Search for Type 2 Diabetes Susceptibility Genes Using Multiple Approaches

Sammanfattning: Type 2 diabetes mellitus is a multifactorial disorder characterized by chronic hyperglycemia resulting from pancreatic dysfunction and insulin resistance. It is a common disorder with a complex pattern of inheritance, likely to reflect the influence of multiple genetic and environmental factors on the diabetes risk. The aim of thesis was to identify genetic risk factors for type 2 diabetes. In a genome wide scan, we identified three putative type 2 diabetes susceptibility loci on chromosomes 9p13-q21, 12q24 and 17p12-q12. Five SNPs in ANXA1, on chromosome 9q21 were identified and tested for association to type 2 diabetes in using the TDT. As no significant association with diabetes was observed, we concluded that the gene is unlikely to be a type 2 diabetes susceptibility gene. We also investigated the contribution of known and unknown genetic causes in families enriched with early onset diabetes. We found that about 25% of diabetes in our families could be explained by known genetic variants. In a subsequent genome wide scan we found three putative EOD susceptibility loci on chromosomes 1p31.11, 20q11 and 22q11-13. We also looked at gene expression profiles from skeletal muscle biopsies from subjects with normal glucose tolerance compared to individuals with hyperglyceamia as well as biopsies taken before and after an euglycemic hyperinsulinemic clamp using microarrays. We identified 131 genes that show differential expression (SNR > 2) between the glycemic stages and 86 genes that show differential expression as an acute insulin response. In summary, we have identified several putative diabetes susceptibility loci and genes. In light of the large number of genetic markers available, along with new knowledge about the haplotype structure of the genome, we plan to further examine these loci and genes with extensive LD mapping in an attempt to identify and confirm genetic causes for type 2 diabetes mellitus.