The goal of the proposed study is to understand the genetic architecture underlying visceral obesity and its associated physiological components. Accumulation of fat deep within the abdomen (i.e., visceral adipose tissue) is known to play a pivotal role in the development of non-insulin dependent diabetes mellitus and cardiovascular disease (CVD). In our proposed study, we aim to disentangle the genetic and environmental factors that explain human variation in visceral adiposity by viewing it as a component of a phenotypic complex that also includes insulin resistance, vascular inflammation, and hormonal variations (the """"""""visceral obesity complex""""""""). The proposed study is built upon an existing study of 1,000 individuals in five large multi-generational kindreds, in which whole-genome genotyping and disease risk factor phenotyping are already underway. The proposed study has three specific aims.
In Specific Aim 1 we will phenotype the study population using MRI and dual energy x-ray absorptiometry to measure the amount and distribution of visceral and subcutaneous adipose tissue, using ELISA to assay concentration of adipocyte-derived hormones, and using a repeated 24-hour dietary recall protocol to characterize current energy and macronutrient intake.
In Specific Aim 2 we will use variance components-based quantitative genetic methods for extended pedigrees to estimate the heritability of the independent components of the visceral obesity complex, identify key environmental variables and covariates (i.e., sex, age, diet, physical activity, hormone usage, smoking and alcohol consumption) that influence the visceral obesity complex alone or in interaction with genetic factors, and examine the extent to which common genetic factors underlie this complex of closely related traits.
In Specific Aim 3, we will use variance components-based linkage methods to identify quantitative trait loci (QTL) harboring genes that influence variation in constituent components of the visceral obesity complex. We also will examine gene-by-environment, gene-by-sex, and gene-by-age interactions in these traits. Fine mapping procedures will be used further localize QTL that are identified. At the conclusion of the proposed study, we will have identified particular genetic loci that influence the visceral obesity complex, and will better understand how particular genotypes may, when confronted with particular environments, predispose individuals to the accumulation of visceral adipose tissue, thereby putting them at increased future risk for developing diabetes and CVD.
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