HIA GENOTYPING AND RISK OF DIABETES: 12

Five different HLA-loci were tested in 53 families with one or more diabetic children. The alleles B15, B18, Cw3, Cw5, BfF1, DRw3, DRw4 were increased in diabetics, and significantly higher frequencies were found for several haplotypes with stronger linkage disequilibrium than in the control population. The strongest associations occured with the DRw3 and DRw4 alleles, suggesting the existence of several "high risk axes" carrying the diabetogenic gene (s) closely linked to the DR-locus. The excess of HLA-identity in multiple affected siblings of 12 families is in agreement with a recessive transmission. Yet the lack of homozygosity does not support a single-gene hypothesis. Moreover, the highly signficant excess heterozygosity DRw3/DRw4 in diabetics (32 %, p < 0.001) provides evidence for a pseudorecessive mechanism, two complementary acting genes being linked to each of the DR-alleles. In conclusion, the low frequency of DRw3/DRw4 heterozygotes in healthy siblings of diabetics (10 %) and their absence in controls, attribute the highest risk of diabetes to related as well as unrelated carriers of this combination.(Relative risk = 5.3 and 46.6, respectively)