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) 和胰岛素分泌都是对 2 型糖尿病 (T2DM) 风险具有显着影响的特征。该提案的首要目标是确定西班牙裔美国人胰岛素抵抗、MCRI 和胰岛素分泌变化背后的遗传变异，西班牙裔美国人是美国最大的少数群体，也是 T2DM 的高风险群体。在 IRAS 家庭研究（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且新颖的表型测量。通过遗传性分析、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措施的重大遗传贡献和潜在的基因组位置。在此更新申请中，我们建议通过开发一个研究联盟来扩展这些发现，这些研究联盟对与 T2DM 风险相关的这些极其重要的表型以及西班牙裔人群 DNA 样本的获取进行了类似的测量。 GUARDIAN 联盟（西班牙裔糖尿病的遗传学）有以下目标：(1) 进行 GWAS，以检测 4685 名西班牙裔多队列谱系中葡萄糖稳态特征潜在变异的位点； (2) 通过在一组约 3500 个 T2DM 病例和约 5500 个对照中进行关联测试，将这些发现转化/扩展到相关的临床疾病 T2DM； (3) 对来自 GWAS 的多达 12 个基因位点进行测序，以确定导致葡萄糖稳态特征变化和 T2DM 易感性变化的特定变异。拟议研究的独特优势包括发现样本中葡萄糖稳态的高度详细的表型，这些表型以前从未在 GWAS 环境中进行过检查，西班牙裔队列中这些措施可提供大量的人口规模，以及我们长期存在的、高生产力的合作团队。该项目具有重大的公共卫生意义，因为它的重点是提高我们对利用糖尿病前期葡萄糖稳态措施预防 T2DM 的认识和机制。 公共卫生相关性： 该项目旨在评估美国少数民族西班牙裔人群中易患 2 型糖尿病的因素的遗传基础，即胰岛素抵抗、胰岛素代谢清除率和胰岛素分泌。该项目对公共卫生的意义在于它有助于加深对 2 型糖尿病这一高度流行疾病的了解。

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.