Genetics of type 1 diabetes: recent progress and future perspectives

Type 1 diabetes (T1D) is a chronic immune-mediated disease, characterised by a selective loss of insulin-producing -cells in the pancreatic islets. Susceptibility is determined by interactions of multiple genes with unknown environmental factors. Around 50% of the genetic risk of the disease is explained by HLA, although other genes with a smaller effect are also involved. Most of the known risk genes for T1D play a role in immunity, mostly through T-cell regulation (CTLA4, PTPN22, IL-2RA) and cytokine production or modulation (VDR, SUMO4) . The insulin gene (INS) represents and exception to this, and is probably the only gene specifi cally associated with T1D and not with other autoimmune diseases. Ongoing genome-wide association studies are providing evidence of multiple known and previously unknown risk genes. New analytical tools are continuously being developed to handle the vast amounts of data produced, as well as to account for multiple comparisons and assess combined effects such as gene-gene and gene-environment interactions. In this review, we will give an overview of the most important genes identifi ed to date, analyse the genetic evidence supporting them as T1D susceptibility genes and discuss the mechanisms mediating their contribution to the pathogenesis of the disease.