Metabolic Basis of Type 2 Diabetes Mellitus: a Genetic Analysis

描述(由申请人提供)：本申请寻求续期一项正在进行的资助，旨在确定2型糖尿病(T2D)相对缺乏胰岛素的遗传基础和代谢原因。该建议提供了一种合理的策略，基于对几个高加索人群中选定的基因组区域进行大规模病例对照基因分型。在这些人中，主要集中的德系犹太人代表了一个特别有价值的群体，因为LD比其他高加索群体更大，遗传异质性更小。提出了三个具体目标。在具体目标1中，将收集德裔对照(n=1000)和数量性状(QT)，以提供足够的能力来检测导致T2D风险的低风险等位基因。QTS将包括拟人化测量和葡萄糖耐量测试。在特定的目标#2中，本实验室确定了染色体20Q上先前与T2D连锁和关联的10Mb区域，将通过多层次策略进行评估，包括病例和对照的SNP基因分型、阳性基因的重新测序、已发现的变异体的基因分型以及评估HNF4a邻近基因作为T2D遗传标记的作用。在特定的AIM 3，85个β细胞基因将在类似于特定的AIM 2的多层次分析中被分析，以评估这些候选基因作为疾病的遗传标记的作用。首席研究人员的实验室拥有相对独特的组合，既有广泛的遗传资源，又有在胰岛生物学方面的既定经验，为探索由遗传手段确定的似乎是危险因素的基因的功能后果提供了机会。识别遗传标记可能会转化为对这种疾病的更好诊断和治疗。

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.