Positional Cloning And Functional Study Of Susceptibility Genes Of Type 2 Diabetes In Han People Of North China

Type 2 diabetes mellitus is a highly heterogeneous polygenic disease with obvious inheritance tendency. The interplay of genetic and environmental determinants leads to the pathogenesis of the disease. As a result, searching for the susceptibility genes of type 2 diabetes has become one of the research hotspots on it. Until now, many research groups in the world have localized type 2 diabetes susceptibility genes to different chromosome regions in different ethnic populations by the method of genome screening.Our research group has been working on the localization of type 2 diabetes susceptibility genes in Han people of North China during the past few years. In the previous work of whole-genome screening in 32 type 2 diabetes pedigrees, we have localized the susceptibility loci to chromosome 1, 12, 18 and 20, respectively. Because the microsatellite markers used in the whole-genome screening distributed sparsely, the resulting genes were localized within a very large interval. We designed to conduct a second scan to narrow down the regions. In this work, we increased the type 2 diabetes pedigrees to 60 by adding 28 new ones and selected a new set of evenly-distributed microsatellite markers with higher heterozygosity in the 10 mapping regions indicated by the first screening. Three regions, 1p36.33-36.23, 1q24.3-25.1 and 1q42.12-42.13 were still shown to be linked with the disease. Especially in the 1p36.33-36.23 region, all the 5 selected markers showed the evidence of linkage, which strongly suggested that there might be susceptibility genes residing in this region.In order to clone the susceptibility genes in the 1p36.33-36.23 region, we conducted case-control study by using the third generation of genetic marker, single nucleotide polymorphism (SNP). Several candidate genes were identified in this region and 25 SNPs in the genes were selected by bioinformatic method and direct sequencing. The results showed that 3 SNPs, resided in PRKCZ, UTS2 and SLC2A5 gene respectively, might be associated with the disease. There was statistical difference of their allele frequency between case and control groups, especially the SNP rs436045 in PRKCZ gene, which showed significant discrepancy and implied possible association with the disease.