HLA-DRB1 alleles encoding an aspartic acid at position 70 protect against development of rheumatoid arthritis

Objective. To determine whether the association between rheumatoid arthritis (RA) and HLA-DRB1 is influenced by the amino acid residue encoded at position 70 (β70) of the third hypervariable region (HVR3) of the HLA-DRβ chain. Methods. The frequencies of HLA-DRB1 alleles encoding different amino acid residues at β70 were compared between patients with RA and controls in a population from the UK and in a confirmatory population from northwestern Spain. HLA-DRB1 typing was done by polymerase chain reaction methods on 476 clinic based patients with RA and 180 healthy controls from Staffordshire and Cheshire in the UK, and on 179 clinic patients and 145 controls from Lugo, Spain. Associations were investigated using chi-square analyses and regression analyses. The extended Mantel-Haenszel procedure was used for trend analysis. Results. Carriage of 2 shared epitope (SE)+ alleles encoding a glutamine at β70 (Q70SE+/Q70SE+) was associated with the greatest risk of RA in the UK and Spanish population (odds ratios 7.93 and 4.66, respectively), while possession of 2 SE- alleles encoding an aspartic acid at β70 (D70SE-/D70SE-) was associated with the lowest risk (OR 0.23 and 0.34, respectively). In individuals carrying one SE+ allele and an accompanying D70SE- allele there was no increased risk of developing RA [OR 0.93 (UK) and 1.30 (Spain)]. Possession of D70SE- was more strongly protective than possession of Q70SE-. Analysis of trend indicated that the strength of association of different DRB1 genotypes with RA could be ranked in order (from Q70SE+/Q70SE+ to D70SE-/D70SE-) according to which amino acid residues were encoded at β70, and whether or not they formed part of a SE sequence. The severity of radiographic damage could not be ranked in the same fashion. Conclusion. The amino acid residue at position 70 of the HVR3 in HLA-DRβ molecules influences susceptibility to RA. The strength of the association of DRB1 genotypes with RA is dependent not only on SE status, but also on which amino acid residues are encoded at β70 of the DRB1 alleles. Presence of an aspartic acid residue at β70 protects against development of RA. However, the severity of erosive damage does not appear to be associated with the amino acid substitution at β70.