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。 有证据表明，胰岛素抵抗的大部分变异可归因于遗传来源。 内脏肥胖是动脉粥样硬化的另一个重要危险因素，与胰岛素抵抗密切相关，而且这种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，内脏肥胖和代谢性心血管疾病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个非裔美国人和西班牙裔背景的家庭，使用胰岛素抵抗动脉粥样硬化研究（IRAS）的参与者作为索引病例。 本研究将招募约1280名额外家庭成员，共计1440名受试者。 胰岛素抵抗将使用频繁采样的静脉葡萄糖耐量试验测量，内脏脂肪将使用计算机断层扫描测量。 还将评估代谢性心血管疾病风险因素。 将对一组370个微卫星标记进行基因分型，为全基因组扫描提供数据，以检测含有影响胰岛素抵抗和内脏肥胖表型变异的数量性状位点（QTL）的染色体区域。 然后，我们将在这些分析中确定的连锁区域与其他标记饱和，然后利用连锁不平衡进一步定位QTL。 本研究的组织与IRAS相似，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学实验室。 维克森林大学将作为本研究的协调中心，负责协调数据收集和数据管理，并进行统计分析。 这个项目将大大有助于我们了解胰岛素抵抗，内脏肥胖的遗传决定因素，并因此动脉粥样硬化的风险。

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.