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Open Access Research article

New classification of HLA-DRB1 alleles in rheumatoid arthritis susceptibility: a combined analysis of worldwide samples

Thomas Barnetche1, Arnaud Constantin12, Alain Cantagrel23, Anne Cambon-Thomsen1 and Pierre-Antoine Gourraud14*

Author Affiliations

1 Department of Epidemiology and Public Health, UMR Inserm U 558, University Paul Sabatier Toulouse III, Faculty of Medicine Purpan, 37 Allées Jules Guesde, Toulouse cedex 7, 31073, France

2 Rheumatology Department, Larrey University Hospital, 24 chemin de Pouvourville, Toulouse cedex 9, 31059, France

3 JE2510, University Paul Sabatier Toulouse III, 118 route de Narbonne, Toulouse, 31062 cedex 9, France

4 UF de Méthodologie de la recherche clinique, Epidemioloy Unit, Toulouse University Hospital, 37 Allées Jules Guesde, Toulouse cedex 7, 31073, France

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Arthritis Research & Therapy 2008, 10:R26  doi:10.1186/ar2379

Published: 28 February 2008

Abstract

Introduction

Rheumatoid arthritis (RA) is a complex polygenic disease of unknown etiology. HLA-DRB1 alleles encoding the shared epitope (SE) (RAA amino acid pattern in positions 72 to 74 of the third hypervariable region of the DRβ1 chain) are associated with RA susceptibility. A new classification of HLA-DRB1 SE alleles has been developed by Tezenas du Montcel and colleagues to refine the association between HLA-DRB1 and RA. In the present study, we used RA samples collected worldwide to investigate the relevance of this new HLA-DRB1 classification in terms of RA susceptibility across various Caucasoid and non-Caucasoid patients.

Methods

Eighteen subsamples were defined from a total number of 759 cases and 789 controls and grouped in 10 samples on the basis of their ethnic origin. HLA-DRB1 alleles were divided into five groups (S1, S2, S3D, S3P, and X) according to the new HLA-DRB1 allele classification. The whole analysis was performed by comparing carrier frequencies for the five HLA-DRB1 allele groups between RA patients and controls across the 10 Caucasoid and non-Caucasoid samples. The Mantel-Haenszel method of meta-analysis provided a global odds ratio (OR) estimate with 95% confidence interval (CI).

Results

A positive association with RA susceptibility was found for S2 allele carriers (OR 2.15, 95% CI 1.54 to 3.00; p < 10-5) and S3P allele carriers (OR 2.74, 95% CI 2.01 to 3.74; p < 10-5). A negative association was found for S1 alleles (OR 0.60, 95% CI 0.48 to 0.76; p < 10-4) and X alleles (OR 0.58, 95% CI 0.39 to 0.84; p = 4 × 10-3). No significant association was highlighted for the S3D group of alleles (OR 0.89, 95% CI 0.69 to 1.14; p = 0.89). The complementary genotype analysis fit with the genotype risk hierarchy previously reported in Caucasoid RA patients.

Conclusion

So far, the present study is the first attempt to investigate the relevance of this new HLA-DRB1 classification in terms of RA susceptibility on both Caucasoid and non-Caucasoid samples. Our results support the hypothesis of a differential role played by different HLA-DRB1 allele groups in RA susceptibility across different ethnic backgrounds and confirm the interest of such an HLA-DRB1 classification in differentiating predisposing and protective alleles.