HLA-dependent GM effects in insulin-dependent diabetes: evidence from pairs of affected siblings

In a recent study of GM allotype frequencies in HLA-defined subsets of patients with insulin-dependent diabetes mellitus (IDDM) and similarly defined healthy sibling controls, we found evidence for an HLA-dependent GM effect on IDDM susceptibility. To circumvent problems inherent in such patient-control studies of complex diseases, we have now examined sharing of genes in the HLA and GM regions in 26 informative pairs of siblings who were both affected with IDDM. We found that: (1) in the total sample of affected sib-pairs, sharing of two HLA haplotypes was increased compared to Mendelian expectations, in agreement with many previous studies; (2) in the total sample, sharing of GM region genes (as measured by GM phenotype concordance) was not different from Mendelian expectations, given the distribution of parental mating types; and (3) affected sib-pairs who shared two HLA haplotypes showed significantly increased sharing of GM region genes compared to affected sib-pairs who shared one or zero HLA haplotypes (P = .018). These results provide new evidence for HLA-dependent effects of a locus at or near GM on susceptibility to IDDM.