Positional Cloning Of A Diabetes Gene On Chromosome 11

11 号染色体上糖尿病基因的定位克隆

• 批准号: 6984166
• 负责人: Leslie J Baier
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6984166
• 关键词: Mexican Americans; Native Americans; Scandinavian; artificial chromosomes; biotechnology; body composition; caucasian American; chromosomes; clinical research; diabetes mellitus genetics; expression cloning; family genetics; genetic mapping; genetic markers; genetic polymorphism; genetic susceptibility; genotype; glucose metabolism; human genetic material tag; human subject; insulin; linkage disequilibriums; linkage mapping; microarray technology; molecular cloning; noninsulin dependent diabetes mellitus; nucleic acid sequence; phenotype; racial /ethnic difference; single nucleotide polymorphism

A prior genomic scan in Pima Indians living in the United States indicated an obesity susceptibility locus on chromosome 11q23-24 (LOD=3.6). There was also evidence that the same genomic region contained a susceptibility locus for type 2 diabetes mellitus (T2DM)(LOD=1.7). Bivariate linkage analysis for the combined phenotype diabesity gave the strongest evidence for a susceptibility locus (LOD= 5.2). Linkage to body mass index (BMI) at this precise genomic region (D11S4464) has been replicated in Caucasians from the Framingham Heart Study and in morbidly obese males in pedigrees from Utah (Myriad Genetics). The region of linkage in Pima Indians spans approximately 24 Mb. Our current goal is to positionally clone the gene(s) responsible for the linkage. Positional candidate genes across the region of linkage are being sequenced to identify genetic variants. In addition, linkage disequilibrium (LD) mapping is being used to narrow the susceptibility region. For LD mapping, single nucleotide polymorphisms (SNPs) are being systematically identified and genotyped at 25 kB intervals across the region of linkage. To date, approximately 1070 SNPs that span our region of linkage have been individually genotyped in 1229 DNA samples, and tested for association with either BMI or T2DM. Two separate regions (BIG1 and BIG2) have been preliminarily identified that contain multiple SNPs significantly associated with BMI and diabetes. To determine whether these regions truly define a susceptibilty locus or whether they represent false positive results, SNPs from both regions are being replicated in other populations. To date, multiple SNPs have been tested in the Framingham Family DNA collection, the FUSION DNA collection, the UK family collection, Mexican Americans from Starr County, and Utah Caucasians. Association results from this wide range of ethnic groups suggests that there are indeed two separate obesity susceptibility loci. One loci is common to Pima Indians, Mexican Americans, Finns (FUSION) and Framingham Caucasians. The second loci is common to Pima Indians and Utah Caucasians. These results are currently being extended by additional collaborative efforts to genotype variants in Mexican Americans from San Antonio and Finns from Botnia.

先前对居住在美国的皮马印第安人进行的基因组扫描表明，染色体 11q23-24 上有一个肥胖易感性位点 (LOD=3.6)。还有证据表明同一基因组区域包含 2 型糖尿病 (T2DM) 的易感位点 (LOD=1.7)。组合表型糖尿病的双变量连锁分析为易感位点提供了最有力的证据（LOD = 5.2）。这一精确基因组区域 (D11S4464) 与体重指数 (BMI) 的关联已在弗雷明汉心脏研究的白种人和来自犹他州 (Myriad Genetics) 谱系的病态肥胖男性中得到复制。皮马印第安人的连接区域大约有 24 Mb。我们当前的目标是按位置克隆负责连锁的基因。正在对连锁区域的位置候选基因进行测序，以鉴定遗传变异。此外，连锁不平衡（LD）图谱也被用来缩小敏感性区域。对于 LD 作图，正在以 25 kB 的间隔对整个连锁区域的单核苷酸多态性 (SNP) 进行系统鉴定和基因分型。迄今为止，已经在 1229 个 DNA 样本中对跨越我们连锁区域的约 1070 个 SNP 进行了单独基因分型，并测试了其与 BMI 或 T2DM 的关联。已初步鉴定出两个独立的区域（BIG1 和 BIG2）包含多个与 BMI 和糖尿病显着相关的 SNP。为了确定这些区域是否真正定义了易感位点，或者它们是否代表假阳性结果，来自这两个区域的 SNP 正在其他人群中复制。迄今为止，多个 SNP 已在弗雷明汉家族 DNA 收藏、FUSION DNA 收藏、英国家庭收藏、斯塔尔县墨西哥裔美国人和犹他州白种人收藏中进行了测试。来自如此广泛的种族群体的关联结果表明，确实存在两个独立的肥胖易感性位点。有一个基因座是皮马印第安人、墨西哥裔美国人、芬兰人（融合）和弗雷明汉白人所共有的。第二个基因座是皮马印第安人和犹他州白种人共有的。这些结果目前正在通过额外的合作努力来扩展，以对来自圣安东尼奥的墨西哥裔美国人和来自博特尼亚的芬兰人的基因型变异进行研究。