Genetic Regulation of Adiposity and Associated CVD Risks

描述（由申请人提供）：拟议研究的主要目标是发现共同影响肥胖和相关心血管疾病（CVD）风险测量的基因，最终目的是阐明新的肥胖基因作为相关CVD风险介质的作用。具体来说，我们建议关注通过磁共振成像（MRI）获得的腹部内脏脂肪和腹部皮下脂肪的测量，以及通过双能x射线吸收仪（DXA）获得的全身脂肪和局部身体脂肪的测量，并确定它们与已知受肥胖影响的特定CVD风险的遗传关联的性质。这些CVD风险包括最近发现的脂肪细胞衍生激素、脂质和脂蛋白浓度、葡萄糖代谢和血管炎症标志物的测量。这些数据将从年龄从8岁到94岁不等的多代大家庭的1013个人中收集，男女比例相等，包括白人和非洲裔美国人。这项拟议的研究利用了已有的费尔斯纵向研究和较新的迈阿密谷家庭老龄化研究提供的现有资源。这项研究将使用新技术来量化体内脂肪组织的数量、类型和分布；检查年龄、性别和种族差异在肥胖测量和相关心血管疾病风险之间的关系；评估脂肪组织作为代谢活跃的内分泌器官的作用；量化新发现的脂肪细胞来源的激素；评估肥胖与血管炎症之间的关系；评估肥胖与脂质和脂蛋白代谢之间的关系。建议的研究包括四个具体目标：1)利用创新技术收集家族性肥胖和相关CVD风险数据；2)在表型水平上检查性别、年龄和种族在肥胖和相关CVD风险方面的差异；3)利用定量遗传分析方法确定共同遗传对肥胖和相关CVD风险影响的一般性质。4)利用基于方差成分的连锁分析方法，鉴定含有共同影响肥胖和相关心血管疾病风险的特定基因的数量性状位点（QTL）。研究人员在身体成分分析、心血管疾病、统计遗传方法学、分子遗传学、生长发育和衰老方面具有专业知识。

DESCRIPTION (provided by applicant): The main goal of the proposed study is to discover genes that jointly influence measures of adiposity and associated cardiovascular disease (CVD) risks, with the ultimate objective being to elucidate the role of new adiposity genes as mediators of related CVD risks. Specifically, we propose to focus on measures of abdominal visceral fat and abdominal subcutaneous fat obtained from magnetic resonance imaging (MRI), and measures of total body fat and regional body fat obtained from dual energy x-ray absorptiometry (DXA), and determine the nature of their genetic associations with particular sets of CVD risks known to be influenced by adiposity. These CVD risks include measures of recently discovered adipocyte-derived hormones, lipid and lipoprotein concentrations, glucose metabolism, and markers of vascular inflammation. These data will be collected from 1,013 individuals in large multi-generation families who range in age from 8 to 94 years, are represented equally by men and women, and include both Whites and African Americans. The proposed study leverages existing resources made available by the established Fels Longitudinal Study and the newer Miami Valley Family Aging Study. The study will use new technologies to quantify the amount, type, and distribution of adipose tissue in the body; examine age, sex, and ethnic differences in the relationships between measures of adiposity and related CVD risks; assess the role of adipose tissue as a metabolically active endocrine organ; quantify newly discovered adipocyte-derived hormones; assess the relationships between adiposity and vascular inflammation; and assess the relationships between adiposity and lipid and lipoprotein metabolism. The proposed study consists of four specific aims: 1) collect familial adiposity and associated CVD risk data using innovative technologies, 2) examine sex, age, and ethnicity differences in adiposity and associated CVD risks at the phenotypic level, 3) determine the general nature of shared genetic influences on adiposity and associated CVD risks using quantitative genetic analysis methods, and 4) identify quantitative trait loci (QTL) containing specific genes that jointly influence adiposity and associated CVD risks using variance components-based linkage analysis methods. Investigators on the proposed study have expertise in body composition analysis, cardiovascular disease, statistical genetic methodology, molecular genetics, growth and development, and aging.