Common Genetic Variation and Quantitative Diabetes Traits

常见的遗传变异和定量糖尿病特征

• 批准号: 8293035
• 负责人: JAMES B MEIGS
• 金额: $ 71.6万
• 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 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8293035
• 关键词: Accounting; Affect; African American; Alleles; Architecture; Asians; Back; Beta Cell; Body Weight Changes; Caring; Cell physiology; Chromosome Mapping; Clinical; Collection; Complex; Coupled; Data; Diabetes Mellitus; Diabetes prevention; Diagnosis; Disease; Environment; Ethnic Origin; Ethnic group; Etiology; European; Evolution; Functional disorder; Funding; General Population; Genes; Genetic; Genetic Research; Genetic Variation; Genomics; Genotype; Glucose; Glycosylated Hemoglobin; Glycosylated hemoglobin A; Goals; Health; Hispanics; Individual; Insulin; Insulin Resistance; Knowledge; Link; Maps; Measures; Meta-Analysis; Metabolic; Metabolic Pathway; Minority Groups; Mutation; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Phenotype; Physiological; Physiology; Population; Prevention; Prevention strategy; Public Health; Quantitative Trait Loci; Resources; Risk; Sampling; Sampling Studies; Staging; Support Groups; Target Populations; Testing; Time; To specify; Translations; Variant; Work; base; clinical application; diabetes mellitus genetics; diabetes risk; fasting glucose; follow-up; gene discovery; gene environment interaction; gene interaction; genetic resource; genome wide association study; improved; next generation; non-diabetic; novel; novel strategies; permissiveness; population based; trait

DESCRIPTION (provided by applicant): The goal of this R01DK78616 renewal is to identify new type 2 diabetes (T2D) quantitative trait (QT) loci in a large trans-four-ethnic sample (N~103,000: ~26K African American, ~46K European, ~14K Hispanic and ~17K Asian) using staged genome-wide association studies with meta-analysis (GWAS-MA). In the trans- ethnic sample we will further test gene-environment and gene-gene interactions and gene pathways, and in longitudinal data, test candidate loci for physiological effects and for T2D prediction. Our links with other NIDDK studies offer immediate follow-up for next-generation sequencing (U01 DK085526) and trials of clinical application of genetics for T2D prevention (R21 DK084527). The significant recent, dramatic increase in T2D in the U.S., especially in minority groups, is an escalating clinical and public health challenge. Variation in genetic background coupled with increasing obesity accounts for rising T2D in the U.S.. In people of European ancestry, large-scale GWAS-MA have successfully outlined T2D common genetic architecture, with consortia studies led by our group and our collaborators recently contributing >50 new T2D risk or T2D QT loci. Large trans-ethnic GWAS-MA is a key next step in T2D gene discovery. Specific Aims are to: 1) Identify novel T2D QT-associated variants using GWAS-MA in large, non-diabetic, trans-ethnic samples. We hypothesize that: a) staged GWAS-MA of T2D QTs in a large non-diabetic African American sample will identify novel loci associated with T2D physiology and T2D risk and b) joining the African American T2D QT GWAS-MA with three other groups for a large trans-four-ethnic T2D QT GWAS-MA will identify additional loci; 2) Use the large trans-ethnic sample to find more loci, fine map, and suggest mechanism by tests of gene-environment, gene-gene and gene pathway analyses, specifically, accounting for SNP x BMI, weight change, ethnicity and other interactors; and 3) Use longitudinal population-based data to iluminate the evolution of T2D physiology over time, define the allelic spectrum of risk in U.S. ethnic groups, and test if novel T2D-related variants aid T2D risk prediction. The trans-four-ethnic GWAS-MA will provide an unparalleled resource for genetic discovery, studies of interactions and pathways hypothesized to underlie T2D and its related QTs, and help better define the value of T2D genetics for physiological targeting, population prediction and personalized prevention to improve health in minority and non-minority groups the U.S..

描述（由申请人提供）：R01DK78616更新的目标是利用分阶段全基因组关联研究和荟萃分析，在大型跨四个种族样本（N~103,000：~26K非裔美国人、~46K欧洲人、~14K西班牙人和~17K亚洲人）中识别新的2型糖尿病（T2D）数量性状（QT）基因座 （GWAS-MA）。在跨种族样本中，我们将进一步测试基因-环境、基因-基因相互作用和基因通路，并在纵向数据中测试候选基因座的生理效应和 T2D 预测。我们与其他 NIDDK 研究的联系为下一代测序 (U01 DK085526) 和遗传学临床应用预防 T2D 的临床应用试验 (R21 DK084527) 提供即时跟进。最近，美国 T2D 病例急剧增加，尤其是在少数群体中，这是一个不断升级的临床和公共卫生挑战。遗传背景的变化加上肥胖的增加是美国 T2D 发病率上升的原因。在欧洲血统的人群中，大规模 GWAS-MA 已成功概述了 T2D 共同遗传结构，由我们小组和我们的合作者领导的联合研究最近贡献了超过 50 个新的 T2D 风险或 T2D QT 位点。大型跨种族 GWAS-MA 是 T2D 基因发现的关键下一步。具体目标是： 1) 使用 GWAS-MA 在大型、非糖尿病、跨种族样本中识别新的 T2D QT 相关变异。我们假设：a）在大型非糖尿病非裔美国人样本中对 T2D QT 进行分阶段 GWAS-MA 将识别与 T2D 生理学和 T2D 风险相关的新位点；b）将非裔美国人 T2D QT GWAS-MA 与其他三个群体联合进行大型跨四个种族 T2D QT GWAS-MA 将识别其他位点； 2）利用大型跨种族样本，通过基因-环境、基因-基因和基因通路分析的测试，找到更多位点、精细图谱，并提出机制建议，特别是考虑SNP x BMI、体重变化、种族和其他相互作用因素； 3) 使用基于人群的纵向数据来阐明 T2D 生理学随时间的演变，定义美国种族群体的等位基因风险谱，并测试新的 T2D 相关变异是否有助于 T2D 风险预测。跨四个种族的 GWAS-MA 将为基因发现、对 T2D 及其相关 QT 的假设相互作用和途径的研究提供无与伦比的资源，并帮助更好地定义 T2D 遗传学在生理目标、人群预测和个性化预防方面的价值，以改善美国少数族裔和非少数族群的健康。