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Gene-environment interaction between HLA-DRB1 shared epitope and heavy cigarette smoking in predicting incident RA
  1. Elizabeth W Karlson (ekarlson{at}partners.org)
  1. Brigham and Women's Hospital, United States
    1. Shun-Chiao Chang (scchang{at}hsph.harvard.edu)
    1. Harvard School of Public Health, United States
      1. Jing Cui (jcui3{at}partners.org)
      1. Brigham and Women's Hospital, United States
        1. Lori B Chibnik (lchibnik{at}rics.bwh.harvard.edu)
        1. Brigham and Women's Hospital, United States
          1. Patricia A. Fraser (patricia.fraser{at}genzyme.com)
          1. Brigham and Women's Hospital, Immune Disease Institute and Genzyme Corporation, United States
            1. Immaculata DeVivo (devivo{at}hsph.harvard.edu)
            1. Brigham and Women's Hospital; Harvard School of Public Health, United States
              1. Karen H Costenbader (kcostenbader{at}partners.org)
              1. Brigham and Women's Hospital; Harvard Medical School, United States

                Abstract

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

                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 on age, menopausal status, and postmenopausal hormone use. High resolution HLA-DRB1 genotyping was performed for SE alleles. HLA-SE, smoking, and HLA-SE *smoking interactions, and RA risk, were assessed using conditional logistic regression models, adjusted for age and reproductive factors. We tested for additive and multiplicative interactions.

                Results: 439 Caucasian matched pairs were included. Mean age at RA diagnosis was 55.2 years; 62% of cases were seropositive. We observed a modest additive interaction between ever smoking and HLA-SE in seropositive RA risk. We found a strong additive interaction (attributable proportion due to interaction (AP) = 0.50; p = 0.0002) between heavy smoking (> 10 pack-years) and any HLA-SE in seropositive RA risk, and significant multiplicative interaction (p = 0.05). The highest risk was in heavy smokers with double copy HLA-SE (OR 7.47 [95% CI, 2.77-20.11]).

                Conclusion: We observed a strong gene-environment interaction 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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