Evolutionary Genetics of the Metabolic Syndrome

描述（由申请人提供）：代谢综合征（MetS）是一组表型，包括2型糖尿病（T2D）、肥胖、高血压和血脂异常。这些表型表明，在最近从传统生活方式转向西方生活方式和饮食的人群中，患病率急剧上升。一个令人信服的假设认为，疾病风险基因型是由于对祖先人群多样化环境的代谢适应造成的。基于这一假设，预计met的易感性变异具有不同的群体遗传变异模式。本研究将变异模式的经验特征与新的统计方法和群体遗传学模型的发展相结合，以阐明met的进化起源。在这篇增刊中，我们计划将这些群体遗传学方法与功能基因组学分析相结合，以阐明糖皮质激素（GC）反应的个体间变异的遗传基础。GCs，如皮质醇，是调节大量生理活动的应激激素。越来越多的临床证据和动物研究表明GC作用与肥胖和胰岛素抵抗有关。因此，生理GC反应的遗传变异可能影响对MetS的遗传易感性。基于表达数量性状位点（eQTL）定位领域的最新进展，我们将利用一组来自不同种族的无亲缘关系个体的淋巴母细胞样细胞系（LCLs）来绘制GC反应个体间变异的遗传基础，如下所示：我们将在LCLs的全基因组水平上识别GR结合位点（通过ChIPseq）；2. 我们将通过分析欧洲和非洲LCLs在使用GC（即地塞米松）或载体（即EtOH）作为对照治疗后的全基因组mRNA水平，绘制与GC介导的转录反应个体间变异相关的遗传变异；3. 我们将进行群体遗传学分析，以确定目标2中确定的遗传变异在不同种族群体中的频率是否有显著差异，以及它们是否是人类进化过程中的选择目标。该补充建立在父母赠款下获得的结果的基础上，采取了利用最近开发的遗传分析资源的新方向。虽然该项目的最终目标保持不变，即了解MetS的进化遗传学，但我们现在计划增加功能基因组学维度，并将其与正在进行的群体遗传学分析相结合。

DESCRIPTION (provided by applicant): The metabolic syndrome (MetS) is a cluster of phenotypes that includes type 2 diabetes (T2D), obesity, hypertension, and dyslipidemia. These phenotypes show dramatic increases in prevalence in populations that recently switched from a traditional subsistence to a Western lifestyle and diet. A compelling hypothesis envisions that the disease risk genotypes result from metabolic adaptations to the diverse environments of ancestral human populations. Based on this hypothesis, the susceptibility variants for the MetS are expected to have distinct patterns of population genetics variation. The parent grant integrated the empirical characterization of patterns of variation with the development of new statistical methodology and population genetics modeling to elucidate the evolutionary origin of the the MetS. In this supplement, we plan to combine those population genetics approaches with functional genomics analyses to elucidate the genetic basis of inter-individual variation in glucocorticoid (GC) response. GCs, such as cortisol, are stress hormones that modulate a large number of physiological actions. Growing clinical evidence and animal studies have linked GC action with obesity and insulin resistance. Thus, genetic variation in the physiologic GC response is likely to influence the genetic susceptibility to the MetS. Building on recent developments in the area of expression quantitative trait locus (eQTL) mapping, we will take advantage of a panel of lymphoblastoid cell lines (LCLs) of unrelated individuals from different ethnic groups to map the genetic bases of inter-individual variation in GC response as follows: 1. We will identify the GR binding sites (by ChIPseq) at the genome-wide levels in LCLs; 2. We will map the genetic variants associated with inter-individual variation in GC-mediated transcriptional response by assaying genome-wide mRNA levels in European and African LCLs following treatment with either a GC (i.e. dexamethasone) or with the vehicle (i.e. EtOH) as a control; 3. We will perform population genetics analyses to determine if the genetic variants identified in aim 2 differ significantly in frequency across ethnic groups and if they were targets of selection during human evolution. This supplement builds on results obtained under the parent grant to take a new direction that exploits recently developed resources for genetic analysis. While the ultimate goal of the project remains unchanged, i.e. to understand the evolutionary genetics of the MetS, we now plan to add a functional genomics dimension and integrate it with the ongoing population genetics analyses. PUBLIC HEALTH RELEVANCE: This project aims to develop and use an experimental system to study the genetic bases of inter-individual and inter-ethnic variation in the physiological response to environmental stress, and in particular in the response to glucocorticoids. This response is key to the susceptibility to a number of common metabolic disorders in humans, including type 2 diabetes, obesity and hypertension. Therefore, this study is likely to help understand the susceptibility to these disorders and develop new treatments.