title: 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).
abstract: 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 χ(2) 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.
authors.affiliation: UMR 1027, INSERM , Toulouse , France ; University Paul Sabatier Toulouse III , Toulouse , France ; Rheumatology Center, Purpan Hospital , Toulouse , France.
authors.forename: Adeline
authors.initials: A
authors.lastname: Ruyssen-Witrand
authors.affiliation: Department of Rheumatology , Leiden University Medical Center , Leiden , The Netherlands.
authors.forename: Hanna W
authors.initials: HW
authors.lastname: van Steenbergen
authors.affiliation: Department of Rheumatology , Leiden University Medical Center , Leiden , The Netherlands.
authors.forename: Jurgen
authors.initials: J
authors.lastname: van Heemst
authors.affiliation: Department of Neurology , University of California San Francisco School of Medicine , San Francisco, California , USA.
authors.forename: Pierre-Antoine
authors.initials: PA
authors.lastname: Gourraud
authors.affiliation: Rheumatology Center, Purpan Hospital , Toulouse , France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Nigon
authors.affiliation: Department of Rheumatology , Lapeyronie Teaching Hospital , Montpellier , France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Lukas
authors.affiliation: Department of Rheumatology , Kremlin Bicetre Hospital , Kremlin Bicetre , France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Miceli-Richard
authors.affiliation: Rheumatology Center, Purpan Hospital , Toulouse , France.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Jamard
authors.affiliation: UMR 1027, INSERM , Toulouse , France ; University Paul Sabatier Toulouse III , Toulouse , France.
authors.forename: Anne
authors.initials: A
authors.lastname: Cambon-Thomsen
authors.affiliation: UMR 1027, INSERM , Toulouse , France ; Rheumatology Center, Purpan Hospital , Toulouse , France.
authors.forename: Alain
authors.initials: A
authors.lastname: Cantagrel
authors.affiliation: Department of Rheumatology , Claude Bernard-Bichat Teaching Hospital, Paris VII University , Paris , France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Dieudé
authors.affiliation: Department of Rheumatology , Leiden University Medical Center , Leiden , The Netherlands.
authors.forename: Annette H M
authors.initials: AH
authors.lastname: van der Helm-van Mil
authors.affiliation: UMR 1027, INSERM , Toulouse , France ; University Paul Sabatier Toulouse III , Toulouse , France ; Rheumatology Center, Purpan Hospital , Toulouse , France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Constantin
keywords: Ant-CCP; Gene Polymorphism; Rheumatoid Arthritis