title: Association of valine and leucine at HLA-DRB1 position 11 with radiographic progression in rheumatoid arthritis, independent of the shared epitope alleles but not independent of anti-citrullinated protein antibodies.
abstract: OBJECTIVE
  For decades it has been known that the HLA-DRB1 shared epitope (SE) alleles are associated with an increased risk of development and progression of rheumatoid arthritis (RA). Recently, the following variations in the peptide-binding grooves of HLA molecules that predispose to RA development have been identified: Val and Leu at HLA-DRB1 position 11, Asp at HLA-B position 9, and Phe at HLA-DPB1 position 9. This study was undertaken to investigate whether these variants are also associated with radiographic progression in RA, independent of SE and anti-citrullinated protein antibody (ACPA) status.
  
  
  METHODS
  A total of 4,911 radiograph sets from 1,878 RA patients included in the Leiden Early Arthritis Clinic (The Netherlands), Umeå (Sweden), Hospital Clinico San Carlos-Rheumatoid Arthritis (Spain), and National Data Bank for Rheumatic Diseases (US) cohorts were studied. HLA was imputed using single-nucleotide polymorphism data from an Immunochip, and the amino acids listed above were tested in relation to radiographic progression per cohort using an additive model. Results from the 4 cohorts were combined in inverse-variance weighted meta-analyses using a fixed-effects model. Analyses were conditioned on SE and ACPA status.
  
  
  RESULTS
  Val and Leu at HLA-DRB1 position 11 were associated with more radiographic progression (meta-analysis P = 5.11 × 10(-7)); this effect was independent of SE status (meta-analysis P = 0.022) but not independent of ACPA status. Phe at HLA-DPB1 position 9 was associated with more severe radiographic progression (meta-analysis P = 0.024), though not independent of SE status. Asp at HLA-B position 9 was not associated with radiographic progression.
  
  
  CONCLUSIONS
  Val and Leu at HLA-DRB1 position 11 conferred a risk of a higher rate of radiographic progression independent of SE status but not independent of ACPA status. These findings support the relevance of these amino acids at position 11.
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: H W
authors.initials: HW
authors.lastname: van Steenbergen
authors.forename: S
authors.initials: S
authors.lastname: Raychaudhuri
authors.forename: L
authors.initials: L
authors.lastname: Rodríguez-Rodríguez
authors.forename: S
authors.initials: S
authors.lastname: Rantapää-Dahlqvist
authors.forename: E
authors.initials: E
authors.lastname: Berglin
authors.forename: R E M
authors.initials: RE
authors.lastname: Toes
authors.forename: T W J
authors.initials: TW
authors.lastname: Huizinga
authors.forename: B
authors.initials: B
authors.lastname: Fernández-Gutiérrez
authors.forename: P K
authors.initials: PK
authors.lastname: Gregersen
authors.forename: A H M
authors.initials: AH
authors.lastname: van der Helm-van Mil
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000000981:diagnostic imaging / Q000235:genetics* / Q000276:immunology; D018450:Disease Progression; D000939:Epitopes; D005260:Female; D033023:Foot Joints / Q000000981:diagnostic imaging*; D005787:Gene Frequency; D059811:HLA-DRB1 Chains / Q000235:genetics*; D050823:Hand Joints / Q000000981:diagnostic imaging*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000276:immunology*; D011859:Radiography
chemical_list: D000939:Epitopes; D059811:HLA-DRB1 Chains; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide