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。虽然遗传性是肥胖发展的一个公认的因素，但这种趋势背后的基因一直很难识别。迄今为止被发现的为数不多的单基因肥胖症之一是由GPCRMC4R突变引起的。鉴于这一先例，以及需要确定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/或遗传学证据表明，20多个GPCR是食物摄入量、体重和/或对进食的享乐(即，奖励)反应的调节器。这些受体中的绝大多数都有多种已知的非同义(即编码序列变化)变体。通过分析前瞻性人群中GPCR基因多态性的患病率、药理功能和共存情况，我们将检验我们的中心假设，即在普通人群中有很大一部分肥胖与异常的GPCR功能有关。我们将首先通过序列和单倍型分析来定义前瞻性人群中的MC4R变体(已知的和新的)。目的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，并解决围绕已知的常见变体(VI031)对肥胖的保护程度的争议。此外，对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)作为体重遗传决定因素的重要性。此外，对MC4R的分析将使其他前瞻性研究人员能够将这一变量作为定义临床易感性的潜在混杂因素考虑在内。在目标2中，我们将在一系列20个食欲不振、厌食症和享乐性GPCR中对非同义编码区多态和单倍型标记进行基因分型，这些GPCR被认为在肥胖的发展中具有病因学作用。这些受体变异体已经从NCBI SNP数据库和文献中鉴定出来。同时，相应的突变型重组GPCRs将在异源细胞系中表达并进行药理学评估。多态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和表型参数之间的相关性。在目标3中，厌食症、厌食症和享乐性受体变异的组合将被评估为肥胖和/或其他前瞻性研究终点的多基因基础下的潜在协同或相加因素。