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（包括肥胖引起的代谢环境）引起的主要公共卫生问题。通过将详细的表型分析和高密度基因分型进行全基因组关联（GWA）研究的融合，已经鉴定出一些糖尿病易感基因。 Framingham Heart Study (FHS) 在与包括糖尿病在内的心血管疾病危险因素相关的综合表型分析方面有着悠久的历史，已经获取了 100K 并将很快获取 550K SNP GWA 研究数据（作为 NHLBI FHS SHARe 研究的一部分），并致力于为糖尿病基因发现贡献 GWA 研究数据。在 FHS 100K GWA 研究中，我们实施了筛选方法来推导一组 SNP，这些 SNP 可能与糖尿病和相关数量性状存在真正的正相关性。这里我们的目标是 1) 连锁不平衡 (LD) 作图并复制 FHS 100K SNP-糖尿病关联：我们假设增加的 550K SNP 密度和更大的 SHARe 受试者数量 (N~9,000) 用于计算机 LD 作图和 100K 关联的复制将产生一个有前途的 100K SNP 子集，这些子集将在独立样本中复制（来自护士健康和健康）专业人士 后续、MGH 和 NHANES III 研究； N~10,000); 2) 将 FHS 550K 数据与其他 GWA 研究（糖尿病遗传学倡议、Wellcome Trust CCC、FUSION；N~11,000）整合以复制有前景的 SNP，反之亦然（以评估其在 FHS 中复制和进一步表征的最佳结果）；因此，独立 GWA 研究中 SNP 的第一阶段计算机复制将指导独立样本中后续的基因分型、复制和 LD 作图； 3) 评估相互作用：我们假设解释基因-环境相互作用（特别是肥胖）将识别新的 SNP，并将加强特定 SNP 与糖尿病特征关联的证据。我们响应 PAR-06-216，}NIDDK 和 NHLBI}研究的辅助研究}，对 NHLBI 资助的母公司弗雷明汉心脏研究进行了一项以糖尿病为导向的辅助研究。初步研究强烈表明，该项目将导致对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. 项目叙述 2 型糖尿病是由遗传易感性和肥胖引起的一个日益严重的重大公共卫生问题。该项目将利用约 30,000 人的全基因组关联研究来揭示 2 型糖尿病的遗传基础，并将测试与增加糖尿病风险的肥胖之间的遗传相互作用。扩大对易患 2 型糖尿病的基因及其与肥胖的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。