Linkage if 15q to Insulin Levels in the Old Order Amish

描述（由申请人提供）：2型糖尿病（T2 DM）是一种多基因异质性疾病，具有大量遗传成分，其特征是同时存在β细胞功能障碍和胰岛素抵抗。我们已经确定了染色体15 q上的一个区域，该区域与旧秩序阿米什人口服葡萄糖耐量试验30分钟时的胰岛素水平有关。染色体15 q上的同一区域与日本人和墨西哥裔美国人的T2 DM有关。我们假设至少有一个T2 DM易感基因位于染色体15 q上，并且该基因可能与β细胞功能/胰岛素分泌有关。这项资助提案的目标是在旧秩序阿米什人中定位克隆染色体15 q上的胰岛素分泌/T2 DM易感基因。我们相信，这一目标可以通过以下方式实现：1）通过用更多的微卫星标记使该区域饱和，进一步定位我们先前检测到与胰岛素30连锁的证据的区域，2）在患有T2 DM的阿米什人和具有极端胰岛素分泌的非糖尿病受试者的子集中筛选位置候选基因的序列变异（高和低），然后进行基于家系的关联分析以检测连锁不平衡和3）使用病例对照设计的连锁不平衡作图。旧秩序阿米什人是这种类型的研究的理想人群，因为他们是一个年轻的创始人人口和连锁不平衡延伸超过更大的间隔比大多数远系繁殖的人口，从而促进我们的能力，以确定相关的SNP和单倍型块，进而致病突变（S）。通过鉴定与T2 DM发生相关的易感基因，我们将为T2 DM的分子、细胞和病理生理机制提供重要见解，这反过来又将为新型治疗药物的设计带来新的预防策略以及新的分子靶点。

DESCRIPTION (provided by applicant): Type 2 diabetes mellitus (T2DM) is a polygenic, heterogeneous disorder with a large inherited component that is characterized by the presence of both beta cell dysfunction and insulin resistance. We have identified a region on chromosome 15q that is linked to insulin levels at 30 minutes on an oral glucose tolerance test in the Old Order Amish. This same region on chromosome 15q has been link to T2DM in Japanese and Mexican Americans. We hypothesize that at least one T2DM susceptibility gene resides on chromosome 15q and it is likely that the gene(s) is involved with beta cell function/insulin secretion. The goal of this grant proposal is to positionally clone the insulin secretion/T2DM susceptibility gene(s) on chromosome 15q in the Old Order Amish population. We believe that this goal can be achieved by 1) further localizing the region to which we have previously detected evidence for linkage to insulin 30 through saturation of this area with more microsatellite markers, 2) screening positional candidate genes for sequence variation in subsets of Amish with T2DM and nondiabetic subjects with extremes of insulin secretion (high and low), and then performing pedigree-based association analyses to detect linkage disequilibrium and 3) linkage disequilibrium mapping using a case control design. The Old Order Amish are an ideal population for this type of study as they are a young founder population and linkage disequilibrium extends over larger intervals than in most outbred populations, thus facilitating our ability to identify associated SNPs and haplotype blocks and in turn the pathogenic mutation(s). By identifying susceptibility genes involved in the development of T2DM, we will provide critical insights into the molecular, cellular, and pathophysiological mechanisms underlying T2DM which in turn will lead to new preventative strategies as well as new molecular targets for the design of novel therapeutic agents.