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（由申请人提供）：R01DK78616更新的目标是通过分阶段全基因组关联研究和荟萃分析（gwasma），在大型跨四个种族样本（N~103,000: ~26K非洲裔美国人，~46K欧洲人，~14K西班牙裔和~17K亚洲人）中识别新的2型糖尿病（T2D）数量性状（QT）位点。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T2D预防遗传学临床应用试验（R21 DK084527）提供了即时跟进。近年来，T2D在美国，尤其是少数群体中显著增加，这是一个不断升级的临床和公共卫生挑战。在美国，遗传背景的变化加上肥胖的增加导致了糖尿病的增加。在欧洲血统的人群中，大规模的GWAS-MA成功地勾勒出了T2D的共同遗传结构，由我们的团队和我们的合作者领导的联盟研究最近贡献了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。具体目的是：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)非糖尿病非洲裔美国人T2D QT分期GWAS-MA将识别出与T2D生理和T2D风险相关的新位点；b)与其他三组一起加入非裔美国人T2D QT GWAS-MA，进行跨四个种族的T2D QT GWAS-MA将识别出更多的位点；2)利用跨种族大样本，通过基因-环境、基因-基因、基因通路等测试分析，找到更多的位点，精细图谱，提示机制，具体考虑SNP x BMI、体重变化、种族等相互作用；3)利用基于人群的纵向数据阐明T2D生理学随时间的演变，定义美国种族群体的风险等位基因谱，并测试新的T2D相关变异是否有助于T2D风险预测。跨四种族GWAS-MA将为T2D及其相关QTs的遗传发现、相互作用和途径的研究提供无与伦比的资源，并有助于更好地定义T2D遗传学在生理靶向、人群预测和个性化预防方面的价值，以改善美国少数民族和非少数民族群体的健康状况。