title: Smoking interacts with HLA-DRB1 shared epitope in the development of anti-citrullinated protein antibody-positive rheumatoid arthritis: results from the Malaysian Epidemiological Investigation of Rheumatoid Arthritis (MyEIRA).
abstract: BACKGROUND
  Rheumatoid arthritis (RA) is a multifactorial autoimmune disease in which genetic and environmental factors interact in the etiology. In this study, we investigated whether smoking and HLA-DRB1 shared-epitope (SE) alleles interact differently in the development of the two major subgroups of rheumatoid arthritis (RA), anti-citrullinated proteins antibody (ACPA)-positive and ACPA-negative disease, in a multiethnic population of Asian descent.
  
  
  METHODS
  A case-control study comprising early diagnosed RA cases was carried out in Malaysia between 2005 and 2009. In total, 1,076 cases and 1,612 matched controls participated in the study. High-resolution HLA-DRB1 genotyping was performed for shared-epitope (SE) alleles. All participants answered a questionnaire on a broad range of issues, including smoking habits. The odds ratio (OR) of developing ACPA-positive and ACPA-negative disease was calculated for smoking and the presence of any SE alleles separately. Potential interaction between smoking history (defined as "ever" and "never" smoking) and HLA-DRB1 SE alleles also was calculated.
  
  
  RESULTS
  In our multiethnic study, both the SE alleles and smoking were associated with an increased risk of developing ACPA-positive RA (OR SE alleles, 4.7; 95% confidence interval (CI), 3.6 to 6.2; OR smoking, 4.1; 95% CI, 1.9 to 9.2). SE-positive smokers had an odds ratio of ACPA-positive RA of 25.6 (95% CI, 10.4 to 63.4), compared with SE-negative never-smokers. The interaction between smoking and SE alleles was significant (attributable proportion due to interaction (AP) was 0.7 (95% CI, 0.5 to 1.0)). The HLA-DRB1*04:05 SE allele, which is common in Asian populations, but not among Caucasians, was associated with an increased risk of ACPA-positive RA, and this allele also showed signs of interaction with smoking (AP, 0.4; 95% CI, -0.1 to 0.9). Neither smoking nor SE alleles nor their combination was associated with an increased risk of ACPA-negative RA.
  
  
  CONCLUSIONS
  The risk of developing ACPA-positive RA is associated with a strong gene-environment interaction between smoking and HLA-DRB1 SE alleles in a Malaysian multiethnic population of Asian descent. This interaction seems to apply also between smoking and the specific HLA-DRB1*04:05 SE allele, which is common in Asian populations but not in Caucasians.
authors.affiliation: Rheumatology Unit, Department of Medicine, Center of Molecular Medicine L8:04, Karolinska University Hospital, 17176 Stockholm, Sweden. toocl@imr.gov.my
authors.forename: Chun Lai
authors.initials: CL
authors.lastname: Too
authors.forename: Abqariyah
authors.initials: A
authors.lastname: Yahya
authors.forename: Shahnaz
authors.initials: S
authors.lastname: Murad
authors.forename: Jasbir Singh
authors.initials: JS
authors.lastname: Dhaliwal
authors.forename: Per Tobias
authors.initials: PT
authors.lastname: Larsson
authors.forename: Nor Asiah
authors.initials: NA
authors.lastname: Muhamad
authors.forename: Nor Aini
authors.initials: NA
authors.lastname: Abdullah
authors.forename: Amal Nasir
authors.initials: AN
authors.lastname: Mustafa
authors.forename: Lars
authors.initials: L
authors.lastname: Klareskog
authors.forename: Lars
authors.initials: L
authors.lastname: Alfredsson
authors.forename: Leonid
authors.initials: L
authors.lastname: Padyukov
authors.forename: Camilla
authors.initials: C
authors.lastname: Bengtsson
mesh_terms: D000328:Adult; D001172:Arthritis, Rheumatoid / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology; D001323:Autoantibodies / Q000096:biosynthesis*; D016022:Case-Control Studies; D002956:Citrulline / Q000378:metabolism; D000939:Epitopes / Q000276:immunology / Q000378:metabolism*; D005260:Female; D059811:HLA-DRB1 Chains / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008296:Malaysia / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D012907:Smoking / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology
chemical_list: D001323:Autoantibodies; D000939:Epitopes; D059811:HLA-DRB1 Chains; C493960:HLA-DRB1*04:05 antigen; D002956:Citrulline