Fine mapping and Positional Cloning of Diabetes Genes

描述（由申请方提供）：非裔美国人糖尿病（AADM）研究代表了在非洲裔美国人的西非祖先人群中鉴定T2 DM易感基因的主要尝试之一。通过非洲和美国研究者之间的国际合作，对来自尼日利亚和加纳的受影响同胞对（ASP）进行了人口统计学、临床和生化测量。通过CIDR进行用于基因组扫描的微卫星基因分型。在染色体12、19和20上观察到T2 DM的连锁，在染色体19上观察到胰岛素的连锁，在染色体5上观察到眼内压（IOP，表明青光眼，T2 DM的眼部并发症之一）的连锁。对T2 DM、胰岛素、葡萄糖和IOP的连锁区域进行了精细定位，标记密度约为2cM。我们观察到以下显著结果：1）T2 DM：染色体5-LOD=3.13，1个单位LOD支持区间117-135 cM; 2）IOP：染色体5- LOD=4.68，支持区间105-158 cM; 3）胰岛素：染色体19-LOD=2.57，支持区间12-33 cM。5号染色体上的T2 DM和IOP连锁区域重叠。19 p区域包含胰岛素受体和胰岛素受体基因。5 q区域包含与胰岛素和瘦素受体相互作用的分选连接蛋白2基因，以及5q22.1上的新的成人发病原发性开角型青光眼位点，命名为GLCIG。根据评审员的建议，我们向CIDR提交了对5号和19号染色体进行SNP分型的申请。在460个同胞（n=1380人）中，共4,608个SNP，基因内的密度为5-6 kb，基因间区域的密度为11-12 kb。将进行连锁和基于家族的关联分析。将对1000例病例和1000例对照中识别的候选基因/位点进行重新测序，并对功能性SNP进行分型，以进行种族匹配的关联和LD作图研究。将评估表型/基因型相关性，并在4组中重复功能相关性-约鲁巴人，尼日利亚; Luyha，肯尼亚; FUSION研究中的非洲裔美国人和芬兰人。

DESCRIPTION (provided by applicant): The African American Diabetes Mellitus (AADM) Study represents 1 of the primary attempts to identify T2DM susceptibility genes in West African ancestral populations of African-Americans. Through an international collaboration between African and US investigators, affected sib-pairs (ASP) from Nigeria and Ghana were characterized for demographic, clinical, and biochemical measurements. Microsatellite genotyping for a genome scan was conducted by CIDR. Linkage was observed for T2DM on chromosomes 12, 19 and 20, for insulin on chromosome 19 and for intraocular pressure (IOP, indicative of glaucoma, 1 of the eye complications of T2DM) on chromosome 5. Fine mapping, at~2 cM marker density, of the linkage regions forT2DM, insulin, glucose, and IOP was performed. We observed the following notable results: 1) T2DM: chromosome 5-LOD=3.13, 1 unit LOD support interval 117-135 cM; 2) IOP: chromosome 5- LOD=4.68, support interval 105-158 cM); and 3) insulin: chromosome 19-LOD=2.57, support interval 12-33 cM. The T2DM and the IOP linkage regions on chromosome 5 overlap. The 19p region contains both the insulin receptor and resistin genes. The 5q region contains the Sorting Nexin 2 gene which interacts with insulin and leptin receptors, as well as a new adult-onset primary open-angle glaucoma locus on 5q22.1 designated GLCIG. Following reviewers' advice, we submitted an application to CIDR to conduct SNP typing on chromosome 5 and 19. A total of 4,608 SNPs in 460 sibships (n=1380 persons) at a density of 5-6 kb within genes and 11-12 kb for intergenic regions was requested. Linkage and family-based association analyses will be conducted. Identified candidate genes/loci will be re-sequenced and functional SNPs will be typed in 1000 cases and 1000 controls to perform ethnically matched association and LD mapping studies. Phenotype/genotype association will be assessed and functional associations will be repeated in 4 groups-Yoruba, Nigeria; Luyha, Kenya; African Americans and Finns in the FUSION study.