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

Open Access
Publisher Website
Google Scholar
Abstract
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.