Non-HLA region genes in insulin dependent diabetes mellitus.

The focus of this chapter is on the contribution of genes outside the HLA region to insulin dependent diabetes mellitus (IDDM) susceptibility. We review laboratory evidence for such genes from published studies and also present unpublished data from our recent research. The existence of genes predisposing to IDDM in the region of the insulin (INS) gene now appears established. Association analysis has demonstrated an increased frequency of class 1 alleles of the 5' INS polymorphism in diabetics compared with controls, and a new method of analysis (AFBAC) has shown that this association is not an artefact of population stratification. Interestingly, the effect of INS region susceptibility on IDDM cannot be detected by linkage analysis, suggesting that if a genetic marker locus is close to a disease susceptibility locus, association analysis may be a more sensitive method than linkage analysis for detecting the susceptibility locus. There is no convincing evidence that genes in the T cell receptor beta chain (TCRB) or alpha chain (TCRA) regions influence predisposition to IDDM, either directly, or indirectly through interaction with HLA region genes. However, we present new evidence for interaction between TCRB and immunoglobulin heavy chain (Gm) region genes in IDDM: diabetics who are positive for the IgG2 allotype G2m(23) have significantly different frequencies of a TCRB restriction fragment length polymorphism (RFLP) than those who are negative for the allotype. Gm region genes also appear to have indirect effects on IDDM susceptibility through interaction with HLA and INS region genes: DR3/4 and non-DR3/4 diabetics have significantly different frequencies of G2m(23), and INS1/1 and non-INS1/1 diabetics also have significantly different frequencies of this allotype. To our knowledge, there are no other studies of Gm-TCRB or Gm-INS interaction in IDDM susceptibility. Evidence for Gm-HLA interaction in IDDM has been published by several other groups of investigators, however the specific phenotypic interaction effects reported have differed. Nevertheless, pooled data from three studies of Gm/HLA haplotype segregation in affected sib pairs shows significantly increased sharing of Gm haplotypes in affected pairs who share both HLA haplotypes. The biological mechanisms underlying the direct (HLA, INS) and indirect (Gm-TCRB, Gm-HLA, Gm-INS) effects of these genetic regions on IDDM susceptibility remain to be elucidated.