Class III alleles and high-risk MHC haplotypes in type I diabetes mellitus, Graves' disease and Hashimoto's thyroiditis.

By typing a large quantity of family-based material for HLA-B, HLA-DR, C4, C2 and factor B, we were able to derive four-gene complement haplotypes (C4A, C4B, C2, BF) and six-gene MHC haplotypes (HLA-B, complement, HLA-DR). Fourteen six-gene MHC haplotypes showed linkage disequilibrium but exact frequencies could not be determined because it was not always possible to assign null C4 alleles in families where null genes were not clearly seen to segregate. Comparison of unrelated type I diabetes, Graves' disease and Hashimoto's thyroiditis patients with healthy unrelated controls revealed the following MHC allele associations: C4B3, HLA-DR3 and HLA-DR4 with type I diabetes; BFF1 and HLA-DR3 with Graves' disease; HLA-DR4 with Hashimoto's thyroiditis. By typing families of type I diabetes and Graves' disease patients we were able to derive two high-risk DR3+ MHC haplotypes for both type I diabetes and Graves' disease. These are HLA-B8 C4AQ0 C4B1 BFS HLA-DR3 and HLA-B18 C4A3 C4BQ0 BFF1 HLA-DR3, and these haplotypes account for most of the associations between these diseases and HLA-DR3. The MHC haplotype HLA-B15 C4A3 C4B3 BFS HLA-DR4 also carries high risk for type I diabetes in this group of patients. Our data suggest that other DR4+ haplotypes, probably containing C4A3 C4B1, carry increased risk for type I diabetes whereas haplotypes containing DR4 and C4 C4A3 C4BQ0 do not. Our phenotype data suggest that DR4 in Hashimoto's thyroiditis is frequently associated with HLA-B44, C4A3, C4B1 and BFS.