The international 1q type 2 diabetes consortium

这项研究的目的是识别糖尿病易感基因，将其映射到 染色体1Q。染色体1q21-25的25Mb区域是目标区域，因为它包含一个极端的 复制良好的2型糖尿病连锁信号，现在在一系列人群中进行的扫描中检测到 包括欧洲人、东亚人、美洲原住民和非裔美国人。假设是 测试表明，这种复制的连锁反映了一个或多个易感基因的作用 对多民族人群2型糖尿病遗传易感性的影响。未来的战略是 采用了系统的、高密度的连锁不平衡作图和详尽的研究相结合的方法 选定的职位候选人。这项提议来自一个独特的国际联盟，该联盟与临床 以及代表具有最有力证据的人群的基础调查人员，这些证据表明1Q与专业知识有关 高通量基因组学、信息学和国际血型图谱领先群体的统计 项目。因此，该联盟在应用基因分型方面的最新进展方面处于有利地位。 技术、信息学和对人类序列变异的理解分析无与伦比 临床资源。对4000多个样本的3000个1Q单核苷酸多态性的初步数据进行了分析 确定了几个与糖尿病有重复关联的基因。我们的具体目标是： 1.完成对整个第一季度感兴趣区域的间接联系不平衡调查 设计了一轮基因分型，以确保全面捕捉共同变异的影响； 2.跟踪通过进一步的SNPs分析和更大的临床样本检测到的关联信号； 3.通过开发专门的数据库，将在生物学背景下获得的关联数据结合起来 信息学工具，并使用这些工具来实现对生物候选的系统评估 区域转录并支持对多态复制的搜索； 4.对这样确定的基因进行直接、全面的分析，以确定致病变种的特征。 识别负责连锁信号的特定变异体(S)将增进我们对 2型糖尿病发生发展过程中的基本分子事件。此信息将 有助于这种疾病的临床治疗方面的未来诊断和治疗进展。

The objective of the research in this application is to identify diabetes-susceptibility genes mapping to chromosome 1q. A 25Mb region of chromosome 1q21-25 has been targeted since it contains an extremely well-replicated type 2 diabetes linkage signal, now detected in scans performedin a range of populations including those of European, East Asian, Native Americanand African Americanorigin. The hypothesis to be tested is that this replicated linkage reflectsthe action of one or more susceptibility genes capable of influencing the inherited predisposition to type 2 diabetes in multiple ethnic groups. The strategy to be adopted combines systematic, high-density linkage disequilibrium mapping with exhaustive examination of selected positional candidates. The proposal comesfrom a unique international consortium that allies clinical and basic investigators representing populations with the strongest evidence for 1q linkage with expertise in high-throughput genomics, informatics and statistics from leading groups in the International HapMap project. This consortium is therefore powerfully-placed to apply the latest developments in genotyping technology, informatics and the understanding of human sequence variation to analysis of unparalleled clinical resources. Analysis of preliminary data from 3000 1q SNPs typed for over 4000 samples has already identified several genes showing replicated associations with diabetes. Our specific aims are: 1. to complete the indirect linkage disequilbrium survey of the entire 1q region of interest through a final round of genotyping designed to ensure comprehensive capture of the effects of common variation; 2. to follow up the association signals detected through analysis of further SNPs and larger clinical samples; 3. to integrate the association data obtained in its biological context through development of dedicated informatics tools, and to use these tools to enable a systematic evaluation of the biological candidacy of regional transcripts and to support a search for polymorphic duplications; 4. to undertake direct, comprehensive analysis of the genes so identified to characterize etiological variants. Identification of the specific variant(s) responsible for the linkage signal will enhance our understanding of the fundamental molecular events involved in the development of type 2 diabetes. This information will contribute to future diagnostic and therapeutic advances in the clinical management of this condition.