GPCR Variants as Genetic Determinants of Obesity

GPCR 变异作为肥胖的遗传决定因素

• 批准号: 7454234
• 负责人: ALAN S KOPIN
• 金额: $ 76.01万
• 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/7454234
• 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％的美国人口的体重指数（BMI）超过30，因此有资格作为肥胖。尽管遗传力是肥胖发展的一个公认的因素，但这种趋势的基因很难识别。迄今为止从突变GPCR（MC4R）确定的少数单基因肥胖形式之一。鉴于这种先例以及需要定义对肥胖症遗传易感性的更常见解释，尤其要注意的是，药理学和/或遗传学证据已将超过20多个GPCR与食物摄入，体重和/或享乐人（即有奖励，有益的）反应有关。这些受体中的绝大多数具有多种已知的非同义词（即编码序列的变化）变体。通过分析GPCR多态性的患病率，药理功能和在未来人群中的共存，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异常GPCR功能有关。我们将首先按顺序和单倍型分析来定义未来人群的MC4R变体（已知和新颖）。 AIM 1将洞悉该受体在大量肥胖糖尿病患者中的作用，并解决围绕已知常见变体（VI031）保护肥胖症的范围的争议。此外，对MC4R的研究将建立一个基线，以探讨其他因素（例如GPCR多态性）作为体重的遗传决定因素的重要性。此外，对MC4R的分析将使其他研究人员能够将此变量视为定义临床敏感性的潜在混淆因素。在AIM 2中，我们将在一系列二十种甲状腺素，厌食症和Hedonic GPCR中基因型非同义编码区域多态性和单倍型标记物，假定在肥胖的发展中具有病因。这些受体变体已从NCBI SNP数据库和文献中鉴定出来。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评估。多态受体将被归类为功能，功能丧失或野生型的增益。功能异常和表型参数之间的相关性将在研究人群中评估。在AIM 3中，将评估厌食症，甲状腺素和享乐受体变体的组合是肥胖和/或其他前面研究终点的多基因基础和/或其他外观的潜在协同或加性因素。