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

Abstract

Objective To further analyze the association of HLA–DRB1 alleles with disease susceptibility in recent‐onset rheumatoid arthritis (RA). Methods One hundred sixty‐seven 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 (SESSs) 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 shared a third hypervariable region motif. Independent homozygosity effects were observed both for susceptibility and for protective alleles. Conclusion Nonsusceptibility alleles differ significantly with regard to RA risk. Protective alleles show clear homology at positions 67–74, often encoding isoleucine at position 67 or aspartic acid at position 70. Susceptibility and protective alleles both show homozygosity effects. Based on these results and on data reported in the literature, in order to incorporate the finding of differential risks among nonsusceptibility alleles, we propose to reshape the shared epitope hypothesis as follows: HLA‐associated risk for RA is encoded by amino acid substitutions at positions 67–74 of the HLA–DRB1 molecule.

A spectrum of susceptibility to rheumatoid arthritis within HLA-DRB1: stratification by autoantibody status in a large UK population

“…27 It has also been proposed that certain HLA-DRB1 alleles protect against development of RA, compared with other HLA-DRB1 non-SE alleles. Proposed protective motifs include: the 70 DERAA 74 sequence, [28][29][30][31] aspartic acid at position 70 (D 70 ), 32,33 , isoleucine at position 67 (I 67 ) 34 or S 1 ( 71 ERAA 74 (S 1E ) with 71 ARAA 74 (S 1A )). 18,20,35 S 3D ( 70 DRRAA 74 ) was 'neutral'.…”

Association between HLA class II genes and autoantibodies to cyclic citrullinated peptides (CCPs) influences the severity of rheumatoid arthritis

“…Not only does carriership of SE alleles increase the risk of RA, but in RA patients, these alleles are also associated with a more severe disease type (4,5). However, since there are differences in the strength of association between SE alleles and RA, and since no convincing demonstration of the mechanisms underlying the associations is currently available, other paradigms that refine or complement the SE hypothesis have been put forward (6,7).…”

Extensive multiallelic analysis of the relationship between HLA-DRB1 and rheumatoid arthritis using a Bayesian partition model

“…The most documented issue is the implication of the highly polymorphic HLA-DRB1 locus that can also be regarded as a biallelic locus through the so-called 'shared epitope' (SE) theory. [3][4][5][6][7] While the association between the SE and RA susceptibility is well established, the gene-dose effect is still controversial. 5,6,8,9 Furthermore, the effects of SE statistical interactions with age and sex on RA susceptibility are poorly documented.…”

“…[3][4][5][6][7] While the association between the SE and RA susceptibility is well established, the gene-dose effect is still controversial. 5,6,8,9 Furthermore, the effects of SE statistical interactions with age and sex on RA susceptibility are poorly documented. These differences could be due to lack of power or to 'population stratification', that is, different genotype frequencies between groups of a given population due to unique characteristics of these groups, such as common genetic and social histories, mating preferences, migration patterns, etc.…”