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。胰岛素抵抗在人群中差异很大，大量证据表明，这种差异很大程度上可归因于遗传来源。内脏肥胖是另一个重要的动脉粥样硬化风险因素，与胰岛素抵抗密切相关，而且这一特征似乎也受到大量遗传控制。拟议研究项目的总体目标是：1)确定胰岛素抵抗和内脏肥胖的遗传决定因素；2)确定胰岛素抵抗、内脏脂肪和代谢性心血管疾病危险因素在多大程度上具有共同的遗传影响。为了实现这些目标，我们将招募160个非裔美国人和西班牙裔背景的家庭参加胰岛素抵抗动脉粥样硬化研究（ERAS）。将再征聘大约1280名家庭成员。胰岛素抵抗将使用频繁采样的静脉葡萄糖耐量试验来测量，内脏脂肪将使用计算机断层扫描来测量。还将评估一组其他代谢性心血管疾病的危险因素。将从DNA中对370个微卫星标记进行基因分型，并进行全基因组扫描以检测包含影响表型变异的位点的染色体区域。然后，我们将用额外的标记使这些分析中确定的连锁区域饱和，然后将进行连锁不平衡分析，以进一步定位假定的位点。本研究的组织将与IRAS类似，设有三个临床中心、一个协调中心、一个中心实验室和一个遗传实验室。这个位于南加州大学的中心将负责执行和协调实验室测量，以及胰岛素敏感性和其他代谢参数的分析。这个项目将大大有助于我们了解胰岛素敏感性的遗传决定因素，从而了解动脉粥样硬化的风险。

Insulin resistance is an important risk factor for atherosclerosis. Insulin resistance varies widely within populations, and substantial evidence indicates that much of this variation can be attributed to genetic sources. Visceral adiposity, another important atherosclerosis risk factor, 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 who are participating in the Insulin Resistance Atherosclerosis Study (ERAS). Approximately 1280 additional family members will be recruited. Insulin resistance will be measured using the frequently sampled intravenous glucose tolerance test, and visceral adiposity will be measured using computed tomography. A panel of other metabolic cardiovascular disease risk factors will also be assessed. 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 then perform linkage disequilibrium analyses in effort 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. This center at the University of Southern California will be responsible for performing and coordinating laboratory measurements, as well as for analysis of insulin sensitivity and other metabolic parameters. This project will contribute substantially to our understanding of the genetic determinants of insulin sensitivity, and consequently to risk of atherosclerosis.