Genetics of Beta Cell Failure in Mexican Americans

描述（由申请人提供）：我们研究的长期目标是了解在相对年轻的西班牙裔美国人中引起2型糖尿病（T2 D）的机制，以便开发更好的预测，预防和早期治疗方法。BetaGene研究的具体目标是确定易患T2 D的基因，并了解这些基因如何促进糖尿病的发展。在BetaGene的前五年，我们对1235名来自墨西哥裔美国家庭的个体进行了口服（oGTT）和静脉（ivGTT）葡萄糖耐量试验和身体成分DEXA，这些个体的先证者在怀孕期间患有妊娠期糖尿病（GDM）或葡萄糖耐量正常。在一个单独的队列中，西班牙裔女性既往GDM，我们已经表明，T2 D的结果从胰腺b细胞功能的进行性丧失，发生在多年的慢性胰岛素抵抗的背景。我们和其他人已经测试了与假定的T2 D基因相关的b细胞功能的横截面差异，充其量是更重要的纵向变化的替代品。该提议的主要假设是一个或多个T2 D基因影响胰岛素抵抗的b细胞补偿的变化率。我们从HNF 4A的初步研究中为我们的假设提供了强有力的证据。我们将实现三个目标，以更充分地检验我们的假设。首先，我们将从BetaGene样本中招募400名个体的随机纵向队列，并在基线检查后3-5年对其进行重新表型。它们将是我们基于b细胞代偿变化进行相关研究的主要资源。其次，我们已经对整个BetaGene队列进行了T2 D和相关数量性状的20个基因的基因分型。我们将对发现的T2 D和T2 D相关表型的相关新基因进行纵向队列基因分型，并对一组祖先信息标记进行基因分型，以评估群体亚结构。第三，我们将分析数据，以测试T2 D和T2 D相关表型的变异与b细胞代偿变化率之间的关联。我们还将测试遗传效应和b细胞环境方面之间的相互作用（例如，肥胖、胰岛素抵抗、饮食、体力活动）对B细胞补偿变化率的影响。我们的研究结果将提供独特的信息，遗传影响的主要生理异常，导致T2 D在年轻的西班牙裔美国人。他们还将提供关于遗传变异与肥胖、胰岛素抵抗和b细胞功能之间相互作用的独特信息。这些信息将有助于指导糖尿病遗传机制的研究。它还将为糖尿病预测、预防和早期治疗的新临床方法提供基础。公共卫生相关性：该项目旨在确定糖尿病风险基因如何影响导致墨西哥裔美国人2型糖尿病的主要异常。这些结果将有助于指导2型糖尿病发病机制的基础研究。研究结果还将有助于指导开发新的方法来预测，预防和早期治疗这一高风险族群的2型糖尿病。

DESCRIPTION (provided by applicant): The long-term objective of our research is to understand the mechanisms that cause type 2 diabetes (T2D) in relatively young Hispanic Americans in order to develop better approaches to prediction, prevention and early treatment. The specific objective of the BetaGene Study is to identify genes that predispose to T2D and understand how those genes contribute to development of diabetes. In the first five years of BetaGene, we performed oral (oGTT) and intravenous (ivGTT) glucose tolerance tests and body composition by DEXA on 1235 individuals from Mexican American families with probands who had either gestational diabetes (GDM) or normal glucose tolerance during pregnancy. In a separate cohort of Hispanic women with prior GDM, we have shown that T2D results from a progressive loss of pancreatic b-cell function that occurs over the course of years on a background of chronic insulin resistance. The cross-sectional differences in b-cell function that we and others have tested for association with putative T2D genes are, at best, surrogates for the more important longitudinal changes. The primary hypothesis underlying this proposal is that one or more T2D genes influence rates of change in b-cell compensation for insulin resistance. We provide strong evidence for our hypothesis from preliminary studies of HNF4A. We will achieve three aims to test our hypothesis more fully. First, we will recruit and re-phenotype a random longitudinal cohort of 400 individuals from the BetaGene sample 3-5 years after their baseline exams. They will be our primary resource for association studies based on changes in b-cell compensation. Second, we are already genotyping the entire BetaGene cohort for 20 genes for T2D and related quantitative traits. We will genotype the longitudinal cohort for relevant new genes underlying T2D and T2D-related phenotypes as they are discovered and for a panel of ancestrally informative markers to assess population substructure. Third, we will analyze data to test for association between variants underlying T2D and T2D-related phenotypes and rates of change in b-cell compensation. We will also test for interactions between genetic effects and aspects of the b-cell environment (e.g., obesity, insulin resistance, diet, physical activity) on rates of change in b-cell compensation. Our results will provide unique information about genetic influences on the primary physiological abnormality that causes T2D in young Hispanic Americans. They will also provide unique information on the interplay among genetic variation and obesity, insulin resistance and b-cell function. The information will help guide mechanistic studies of the genetic contribution to diabetes. It will also provide a basis for new clinical approaches to diabetes prediction, prevention and early treatment. PUBLIC HEALTH RELEVANCE: This project is designed to determine how diabetes risk genes affect the major abnormalities that lead to type 2 diabetes in Mexican Americans. The results will be useful in guiding basic studies into the mechanisms of type 2 diabetes. The results will also help to guide the development of new approaches to the prediction, prevention and early treatment of type 2 diabetes in this high-risk ethnic group.