HLA-DPB1 polymorphisms on the MHC-extended haplotypes of families of patients with Graves' disease: two distinct HLA-DR17 haplotypes.

HLA-DPB1 polymorphisms were investigated in 217 members of 21 multiplex families of patients with Graves' disease, who had previously been haplotyped, using in vitro enzymatic DNA amplification and hybridization with sequence-specific oligonucleotide probes. Using the strategy of group-specific amplification, we were able to assign 19 DPB1 alleles with the use of 13 sequence specific oligonucleotide probes. No recombination was found between HLA-DPB1 and the HLA-DR/DQ complex in 243 informative meioses. HLA-DPB1*0401 was found to be the most common allele followed by DPB1*0101, *0201 and 0402 with allele frequencies of 0.4214, 0.1132, 0.1069 and 0.1006, respectively. Besides the strong linkage disequilibrium between HLA-DPB1*0101 allele and the HLA-B8, DR17/DQ2 haplotype; HLA-DPB1*0202 and *1101 alleles were also found to be significantly associated with HLA-B18 and DR7 with Pc < 0.001 and Pc < 0.009, respectively. HLA-DR17/DQ2 was found to be more commonly associated with HLA-DPB1*0101 on the Affected haplotypes (from family members affected with Graves' disease) while associated with DPB1*0401 on the Ab + ve haplotypes (deduced from thyroid autoantibody positive unaffected members). The differences in the frequency of this preferential association on the Affected and Ab + ve haplotypes was statistically significant (ch 2 = 10.18, df = 2, P < 0.007). Though it is rater unlikely that the HLA-DPBI polymorphism by itself could contribute a direct role towards the genetic susceptibility for the development of autoimmune thyroid disease, it could serve as a marker in identifying family members with the HLA-DR17/DQ2 haplotype who are more likely to develop Grave's disease or thyroid autoantibodies.