The international 1q type 2 diabetes consortium

描述（由申请人提供）：本申请的研究目的是确定1q染色体上的糖尿病易感基因。染色体1q21-25的一个25Mb区域已经成为研究的目标，因为它包含一个复制非常好的2型糖尿病连锁信号，现在在包括欧洲人、东亚人、美洲原住民和非洲裔美国人在内的一系列人群中进行了扫描。有待检验的假设是，这种重复的联系反映了一个或多个易感基因的作用，这些易感基因能够影响多个种族群体对2型糖尿病的遗传易感性。所采用的策略结合了系统的、高密度的联动不平衡映射和对选定位置候选者的详尽检查。该提案来自一个独特的国际联盟，该联盟将临床和基础研究人员与高通量基因组学、信息学和统计学方面的专家联合起来，这些专家来自国际HapMap项目的领先团队，他们代表了1q关联的最有力证据。因此，该联盟在应用基因分型技术、信息学和对人类序列变异的理解的最新发展来分析无与伦比的临床资源方面具有强大的优势。对4000多个样本的3000个1q snp分型的初步数据分析已经确定了几个与糖尿病重复相关的基因。我们的具体目标是：1。通过最后一轮基因分型来完成整个1q区域的间接连锁不平衡调查，以确保全面捕获共同变异的影响；2. 通过分析更多的snp和更大的临床样本，跟踪检测到的关联信号；3. 通过开发专用信息学工具，整合在其生物学背景下获得的关联数据，并使用这些工具对区域转录本的生物学候选性进行系统评估，并支持对多态性复制的搜索；4. 对已鉴定的基因进行直接、全面的分析，以确定病因变异的特征。确定与连锁信号有关的特定变异将增强我们对2型糖尿病发展中涉及的基本分子事件的理解。这一信息将有助于未来的诊断和治疗进展的临床管理这种情况。

DESCRIPTION (provided by applicant): 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 performed in a range of populations including those of European, East Asian, Native American and African American origin. The hypothesis to be tested is that this replicated linkage reflects the 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 comes from 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 disequilibrium 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.