Reshaping the shared epitope hypothesis: HLA‐associated risk for rheumatoid arthritis is encoded by amino acid substitutions at positions 67–74 of the HLA–DRB1 molecule

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Abstract
Objective To further analyze the association of HLA–DRB1 alleles with disease susceptibility in recent‐onset rheumatoid arthritis (RA). Methods One hundred sixty‐seven Caucasian RA patients and 166 healthy controls were typed for HLA–DRB1. Results The association of susceptibility to RA with the group of alleles encoding the shared epitope susceptibility sequences (SESSs) was confirmed in recent‐onset RA. Among non‐SESS alleles, DRB1*07, *1201, *1301, and *1501 showed significant protective effects. Even after correction for the influence of SESS alleles, significant independent protective effects of DRB1 alleles were observed. Protective alleles shared a third hypervariable region motif. Independent homozygosity effects were observed both for susceptibility and for protective alleles. Conclusion Nonsusceptibility alleles differ significantly with regard to RA risk. Protective alleles show clear homology at positions 67–74, often encoding isoleucine at position 67 or aspartic acid at position 70. Susceptibility and protective alleles both show homozygosity effects. Based on these results and on data reported in the literature, in order to incorporate the finding of differential risks among nonsusceptibility alleles, we propose to reshape the shared epitope hypothesis as follows: HLA‐associated risk for RA is encoded by amino acid substitutions at positions 67–74 of the HLA–DRB1 molecule.