GPCR Variants as Genetic Determinants of Obesity

GPCR 变异作为肥胖的遗传决定因素

• 批准号: 7249490
• 负责人: ALAN S KOPIN
• 金额: $ 75.88万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7249490
• 关键词: Accounting; Address; American; Appendix; Body Composition; Body Weight; Body Weight Changes; Body Weight decreased; Body mass index; Cell Line; Childhood; Clinical; Clinical Data; Code; Combination Drug Therapy; Confounding Factors (Epidemiology); Databases; Development; Disease; Drug Delivery Systems; Eating; End Point; Ensure; Failure; Frequencies; G-Protein-Coupled Receptors; General Population; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Genetic Predisposition to Disease; Genotype; Haplotypes; Health Campaign; Heritability; Human; In Vitro; Individual; Intervention; Laboratories; Light; Link; Literature; Medical; Melanocortin 4 Receptor; Methodology; Morbid Obesity; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Numbers; Obesity; Population; Population Study; Predisposition; Prevalence; Protein Isoforms; Proteins; Public Health; Qualifying; Receptor Gene; Recombinants; Research Personnel; Review Literature; Rewards; Role; Screening procedure; Series; Subgroup; Testing; United States; Variant; Weight; Weight Gain; base; cohort; diabetic; feeding; gain of function; gene environment interaction; gene interaction; genetic variant; hedonic; in vitro Assay; in vivo; insight; lifestyle intervention; link protein; loss of function; mutant; novel; obesity treatment; programs; receptor; receptor function; response

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.

描述（由申请人提供）： 超过 26% 的美国人的体重指数 (BMI) 超过 30，因此属于肥胖。尽管遗传性是肥胖发展的一个公认因素，但导致这种趋势的基因却很难识别。迄今为止发现的少数单基因肥胖形式之一是由 GPCR MC4R 突变引起的。鉴于这一先例以及需要定义肥胖遗传易感性的更常见解释，特别值得注意的是，药理学和/或遗传证据表明二十多种 GPCR 作为食物摄入、体重和/或对喂养的享乐（即奖励）反应的调节剂。这些受体中的绝大多数具有多种已知的非同义（即编码序列的变化）变体。通过分析 Look AHEAD 人群中 GPCR 多态性的患病率、药理功能和共存，我们将检验我们的中心假设，即普通人群中很大一部分肥胖与 GPCR 功能异常有关。我们将首先通过序列和单倍型分析来定义 Look AHEAD 群体中的 MC4R 变体（已知的和新颖的）。目标 1 将深入了解该受体在一大群肥胖糖尿病受试者中的作用，并解决围绕已知常见变体 (VI031) 预防肥胖的程度的争议。此外，MC4R 的研究将建立一个基线，在此基础上探索其他因素（例如 GPCR 多态性）作为体重遗传决定因素的重要性。此外，MC4R 的分析将使其他 Look AHEAD 研究人员能够将此变量作为定义临床敏感性的潜在混杂因素考虑在内。在目标 2 中，我们将对一系列 20 个促食欲、厌食和享乐 GPCR 中的非同义编码区多态性和单倍型标记进行基因分型，这些 GPCR 假定在肥胖的发展中具有病因学作用。这些受体变体已从 NCBI SNP 数据库和文献中鉴定出来。与此同时，相应的突变重组 GPCR 将在异源细胞系中表达并进行药理学评估。多态性受体可分为功能获得型、功能丧失型或野生型。将在研究人群中评估功能异常和表型参数之间的相关性。在目标 3 中，将评估厌食、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附加因素。