Fine mapping and Positional Cloning of Diabetes Genes

点击翻译按钮获取中文摘要

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