IRAS FAMILY STUDY: GENETICS OF INSULIN RESISTANCE

胰岛素抵抗是动脉粥样硬化的重要危险因素。胰岛素敏感性在不同人群中差异很大，大量证据表明，这种差异很大程度上可以归因于遗传因素。内脏肥胖，另一个重要的动脉粥样硬化危险因素，似乎也是由基因决定的，并与胰岛素抵抗密切相关。这项建议的总体目标是：1)确定胰岛素敏感性和内脏肥胖症的遗传决定因素；2)确定胰岛素敏感性、内脏肥胖症和代谢性心血管危险因素共享共同遗传影响的程度。为了实现这些目标，我们将招募160名非洲裔美国人和西班牙裔男性和女性的家庭成员，他们目前正在参与胰岛素抵抗动脉粥样硬化研究(IRAS)。将招募约1280名家庭成员。胰岛素敏感性将使用频繁采样的静脉葡萄糖耐量试验和最小模型分析进行测量。内脏肥胖症将用计算机断层扫描进行评估，传统的代谢性心血管危险因素将被测量。一组370个微卫星标记将根据DNA进行基因分型，并将进行全基因组扫描，以检测包含影响表型变异的基因座的染色体区域。然后，我们将用额外的标记饱和这些分析中确定的连锁区域，并将进行连锁不平衡分析，以进一步定位可能的基因座。这项研究的组织将类似于IRAS，由三个临床中心、一个协调中心、一个中心实验室和一个遗传实验室组成。我们的中心将检查IRAS中54名非裔美国人的432名家庭成员。该项目将大大有助于我们理解胰岛素敏感性、内脏肥胖和动脉粥样硬化风险的遗传决定因素。

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.