IRAS FAMILY STUDY--MOLECULAR GENETICS

IRAS 家族研究--分子遗传学

• 批准号: 6527178
• 负责人: DONALD W BOWDEN
• 金额: $ 32.36万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-15 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6527178
• 关键词: African American; Hispanic Americans; atherosclerosis; blood lipid; clinical research; family genetics; genetic mapping; genetic markers; genetic susceptibility; human genetic material tag; insulin sensitivity /resistance; linkage disequilibriums; molecular genetics; quantitative trait loci

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 (IRAS). 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 at the Mammalian Genotyping Service 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 genetics laboratory. This Molecular Genetics component of the study will (1) carry out genomic DNA isolation and quality control, (2) fill significant gaps and correct errors in data from the whole genome screen, and (3) carry out detailed analysis of chromosome regions which show evidence for linkage. This project will contribute substantially to our understanding of the genetic determinants of insulin sensitivity, and consequently to risk of atherosclerosis.

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，这种差异大部分可归因于遗传来源。 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，他们正在参加胰岛素抵抗动脉粥样硬化研究（IRAS）。 大约1280名家庭成员将被招募。 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。 还将评估一组其他代谢性心血管疾病风险因素。 将从DNA中对一组370个微卫星标记进行基因分型，并在哺乳动物基因分型服务处进行全基因组扫描，以检测含有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使这些分析中鉴定的连锁区域饱和，然后进行连锁不平衡分析，以进一步定位推定的基因座。 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。 该研究的分子遗传学部分将（1）进行基因组DNA分离和质量控制，（2）填补全基因组筛选数据中的重大空白并纠正错误，以及（3）对显示连锁证据的染色体区域进行详细分析。 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，从而动脉粥样硬化的风险。