Recent studies have shown that the risk conferred by the high-risk DQAl*03-DQBl*0302 (DQ8) haplotype is modified by the DRB1*O4 allele that is also carried by this haplotype. However, many of these studies suffer from lack of sufficient numbers of DQ-matched control subjects, which are necessary because there is a strong linkage disequilibrium between genes in the HLA complex. In the present study, using a large material of IDDM patients and DQ-matched control subjects, we have addressed the contribution of DR4 subtypes to IDDM susceptibility. Our data, together with recent data from others, clearly demonstrate that some DR4-DQ8 haplotypes are associated with disease susceptibility, while others are associated with protection, depending on the DRB1*O4 allele carried by the same haplotype. In particular, our data demonstrate that DRBl*0401 confers a higher risk than DRBl*0404. Based on combined available data on the genetic susceptibility encoded by various DR4-DQ8 haplotypes and the amino acid composition of the involved DRβ*04 chains as well as the ligand motifs for these DR4 subtypes, we have developed a unifying hypothesis explaining the different risks associated with different DR4-DQ8 haplotypes. We suggest that disease susceptibility is mainly conferred by DQ8 while DR4 subtypes confer different degrees of protection. Some DR4 subtypes (i.e., DRB1*0405, 0402, and 0401) confer little or no protection, while others (i.e., DRB 1*0404, 0403, and 0406) cause an increasing degree of protection, possibly by binding a common protective peptide. Features of a protective peptide that fit such a model are briefly discussed.
HLA-Encoded Genetic Predisposition in IDDM: DR4 Subtypes May Be Associated With Different Degrees of Protection
aa, amino acid; AR, absolute risk; IHWS, International Histocompatibility Workshop and Conference; NBMDR, Norwegian Bone Marrow Donor Registry; PCR, polymerase chain reaction; RR, relative risk; SSO, sequence-specific oligonucleotide probe.
Dag E Undlien, Thomas Friede, Hans-Georg Rammensee, Geir Joner, Knut Dahl-Jörgensen, Oddmund Sövik, Hanne E Akselsen, Ingebjörg Knutsen, Kjershi S Rönningen, Erik Thorsby; HLA-Encoded Genetic Predisposition in IDDM: DR4 Subtypes May Be Associated With Different Degrees of Protection. Diabetes 1 January 1997; 46 (1): 143–149. https://doi.org/10.2337/diab.46.1.143
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