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

Objective. To determine whether the association between rheumatoid arthriti s (RA) and HLA-DRB1 is influenced by the amino acid residue encoded at posi tion 70 (beta 70) of the third hypervariable region (HVR3) of the HLA-DR be ta chain. Methods. The frequencies of HLA-DRB1 alleles encoding different amino acid residues at beta 70 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 47 6 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 L ugo, Spain. Associations were investigated using chi-square analyses and re gression analyses. The extended Mantel-Haenszel procedure was used for tren d analysis. Results. Carriage of 2 shared epitope (SE)+ alleles encoding a glutamine at beta 70 (Q(70SE+)/(Q70SE+)) was associated with the greatest risk of RA in the UK and Spanish population (odds ratios 7.93 and 4.66. respectively). w hile possession of 2 SE- alleles encoding an aspartic acid at beta 70 (D70S E-/D70SE-) was associated with the lowest risk (OR 0.23 and 0.34, respectiv ely). In individuals carrying one SE+ allele and an accompanying D70SE- all ele there was no increased risk of developing RA [OR 0.93 (UK) and 1.30 (Sp ain)]. Possession of D70SE- was more strongly protective than possession of Q(70SE-). Analysis of trend indicated that the strength of association of different DRB1 genotypes with RA could be ranked in order (from Q(70SE+)/Q( 70SE+) to D70SE-/D70SE-) according to which amino acid residues were encode d at beta 70. and whether or not they formed part of a SE sequence. The sev erity of radiographic damage could not be ranked in the same fashion. Conclusion. The amino acid residue at position 70 of the HVR3 in HLA-DR bet a molecules influences susceptibility to RA. The strength of the associatio n of DRB1 genotypes with RA is dependent not only on SE status, but also on which amino acid residues are encoded at beta 70 of the DRB1 alleles. Pres ence of an aspartic acid residue at beta 70 protects against development of RA. However, the severity of erosive damage does not appear to be associat ed with the amino acid substitution at beta 70.