Cellular and molecular pathogenesis of type 1A diabetes.

Type 1A diabetes is an organ-specific autoimmune disease resulting from destruction of insulin-producing pancreatic beta-cells. The main susceptibility genes code for polymorphic HLA molecules and in particular alleles of class II MHC genes (DR, DQ and DP). Polymorphisms of individual genes outside the MHC also contribute to diabetes risk but recent evidence suggests that there are additional non-HLA genes determining susceptibility linked to the MHC. It is now possible using genetic and autoantibody assays to predict the development of type 1A diabetes in the majority of individuals, and trials of diabetes prevention are underway.

A polymorphism in the promoter region of the gene for interleukin-6 is associated with susceptibility to type 1 diabetes mellitus.

Type 1 diabetes mellitus is an autoimmune disease characterized by the destruction of the insulin-producing islet beta cells. It is likely that several genetic and environmental factors contribute to this process. There is increasing evidence showing that polymorphisms in cytokine genes may play an important role in modifying the immune response. Interleukin-6 (IL-6) is a cytokine that has been implicated in a number of immune-mediated diseases. Further, there is a polymorphism at position -174 (G(-174)C) of the promoter region of the IL-6 gene that may alter the expression of the gene. In this study, the G(-174)C polymorphism was investigated in 257 Caucasoid patients with type 1 diabetes, 53 two-parent-proband trios, and 120 normal, healthy controls. DNA was amplified using amplimers that flank the G(-174)C site, and the products were digested with the restriction endonuclease NlaIII to detect the G or the C allele. The homozygous G,G(-174) genotype was increased in the patients compared with the normal controls (50.6% vs. 33.3%, p < 0.002), with a decrease in the C,C genotype in the patients compared with the controls (12.5% vs. 24.2%, respectively, p < 0.004). In the 53 trios studied, the G allele was transmitted in 29 of 53 informative meioses. There was no association with age at onset of diabetes or the presence of diabetic complications. In conclusion, these results suggest that the IL-6 gene may contribute to the genetic susceptibility to type 1 diabetes.