Fine mapping and Positional Cloning of Diabetes Genes

描述（由申请人提供）：非洲-美洲糖尿病（AADM）研究是鉴定西非非洲裔美国人祖先人群中2型糖尿病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，来自尼日利亚和加纳的受影响兄弟姐妹对（ASP）进行了人口统计学、临床和生化测量。由CIDR进行基因组扫描的微卫星基因分型。在第12、19和20染色体上观察到T2DM的连锁，在第19染色体上观察到胰岛素的连锁，在第5染色体上观察到眼压（IOP，表明青光眼，T2DM的眼部并发症之一）的连锁。在约2 cM的标记密度下，对for2dm、胰岛素、葡萄糖和IOP的连锁区域进行精细定位。我们观察到以下显著结果：1)T2DM: 5号染色体- LOD=3.13, 1单位LOD支持间隔117-135 cM；2) IOP: 5号染色体- LOD=4.68，支撑间距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T2DM和IOP连锁区重叠。19p区包含胰岛素受体和抵抗素基因。5q区域包含与胰岛素和瘦素受体相互作用的排序连接蛋白2基因，以及5q22.1上一个新的成人发病原发性开角型青光眼位点GLCIG。根据审稿人的建议，我们向CIDR提交了对5号染色体和19号染色体进行SNP分型的申请。在460个兄弟姐妹（n=1380人）中，基因内密度为5-6 kb，基因间密度为11-12 kb，共获得4608个snp。将进行联系和基于家庭的关联分析。将对已确定的候选基因/位点进行重新测序，并对1000例病例和1000例对照进行功能snp分型，以进行种族匹配关联和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：尼日利亚约鲁巴；Luyha,肯尼亚;非裔美国人和芬兰人在FUSION研究中

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