title: Reevaluation of the interaction between HLA-DRB1 shared epitope alleles, PTPN22, and smoking in determining susceptibility to autoantibody-positive and autoantibody-negative rheumatoid arthritis in a large UK Caucasian population.
abstract: OBJECTIVE
  To define interactions between the HLA-DRB1 shared epitope (SE), PTPN22, and smoking in cyclic citrullinated peptide (CCP) antibody- and rheumatoid factor (RF)-positive and -negative rheumatoid arthritis (RA).
  
  
  METHODS
  Data on approximately 5,000 RA patients and approximately 3,700 healthy controls recruited from 6 centers in the UK were analyzed; not all centers had both genotype data and smoking data available for study. The magnitude of association was assessed in autoantibody-positive and -negative subgroups. The effect of smoking on antibody status among cases was assessed following adjustment for year of birth and center, using Mantel-Haenszel analysis. Analyses of the combined effects of PTPN22, HLA-DRB1 SE, and smoking were performed using additive and multiplicative models of interaction within a logistic regression framework.
  
  
  RESULTS
  The combined effects of PTPN22, HLA-DRB1 SE, and smoking were defined, with no evidence of departure from a multiplicative model. Within the case population, all 3 factors were independently associated with the generation of CCP antibodies (odds ratio [OR] 11.1, P < 0.0001), whereas only HLA-DRB1 SE and smoking were independently associated with RF production (OR 4.4, P < 0.0001). There was some evidence of increasing likelihood of antibody positivity with heavier smoking. Finally, we demonstrated that smoking was associated with the generation of both CCP and RF antibodies (OR 1.7, P = 0.0001).
  
  
  CONCLUSIONS
  PTPN22 appears to be primarily associated with anticitrulline autoimmunity, whereas HLA-DRB1 SE is independently associated with RF. This study has confirmed associations of specific gene-environment combinations with a substantially increased risk of developing RA. Further work is needed to determine how these data can be used to inform clinical practice.
authors.affiliation: Leeds Musculoskeletal Biomedical Research Unit, Institute of Molecular Medicine, University of Leeds, St. James' University Hospital, Leeds, UK. a.w.morgan@leeds.ac.uk
authors.forename: Ann W
authors.initials: AW
authors.lastname: Morgan
authors.forename: Wendy
authors.initials: W
authors.lastname: Thomson
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Martin
authors.forename: Angela M
authors.initials: AM
authors.lastname: Carter
authors.forename: Henry A
authors.initials: HA
authors.lastname: Erlich
authors.forename: Anne
authors.initials: A
authors.lastname: Barton
authors.forename: Lynne
authors.initials: L
authors.lastname: Hocking
authors.forename: David M
authors.initials: DM
authors.lastname: Reid
authors.forename: Pille
authors.initials: P
authors.lastname: Harrison
authors.forename: Paul
authors.initials: P
authors.lastname: Wordsworth
authors.forename: Sophia
authors.initials: S
authors.lastname: Steer
authors.forename: Jane
authors.initials: J
authors.lastname: Worthington
authors.forename: Paul
authors.initials: P
authors.lastname: Emery
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Wilson
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Barrett
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D001323:Autoantibodies / Q000235:genetics*; D016022:Case-Control Studies; D000939:Epitopes / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D010456:Peptides, Cyclic / Q000235:genetics; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics*; D012217:Rheumatoid Factor / Q000235:genetics; D012907:Smoking; D006113:United Kingdom; D044465:White People / Q000235:genetics*; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D000939:Epitopes; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide; D012217:Rheumatoid Factor; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22