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A new classification of HLA-DRB1 alleles based on acid–base properties of the amino acids located at positions 13, 70 and 71: impact on ACPA status or structural progression, and meta-analysis on 1235 patients with rheumatoid from two cohorts (ESPOIR and EAC cohort)
  1. Adeline Ruyssen-Witrand1,2,3,
  2. Hanna W van Steenbergen4,
  3. Jurgen van Heemst4,
  4. Pierre-Antoine Gourraud5,
  5. Delphine Nigon3,
  6. Cédric Lukas6,
  7. Corinne Miceli-Richard7,
  8. Bénédicte Jamard3,
  9. Anne Cambon-Thomsen1,2,
  10. Alain Cantagrel1,3,
  11. Philippe Dieudé8,
  12. Annette H M van der Helm-van Mil4 and
  13. Arnaud Constantin1,2,3
  1. 1UMR 1027, INSERM, Toulouse, France
  2. 2University Paul Sabatier Toulouse III, Toulouse, France
  3. 3Rheumatology Center, Purpan Hospital, Toulouse, France
  4. 4Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
  5. 5Department of Neurology, University of California San Francisco School of Medicine, San Francisco, California, USA
  6. 6Department of Rheumatology, Lapeyronie Teaching Hospital, Montpellier, France
  7. 7Department of Rheumatology, Kremlin Bicetre Hospital, Kremlin Bicetre, France
  8. 8Department of Rheumatology, Claude Bernard-Bichat Teaching Hospital, Paris VII University, Paris, France
  1. Correspondence to Dr Adeline Ruyssen-Witrand; adruyssen{at}


Objective To group HLA-DRB1 alleles based on acid–base properties of amino acids at positions 13, 70 and 71 and analyse their association with the presence of anticitrullinated peptide antibodies (ACPA) and structural progression in 2 cohorts of early rheumatoid arthritis (RA).

Methods Patients with RA (N=612) from ESPOIR cohort and from EAC cohort (n=624) were genotyped for HLA-DRB1 alleles. The alleles containing the RAA sequence at positions 72–74 were classified into 3 groups according to the amino acid at positions 13, 70 and 71: BB encoding basic amino acids at positions 13, 70 and 71; A encoding acidic amino acids at positions 70 and 71; and BN encoding either neutral amino acids at position 13 and basic amino acids at positions 70 and 71, or basic amino acid at position 13 and neutral amino acids at positions 70 and 71. The associations between the different alleles and (1) the ACPA presence, and (2) the structural progression were assessed by χ2 test; a meta-analysis was performed on the 2 cohorts using the Mantel-Haenszel method.

Results After meta-analysis, BB alleles were significantly associated with ACPA presence (OR (95% CI) 4.08 (3.14 to 5.31)) and structural progression (OR (95% CI) 2.33 (1.76 to 3.09)). The alleles protected significantly against ACPA presence (OR (95% CI) 0.37 (0.28 to 0.50)) and structural progression (OR (95% CI) 0.34 (0.23 to 0.50)). This acid–base classification allowed to separate another group BN with an intermediate risk of ACPA production (OR (95% CI) 1.14 (0.91 to 1.44)) and structural progression (OR (95% CI) 1.01 (0.77 to 1.33)).

Conclusions This new classification permitted to make a hierarchy of HLA-DRB1 alleles in terms of association with ACPA presence or structural progression in early RA.

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  • Received March 20, 2015.
  • Revision received August 18, 2015.
  • Accepted August 22, 2015.
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