The shared epitope hypothesis in rheumatoid arthritis: Evaluation of alternative classification criteria in a large UK Caucasian cohort

Abstract

Objective. Many classification systems for the HLA-DRB1 allelic association with rheumatoid arthritis (RA) have been reported, but few have been validated in additional populations. We sought to evaluate 3 different DRB1 allele classification systems in a large cohort of Caucasian RA patients and control subjects in the UK.Methods. HLA-DRB1 typing was undertaken in 1,325 Caucasian RA patients and 462 healthy Caucasian controls who were residents of the UK. Logistic regression analyses were performed to investigate the different classification systems.Results. We confirmed the association between the susceptibility alleles S 2 and S 3P , as proposed by Tezenas du Montcel, and the presence of RA in UK Caucasians. A significant hierarchy of risk was observed within the S 3P allele group. There was no evidence of a significant association between DRB1*1001 and RA. Our data did not support the hypothesis that an isoleucine at position 67 conferred protection against RA, other than in contrast to the susceptibility alleles. However, the presence of an aspartic acid at amino acid 70 did appear to confer some degree of protection.Conclusion. We were unable to fully substantiate any of the 3 recent revisions of the shared epitope hypothesis in this large cohort of Caucasian RA patients and control subjects in the UK. This reinforces the importance of evaluating disease susceptibility alleles in different Caucasian populations as well as in other ethnic groups. In particular, it will be important to clarify the precise DRB1 association in a given population before DRB1 genotyping is incorporated into clinical diagnostic or treatment algorithms.

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

“…As in previous work, 20 we further divided the 70 QRRAA 74 alleles into *01 and *04 alleles, giving four HLA-DRB1 SE allele groups: (HLA-DRB1*0401 group (*04 alleles with 70 QKRAA 74 ), *0101 group (*01 alleles with 70 QRRAA 74 ), *0404 group (*04 alleles with 70 QRRAA 74 ), and *1001 (alleles with 70 RRRAA 74 ). Where only low-resolution or ambiguous high-resolution HLA-DRB1 genotyping data were available (269 individuals), the alleles were assigned to the most likely group, if probability 40.70 based on published population frequencies, otherwise set to missing (29 alleles in 24 individuals).…”

“…18,19 Furthermore, dividing HLA-DRB1 QRRAA alleles into HLA-DRB1*04-QRRAA and HLA-DRB1*01-QRRAA subgroups, a per-allele hierarchy of risk was observed: *0401-QKRAA4*0404-QRRAA4 *0101-QRRAA4*1001-RRRAA. 20 Compound heterozygosity (*0401/*0404 heterozygosity) has been associated with a maximal genotypic risk for RA susceptibility and severity, [21][22][23][24][25] including vasculitis 26 and cardiovascular mortality. 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'. 35 The overlap between all these models makes comparison of the different models challenging, but, in a different cohort, we found that the D 70 model performed best.…”

“…35 The overlap between all these models makes comparison of the different models challenging, but, in a different cohort, we found that the D 70 model performed best. 20 In this study, we used HLA-DRB1 data from the UK Rheumatoid Arthritis Genetics Consortium 36 to validate the above-mentioned susceptibility and protective models for RA. Importantly, this cohort was large enough to stratify by both RF and ACPA.…”

Genetic variants of the HLA-A, HLA-B and AIF1 loci show independent associations with type 1 diabetes in Norwegian families

“…Each of these loci are most likely to act as confounding factors, illustrated by the growing body of evidence for T1D associations attributable to LD with HLA-B alleles, in addition to the known primary susceptibility loci DRB1-DQA1-DQB1. Moreover, definitions of risk alleles at identified primary loci may vary (for example, controversies about the 'shared epitope' hypothesis in rheumatoid arthritis 45 ), possibly leading to insufficient adjustment for confounding factors even if conditional approaches are used. Hence, conflicting association reports in this region are not surprising.…”