Insulin resistance is an important risk factor for atherosclerosis. Insulin sensitivity varies widely within populations and substantial evidence indicates that much of the variation can be attributed to genetic factors. Visceral adiposity, another important atherosclerosis risk factor, appears also to be genetically determined and correlates strongly with insulin resistance. The overall goals of this proposal are to: 1) identify the genetic determinants of insulin sensitivity and visceral adiposity; 2) determine the extent to which insulin sensitivity, visceral adiposity, and metabolic cardiovascular risk factors share common genetic influences. To address these goals, we will enroll family members of 160 African-American and Hispanic men and women who are currently participating in the Insulin Resistance Atherosclerosis Study (IRAS). Approximately 1280 family members will be recruited. Insulin sensitivity will be measured using the frequently sampled intravenous glucose tolerance test with minimal model analysis. Visceral adiposity will be assessed with computed tomography and traditional metabolic cardiovascular risk factors will be measured. A panel of 370 microsatellite markers will be genotyped from DNA and a genome-wide scan will be performed to detect chromosomal regions containing loci that influence phenotypic variation. We will then saturate the regions of linkage identified in these analyses with additional markers and will perform linkage disequilibrium analysis to localize further the putative loci. The organization of this study will be similar to that of IRAS, with three clinical centers, a coordinating center, a central laboratory, and a genetic laboratory. Our center will examine 432 family members of 54 African-American participants in the IRAS. This project will contribute substantially to our understanding of the genetic determinants of insulin sensitivity, visceral adiposity, and the risk of atherosclerosis.
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