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

描述（由申请人提供）：2型糖尿病（T2DM）是一种多基因异质性疾病，具有大量遗传成分，其特征是存在β细胞功能障碍和胰岛素抵抗。我们在旧秩序阿米什人的口服葡萄糖耐量测试中发现了染色体15q上的一个区域与30分钟内的胰岛素水平有关。15q染色体上的同一区域与日裔和墨西哥裔美国人的2型糖尿病有关。我们假设至少有一个T2DM易感基因位于染色体15q上，该基因可能与β细胞功能/胰岛素分泌有关。这项拨款提案的目标是在Old Order Amish人群中定位克隆染色体15q上的胰岛素分泌/ 2型糖尿病易感基因。我们相信这一目标可以通过以下方式实现：1)进一步定位我们之前发现的与胰岛素30相关的区域，通过更多的微卫星标记使该区域饱和；2)筛选Amish 2型糖尿病患者和非糖尿病患者（胰岛素分泌极端（高和低））序列变异的位置候选基因；然后使用病例对照设计进行基于系谱的关联分析以检测连锁不平衡和3)连锁不平衡映射。旧秩序阿米什人是这类研究的理想群体，因为他们是一个年轻的创始群体，与大多数近亲繁殖群体相比，连锁不平衡扩展的间隔更大，因此有助于我们识别相关的snp和单倍型块，进而识别致病突变。通过识别参与T2DM发展的易感基因，我们将为T2DM的分子、细胞和病理生理机制提供重要的见解，从而为设计新的治疗药物提供新的预防策略和新的分子靶点。

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.