Visceral Adiposity: Genetic and Environmental Influences

描述（由申请人提供）：拟议研究的目的是了解内脏肥胖及其相关生理成分的遗传结构。腹部深处的脂肪堆积（即，内脏脂肪组织）已知在非胰岛素依赖型糖尿病和心血管疾病（CVD）的发展中起关键作用。在我们提出的研究中，我们的目标是解开解释人类内脏肥胖变异的遗传和环境因素，将其视为表型复合体的一个组成部分，还包括胰岛素抵抗，血管炎症和激素变异（“内脏肥胖复合体”）。这项拟议的研究是建立在对五个大型多代亲属中1,000名个体的现有研究基础上的，其中全基因组基因分型和疾病风险因素表型已经在进行中。 拟议的研究有三个具体目标。在具体目标1中，我们将使用MRI和双能X射线吸收测定法对研究人群进行表型分析，以测量内脏和皮下脂肪组织的数量和分布，使用ELISA测定脂肪细胞衍生激素的浓度，并使用重复的24小时饮食回忆方案来表征当前的能量和大量营养素摄入。在具体目标2中，我们将使用基于方差分量的定量遗传方法来估计内脏肥胖复合体独立分量的遗传力，确定关键环境变量和协变量（即，性别、年龄、饮食、体力活动、激素使用、吸烟和饮酒）单独或与遗传因素相互作用影响内脏肥胖复合体，并检查共同遗传因素在多大程度上构成这种密切相关特征的复合体。在具体目标3中，我们将使用方差分量为基础的连锁方法，以确定数量性状位点（QTL）窝藏的基因，影响内脏肥胖复合体的组成成分的变化。我们还将研究基因与环境、基因与性别、基因与年龄在这些性状中的相互作用。精细作图程序将用于进一步定位所鉴定的QTL。 在拟议的研究结束时，我们将确定影响内脏肥胖复合体的特定遗传基因座，并将更好地了解特定基因型在面对特定环境时如何使个体易于积累内脏脂肪组织，从而使他们未来患糖尿病和心血管疾病的风险增加。

DESCRIPTION (provided by applicant): The goal of the proposed study is to understand the genetic architecture underlying visceral obesity and its associated physiological components. Accumulation of fat deep within the abdomen (i.e., visceral adipose tissue) is known to play a pivotal role in the development of non-insulin dependent diabetes mellitus and cardiovascular disease (CVD). In our proposed study, we aim to disentangle the genetic and environmental factors that explain human variation in visceral adiposity by viewing it as a component of a phenotypic complex that also includes insulin resistance, vascular inflammation, and hormonal variations (the "visceral obesity complex"). The proposed study is built upon an existing study of 1,000 individuals in five large multi-generational kindreds, in which whole-genome genotyping and disease risk factor phenotyping are already underway. The proposed study has three specific aims. In Specific Aim 1 we will phenotype the study population using MRI and dual energy x-ray absorptiometry to measure the amount and distribution of visceral and subcutaneous adipose tissue, using ELISA to assay concentration of adipocyte-derived hormones, and using a repeated 24-hour dietary recall protocol to characterize current energy and macronutrient intake. In Specific Aim 2 we will use variance components-based quantitative genetic methods for extended pedigrees to estimate the heritability of the independent components of the visceral obesity complex, identify key environmental variables and covariates (i.e., sex, age, diet, physical activity, hormone usage, smoking and alcohol consumption) that influence the visceral obesity complex alone or in interaction with genetic factors, and examine the extent to which common genetic factors underlie this complex of closely related traits. In Specific Aim 3, we will use variance components-based linkage methods to identify quantitative trait loci (QTL) harboring genes that influence variation in constituent components of the visceral obesity complex. We also will examine gene-by-environment, gene-by-sex, and gene-by-age interactions in these traits. Fine mapping procedures will be used further localize QTL that are identified. At the conclusion of the proposed study, we will have identified particular genetic loci that influence the visceral obesity complex, and will better understand how particular genotypes may, when confronted with particular environments, predispose individuals to the accumulation of visceral adipose tissue, thereby putting them at increased future risk for developing diabetes and CVD.