A Whole Genome Association Search for Type 2 Diabetes Genes in African Americans

描述(由申请人提供)： 这项雄心勃勃的计划的培训目标是以循序渐进的方式，在复杂疾病的跨学科研究中为研究员提供越来越多的独立性和责任感。这项建议的研究目标是确定在非裔美国人中导致2型糖尿病(T2 DM)易感性的基因变异，并深入了解它们的作用机制。这一目标将通过以下方式实现：1)复制从与T2 DM相关的650,000个SNP的全基因组关联(GWA)分析中确定的重要结果，2)验证T2 DM关联并探索这些变异通过其调节额外人群中T2 DM易感性的生理机制，3)对始终显示与T2 DM相关的基因组区域进行精细绘制，并识别易患特性的变异，最终利用分子生物学技术来确定识别T2 DM易感变异在体内发挥作用的生物学机制。这些实验将提供与疾病进展有关的确认，并确定这些基因座在体内的作用。综上所述，这一建议结合了现代基因组学方法、临床方法和生化分析，以增加识别导致T2 DM易感性的基因的可能性。通过这种方法，将通过流行病学、统计学、生物化学和生理学领域的互动研究人员的全面网络，支持研究员发展独立性。这将为独立指导常见疾病遗传学的跨学科研究提供技能和经验。

DESCRIPTION (provided by applicant): The training goal for this ambitious proposal is to provide the fellow, in a stepwise fashion, with increasing levels of independence and responsibility in an interdisciplinary study of complex disease. The research goal of this proposal is to identify the genetic variants which confer susceptibility to type 2 diabetes mellitus (T2DM) in African Americans and gain insight into their mechanism of action. This goal will be attained through 1) Replication of significant findings identified from the genome wide association (GWA) analysis of >650,000 SNPs for association with T2DM, 2) Validation of T2DM associations and exploration of the physiological mechanism through which these variants modulate T2DM susceptibility in additional populations, 3) Fine mapping of the genomic regions consistently showing association with T2DM and identifying trait predisposing variants and ultimately 4) Utilize molecular biology techniques to determine the biological mechanism through which identified T2DM-susceptibility variants exert their effects in vivo. These experiments will provide confirmation of involvement in disease progression and determine the role of these loci in vivo. Taken together, this proposal integrates modern genomic approaches, clinical methodologies and biochemical assays to increase the likelihood of identifying genes which contribute to T2DM susceptibilty. With this approach, the fellow will be supported to develop independence through a comprehensive network of interactive researchers in the fields of epidemiology, statistics, biochemistry, physiology. This will provide the skills and experience to independently direct an interdisciplinary study of the genetics of common disease.