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Gene–environment interaction between HLA-DRB1 shared epitope and heavy cigarette smoking in predicting incident rheumatoid arthritis
  1. E W Karlson1,
  2. S-C Chang2,
  3. J Cui1,
  4. L B Chibnik1,
  5. P A Fraser1,3,4,
  6. I De Vivo2,5,
  7. K H Costenbader1
  1. 1
    Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
  2. 2
    Harvard School of Public Health, Boston, Massachusetts, USA
  3. 3
    Immune Disease Institute, Boston, Massachusetts, USA
  4. 4
    Genzyme Corporation, Boston, Massachusetts, USA
  5. 5
    Channing Laboratory, Brigham and Women’s Hospital, Boston, Massachusetts, USA
  1. Correspondence to E W Karlson, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA; ekarlson{at}


Background: Previous studies have reported an interaction between ever cigarette smoking and the presence of the human leukocyte antigen (HLA)-DRB1 shared epitope (SE) genotype and rheumatoid arthritis (RA) risk. To address the effect of dosage, a case-control study nested within two prospective cohorts to determine the interaction between heavy smoking and the HLA-SE was conducted.

Methods: Blood was obtained from 32 826 women in the Nurses’ Health Study and 29 611 women in the Nurses’ Health Study II. Incident RA diagnoses were validated by chart review. Controls were matched for age, menopausal status and postmenopausal hormone use. High-resolution HLA-DRB1 genotyping was performed for SE alleles. HLA-SE, smoking, HLA-SE* smoking interactions and RA risk, were assessed using conditional logistic regression models, adjusted for age and reproductive factors. Additive and multiplicative interactions were tested.

Results: In all, 439 Caucasian matched pairs were included. Mean age at RA diagnosis was 55.2 years; 62% of cases were seropositive. A modest additive interaction was observed between ever smoking and HLA-SE in seropositive RA risk. A strong additive interaction (attributable proportion due to interaction (AP) = 0.50; p<0.001) and significant multiplicative interaction (p = 0.05) were found between heavy smoking (>10 pack-years) and any HLA-SE in seropositive RA risk. The highest risk was in heavy smokers with double copy HLA-SE (odds ratio (OR) 7.47, 95% CI 2.77 to 20.11).

Conclusions: A strong gene–environment interaction was observed between HLA-SE and smoking when stratifying by pack-years of smoking rather than by ever smoking. Future studies should assess cumulative exposure to cigarette smoke when testing for gene–smoking interactions.

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  • ▸ Additional data (supplementary information) are published online only at

  • Funding Supported by NIH grants R01 AR49880, CA87969, P60 AR047782, K24 AR0524-01 and BIRCWH K12 HD051959 (supported by NIMH, NIAID, NICHD and OD). KHC is the recipient of an Arthritis Foundation/American College of Rheumatology Arthritis Investigator Award and a Katherine Swan Ginsburg Memorial Award.

  • Competing interests None declared.

  • Ethics approval Ethics approval was granted by the Partners Human Subjects Committee.

  • Provenance and Peer review Not commissioned; externally peer reviewed.