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以归因于遗传来源。内脏肥胖是动脉粥样硬化的另一个重要危险因素，它与胰岛素抵抗密切相关，而且这一特征似乎也受到实质性的基因控制。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症的遗传决定因素；2)确定胰岛素抵抗、内脏肥胖症和代谢性心血管疾病风险因素共享共同遗传影响的程度。为了实现这些目标，我们将以胰岛素抵抗动脉粥样硬化研究(IRAS)的参与者为指标病例，招募160个非裔美国人和西班牙裔背景的家庭。约1280名家庭成员将被招募参加这项研究，总共有1440名参与者。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，内脏肥胖症将使用计算机断层扫描来测量。代谢性心血管疾病的风险因素也将被评估。一组370个微卫星标记将进行基因分型，为全基因组扫描提供数据，以检测包含数量性状基因座(QTL)的染色体区域，QTL影响胰岛素抵抗和内脏肥胖症的表型变异。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，然后利用连锁不平衡来进一步定位QTL。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学实验室组成。维克森林大学将负责作为这项研究的协调中心，负责协调数据收集和数据管理，并进行统计分析。该项目将大大有助于我们理解胰岛素抵抗、内脏肥胖以及动脉粥样硬化风险的遗传决定因素。

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.