Generalization and fine mapping of European ancestry-based central adiposity variants in African ancestry populations.

BACKGROUND/OBJECTIVES: Central adiposity measures such as waist circumference (WC) and waist-to-hip ratio (WHR) are associated with cardiometabolic disorders independently of body mass index (BMI) and are gaining clinically utility. Several studies report genetic variants associated with central adiposity, but most utilize only European ancestry populations. Understanding whether the genetic associations discovered among mainly European descendants are shared with African ancestry populations will help elucidate the biological underpinnings of abdominal fat deposition. SUBJECTS/METHODS: To identify the underlying functional genetic determinants of body fat distribution, we conducted an array-wide association meta-analysis among persons of African ancestry across seven studies/consortia participating in the Population Architecture using Genomics and Epidemiology (PAGE) consortium. We used the Metabochip array, designed for fine-mapping cardiovascular-associated loci, to explore novel array-wide associations with WC and WHR among 15 945 African descendants using all and sex-stratified groups. We further interrogated 17 known WHR regions for African ancestry-specific variants. RESULTS: Of the 17 WHR loci, eight single-nucleotide polymorphisms (SNPs) located in four loci were replicated in the sex-combined or sex-stratified meta-analyses. Two of these eight independently associated with WHR after conditioning on the known variant in European descendants (rs12096179 in TBX15-WARS2 and rs2059092 in ADAMTS9). In the fine-mapping assessment, the putative functional region was reduced across all four loci but to varying degrees (average 40% drop in number of putative SNPs and 20% drop in genomic region). Similar to previous studies, the significant SNPs in the female-stratified analysis were stronger than the significant SNPs from the sex-combined analysis. No novel associations were detected in the array-wide analyses. CONCLUSIONS: Of 17 previously identified loci, four loci replicated in the African ancestry populations of this study. Utilizing different linkage disequilibrium patterns observed between European and African ancestries, we narrowed the suggestive region containing causative variants for all four loci.

Circulating cellular adhesion molecules and risk of diabetes: the Multi-Ethnic Study of Atherosclerosis (MESA).

AIMS: To test the hypothesis that soluble cellular adhesion molecules would be positively and independently associated with risk of diabetes. METHODS: Soluble levels of six cellular adhesion molecules (ICAM-1, E-selectin, VCAM-1, E-cadherin, L-selectin and P-selectin) were measured in participants in the Multi-Ethnic Study of Atherosclerosis, a prospective cohort study. Participants were then followed for up to 10 years to ascertain incident diabetes. RESULTS: Sample sizes ranged from 826 to 2185. After adjusting for age, sex, race/ethnicity, BMI and fasting glucose or HbA1c , four cellular adhesion molecules (ICAM-1, E-selectin, VCAM-1 and E-cadherin) were positively associated with incident diabetes and there was a statistically significant trend across quartiles. Comparing the incidence of diabetes in the highest and lowest quartiles of each cellular adhesion molecule, the magnitude of association was largest for E-selectin (hazard ratio 2.49; 95% CI 1.26-4.93) and ICAM-1 (hazard ratio 1.76; 95% CI 1.22-2.55) in fully adjusted models. Tests of effect modification by racial/ethnic group and sex were not statistically significant for any of the cellular adhesion molecules (P > 0.05). CONCLUSIONS: The finding of significant associations between multiple cellular adhesion molecules and incident diabetes may lend further support to the hypothesis that microvascular endothelial dysfunction contributes to risk of diabetes.

Genetic admixture is associated with plasma hemostatic factor levels in self-identified African Americans and Hispanics: the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Epidemiologic studies report that self-identified African Americans typically have higher hemostatic factor levels than do self-identified Caucasians or Hispanics. OBJECTIVE: To enhance understanding of phenotypic variation in hemostatic factor levels by race/ethnicity, we evaluated the relationship between genetic ancestry and hemostatic factor levels among Multi-Ethnic Study of Atherosclerosis (MESA) study participants. PATIENTS/METHODS: Our sample included 712 African American and 701 Hispanic men and women aged 45 to 84 years. Individual global ancestry was estimated from 199 genetic markers using STRUCTURE. Linear regression models were used to evaluate the relationship between ancestry and hemostatic factor levels, adjusting for age, gender, education, income and study site. RESULTS: Among African Americans, mean ± standard deviation (SD) ancestry was estimated as 79.9% ± 15.9% African and 20.1% ± 15.9% European. Each SD (16%) greater African ancestry was associated with 2.1% higher fibrinogen levels (P = 0.007) and 3.5% higher plasmin-antiplasmin (PAP) levels (P = 0.02). Ancestry among African Americans was not related to levels of factor (F)VIII or D-dimer. Mean ± SD estimated ancestry among Hispanics was 48.3% ± 23.8% Native American, 38.8% ± 21.9% European, and 13.0% ± 8.9% African. In Hispanics, each SD (19%) greater African ancestry was associated with 2.7% higher fibrinogen levels (P = 0.009) and 7.9% higher FVIII levels (P = 0.0002). In Hispanics, there was no relation between African ancestry and D-dimer or PAP levels, or between European ancestry and hemostatic factor levels. CONCLUSIONS: Greater African ancestry among African Americans and Hispanics was associated with higher levels of several hemostatic factors, notably fibrinogen. These results suggest that genetic heterogeneity contributes, albeit modestly, to racial/ethnic differences in hemostatic factor levels.

Prevalence and correlates of diabetes in South asian indians in the United States: findings from the metabolic syndrome and atherosclerosis in South asians living in america study and the multi-ethnic study of atherosclerosis.

BACKGROUND: Individuals from South Asia have high diabetes prevalence despite low body weight. We compared the prevalence of diabetes among South Asian Indians with other U.S. ethnic groups and explored correlates of diabetes. METHODS: This was a cross-sectional study of 150 South Asian Indians (ages 45-79) in California, using similar methods to the Multi-Ethnic Study of Atherosclerosis (MESA). Type 2 diabetes was classified by fasting plasma glucose (FPG) >or=126 mg/dL, 2-h postchallenge glucose >or=200 mg/dL, or use of hypoglycemic medication. RESULTS: A total of 29% of Asian Indians had diabetes, 37% had prediabetes, and 34% had normal glucose tolerance. After full adjustment for covariates, Indians still had significantly higher odds of diabetes compared to whites and Latinos, but not significantly different from African Americans and Chinese Americans in MESA: Indians [odds ratio (OR), 1.0], whites [OR, 0.29; 95% confidence interval (CI), 0.17-0.49], Latinos (OR, 0.59; CI, 0.34-1.00) African Americans (OR, 0.77; CI 0.45-1.32), Chinese Americans (OR, 0.78, CI, 0.45-1.32). Variables associated with prediabetes or diabetes among Indians included hypertension, fatty liver, visceral adiposity, microalbuminuria, carotid intima media thickness, and stronger traditional Indian beliefs. CONCLUSIONS: Indian immigrants may be more likely to have diabetes than other U.S. ethnic groups, and cultural factors may play a role, suggesting that this is a promising area of research.

Association of adiponectin with mortality in older adults: the Health, Aging, and Body Composition Study.

AIMS/HYPOTHESIS: Despite inverse associations with insulin resistance and adiposity, adiponectin has been associated with both increased and decreased risk of cardiovascular disease. We examined whether adiponectin is associated with total and cardiovascular mortality in older adults with well-characterised body composition. METHODS: We analysed data from 3,075 well-functioning adults aged 69-79 years at baseline. Mortality data were obtained over 6.6 +/- 1.6 years. We used Cox proportional hazards models adjusting for covariates in stages to examine the association between adiponectin and total and cardiovascular mortality. RESULTS: There were 679 deaths, 36% of which were from cardiovascular disease. Unadjusted levels of adiponectin were not associated with total or cardiovascular mortality. However, after adjusting for sex and race, adiponectin was associated with an increased risk of both total mortality (hazard ratio 1.26, 95% CI 1.15-1.37, per SD) and cardiovascular mortality (hazard ratio 1.35, 95% CI 1.17-1.56, per SD). Further adjustment for study site, smoking, hypertension, diabetes, prevalent heart disease, HDL-cholesterol, LDL-cholesterol, renal function, fasting insulin, triacylglycerol, BMI, visceral fat, thigh intermuscular fat and thigh muscle area did not attenuate this association. This association between adiponectin and increased mortality risk did not vary by sex, race, body composition, diabetes, prevalent cardiovascular disease, smoking or weight loss. CONCLUSIONS/INTERPRETATION: Higher levels of adiponectin were associated with increased risks of total and cardiovascular mortality in this study of older persons.