Rheumatology Advance Access published online on November 17, 2009
Rheumatology, doi:10.1093/rheumatology/kep338
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New classification of the shared epitope in rheumatoid arthritis: impact on the production of various anti-citrullinated protein antibodies
1Laboratory of Immunology, 3rd Department of Medicine, 2Department of Rheumatology, Institute of Medicine, University of Debrecen Medical and Health Science Center, 3Autoimmune Disease Research Group, Hungarian Academy of Sciences, Debrecen, Hungary and 4TheraTest Laboratories, Lombard, IL, USA.
Correspondence to:
Zoltán Szekanecz, Department of Rheumatology, Institute of Medicine, University of Debrecen Medical and Health Science Center, 98 Nagyerdei street, Debrecen, H-4012, Hungary. E-mail: szekanecz.zoltan{at}med.unideb.hu
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Abstract |
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Objective. HLA-DR [shared epitope (SE)] alleles have recently been re-classified into S1, S2, S3P and S3D groups. S2 and S3P have been associated with increased risk for RA. We assessed the impact of S1, S2, S3P and S3D alleles on anti-citrullinated protein antibody (ACPA) production. Instead of comparing allele-carriers to non-carriers, we studied each allele group individually, using the X/X (non-SE) genotype as reference.
Methods. Serum and genomic DNA samples of 91 RA patients and 78 healthy controls were obtained. Various ACPAs and IgM RF were determined by ELISA. HLA-DRB1 genotyping and subtyping was performed by PCR. HLA-DRB1 alleles were re-classified as described above. Correlations between SE and ACPAs were determined.
Results. Not only S2 and S3P, but, to a lesser extent, S1 and S3D alleles also predisposed to anti-cyclic citrullinated peptide (CCP) production (P < 0.0001, P = 0.004, P = 0.01 and P = 0.027, respectively), with the following hierarchy of association: S2+S3P > S1+S3D > X/X. Similar associations were observed for anti-citrullinated vimentin. Anti-citrullinated fibrinogen (CF) exerted a different association pattern with the strongest correlation with S1 alleles [odds ratio (OR) 16.00; P = 0.05]. In addition, HLA-DRB1*15 alleles may represent a special predisposing effect for anti-CF antibody production. Finally, in this study, RF production was associated only with the HLA-DRB1*0401 SE allele (P = 0.04).
Conclusions. Our approach of comparing individual S allele carriers with X/X genotype patients allowed us to perform unequivocal analyses and demonstrate new associations. Thus, novel subgroups of RA could be identified with potential relevance for prognosis and therapy.
KEY WORDS: Rheumatoid arthritis, Shared epitope, Anti-citrullinated protein antibodies, Anti-cyclic citrullinated peptide, Anti-citrullinated vimentin, Anti-citrullinated fibrinogen, Rheumatoid factor
Submitted 18 April 2009;
revised version accepted 23 September 2009.
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