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

旧秩序阿米什人中 15q 与胰岛素水平的联系

• 批准号: 6926177
• 负责人: KRISTI SILVER
• 金额: $ 30.44万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6926177
• 关键词: Mennonite; adult human (21+); biotechnology; clinical research; diabetes mellitus genetics; family genetics; gene mutation; genetic markers; genetic susceptibility; glucose tolerance test; human genetic material tag; human subject; insulin; linkage disequilibriums; molecular cloning; noninsulin dependent diabetes mellitus; nucleic acid repetitive sequence; pancreatic islets; single nucleotide polymorphism

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.

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，其特征是同时存在 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 15q 染色体上的一个区域，该区域与 30 分钟后的胰岛素水平有关。 15q 染色体上的同一区域与日本人和墨西哥裔美国人的 T2DM 有关。我们假设至少有一个 T2DM 易感基因位于 15q 染色体上，并且该基因很可能与 β 细胞功能/胰岛素分泌有关。该拨款提案的目标是在旧秩序阿米什人群的 15q 染色体上定位克隆胰岛素分泌/T2DM 易感基因。我们相信，这一目标可以通过以下方式实现：1) 通过用更多微卫星标记饱和该区域，进一步定位我们之前检测到与胰岛素 30 连锁的证据的区域，2) 在患有 T2DM 的阿米什人和具有极端胰岛素分泌（高和低）的非糖尿病受试者亚群中筛选位置候选基因的序列变异，然后进行基于谱系的关联分析以检测连锁 不平衡和 3) 使用病例对照设计进行连锁不平衡作图。旧秩序阿米什人是此类研究的理想群体，因为他们是年轻的创始群体，并且连锁不平衡比大多数远交群体延伸更大的间隔，从而促进我们识别相关 SNP 和单倍型块以及致病突变的能力。通过鉴定参与 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，这反过来又会带来新的预防策略以及用于设计新型治疗药物的新分子靶点。