Mapping T2DM Genes in GENNID Families

GENNID 家族中 T2DM 基因的定位

• 批准号: 7190576
• 负责人: Steven C Elbein
• 金额: $ 49.56万
• 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/7190576
• 关键词: Abbreviations; Acute; Affect; African American; Alleles; American; Animal Model; Body mass index; Candidate Disease Gene; Caucasians; Caucasoid Race; Chromosome Mapping; Collaborations; Collection; Complex; DNA; Data; Data Analyses; Data Set; Databases; Diabetes Mellitus; Disease; Employee Strikes; Ethnic group; Event; Family; Fasting; Frequencies; Funding; Future; Genes; Genetic; Genetic Predisposition to Disease; Genome; Genome Scan; Genotype; Glucose; Goals; Haplotypes; Hepatic; Heritability; Hispanics; Human; Hyperglycemia; IFNG gene; Impaired fasting glycaemia; Individual; Inherited; Insulin; Insulin Resistance; International; Laboratories; Lead; Linkage Disequilibrium; Lod Score; Maps; Methods; Mexican Americans; Microsatellite Repeats; Minisatellite Repeats; Minority; Modeling; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Pathogenesis; Pathway interactions; Peripheral; Physiology; Population; Predisposition; Preparation; Prevalence; Publishing; Reporting; Research; Research Personnel; Resources; Risk; Sampling; Scanning; Screening procedure; Signal Transduction; Single Nucleotide Polymorphism; Single Nucleotide Polymorphism Map; Staging; Susceptibility Gene; Tandem Repeat Sequences; Testing; United States; Update; Variant; Waist-Hip Ratio; base; calpain 10; density; genetic association; genetic pedigree; genome wide association study; glucose production; impaired glucose tolerance; insulin secretion; interest; member; response; size; transmission process

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 (T2DM) 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。绘制 T2DM 基因图谱的主要资源是由美国糖尿病协会 (GENNID) 在 1993 年至 2003 年资助的一项多中心、多种族研究中收集的，该研究涉及 6000 多名个体，其中包括 770 名非裔美国人、1180 名白人和 1190 名西班牙裔同胞。该资源中不到 1/3 已进行基因分型。我们建议使用 0.6 cM 单核苷酸多态性 (SNP) 图谱对所有样本进行完整的基因组扫描，以原始形式和经过净化的形式公开基因型、谱系和表型数据，并使用此资源来检验 T2DM 将以多个相互作用的基因座为特征的假设，其中一些是种族特异性的，另一些是跨种族的。 5 个具体目标将包括 1) 基因组扫描的样本和数据准备； 2) 使用应用于完整数据集和种族特定数据的多点受影响同胞对方法分析基因组扫描数据，以及二级参数、有序子集和交互分析； 3) 使用密集 (100 kb) SNP 图谱对多达 12 个新区域的连锁峰进行精细定位，并对精细图谱数据进行重新分析； 4) 在初始 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映射数据； 5) 通过从公共数据库中选择 tagSNP 并在需要时进行基因筛选，对每个连锁峰下可能的易感基因进行位置候选基因搜索。我们将使用密集的 SNP 图谱测试基于家族的关联，并测试来自 GENNID 家族的 400-500 个不相关病例和 400-500 个对照的关联。这些研究将为未来确定已知候选基因中的致病突变或使用连锁不平衡来确定其他 T2DM 易感位点的提议奠定基础。拟议的研究将确定增加个体​​患 2 型糖尿病风险的特定基因，并将确定美国主要种族群体糖尿病患病率的显着差异是否可以部分由风险基因的不同频率来解释。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，这反过来可能会导致针对特定遗传缺陷或种族特定途径的 2 型糖尿病新疗法。