IRAS FAMILY STUDY--GENETICS OF INSULIN RESISTANCE

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Insulin resistance is an important risk factor for atherosclerosis. There is evidence indicating that much of the variation in insulin resistance can be attributed to genetic sources. Visceral adiposity, another important risk factor for atherosclerosis, is strongly correlated with insulin resistance, and this trait also appears to be under substantial genetic control. The overall goals of the proposed research project are to: 1) identify the genetic determinants of insulin resistance and visceral adiposity; and 2) determine the extent to which insulin resistance, visceral adiposity, and metabolic cardiovascular disease risk factors share common genetic influences. To address these goals, we will enroll 160 families of African-American and Hispanic background using participants of the Insulin Resistance Atherosclerosis Study (IRAS) as index cases. Approximately 1280 additional family members will be recruited to the study for a total of 1440 participants. Insulin resistance will be measured using the frequently sampled intravenous glucose tolerance test, and visceral adiposity will be measured using computed tomography. Metabolic cardiovascular disease risk factors will also be assessed. A panel of 370 microsatellite markers will be genotyped to provide data for a genome-wide scan to detect chromosomal regions containing quantitative trait loci (QTLs) that influence phenotypic variation for insulin resistance and visceral adiposity. We will then saturate the regions of linkage identified in these analyses with additional markers and then utilize linkage disequilibrium to localize further the QTLs. The organization of this study will be similar to that of IRAS, with three clinical centers, a coordinating center, a central laboratory and a genetics laboratory. Wake Forest University will be responsible for serving as the coordinating center for the study, with the responsibility for coordinating the data collection and data management and conducting statistical analyses. This project will contribute substantially to our understanding of the genetic determinants of insulin resistance, visceral adiposity, and, consequently to risk of atherosclerosis.