PMID- 19151010 OWN - NLM STAT- MEDLINE DCOM- 20100201 LR - 20220311 IS - 1468-2060 (Electronic) IS - 0003-4967 (Print) IS - 0003-4967 (Linking) VI - 69 IP - 1 DP - 2010 Jan TI - Gene-environment interaction between HLA-DRB1 shared epitope and heavy cigarette smoking in predicting incident rheumatoid arthritis. PG - 54-60 LID - 10.1136/ard.2008.102962 [doi] AB - 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. FAU - Karlson, E W AU - Karlson EW AD - Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA. ekarlson@partners.org FAU - Chang, S-C AU - Chang SC FAU - Cui, J AU - Cui J FAU - Chibnik, L B AU - Chibnik LB FAU - Fraser, P A AU - Fraser PA FAU - De Vivo, I AU - De Vivo I FAU - Costenbader, K H AU - Costenbader KH LA - eng GR - P60 AR047782-090005/AR/NIAMS NIH HHS/United States GR - CA87969/CA/NCI NIH HHS/United States GR - P60 AR047782/AR/NIAMS NIH HHS/United States GR - K24 AR052403/AR/NIAMS NIH HHS/United States GR - R01 AR49880/AR/NIAMS NIH HHS/United States GR - K12 HD051959-06/HD/NICHD NIH HHS/United States GR - R01 AR049880/AR/NIAMS NIH HHS/United States GR - K24 AR052403-07/AR/NIAMS NIH HHS/United States GR - R01 AR049880-08/AR/NIAMS NIH HHS/United States GR - K12 HD051959/HD/NICHD NIH HHS/United States GR - K24 AR0524-01/AR/NIAMS NIH HHS/United States GR - P01 CA087969/CA/NCI NIH HHS/United States PT - Journal Article PT - Multicenter Study PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - England TA - Ann Rheum Dis JT - Annals of the rheumatic diseases JID - 0372355 RN - 0 (Epitopes) RN - 0 (HLA-DR Antigens) RN - 0 (HLA-DRB1 Chains) SB - IM MH - Adult MH - Arthritis, Rheumatoid/epidemiology/*genetics/immunology MH - Case-Control Studies MH - Epitopes/genetics MH - Female MH - Genetic Predisposition to Disease MH - Genotype MH - HLA-DR Antigens/*genetics MH - HLA-DRB1 Chains MH - Humans MH - Middle Aged MH - Smoking/adverse effects/epidemiology/*genetics MH - United States/epidemiology PMC - PMC2952498 MID - NIHMS233988 COIS- Competing interests: None declared. EDAT- 2009/01/20 09:00 MHDA- 2010/02/02 06:00 PMCR- 2009/01/16 CRDT- 2009/01/20 09:00 PHST- 2009/01/20 09:00 [entrez] PHST- 2009/01/20 09:00 [pubmed] PHST- 2010/02/02 06:00 [medline] PHST- 2009/01/16 00:00 [pmc-release] AID - ard.2008.102962 [pii] AID - ar102962 [pii] AID - 10.1136/ard.2008.102962 [doi] PST - ppublish SO - Ann Rheum Dis. 2010 Jan;69(1):54-60. doi: 10.1136/ard.2008.102962.