Genetic and Epidemiological Predictors of Glucose Homeostasis Measures

摘要 胰岛素敏感性和胰岛素分泌是对2型糖尿病风险有重大影响的特征 (T2D)。这一建议的总体目标是了解潜在的病理生理学变化。 这些中间表型在墨西哥裔美国人中存在，墨西哥裔美国人是美国最大的少数民族，也是罹患癌症的高危人群 T2D。拉美裔美国人糖尿病的遗传学基础(卫报)联盟是为 确定糖尿病相关中间表型(DK085175)的遗传决定因素。在.期间 在之前的资助期，全基因组关联研究(GWAS)专注于共同的遗传变异 确定了四个基因组范围内葡萄糖动态平衡性状潜在变异的显着基因座，这些基因座 到临床终点，T2D。在本应用程序中，我们将以先前的重大遗传学发现为基础 生物学(代谢组学)和分析(等级聚类和相互作用分析)的结合 进一步提纯胰岛素抵抗和胰岛素分泌表型并探讨其生物学意义的途径 基础。AIM 1将开发一种新的方法，使用现有的GWAS和代谢组学数据来归因于 基因调节代谢物(GREM)及其与血糖动态平衡指标的相关性 守护者联盟。目标2将提炼与T2D和相关的已知和新的变体 通过层级聚类进行表型分析，并执行利用双峰特性的交互分析 以确定额外的胰岛素抵抗基因座。目标3将确定动态的遗传决定因素 测量不同人群中的葡萄糖动态平衡，并将这些基因座转化为T2D。独一无二的 这一建议的优点包括尚未广泛研究的葡萄糖稳态的详细表型。 在GWAS的背景下进行了审查，重点关注墨西哥裔美国人人口，以及我们长期高度 富有成效的协作团队。该项目具有重大的公共卫生意义，因为它专注于增加 我们对使用糖尿病前期措施预防T2D的生物学理解和结果机制 葡萄糖的动态平衡。

Summary Insulin sensitivity and insulin secretion are traits that have a significant impact on the risk of type 2 diabetes (T2D). The over-arching goal of this proposal is to understand the pathophysiology underlying variation of these intermediate phenotypes in Mexican Americans, the largest US minority group and one at high risk of T2D. The Genetics Underlying Diabetes in Hispanics (GUARDIAN) Consortium represents the largest effort to identify the genetic determinants underlying diabetes-related intermediate phenotypes (DK085175). During the previous funding period, genome-wide association studies (GWAS) focused on common genetic variation identified four genome-wide significant loci underlying variation in glucose homeostasis traits which translated to the clinical endpoint, T2D. In this application, we will build upon significant prior genetic findings with integration of biological (metabolomics) and analytical (hierarchical clustering and interaction analysis) approaches to further refine insulin resistance and insulin secretion phenotypes and explore their biological basis. Aim 1 will develop a novel methodology using existing GWAS and metabolomics data to impute genetically regulated metabolites (GReM) and test their association with measures of glucose homeostasis in the GUARDIAN Consortium. Aim 2 will refine known and novel variants associated with T2D and related phenotypes through hierarchical clustering and perform interaction analyses which exploit the bimodal nature of T2D to identify additional insulin resistance loci. Aim 3 will identify genetic determinants of dynamic measures of glucose homeostasis in diverse human populations and translate these loci to T2D. The unique strengths of this proposal include detailed phenotypes for glucose homeostasis that have not been extensively examined in the GWAS setting, a focus on the Mexican American population, and our long-standing, highly productive collaborative team. This project has great public health significance as it is focused on increasing our biological understanding and resultant mechanisms for the prevention of T2D using pre-diabetic measures of glucose homeostasis.