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Rheumatoid Arthritis
Gene–environment interaction between the DRB1 shared epitope and smoking in the risk of anti–citrullinated protein antibody–positive rheumatoid arthritis: All alleles are important
Article first published online: 28 MAY 2009
DOI: 10.1002/art.24572
Copyright © 2009 by the American College of Rheumatology
1529-0131/asset/cover.gif?v=1&s=104d5c2bb8ef72deba26790b855af7ab80697a0e "Arthritis & Rheumatism")
Additional Information
How to Cite
Lundström, E., Källberg, H., Alfredsson, L., Klareskog, L. and Padyukov, L. (2009), Gene–environment interaction between the DRB1 shared epitope and smoking in the risk of anti–citrullinated protein antibody–positive rheumatoid arthritis: All alleles are important. Arthritis & Rheumatism, 60: 1597–1603. doi: 10.1002/art.24572
Publication History
- Issue published online: 28 MAY 2009
- Article first published online: 28 MAY 2009
- Manuscript Accepted: 9 MAR 2009
- Manuscript Received: 3 JUN 2008
Funded by
- Swedish Research Council. Grant Number: 521-2006-5752
- Swedish Council for Working Life and Social Research
- NIH. Grant Numbers: P60-AR-47782, P60-AR-47782
- IMAGEN project. Grant Number: U19-AI-067152
- European Union Sixth Framework Programme (AutoCure project)
- Swedish Combine program
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- Cited By
Abstract
Objective
An interaction effect for developing rheumatoid arthritis (RA) was previously observed between HLA–DRB1 shared epitope (SE) alleles and smoking. We aimed to further investigate this interaction between distinct SE alleles and smoking regarding the risk of developing RA with and without anti–citrullinated protein antibodies (ACPAs).
Methods
We used data regarding smoking habits and HLA–DRB1 genotypes from 1,319 patients and 943 controls from the Epidemiological Investigation of Rheumatoid Arthritis, in which 972 patients and 488 controls were SE positive. Subsequently, 759 patients and 328 controls were subtyped for specific alleles within the DRB1*04 group. Odds ratios with 95% confidence intervals (95% CIs) were calculated by means of logistic regression. Interaction was evaluated by calculating attributable proportion due to interaction, with 95% CIs.
Results
A strong interaction between smoking and SE alleles in the development of ACPA-positive RA was observed for all DRB1*04 SE alleles taken as a group (relative risk [RR] 8.7 [95% CI 5.7–13.1]) and for the *0401 and *0404 alleles (RR 8.9 [95% CI 5.8–13.5]) and the *01 and *10 alleles (RR 4.9 [95% CI 3.0–7.8]) as specific, separate groups, with similar strength of interaction for the different groups (attributable proportion due to interaction 0.4 [95% CI 0.2–0.6], 0.5 [95% CI 0.3–0.7], and 0.6 [95% CI 0.4–0.8], respectively).
Conclusion
There is a statistically significant interaction between distinct DRB1 SE alleles and smoking in the development of ACPA-positive RA. Interaction occurs with the *04 group as well as the *01/*10 group, demonstrating that regardless of fine specificity, all SE alleles strongly interact with smoking in conferring an increased risk of ACPA-positive RA.