Common Genetic Variation and Diabetes Traits in Framingham

弗雷明汉的常见遗传变异和糖尿病特征

• 批准号: 7577497
• 负责人: JAMES B MEIGS
• 金额: $ 60.96万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7577497
• 关键词: Accounting; Ancillary Study; Arts; Bioinformatics; Candidate Disease Gene; Cardiovascular Diseases; Chromosomes, Human, Pair 1; Clinical Research; Communities; Computer Simulation; Data; Diabetes Mellitus; Environment; Environmental Exposure; Epidemic; Finland; Follow-Up Studies; Framingham Heart Study; Funding; General Hospitals; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genetic screening method; Genotype; Health; Health Professional; IL6 gene; Investigation; Knowledge; Lead; Linkage Disequilibrium; Linkage Disequilibrium Mapping; Massachusetts; Metabolic; Methods; National Health and Nutrition Examination Survey; National Heart, Lung, and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Insulin-Dependent Diabetes Mellitus; Nurses; Obesity; Parents; Pathway interactions; Penetrance; Phenotype; Positioning Attribute; Predisposition; Prevention; Prevention approach; Public Health; Recording of previous events; Research; Risk Factors; Sampling; Sampling Studies; Screening procedure; Single Nucleotide Polymorphism; Staging; Statistical Methods; Study Subject; Susceptibility Gene; Trust; United States; base; cardiovascular disorder risk; case control; density; diabetes mellitus genetics; diabetes risk; follow-up; gene discovery; gene environment interaction; genome wide association study; genome-wide; novel; novel strategies; research study; trait

DESCRIPTION (provided by applicant): Type 2 diabetes is a major public health problem arising from polygenic susceptibility and environmental exposures, including the metabolic environment induced by obesity. Several diabetes susceptibility genes have been identified by convergence of detailed phenotyping and high-density genotyping for genome-wide association (GWA) studies. The Framingham Heart Study (FHS) has a long history of comprehensive phenotyping related to cardiovascular disease risk factors including diabetes, has acquired 100K and will soon acquire 550K SNP GWA study data (as part of the NHLBI FHS SHARe study), and is positioned to contribute GWA study data to diabetes gene discovery. In the FHS 100K GWA study we implemented screening methods to derive a set of SNPs probably enriched for true positive associations with diabetes and related quantitative traits. Here our Aims are to 1) linkage disequilibrium (LD) map and replicate FHS 100K SNP-diabetes associations: we hypothesize that increased 550K SNP density and greater SHARe subject numbers (N~9,000) used for in silico LD mapping and replication of 100K associations will produce a promising subset of 100K SNPs that will replicate in independent samples (from the Nurses' Health and Health Professionals Follow-Up, MGH and NHANES III Studies; N~10,000); 2) integrate FHS 550K data with other GWA studies (Diabetes Genetics Initiative, Wellcome Trust CCC, FUSION; N~11,000) to replicate promising SNPs, and vice versa (to assess their top results for replication and further characterization in FHS); thus, first-stage in silico replication of SNPs in independent GWA studies will guide subsequent genotyping, replication and LD mapping in independent samples; and 3) assess interaction: we hypothesize that accounting for gene-environment interaction (specifically, obesity) will identify novel SNPs and will strengthen evidence for association of specific SNPs with diabetes traits. We respond to PAR-06-216, }Ancillary Studies to } NIDDK and NHLBI} Research Studies} with a diabetes-oriented ancillary study to the NHLBI-funded parent Framingham Heart Study. Preliminary studies strongly suggest that the project will lead to replicated identification of novel diabetes susceptibility genes important in the community. Knowledge of the genetic basis of type 2 diabetes is critical to identify new approaches to prevention and control of the worldwide diabetes epidemic. 7. Project Narrative Type 2 diabetes is a major, increasing public health problem caused by genetic susceptibility and obesity. This project will use genome-wide association studies in about 30,000 people to reveal the genetic basis of type 2 diabetes, and will test genetic interactions with obesity that increase risk for diabetes. Expanded knowledge of genes predisposing to type 2 diabetes and their interaction with obesity is critical to identify novel strategies for prevention and control of the worldwide diabetes epidemic.

描述（由申请人提供）： 2型糖尿病是由多基因易感性和环境暴露引起的主要公共卫生问题，包括肥胖引起的代谢环境。通过全基因组关联（GWA）研究的详细表型分型和高密度基因分型的融合，已经确定了几个糖尿病易感基因。FHS在与包括糖尿病在内的心血管疾病风险因素相关的综合表型方面有着悠久的历史，已经获得了10万个SNP GWA研究数据，并将很快获得55万个SNP GWA研究数据（作为NHLBI FHS SHARe研究的一部分），并将为糖尿病基因发现贡献GWA研究数据。在FHS 100 K GWA研究中，我们实施了筛选方法，以获得一组可能富集了与糖尿病和相关数量性状的真阳性关联的SNP。我们的目的是1）连锁不平衡（LD）映射和复制FHS 100 K SNP-糖尿病关联：我们假设增加的550 K SNP密度和更多的SHARe受试者数量（N~9，000）将产生100 K SNP的有希望的子集，其将在独立样品中复制（来自护士健康和健康专业人员随访、MGH和NHANES III研究; N~ 10，000）; 2）将FHS 550 K数据与其他GWA研究整合（糖尿病遗传学倡议，惠康信托CCC，融合; N~ 11，000）复制有希望的SNP，反之亦然（评估其在FHS中复制和进一步表征的最佳结果）;因此，在独立GWA研究中SNP的第一阶段计算机模拟复制将指导独立样品中的后续基因分型、复制和LD作图;以及3）评估相互作用：我们假设考虑基因-环境相互作用（特别是肥胖）将鉴定新的SNPs，并将加强特定SNPs与糖尿病性状相关的证据。我们对PAR-06-216，} NIDDK和NHLBI研究的辅助研究}做出回应，对NHLBI资助的母体心脏病研究进行了一项针对糖尿病的辅助研究。初步研究强烈表明，该项目将导致在社区中重要的新型糖尿病易感基因的重复鉴定。了解2型糖尿病的遗传基础对于确定预防和控制全球糖尿病流行的新方法至关重要。7. 2型糖尿病是由遗传易感性和肥胖引起的一个主要的、日益严重的公共卫生问题。该项目将在大约30，000人中使用全基因组关联研究来揭示2型糖尿病的遗传基础，并将测试与肥胖的遗传相互作用，增加糖尿病的风险。扩大对2型糖尿病易感基因及其与肥胖相互作用的了解对于确定预防和控制全球糖尿病流行的新策略至关重要。