Genetics of Beta Cell Failure in Mexican Americans

描述（由申请人提供）：在怀孕期间发生妊娠期糖尿病（GDM）的年轻西班牙女性中，我们已经确定了相对早发性和进行性胰岛素分泌丧失，这先于并预测了2型糖尿病（T2DM）的发展。胰岛素分泌缺陷似乎是由胰岛素抵抗引起或加重的，并且在GDM先证家族中具有高度遗传性。基于这些观察结果，我们假设存在导致这些年轻女性发生2型糖尿病的胰岛素分泌缺陷的遗传决定因素。我们在西班牙裔美国人的大型队列（包括一个大型家庭队列）中，在详细表型分析以量化胰岛素分泌和胰岛素抵抗方面有丰富的经验。我们也有机会接触到大量有GDM先证者的大家庭。因此，我们建议使用详细的表型分析结合候选基因和全基因组QTL连锁分析来寻找我们已经确定的β细胞缺陷的遗传决定因素。目前的应用主要集中在墨西哥裔美国女性GDM及其兄弟姐妹和表亲（即富含b细胞缺陷的家庭）的招募和表型分析，以及在怀孕期间保持正常糖耐量（强大的b细胞功能）的匹配对照女性。所有这些人都将接受详细的b细胞功能、胰岛素敏感性和身体成分研究。其他家庭成员将提供DNA，用于评估遗传身份，并用于未来构建GDM先证和匹配对照的单倍型。在此奖励期间，将对GDM和T2DM的候选基因进行研究。对全基因组扫描的支持将单独寻求，随后将对候选区域和基因进行精细的定位和关联研究。最终，该项目的结果对于实现我们的长期目标(a)了解年轻西班牙裔美国人2型糖尿病的根本原因(s)和(b)制定策略，在其演变的相对早期阶段预测和预防该疾病至关重要。

DESCRIPTION (provided by applicant): In young Hispanic women who developed gestational diabetes mellitus (GDM) during pregnancy, we have identified relatively early-onset and progressive loss of insulin secretion that precedes and predicts the development of type 2 diabetes mellitus (T2DM). The defect in insulin secretion appears to be caused or worsened by insulin resistance and it is highly heritable in families of GDM probands. Based on these observations, we hypothesize that there are genetic determinants of the defect in insulin secretion that leads to T2DM in these young women. We have extensive experience with the performance of detailed phenotyping to quantify insulin secretion and insulin resistance in large cohorts of Hispanic Americans, including one large family-based cohort. We also have access to a large number of large families with a GDM proband. Accordingly, we propose to search for genetic determinants of the beta-cell defect that we have identified, using detailed phenotyping combined with candidate gene and genome-wide QTL linkage analysis. The present application is focused on the recruitment and phenotyping of Mexican American women with GDM and their siblings and first cousins (i.e., families enriched with the B-cell defect) and of matched control women who maintained normal glucose tolerance during pregnancy (robust B-cell function). All of these individuals will have detailed studies of B-cell function, insulin sensitivity and body composition. Additional family members will provide DNA for assessment of identity-by-descent and for future construction of haplotypes in GDM probands and matched controls. Studies of selected candidate genes for GDM and T2DM will be conducted during this award period. Support for a genome-wide scan will be sought separately and will be followed by fine mapping and association studies of positional candidate regions and genes. Ultimately, the results of this project will be crucial in attaining our long-term goals of (a) understanding the fundamental cause(s) of T2DM in young Hispanic Americans and (b) developing strategies to predict and prevent that disease at relatively early stages in its evolution.