Genetics of Beta Cell Failure in Mexican Americans

墨西哥裔美国人β细胞衰竭的遗传学

• 批准号: 6698090
• 负责人: Thomas A Buchanan
• 金额: $ 137.93万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-20 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6698090
• 关键词: Genetics; Beta; Cell; Failure; Mexican

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.

描述（由申请人提供）：在妊娠期间发生妊娠期糖尿病（GDM）的年轻西班牙裔女性中，我们发现了相对早发型和进行性胰岛素分泌丧失，这是2型糖尿病（T2 DM）的先兆和预测因素。胰岛素分泌缺陷似乎是由胰岛素抵抗引起或恶化的，并且在GDM先证者的家族中具有高度遗传性。基于这些观察结果，我们假设这些年轻女性中存在导致T2 DM的胰岛素分泌缺陷的遗传因素。我们有丰富的经验，详细的表型量化胰岛素分泌和胰岛素抵抗的西班牙裔美国人，包括一个大型的家庭为基础的队列的性能。我们也有机会接触到大量的GDM先证者的大家庭。因此，我们建议使用详细的表型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。本申请集中于患有GDM的墨西哥裔美国妇女及其兄弟姐妹和第一堂兄弟姐妹（即，B细胞缺陷的家庭）和在怀孕期间保持正常葡萄糖耐量（强健的B细胞功能）的匹配对照妇女。所有这些人都将对B细胞功能、胰岛素敏感性和身体成分进行详细的研究。额外的家庭成员将提供DNA评估身份的血统和未来的建设单倍型GDM先证者和匹配的控制。研究选定的候选基因GDM和T2 DM将在此期间进行奖励。将单独寻求对全基因组扫描的支持，然后对位置候选区域和基因进行精细绘图和关联研究。最终，该项目的结果将对实现我们的长期目标至关重要：（a）了解年轻西班牙裔美国人T2 DM的根本原因;（B）制定在疾病演变的相对早期阶段预测和预防该疾病的策略。