A functional analysis of the IDDM2 susceptibility locus in type 1 diabetes /

Type 1 diabetes is an autoimmune disease characterized by destruction of the insulin-producing pancreatic beta-cells. Genetic predisposition, encoded by a number of loci, plays a large role in the probability of disease development. The IDDM2 susceptibility locus maps to the insulin gene (INS) variable number of tandem repeats (VNTR) minisatellite, which has two main clusters of alleles. As a whole, alleles of the class III cluster reduce the probability of developing type 1 diabetes and those of the class I cluster predispose to type 1 diabetes. To determine the functional basis of this susceptibility and protection, we tested the hypothesis that the IDDM2 effect is mediated through INS VNTR effects on transcription levels of the nearby INS and insulin-like growth factor 2 (IGF2) genes, in tissues known to be of importance in the pathogenesis of the disease. We have found evidence to suggest that protective INS VNTR alleles are associated with different levels of INS expression in the thymus than predisposing alleles, and that these levels correlate with the level of protection conferred by the INS VNTR alleles in population studies. Thus, alleles associated with high expression are protective, while alleles associated with no expression are very predisposing. This suggests that IDDM2-encoded susceptibility is mediated, at least in part, through variable expression of thymic INS which may in turn affect the efficiency of central immune tolerance induction to INS-encoded antigenic epitopes and the probability of an autoimmune response against the beta-cells. Furthermore, we did not detect any significant difference in IGF2 mRNA levels associated with the protective INS VNTR class of alleles as compared to the predisposing class in thymus, pancreas and leukocytes. This argues against IGF2 as a target gene through which INS VNTR alleles mediate susceptibility to type 1 diabetes