Genetic & Epidemiologic Predictors of Glucose Homeostasis Measures in Hispanics

描述（由申请人提供）：胰岛素敏感性、胰岛素代谢清除率（MCRI）和胰岛素分泌是对2型糖尿病（T2DM）风险有显著影响的特征。该提案的总体目标是确定西班牙裔美国人（美国最大的少数民族和T2DM高危人群）胰岛素抵抗、MCRI和胰岛素分泌变异的遗传变异。在IRAS家族研究（由NHLBI资助的两个五年周期）中，我们招募了一个大型西班牙裔队列，并获得了葡萄糖稳态、肥胖和其他特征的详细和新颖的表型测量。通过遗传力分析、连锁分析、候选基因关联研究以及最近的试点全基因组关联扫描（GWAS），我们已经确定了许多这些测量的大量遗传贡献和潜在的基因组位置。在这项更新申请中，我们建议通过开展一系列研究来扩展这些发现，这些研究对与2型糖尿病风险相关的这些至关重要的表型有类似的测量，并获得西班牙裔人群的DNA样本。GUARDIAN联盟（西班牙裔糖尿病的遗传学基础）有以下目标：(1)在4685名西班牙裔多队列家谱中进行GWAS检测葡萄糖稳态性状变异的基因座；(2)通过对约3500例T2DM患者和约5500例对照者的相关性检测，将这些发现转化/扩展到相关的临床疾病——T2DM；(3)从我们的GWAS中对多达12个基因位点进行测序，以确定导致葡萄糖稳态性状变化和对2型糖尿病易感性的特定变异。该研究的独特优势包括：发现样本中葡萄糖稳态的非常详细的表型，这在以前的GWAS环境中没有被检查过；在西班牙裔队列中，这些测量方法具有很大的人口规模；以及我们长期高效的合作团队。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的理解和机制，以预防2型糖尿病前期的血糖稳态措施。

DESCRIPTION (provided by applicant): Insulin sensitivity, metabolic clearance rate of insulin (MCRI), and insulin secretion are traits that all have a significant impact on the risk of type 2 diabetes (T2DM). The over-arching goal of this proposal is to identify the genetic variants underlying variation in insulin resistance, MCRI, and insulin secretion in Hispanic Americans, the largest US minority group and one at high risk of T2DM. In the IRAS Family Study (funded for two five-year cycles by NHLBI), we have recruited a large Hispanic cohort and obtained detailed and novel phenotypic measures of glucose homeostasis, obesity and other traits. We have identified a substantial genetic contribution and potential genomic locations to many of these measures through heritability analysis, linkage analysis, candidate gene association studies and, most recently, a pilot genome-wide association scan (GWAS). In this renewal application, we propose to extend these findings by developing a consortium of studies that have similar measures of these critically important phenotypes related to T2DM risk and access to DNA samples in Hispanic cohorts. The GUARDIAN Consortium (Genetics Underlying Diabetes in Hispanics) has the following goals: (1) to perform a GWAS to detect loci underlying variation in glucose homeostasis traits in a multi-cohort pedigree-based set of 4685 Hispanics; (2) to translate/extend these findings to the relevant clinical disease, T2DM, by testing for association in a set of ~3500 T2DM cases and ~5500 controls; and (3) to sequence up to 12 genetic loci from our GWAS in order to identify specific variants contributing to variation in glucose homeostasis traits and susceptibility to T2DM. The unique strengths of the proposed study include the highly detailed phenotypes of glucose homeostasis in the discovery sample that have not been previously examined in the GWAS setting, the large population size available with these measures in a Hispanic cohort, and our long-standing, highly productive collaborative team. This project has great public health significance as it is focused on increasing our understanding and mechanisms for the prevention of T2DM using pre-diabetic measures of glucose homeostasis. PUBLIC HEALTH RELEVANCE: This project proposes to evaluate the genetic basis of factors that predispose to type 2 diabetes, namely insulin resistance, metabolic clearance rate of insulin, and insulin secretion, in a US minority population, Hispanics. The public health significance of this project is its contribution toward an improved understanding of type 2 diabetes, a highly prevalent condition.