Mapping T2DM Genes in GENNID Families

GENNID 家族中 T2DM 基因的定位

• 批准号: 7030494
• 负责人: Steven C Elbein
• 金额: $ 54.33万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7030494
• 关键词: clinical research; diabetes mellitus genetics; diabetes risk; family genetics; genetic mapping; genetic screening; genetic susceptibility; human data; human genetic material tag; human tissue; noninsulin dependent diabetes mellitus; racial /ethnic difference; single nucleotide polymorphism

DESCRIPTION (provided by applicant): Compelling data support a genetic basis for type 2 diabetes (T2DM), and completed genome scans suggest at least 7 likely susceptibility regions. A major resource to map genes for T2DM was assembled in a multicenter, multiethnic study funded by the American Diabetes Association (GENNID) from 1993-2003 which comprises over 6000 individuals including 770 African-American, 1180 Caucasian, and 1190 Hispanic sib pairs. Under 1/3 of this resource has been genotyped. We propose a complete genome scan on all samples using a 0.6 cM single nucleotide polymorphism (SNP) map, to make the genotype, pedigree, and phenotypic data publicly available in both raw and cleaned forms, and to use this resource to test the hypothesis that T2DM will be characterized by multiple interacting loci, some that are ethnic-specific and others that will cross ethnic groups. The 5 Specific Aims will include 1) sample and data preparation for the genome scan; 2) analysis of the genome scan data using multipoint affected sib pair methods applied to both the full data set and ethnic-specific data, along with secondary parametric, ordered subset, and interaction analyses; 3) fine mapping of linkage peaks with dense (100 kb) SNP maps across up to 12 new regions and reanalysis of the fine map data; 4) distribution of initial and fine mapping data to all interested diabetes investigators upon initialCIDR release and at each stage of cleaning or new data analysis; and 5) a positional candidate gene search for likely susceptibility genes under each linkage peak by choosing tagSNPs from public databases and gene screening where needed. We will test for family based association using the dense SNP map, and for an association in 400-500 unrelated cases drawn from GENNID families and 400- 500 controls. These studies will provide the basis for future proposals to identify the causative mutations in known candidate genes or to use linkage disequilibrium to identify additional T2DM susceptibility loci. The proposed studies will identify the specific genes that increase an individual's risk of getting type 2 diabetes, and will determine whether striking differences in diabetes prevalence across major United States ethnic groups can be explained in part by different frequencies of risk genes. These studies will determine whether different pathways cause type 2 diabetes in different ethnic groups, which in turn may lead to new therapies for type 2 diabetes that may target specific genetic defects or ethnic-specific pathways.

描述(由申请人提供)：令人信服的数据支持2型糖尿病(T2 DM)的遗传基础，完整的基因组扫描表明至少有7个可能的易感区域。一项由美国糖尿病协会(GENNID)在1993-2003年间资助的多中心、多种族研究汇集了一项绘制T2 DM基因图谱的主要资源，该研究包括6000多人，其中包括770对非裔美国人、1180对高加索人和1190对西班牙裔同胞。不到1/3的资源已经进行了基因分型。我们建议使用0.6 cM的单核苷酸多态(SNP)图谱对所有样本进行完整的基因组扫描，以使原始形式和净化形式的基因型、系谱和表型数据公开，并使用该资源来检验T2 DM将由多个相互作用的基因座表征的假设，其中一些是种族特有的，另一些将跨种族群体。5个具体目标将包括1)基因组扫描的样本和数据准备；2)使用适用于全部数据集和特定种族数据的多点受影响同胞对方法分析基因组扫描数据，以及次级参数、有序子集和相互作用分析；3)利用高达12个新区域的密集(100 Kb)SNP图谱精细绘制连锁峰，并重新分析精细图谱数据；4)在最初CIDR发布时以及在清理或新数据分析的每个阶段，向所有感兴趣的糖尿病研究人员分发初始和精细图谱数据；5)通过从公共数据库中选择标签SNP并在需要的地方进行基因筛选，在每个连锁高峰下定位候选基因以寻找可能的易感基因。我们将使用密集的SNP图谱测试基于家族的关联性，并在来自GENNID家族和400-500个对照的400-500个无关病例中测试关联性。这些研究将为将来提出识别已知候选基因的致病突变或利用连锁不平衡来识别额外的T2 DM易感基因座提供基础。这项拟议中的研究将确定增加个人患2型糖尿病风险的特定基因，并将确定美国主要种族之间糖尿病患病率的显著差异是否可以部分解释为风险基因的不同频率。这些研究将确定不同的途径是否会导致不同种族的2型糖尿病，这反过来可能导致针对特定遗传缺陷或种族特定途径的2型糖尿病的新疗法。