title: Anticitrullinated protein antibody (ACPA) in rheumatoid arthritis: influence of an interaction between HLA-DRB1 shared epitope and a deletion polymorphism in glutathione S-transferase in a cross-sectional study.
abstract: BACKGROUND
  A deletion polymorphism in glutathione S-transferase Mu-1 (GSTM1-null) has previously been implicated to play a role in rheumatoid arthritis (RA) risk and progression, although no prior investigations have examined its associations with anticitrullinated protein antibody (ACPA) positivity. The purpose of this study was to examine the associations of GSTM1-null with ACPA positivity in RA and to assess for evidence of interaction between GSTM1 and HLA-DRB1 shared epitope (SE).
  
  
  METHODS
  Associations of GSTM1-null with ACPA positivity were examined separately in two RA cohorts, the Veterans Affairs Rheumatoid Arthritis (VARA) registry (n = 703) and the Study of New-Onset RA (SONORA; n = 610). Interactions were examined by calculating an attributable proportion (AP) due to interaction.
  
  
  RESULTS
  A majority of patients in the VARA registry (76%) and SONORA (69%) were positive for ACPA with a similar frequency of GSTM1-null (53% and 52%, respectively) and HLA-DRB1 SE positivity (76% and 71%, respectively). The parameter of patients who had ever smoked was more common in the VARA registry (80%) than in SONORA (65%). GSTM1-null was significantly associated with ACPA positivity in the VARA registry (odds ratio (OR), 1.45; 95% confidence interval (CI), 1.02 to 2.05), but not in SONORA (OR, 1.00; 95% CI, 0.71 to 1.42). There were significant additive interactions between GSTM1 and HLA-DRB1 SE in the VARA registry (AP, 0.49; 95% CI, 0.21 to 0.77; P < 0.001) in ACPA positivity, an interaction replicated in SONORA (AP, 0.38; 95% CI, 0.00 to 0.76; P = 0.050).
  
  
  CONCLUSIONS
  This study is the first to show that the GSTM1-null genotype, a common genetic variant, exerts significant additive interaction with HLA-DRB1 SE on the risk of ACPA positivity in RA. Since GSTM1 has known antioxidant functions, these data suggest that oxidative stress may be important in the development of RA-specific autoimmunity in genetically susceptible individuals.
authors.affiliation: Omaha Veterans Affairs Medical Center and Nebraska Arthritis Outcomes Research Center, University of Nebraska Medical Center, 986270 Nebraska Medical Center, Omaha, NE 68198-6270, USA. tmikuls@unmc.edu
authors.forename: Ted R
authors.initials: TR
authors.lastname: Mikuls
authors.forename: Karen A
authors.initials: KA
authors.lastname: Gould
authors.forename: Kimberly K
authors.initials: KK
authors.lastname: Bynoté
authors.forename: Fang
authors.initials: F
authors.lastname: Yu
authors.forename: Tricia D
authors.initials: TD
authors.lastname: Levan
authors.forename: Geoffrey M
authors.initials: GM
authors.lastname: Thiele
authors.forename: Kaleb D
authors.initials: KD
authors.lastname: Michaud
authors.forename: James R
authors.initials: JR
authors.lastname: O'Dell
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Reimold
authors.forename: Roderick
authors.initials: R
authors.lastname: Hooker
authors.forename: Liron
authors.initials: L
authors.lastname: Caplan
authors.forename: Dannette S
authors.initials: DS
authors.lastname: Johnson
authors.forename: Gail
authors.initials: G
authors.lastname: Kerr
authors.forename: J Steuart
authors.initials: JS
authors.lastname: Richards
authors.forename: Grant W
authors.initials: GW
authors.lastname: Cannon
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Criswell
authors.forename: Janelle A
authors.initials: JA
authors.lastname: Noble
authors.forename: S Louis
authors.initials: SL
authors.lastname: Bridges
authors.forename: Laura
authors.initials: L
authors.lastname: Hughes
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
mesh_terms: D001172:Arthritis, Rheumatoid / Q000097:blood / Q000235:genetics* / Q000276:immunology; D001323:Autoantibodies / Q000097:blood / Q000235:genetics* / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D003430:Cross-Sectional Studies; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000235:genetics* / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006801:Humans; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D000939:Epitopes; D005982:Glutathione Transferase; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains