New classification of HLA-DRB1 alleles supports the shared epitope hypothesis of rheumatoid arthritis susceptibility

Arthritis Rheum. 2005 Apr;52(4):1063-8. doi: 10.1002/art.20989.


Objective: The shared epitope hypothesis was formulated to explain the involvement of HLA-DRB1 in rheumatoid arthritis (RA). However, several studies, which considered only the HLA-DRB1 alleles shown to be associated with RA risk, rejected this hypothesis. In this report, we propose that a different classification of HLA-DRB1 alleles be considered, based on the amino acid sequence at position 70-74.

Methods: The fit of both HLA-DRB1 classifications was tested in 2 groups of RA patients. All subjects were recruited through the European Consortium on Rheumatoid Arthritis Families, and included 100 patients with isolated RA and 132 patients with at least 1 affected sibling.

Results: The new classification produced risk estimates that fit all of the observed data, i.e., the distribution of the HLA-DRB1 genotype in the 2 patient groups, and the distribution of parental alleles shared by affected sibpairs. The risk of developing RA under this new classification depends on whether the RAA sequence occupies position 72-74 but is modulated by the amino acid at position 71 (K confers the highest risk, R an intermediate risk, A and E a lower risk) and by the amino acid at position 70 (Q or R confers a higher risk than D).

Conclusion: A new classification based on amino acid sequence allows us to show that the shared epitope RAA sequence at position 72-74 explains the data, with the risk of developing RA modulated by the amino acids at positions 70 and 71.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles*
  • Amino Acid Sequence
  • Arthritis, Rheumatoid / genetics*
  • Epitopes / genetics*
  • Genetic Predisposition to Disease*
  • HLA-DR Antigens / classification*
  • HLA-DR Antigens / genetics*
  • HLA-DRB1 Chains
  • Humans
  • Molecular Sequence Data


  • Epitopes
  • HLA-DR Antigens
  • HLA-DRB1 Chains