien-Yin A1 - Yanek, Lisa R A1 - Kathiresan, Sekar A1 - Rader, Daniel J A1 - Rotter, Jerome I A1 - Boehnke, Michael A1 - McCarthy, Mark I A1 - Willer, Cristen J A1 - Natarajan, Pradeep A1 - Flannick, Jason A A1 - Khera, Amit V A1 - Peloso, Gina M KW - Alleles KW - Blood Glucose KW - Case-Control Studies KW - Computational Biology KW - Databases, Genetic KW - Diabetes Mellitus, Type 2 KW - Exome KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genetics, Population KW - Genome-Wide Association Study KW - Humans KW - Lipid Metabolism KW - Lipids KW - Liver KW - Molecular Sequence Annotation KW - Multifactorial Inheritance KW - Open Reading Frames KW - Phenotype KW - Polymorphism, Single Nucleotide AB -

Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency < 1%) predicted damaging coding variation by using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels; some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples. We prioritize 32 genes in array-based genome-wide association study (GWAS) loci based on aggregations of rare coding variants; three (EVI5, SH2B3, and PLIN1) had no prior association of rare coding variants with lipid levels. Most of our associated genes showed evidence of association among multiple ancestries. Finally, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes and for genes closest to GWAS index single-nucleotide polymorphisms (SNPs). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.

VL - 109 IS - 1 ER - TY - JOUR T1 - Whole genome sequence association analysis of fasting glucose and fasting insulin levels in diverse cohorts from the NHLBI TOPMed program. JF - Commun Biol Y1 - 2022 A1 - DiCorpo, Daniel A1 - Gaynor, Sheila M A1 - Russell, Emily M A1 - Westerman, Kenneth E A1 - Raffield, Laura M A1 - Majarian, Timothy D A1 - Wu, Peitao A1 - Sarnowski, Chloe A1 - Highland, Heather M A1 - Jackson, Anne A1 - Hasbani, Natalie R A1 - de Vries, Paul S A1 - Brody, Jennifer A A1 - Hidalgo, Bertha A1 - Guo, Xiuqing A1 - Perry, James A A1 - O'Connell, Jeffrey R A1 - Lent, Samantha A1 - Montasser, May E A1 - Cade, Brian E A1 - Jain, Deepti A1 - Wang, Heming A1 - D'Oliveira Albanus, Ricardo A1 - Varshney, Arushi A1 - Yanek, Lisa R A1 - Lange, Leslie A1 - Palmer, Nicholette D A1 - Almeida, Marcio A1 - Peralta, Juan M A1 - Aslibekyan, Stella A1 - Baldridge, Abigail S A1 - Bertoni, Alain G A1 - Bielak, Lawrence F A1 - Chen, Chung-Shiuan A1 - Chen, Yii-Der Ida A1 - Choi, Won Jung A1 - Goodarzi, Mark O A1 - Floyd, James S A1 - Irvin, Marguerite R A1 - Kalyani, Rita R A1 - Kelly, Tanika N A1 - Lee, Seonwook A1 - Liu, Ching-Ti A1 - Loesch, Douglas A1 - Manson, JoAnn E A1 - Minster, Ryan L A1 - Naseri, Take A1 - Pankow, James S A1 - Rasmussen-Torvik, Laura J A1 - Reiner, Alexander P A1 - Reupena, Muagututi'a Sefuiva A1 - Selvin, Elizabeth A1 - Smith, Jennifer A A1 - Weeks, Daniel E A1 - Xu, Huichun A1 - Yao, Jie A1 - Zhao, Wei A1 - Parker, Stephen A1 - Alonso, Alvaro A1 - Arnett, Donna K A1 - Blangero, John A1 - Boerwinkle, Eric A1 - Correa, Adolfo A1 - Cupples, L Adrienne A1 - Curran, Joanne E A1 - Duggirala, Ravindranath A1 - He, Jiang A1 - Heckbert, Susan R A1 - Kardia, Sharon L R A1 - Kim, Ryan W A1 - Kooperberg, Charles A1 - Liu, Simin A1 - Mathias, Rasika A A1 - McGarvey, Stephen T A1 - Mitchell, Braxton D A1 - Morrison, Alanna C A1 - Peyser, Patricia A A1 - Psaty, Bruce M A1 - Redline, Susan A1 - Shuldiner, Alan R A1 - Taylor, Kent D A1 - Vasan, Ramachandran S A1 - Viaud-Martinez, Karine A A1 - Florez, Jose C A1 - Wilson, James G A1 - Sladek, Robert A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Lin, Xihong A1 - Dupuis, Josée A1 - Meigs, James B A1 - Wessel, Jennifer A1 - Manning, Alisa K KW - Diabetes Mellitus, Type 2 KW - Fasting KW - Glucose KW - Humans KW - Insulin KW - National Heart, Lung, and Blood Institute (U.S.) KW - Nerve Tissue Proteins KW - Polymorphism, Single Nucleotide KW - Precision Medicine KW - Receptors, Immunologic KW - United States AB -

The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI's Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, PTPRT, and ROBO1. Functional annotation resources including the Diabetes Epigenome Atlas were compiled for each signal (chromatin states, annotation principal components, and others) to elucidate variant-to-function hypotheses. We provide a catalog of nucleotide-resolution genomic variation spanning intergenic and intronic regions creating a foundation for future sequencing-based investigations of glycemic traits.

VL - 5 IS - 1 ER -