Genetic & Epidemiologic Predictors of Glucose Homeostasis Measures in Hispanics

描述(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(T2 DM)风险有重大影响的特征。这项提案的总体目标是确定西班牙裔美国人在胰岛素抵抗、MCRI和胰岛素分泌方面潜在的遗传变异，拉美裔美国人是美国最大的少数群体，也是T2 DM的高危群体。在IRAS家庭研究(由NHLBI资助的两个五年周期)中，我们招募了大量的西班牙裔队列，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。我们已经通过遗传力分析、连锁分析、候选基因关联研究和最近的试点全基因组关联扫描(GWAS)，确定了对其中许多指标的重大遗传贡献和潜在的基因组位置。在这一更新申请中，我们建议通过发展一个研究联盟来扩展这些发现，这些研究对这些与T2 DM风险和获得西班牙裔队列中的DNA样本相关的至关重要的表型具有类似的测量。该监护联盟(拉美裔美国人糖尿病的遗传学基础)有以下目标：(1)在4685名拉美裔多队列人群中检测血糖稳态特征的潜在变异的基因座；(2)通过在一组约3,500例T2 DM病例和约5500名对照中测试关联，将这些发现翻译/扩展到相关的临床疾病T2 DM；以及(3)对我们的GWAS中最多12个基因座进行测序，以确定导致血糖稳态特征变化和T2 DM易感性的特定变异。这项拟议研究的独特优势包括：DISCOVERY样本中高度详细的葡萄糖动态平衡表型，这是以前在GWAS环境中从未进行过检查的；西班牙裔队列中可利用这些测量方法获得的大量人口；以及我们长期高效的合作团队。这个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血糖稳态措施预防T2 DM的理解和机制。 公共卫生相关性： 该项目建议评估在美国少数族裔拉美裔人群中易患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。该项目的公共卫生意义在于它有助于增进对2型糖尿病的了解，2型糖尿病是一种高度流行的疾病。

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.