Genetic and Epidemiological Predictors of Glucose Homeostasis Measures

总结 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性状 （T2D）。本提案的主要目标是了解以下变化的病理生理学 墨西哥裔美国人是美国最大的少数民族，也是最有可能患上癌症的人群之一。 2型糖尿病西班牙裔糖尿病遗传学基础（GUARDIAN）联盟代表了最大的努力， 确定糖尿病相关中间表型的遗传决定因素（DK085175）。期间 在上一个资助期，全基因组关联研究（GWAS）侧重于常见的遗传变异 确定了四个基因组范围内的显着位点的葡萄糖稳态性状的变化，翻译 临床终点T2D。在本申请中，我们将建立在重要的遗传学发现的基础上， 生物学（代谢组学）和分析（分层聚类和相互作用分析）的整合 进一步完善胰岛素抵抗和胰岛素分泌表型并探索其生物学特性的方法 基础目标1将开发一种新的方法，使用现有的GWAS和代谢组学数据来插补 遗传调节代谢物（GReM），并测试其与葡萄糖稳态的相关性， 守护者联盟目标2将细化与T2D相关的已知和新变体以及相关的 表型通过层次聚类和执行交互作用分析，利用双峰性质 以确定其他胰岛素抵抗基因座。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稳态，并将这些基因座转化为T2D。独特的 该建议的优点包括葡萄糖稳态的详细表型， 在GWAS环境中进行了检查，重点是墨西哥裔美国人，以及我们长期以来，高度重视 高效的协作团队。该项目具有重大的公共卫生意义，因为它的重点是增加 我们对使用糖尿病前期措施预防T2D的生物学理解和产生的机制 葡萄糖稳态的关键

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.