GPCR Variants as Genetic Determinants of Obesity

描述（由申请人提供）： 超过26%的美国人口的身体质量指数（BMI）超过30，因此符合肥胖标准。虽然遗传性是肥胖症发展的一个公认因素，但这种倾向背后的基因一直难以确定。迄今为止鉴定的少数单基因形式的肥胖症之一是由突变GPCR，MC 4 R引起的。鉴于这一先例和需要定义肥胖遗传易感性背后的更常见解释，特别值得注意的是，药理学和/或遗传学证据已经涉及超过20种GPCR作为食物摄入、体重和/或享乐（即，奖励）对喂食的反应。这些受体中的绝大多数具有多个已知的非同义（即，编码序列的变化）变体。通过分析GPCR多态性在Look AHEAD人群中的患病率、药理学功能和共存情况，我们将检验我们的中心假设，即普通人群中有相当一部分肥胖与GPCR功能异常有关。我们将首先通过序列和单倍型分析确定Look AHEAD人群中的MC 4 R变体（已知和新）。目的1将提供深入了解这种受体在肥胖糖尿病受试者的大队列中的作用，以及解决围绕已知的常见变体（VI 031）对肥胖的保护程度的争议。此外，对MC 4 R的研究将建立一个基线，在此基础上探索其他因素的重要性（例如，GPCR多态性）作为体重的遗传决定因素。此外，MC 4 R的分析将使其他Look AHEAD研究者能够将该变量作为定义临床可行性的潜在混杂因素加以考虑。在目标2中，我们将在一系列20个食欲、食欲和享乐GPCR中对非同义编码区多态性和单倍型标记进行基因分型，这些GPCR被认为在肥胖的发生中具有病因学作用。这些受体变体已从NCBI SNP数据库和文献中鉴定。平行地，相应的突变重组GPCR将在异源细胞系中表达并进行测序评估。多态性受体将被分类为功能获得、功能丧失或野生型。将在研究人群中评估功能异常与表型参数之间的相关性。在目标3中，将评估促食欲、促食欲和享乐受体变体的组合作为肥胖和/或其他Look AHEAD研究终点的多基因基础的潜在协同或累加因素。

DESCRIPTION (provided by applicant): More than 26 percent of the U.S. population has a body mass index (BMI) in excess of 30 and thus qualifies as obese. Although heritability is a well-established factor in the development of obesity, the genes underlying this tendency have been difficult to identify. One of the few monogenic forms of obesity identified to date results from mutations GPCR, MC4R. In light of this precedent and the need to define more common explanations underlying genetic susceptibility to obesity, it is of particular note that pharmacologic and/or genetic evidence has implicated more than twenty GPCRs as modulators of food intake, body weight and/or the hedonic (i.e., rewarding) response to feeding. The vast majority of these receptors have multiple known non-synonymous (i.e., changes in coding sequence) variants. By analyzing the prevalence, pharmacologic function, and co-existence of GPCR polymorphisms in the Look AHEAD population we will test our central hypothesis that a significant portion of obesity in the general population is linked with abnormal GPCR function. We will first define the MC4R variants (known and novel) in the Look AHEAD population by sequence and haplotype analysis. Aim 1 will provide insight into the role of this receptor in a large cohort of obese diabetic subjects as well as address the controversy surrounding the extent to which a known common variant (VI031) is protective against obesity. In addition, study of the MC4R will establish a baseline on which to explore the importance of other factors (e.g., GPCR polymorphisms) as genetic determinants of body weight. Furthermore, the analysis of the MC4R will enable other Look AHEAD investigators to take this variable into account as a potentially confounding factor in defining clinical susceptibilities. In Aim 2, we will genotype non-synonymous coding region polymorphisms and haplotype markers in a series of twenty orexigenic, anorexigenic and hedonic GPCRs postulated to have an etiologic role in the development of obesity. These receptor variants have been identified from the NCBI SNP database and from the literature. In parallel, corresponding mutant recombinant GPCRs will be expressed in heterologous cell lines and pharmacologically assessed. Polymorphic receptors will be classified as gain of function, loss of function, or wild type. The correlation between functional abnormalities and phenotypic parameters will be assessed within the study population. In Aim 3, combinations of anorexigenic, orexigenic and hedonic receptor variants will be assessed as potential synergistic or additive factors underlying the polygenic basis of obesity and/or other Look AHEAD study endpoints.