Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2009 Jun;60(6):1597-603.
doi: 10.1002/art.24572.

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

Emeli Lundström  1 , Henrik Källberg, Lars Alfredsson, Lars Klareskog, Leonid Padyukov
Affiliations

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

Emeli Lundström et al. Arthritis Rheum. 2009 Jun.

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.

PubMed Disclaimer

Figures

Fig 1
Fig 1
Relative risk and 95% CI in smokers and non-smokers having zero, one or two copies of the SE alleles HLA-DRB1*0401 and *0404.
See this image and copyright information in PMC

References

    1. Begovich AB, Carlton VE, Honigberg LA, Schrodi SJ, Chokkalingam AP, Alexander HC, et al. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet. 2004;75(2):330–7. - PMC - PubMed
    1. Plenge RM, Padyukov L, Remmers EF, Purcell S, Lee AT, Karlson EW, et al. Replication of putative candidate-gene associations with rheumatoid arthritis in >4,000 samples from North America and Sweden: association of susceptibility with PTPN22, CTLA4, and PADI4. Am J Hum Genet. 2005;77(6):1044–60. - PMC - PubMed
    1. Remmers EF, Plenge RM, Lee AT, Graham RR, Hom G, Behrens TW, et al. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med. 2007;357(10):977–86. - PMC - PubMed
    1. Plenge RM, Seielstad M, Padyukov L, Lee AT, Remmers EF, Ding B, et al. TRAF1-C5 as a risk locus for rheumatoid arthritis--a genomewide study. N Engl J Med. 2007;357(12):1199–209. - PMC - PubMed
    1. Burton PR, Clayton DG, Cardon LR, Craddock N, Deloukas P, Duncanson A, et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet. 2007;39(11):1329–37. - PMC - PubMed

Publication types