Fine mapping and Positional Cloning of Diabetes Genes

描述(由申请人提供)：非洲-美洲糖尿病(AADM)研究是在非洲裔美国人的西非祖先人口中确定T2 DM易感基因的主要尝试之一。通过非洲和美国研究人员之间的国际合作，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。基因组扫描的微卫星基因分型由CIDR进行。在12、19和20号染色体上观察到T2 DM的连锁，在19号染色体上观察到胰岛素的连锁，在5号染色体上观察到眼压(眼压，指示青光眼，T2 DM的眼部并发症之一)。在~2 cm的标记密度下，对T2 DM、胰岛素、血糖和眼压的连锁区域进行了精细定位。我们观察到以下显著结果：1)T2 DM：染色体5-LOD=3.13，1单位LOD支持间隔117-135 cM；2)IOP：染色体5-LOD=4.68，支持间隔105-158 cM)；3)胰岛素：染色体19-LOD=2.57，支持间隔12-33 cM。5号染色体上的T2 DM和IOP连锁区重叠。19P区同时含有胰岛素受体和抵抗素基因。5q区包含与胰岛素和瘦素受体相互作用的分类nexin 2基因，以及5q22.1上一个新的成人发病的原发开角型青光眼基因，命名为GLCIG。根据审查者的建议，我们向CIDR提交了在5号和19号染色体上进行SNP分型的申请。总共要求在460个同胞(n=1380人)中进行SNP分型，基因内密度为5-6kb，基因间区密度为11-12kb。将进行联系和以家庭为基础的联系分析。已确定的候选基因/基因座将被重新测序，并将在1000个病例和1000个对照中对功能SNPs进行分型，以进行种族匹配的关联和LD图谱研究。将评估表型/基因型关联，并在四个组中重复功能关联--尼日利亚的约鲁巴；肯尼亚的鲁伊哈；Fusion研究中的非裔美国人和芬兰人

DESCRIPTION (provided by applicant): The Africa America Diabetes Mellitus (AADM) Study represents one 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, one 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 four groups - Yoruba, Nigeria; Luyha, Kenya; African Americans and Finns in the FUSION study