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: 8486419
• 负责人: JAMES B MEIGS
• 金额: $ 64.89万
• 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/8486419
• 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 sequencing; 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(申请人提供)：R01DK78616更新的目标是利用阶段性全基因组关联研究和荟萃分析(GWAS-MA)在大的跨四种族样本(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。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途径，在纵向数据中，测试候选基因的生理效应和T2D预测。我们与其他NIDDK研究的联系为下一代测序(U01 DK085526)和T2D预防遗传学临床应用试验(R21 DK084527)提供了即时跟进。最近美国T2D的显著增加，特别是在少数群体中，是一个不断升级的临床和公共卫生挑战。遗传背景的变化和日益增加的肥胖症是美国T2D上升的原因。在欧洲血统的人中，大规模的GWAS-MA已经成功地勾勒出T2D共同的遗传结构，由我们的团队领导的财团研究最近贡献了&gt；50个新的T2D风险或T2D QT基因座。大的跨种族GWAS-MA是T2D基因发现的关键下一步。具体目标是：1)在大的、非糖尿病的、跨种族的样本中使用GWAS-MA识别新的T2D QT相关变种。我们假设：a)在非糖尿病非裔美国人的大样本中进行T2D QTS的GWAS-MA将识别与T2D生理和T2D风险相关的新的基因座；b)与其他三组人一起加入非裔美国人的T2D QT GWAS-MA将识别额外的基因座；2)利用跨种族的大样本发现更多的基因座，精细作图，并通过基因-环境、基因-基因和基因通路分析，特别是考虑SNP x BMI、体重变化、种族和其他交互作用，提出机制；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，定义美国种族中的风险等位基因谱，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、相互作用和路径研究提供无与伦比的资源，以支持T2D及其相关QTS，并有助于更好地确定T2D遗传学在生理靶向、人口预测和个性化预防方面的价值，以改善美国少数和非少数群体的健康。