Genetics of Adiposity and Glucose Homeostasis

描述（由申请人提供）：IRAS家族研究最初于1999年以6个相关r01资助，是一个多中心项目，旨在研究肥胖和葡萄糖稳态的遗传流行病学。招募和表型成分已在三个临床中心完成。所有家庭都是非裔美国人或西班牙裔。本文研究了132个大家庭（1861名受试者）通过腹部CT扫描测量肥胖和使用胰岛素改良频繁取样静脉葡萄糖耐量试验（FSIGT）测量葡萄糖稳态。这些研究已经确定了对肥胖（内脏和皮下脂肪、BMI和腰围）和葡萄糖稳态（胰岛素敏感性、葡萄糖有效性、急性胰岛素对葡萄糖的反应、处置指数、空腹血糖和空腹胰岛素）测量的实质性遗传贡献。IRAS家族研究DNA的10厘米基因组扫描已经完成。连锁分析已经确定了几个与肥胖和葡萄糖稳态相关的基因组区域。其中的一些信号已经被精确地绘制出来。这一更新申请题为《肥胖和葡萄糖稳态遗传学》，旨在进一步探索肥胖和葡萄糖稳态变异基因的基因组区域和位置克隆。定位候选基因将被确定。我们还将重新联系原始队列，重复一些主要表型以测量变化（腹部CT扫描和空腹胰岛素），并添加一些重要的新表型，以加深我们对肥胖和葡萄糖稳态的评估（DXA和脂肪细胞因子的全身脂肪，包括脂联素和可溶性tnf - α受体1和2）。一组营养、饮食和饮食行为将被评估，以研究遗传效应。利用现有的基因组扫描数据和基于方差成分的连锁分析方法，将检测到导致这些新表型和变化表型变异的基因组区域。该研究的独特之处在于它在多种族（非多数）样本中发现了肥胖和葡萄糖稳态，同时检查了这些和其他代谢表型之间的遗传和环境相关性。

DESCRIPTION (provided by applicant): The IRAS Family Study, initially funded as six linked R01s in 1999, is a multicenter project designed to study the genetic epidemiology of adiposity and glucose homeostasis. The recruitment and phenotyping components have been completed in the three clinical centers. All families were of African-American or Hispanic descent. A total of 132 extended families (1861 subjects) have been studied for measurement of adiposity by abdominal CT scan and glucose homeostasis using the insulin-modified frequently sampledintravenous glucose tolerance test (FSIGT). These investigations have identified substantial genetic contribution to measures of adiposity (visceral and sub-cutaneous fat, BMI and waist circumference) and glucose homeostasis (insulin sensitivity, glucose effectiveness, acute insulin response to glucose, disposition index, fasting glucose and fasting insulin). A 10 cM genome scan of the IRAS Family Study DNA has been completed. Linkage analyses have identified several genomic regions related to adiposity and glucose homeostasis. Several of these signals have been followed-up with fine mapping. This renewal application, entitled Genetics of Adiposity and Glucose Homeostasis, targets the further exploration of genomic regions and positional cloning of genes contributing to variation in adiposity and glucose homeostasis. Positional candidate genes will be identified. We will also re-contact the original cohort to repeat some of the primary phenotypes for measures of change (abdominal CT scan and fasting insulin) and add several important new phenotypes to add depth to our assessment of adiposity and glucose homeostasis (total body fat by DXA and adipocytokines, including adiponectin and soluble TNF-alpha receptors 1 and 2). A panel of nutritional, dietary, and eating behaviors will be assessed in which to study the genetic effects. Using the existing genome scan data and variance-components-based linkage analysis methods, regions of the genome will be detected that contribute to variation in these new phenotypes and in the change phenotypes. The proposed study is unique in its performance of gone discovery for adiposity and glucose homeostasis in a multi-ethnic (non-majority) sample while simultaneously examining the genetic and environmental correlations among these and other metabolic phenotypes.