HLA antigens and susceptibility to juvenile diabetes: do additive relative risks imply genetic heterogeneity?

The relative risk of B8/B15 heterozygotes for juvenile-onset diabetes is higher than the risk for people having B8 or B15 alone. This has been cited as evidence for genetic heterogeneity in juvenile diabetes. However, the observed relative risks are compatible with a single susceptibility allele. If disease susceptibility is recessive, for example, then an individual with two disease associated antigens is more likely to be susceptible than an individual with only one associated antigen. The relative risk for an HLA heterozygote should be intermediate between that of the respective homozygotes, so that an interaction effect of two alleles can only be supported if the heterozygote risk is significantly greater than both homozygote risks. The estimated relative risks for B8 and B15 homozygotes, based on data from four different populations, is approximately equal to the risk for B8/B15 heterozygotes. Moreover, disease manifestations which are differentially associated with B8 and B15, such as antibody production to exogenous insulin, may be due to linkage disequilibrium between HLA and other loci which are not directly related to susceptibility of juvenile diabetes. Therefore, while the susceptibility to juvenile diabetes may have several genetic forms, there is no support for distinct B8-associated and B15-associated forms of susceptibility.