Genetic & Epidemiologic Predictors of Glucose Homeostasis Measures in Hispanics

描述（由申请方提供）：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（T2 DM）风险有显著影响的特征。该提案的首要目标是确定西班牙裔美国人胰岛素抵抗、MCRI和胰岛素分泌变异的遗传变异，西班牙裔美国人是美国最大的少数群体，也是T2 DM的高风险群体之一。在IRAS家族研究（由NHLBI资助两个五年周期）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，肥胖和其他性状的详细和新颖的表型指标。我们已经确定了大量的遗传贡献和潜在的基因组位置，许多这些措施，通过遗传力分析，连锁分析，候选基因关联研究，最近，试点全基因组关联扫描（GWAS）。在本次更新申请中，我们建议通过开发一个研究联盟来扩展这些发现，这些研究联盟对西班牙裔队列中与T2 DM风险和DNA样本获取相关的这些至关重要的表型具有相似的测量。GUARDIAN财团（西班牙裔糖尿病的遗传学基础）有以下目标：（1）进行GWAS，以检测4685名西班牙裔多队列家系组中葡萄糖稳态性状变异的基础基因座;（2）通过在一组约3500例T2 DM病例和约5500例对照中检测相关性，将这些发现转化/扩展到相关临床疾病T2 DM;和（3）对来自我们的GWAS的多达12个遗传基因座进行测序，以鉴定有助于葡萄糖稳态性状和T2 DM易感性变化的特定变体。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，这些表型以前在GWAS环境中没有进行过检查，西班牙裔队列中这些措施的人群规模很大，以及我们长期以来，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，预防T2 DM使用糖尿病前期血糖稳态的措施。 公共卫生相关性： 该项目旨在评估美国少数民族人群（西班牙裔）中易患2型糖尿病的因素（即胰岛素抵抗、胰岛素代谢清除率和胰岛素分泌）的遗传基础。该项目的公共卫生意义在于它有助于提高对2型糖尿病的认识，这是一种非常普遍的疾病。

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.