HLA-ENCODED GENETIC PREDISPOSITION IN IDDM - DR4 SUBTYPES MAY BE ASSOCIATED WITH DIFFERENT DEGREES OF PROTECTION

Recent studies have shown that the risk conferred by the high-risk DOA 103-DQB1*0302 (DQ8) haplotype is modified by the DRB1*04 allele that is also carried by this haplotype. However, many of these studies suff er from lack of sufficient numbers of DQ-matched control subjects, whi ch are necessary because there is a strong linkage disequilibrium betw een genes in the HLA complex. In the present study, using a large mate rial of IDDM patients and DQ-matched control subjects, we have address ed the contribution of DR4 subtypes to IDDM susceptibility. Our data, together with recent data from others, clearly demonstrate that some D R4-DQ8 haplotypes are associated with disease susceptibility, while ot hers are associated with protection, depending on the DRB104 allele c arried by the same haplotype. In particular, our data demonstrate that DRB10401 confers a higher risk than DRB1*0404. Based on combined ava ilable data on the genetic susceptibility encoded by various DR4-DQ8 h aplotypes and the amino acid composition of the involved DR beta 04 ch ains as well as the ligand motifs for these DR4 subtypes, we have deve loped a unifying hypothesis explaining the different risks associated with different DR4-DQ8 haplotypes. We suggest that disease susceptibil ity is mainly conferred by DQ8 while DR4 sub-types confer different de grees of protection. Some DR4 subtypes (i.e., DRB10405, 0402, and 040 1) confer little or no protection, while others (i.e., DRB10404, 0403 , and 0406) cause an increasing degree of protection, possibly by bind ing a common protective peptide. Features of a protective peptide that fit such a model are briefly discussed.