Evolutionary Genetics of the Metabolic Syndrome

描述(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，在最近从传统生存方式转变为西方生活方式和饮食的人群中，患病率大幅上升。一种令人信服的假说设想，疾病风险基因型别是新陈代谢适应人类祖先群体多样化环境的结果。根据这一假设，METs的易感变异体预计会有不同的群体遗传学变异模式。家长赠款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结合起来，以阐明大都会大学的进化起源。在本补充资料中，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)反应个体间差异的遗传基础。皮质醇等GCS是调节大量生理活动的压力荷尔蒙。越来越多的临床证据和动物研究已经将GC的作用与肥胖和胰岛素抵抗联系起来。因此，生理性GC反应中的遗传变异可能会影响Met的遗传易感性。基于表达区域数量性状基因座(EQTL)定位的最新进展，我们将利用一组来自不同种族的无关个体的淋巴母细胞系(LCLS)来定位GC反应个体间差异的遗传基础如下：1.我们将在全基因组水平上确定LCLS中的GR结合位点(通过ChIPseq)；2.我们将通过分析GC(即地塞米松)或载体(即Etoh)处理后欧洲和非洲LCL的全基因组mRNA水平来定位与GC介导的转录反应的个体间差异相关的遗传变异；3.我们将进行群体遗传学分析，以确定目标2中发现的遗传变异在种族群体中的频率是否显著不同，以及它们是否是人类进化过程中选择的目标。这一补充建立在父母资助下获得的结果的基础上，以采取新的方向，利用最近开发的资源进行遗传分析。虽然该项目的最终目标保持不变，即了解大都会体育队的进化遗传学，但我们现在计划增加一个功能基因组学维度，并将其与正在进行的群体遗传学分析相结合。 公共卫生相关性：该项目旨在开发和使用一个实验系统来研究个体间和种族间在对环境应激的生理反应，特别是对糖皮质激素的反应中的遗传基础。这种反应是人类对一些常见代谢紊乱的易感性的关键，包括2型糖尿病、肥胖症和高血压。因此，这项研究可能有助于了解这些疾病的易感性，并开发新的治疗方法。

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.