The genetics of susceptibility to insulin-dependent diabetes mellitus--possible new markers

Abstract

It is well established that the HLA-DR3 and HLA-DR4 genes at the HLA-DR locus on chromosome 6 are strongly associated with increased susceptibility to insulin-dependent diabetes, and that the predisposition is greatest among individuals who possess both of these genes (that is, are HLA-DR3/4 heterozygotes). We report evidence from our Alberta study that the HLA-DR1 gene is also associated with increased susceptibility, primarily when it occurs in heterozygous combination with HLA-DR4 (frequency of HLA-DR1/4 heterozygotes among diabetics: expected = 3%, observed = 11%, p = 0.03). In addition, we report evidence that genes in the region of the GM locus on chromosome 14 also influence susceptibility by interacting with HLA-DR region genes. Alberta diabetics who were HLA-DR3/4 heterozygotes had an increased frequency of the G1m(1) antigen and the G1m(2) antigen compared with non-DR3/4 diabetics; the latter increase was statistically significant (p = .025). When data from all three previously published studies, our Alberta study, and an unpublished American study were pooled. HLA-DR3/4 diabetics had significantly increased frequencies of both G1m(1) (p = 0.001) and G1m(2) (p = 0.014). Finally, we report possible evidence (not statistically significant) that genes in the region of the KM locus on chromosome 2 may exert HLA-dependent effects on susceptibility to diabetes: in our Alberta study and the one other study which employed control subjects, DR4-positive diabetics had higher frequencies of Km(1) than either DR4-positive controls or DR4-negative diabetics.