The main goal of the proposed study is to discover genes that jointly influence measures of adiposity and associated cardiovascular disease (CVD) risks, with the ultimate objective being to elucidate the role of new adiposity genes as mediators of related CVD risks. Specifically, we propose to focus on measures of abdominal visceral fat and abdominal subcutaneous fat obtained from magnetic resonance imaging (MRI), and measures of total body fat and regional body fat obtained from dual energy x-ray absorptiometry (DXA), and determine the nature of their genetic associations with particular sets of CVD risks known to be influenced by adiposity. These CVD risks include measures of recently discovered adipocyte-derived hormones, lipid and lipoprotein concentrations, glucose metabolism, and markers of vascular inflammation. These data will be collected from 1,013 individuals in large multi-generation families who range in age from 8 to 94 years, are represented equally by men and women, and include both Whites and African Americans. The proposed study leverages existing resources made available by the established Fels Longitudinal Study and the newer Miami Valley Family Aging Study. The study will use new technologies to quantify the amount, type, and distribution of adipose tissue in the body; examine age, sex, and ethnic differences in the relationships between measures of adiposity and related CVD risks; assess the role of adipose tissue as a metabolically active endocrine organ; quantify newly discovered adipocyte-derived hormones; assess the relationships between adiposity and vascular inflammation; and assess the relationships between adiposity and lipid and lipoprotein metabolism. The proposed study consists of four specific aims: 1) collect familial adiposity and associated CVD risk data using innovative technologies, 2) examine sex, age, and ethnicity differences in adiposity and associated CVD risks at the phenotypic level, 3) determine the general nature of shared genetic influences on adiposity and associated CVD risks using quantitative genetic analysis methods, and 4) identify quantitative trait loci (QTL) containing specific genes that jointly influence adiposity and associated CVD risks using variance components-based linkage analysis methods. Investigators on the proposed study have expertise in body composition analysis, cardiovascular disease, statistical genetic methodology, molecular genetics, growth and development, and aging.
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