Genetics of type 1 diabetes

Abstract

Type 1 diabetes has a strong genetic component but additional environmental factors have also an essential role. This is demonstrated by the multifold rise in incidence of the disease during the last decades in most industrialized countries. The most important genes are located within the HLA region, where class II genes largely define the disease risk. This region contributes roughly half of the genetic component. Outside the HLA region INS, PTPN22, and CTLA4 were identified using candidate gene approach and subsequently recent genome-wide association studies have increased the number of risk-associated loci up to 50. Although the effects of common SNP polymorphisms in lately identified genes are small, their combined influence may still be considerable in complex pathways associated with activation of autoimmune process. The presence of rare mutants associated with disease risk has also generated enthusiasm since their identification for the first time in the IFIH1 gene, where rare mutants and deteriorating gene function are in fact strongly protective. This gene is an intracellular receptor for enterovirus RNA, and the finding suggests that enterovirus infection-associated innate immune response is important in beta-cell damage. Several alternative gene combinations may also be important in individual cases reflecting existence of different routes to beta-cell destruction. Type 1 diabetes is generated by interaction of genetic susceptibility and environmental factors. Main genetic contribution is located within the HLA class II region. In addition, up to 50 genes have been identified outside the HLA region. Rare mutants in some of these genes may have potent effects. Different gene combinations may be important in individual cases of the disease. The IFIH1 gene serving as intracellular enterovirus RNA receptor represents a possible link between virus infection and type 1 diabetes.