Visceral Adiposity: Genetic and Environmental Influences

描述(由申请人提供)：拟议研究的目标是了解内脏肥胖的遗传结构及其相关的生理成分。腹部深层脂肪(即内脏脂肪组织)的积累在非胰岛素依赖型糖尿病和心血管疾病(CVD)的发展中起着关键作用。在我们提出的研究中，我们的目标是通过将内脏肥胖症视为表型复合体的组成部分来理清解释人类内脏肥胖症变异的遗传和环境因素，该表型复合体还包括胰岛素抵抗、血管炎症和荷尔蒙变化(“内脏肥胖复合体”)。这项拟议的研究建立在一项现有研究的基础上，该研究对五个多代大家族的1000个人进行了研究，其中全基因组基因分型和疾病风险因素表型研究已经在进行中。 这项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射线吸收法来测量内脏和皮下脂肪组织的数量和分布，使用ELISA法来检测脂肪细胞衍生激素的浓度，并使用重复的24小时饮食召回方案来表征当前的能量和大量营养素的摄入量。在具体目标2中，我们将使用扩展家系的基于方差分量的数量遗传学方法来估计内脏肥胖复合体的独立成分的遗传力，确定影响内脏肥胖复合体的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)以及与遗传因素相互作用的影响，并检查共同遗传因素在多大程度上构成这一密切相关性状复合体的基础。在具体目标3中，我们将使用基于方差分量的连锁方法来识别含有影响内脏肥胖复合体组成成分变异的基因的数量性状基因座(QTL)。我们还将研究这些性状中的基因与环境、基因与性别和基因与年龄的交互作用。精细作图程序将用于进一步定位已识别的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基因座，并将更好地了解特定的基因类型如何在面对特定环境时使个人易于内脏脂肪组织堆积，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.