Metabolic Basis of Type 2 Diabetes Mellitus: a Genetic Analysis

描述（由申请人提供）：本申请寻求更新正在进行的资助，旨在确定遗传基础，从而确定2型糖尿病（T2D）相对缺乏胰岛素的代谢原因。该建议提供了一个合理的战略的基础上，大规模的病例对照基因分型选择的基因组区域在几个高加索人群。其中，德系犹太人，一个主要的焦点，代表了一个特别有价值的人口，LD是更大的和遗传异质性低于其他高加索群体。提出了三个具体目标。在特定目标1中，将收集德系犹太人对照（n=1000），并表征数量性状（QT），以提供足够的把握度来检测导致T2D风险的低风险等位基因。QT将包括拟人测量和葡萄糖耐量试验。在特定目标#2中，将通过多层策略评估染色体20 q上的10 Mb区域，其中该实验室先前确定了与T2D的连锁和关联，包括病例和对照中的SNP基因分型、阳性基因的重测序、发现的变体的基因分型和功能研究，以评估HNF4A邻近基因作为T2D遗传标记的贡献。在特异性目标3中，将在与特异性目标2相似的多层次分析中分析85个β细胞基因，以评估这些候选基因作为疾病遗传标志物的作用。首席研究员的实验室拥有相对独特的广泛遗传资源组合，加上胰岛生物学方面的经验，为探索基因的功能后果提供了机会，这些基因似乎是通过遗传手段确定的风险因素。识别遗传标记可能会转化为更好的诊断和治疗这种疾病。

DESCRIPTION (provided by applicant): This application seeks renewal of an ongoing grant that aims to define the genetic basis and thus the metabolic cause for the relative lack of insulin in type 2 diabetes (T2D). The proposal offers a rational strategy based on large-scale case-control genotyping of chosen genomic regions in several Caucasian populations. Among these, Ashkenazi Jews, a major focus, represent a particularly valuable population, as LD is greater and genetic heterogeneity less than in other Caucasian groups. Three specific aims are proposed. In Specific Aim 1 Ashkenazi controls (n=1000) will be collected and quantitative traits (QTs) characterized to provide adequate power for detecting low-risk alleles contributing to the T2D risk. QTs will include anthropomorphic measures and glucose tolerance testing. In Specific Aim #2, a 10Mb region on chromosome 20q where previous linkage and association with T2D was identified by this lab, will be assessed by a multi-tiered strategy including SNP genotyping in cases and controls, resequencing of positive genes, genotyping of variants discovered, and functional studies to assess the contribution of HNF4A neighboring genes as genetic markers for T2D. In-Specific Aim 3, 85 beta cell genes will be analyzed in a multi-tiered analysis similar to that of Specific Aim 2 to assess the role of these candidate genes as genetic markers for the disease. The laboratory of the principal investigator has a relatively unique combination of extensive genetic resources coupled with established experience in islet biology, providing the opportunity to explore the functional consequences of genes that appear to be risk factors as identified by genetic means. Identifying genetic markers will likely translate into better diagnosis and treatment of this disease.