Mapping T2DM Genes in GENNID Families

GENNID 家族中 T2DM 基因的定位

• 批准号: 7386623
• 负责人: Steven C Elbein
• 金额: $ 49.46万
• 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/7386623
• 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

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 susceptiblity 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.

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 7 个可能的易感区域。绘制 T2DM 基因图谱的主要资源是在 1993-2003 年由美国糖尿病协会 (GENNID) 资助的多中心、多种族研究 其中包括 6000 多人，其中包括 770 名非裔美国人、1180 名白人和 1190 名西班牙裔 同胞对。该资源中不到 1/3 已进行基因分型。我们建议对所有患者进行完整的基因组扫描 使用 0.6 cM 单核苷酸多态性 (SNP) 图谱对样本进行基因型、谱系和 以原始形式和经过净化的形式公开提供的表型数据，并使用此资源来测试 假设 T2DM 的特征是多个相互作用的基因座，其中一些是种族特异性的， 其他将跨越种族群体。 5 个具体目标将包括 1) 样品和数据准备 基因组扫描； 2) 使用应用于两者的多点受影响同胞对方法分析基因组扫描数据 完整的数据集和特定种族的数据，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绘制 精细地图数据的重新分析； 4) 将初始和精细绘图数据分发给所有感兴趣的糖尿病 初始 CIDR 发布以及清理或新数据分析的每个阶段的调查员； 5) 位置 通过选择 tagSNP，在每个连锁峰下候选基因搜索可能的易感基因 公共数据库和基因筛查（如有需要）。我们将使用以下方法测试基于家庭的关联 密集的 SNP 图，以及来自 GENNID 家族的 400-500 个不相关病例和 400- 500 个控制。这些研究将为未来确定致病突变的建议提供基础。 已知的候选基因或使用连锁不平衡来识别其他 T2DM 易感位点。这 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的糖尿病患病率是否存在显着差异 不同的群体可以部分地通过风险基因的不同频率来解释。这些研究将决定是否 不同的途径导致不同种族的2型糖尿病，这反过来可能会带来新的治疗方法 针对 2 型糖尿病，可能针对特定的遗传缺陷或种族特定的途径。