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

Objective and methods

To further analyze the association of HLA-DRB1 alleles with disease susceptibility in recent onset rheumatoid arthritis (RA), 167 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 (SESS) 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 share a third hypervariable region motif. Independent homozygosity effects were observed both for susceptibility and protective alleles.

Conclusion

Non-susceptibility alleles differ significantly regarding RA risk. Protective alleles show clear homology at positions 67–74, often encoding Isoleucine at position 67 or Aspartic acid at position 70. Both susceptibility and protective alleles show homozygosity effects. Based on these results and literature data, in order to incorporate differential risks among non-susceptibility alleles, we propose to reshape the shared epitope hypothesis to, "HLA-associated risk for rheumatoid arthritis is encoded by amino acid substitutions at position 67 to 74 of the HLA-DRB1 molecule".