RESEARCH - Gene-environment interaction between HLA-DRB1 shared epitope and heavy cigarette smoking in predicting incident RA

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Ann Rheum Dis. Published Online First: 16 January 2009.

doi:10.1136/ard.2008.102962

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Extended Report

Gene-environment interaction between HLA-DRB1 shared epitope and heavy

cigarette smoking in predicting incident RA

W Karlson 1*, Shun-Chiao Chang 2, Jing Cui 1, Lori B Chibnik

1, A. Fraser 3, Immaculata DeVivo 4 and H Costenbader 5

1 Brigham and Women's Hospital, United States

2 Harvard School of Public Health, United States

3 Brigham and Women's Hospital, Immune Disease Institute and Genzyme

Corporation, United States

4 Brigham and Women's Hospital; Harvard School of Public Health, United States

5 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.

http://ard.bmj.com/cgi/content/abstract/ard.2008.102962v1?papetoc

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