A gene-environment interaction between smoking and shared epitope genes in HLA-DR provides a high risk of seropositive rheumatoid arthritis.

By L. Padyukov, Camilla Silva, P. Stolt, L. Alfredsson, L. Klareskog. Arthritis & Rheumatism, 2004

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OBJECTIVE The main genetic risk factor for rheumatoid arthritis (RA) is the shared epitope (SE) of HLA-DR, while smoking is an important environmental risk factor. We studied a potential gene-environment interaction between SE genes and smoking in the etiology of the 2 major subgroups of RA: rheumatoid factor (RF)-seropositive and RF-seronegative disease. METHODS A population-based case-control study involving incident cases of RF-seropositive and RF-seronegative RA (858 cases and 1,048 controls) was performed in Sweden. Cases and controls were classified according to their cigarette smoking status and HLA-DRB1 genotypes. The relative risk of developing RA was calculated for different gene/smoking combinations and was compared with the relative risk in never smokers without SE genes. RESULTS The relative risk of RF-seropositive RA was 2.8 (95% confidence interval [95% CI] 1.6-4.8) in never smokers with SE genes, 2.4 (95% CI 1.3-4.6) in current smokers without SE genes, and 7.5 (95% CI 4.2-13.1) in current smokers with SE genes. Smokers carrying double SE genes displayed a relative risk of RF-seropositive RA of 15.7 (95% CI 7.2-34.2). The interaction between smoking and SE genes was significant, as measured by the attributable proportion due to interaction, which was 0.4 (95% CI 0.2-0.7) for smoking and any SE, and 0.6 (95% CI 0.4-0.9) for smoking and a double SE. Neither smoking nor SE genes nor the combination of these factors increased the risk of developing RF-seronegative RA. CONCLUSION The disease risk of RF-seropositive RA associated with one of the classic genetic risk factors for immune-mediated diseases (the SE of HLA-DR) is strongly influenced by the presence of an environmental factor (smoking) in the population at risk.

Subfields: Genetics, Immunology, Rheumatology

View Paper: https://www.semanticscholar.org/paper/3b305200e1ed112990728284e49122d658d19f13

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Citations in the corpus

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. (2005, methodology): “—Details on the EIRA cohort (Stolt et al. 2003; Padyukov et al. 2004) and NARAC cohort”
Five years of GWAS discovery. (2012, background): “CTLA4 (MIM 123890) and CD28 (MIM 186760) polymorphisms are associated with RA.”
A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. (2006, methodology): “RFs deserve special attention, since they are part of the definition of RA (19), since the presence of both HLA–DR SE genes and smoking has previously been linked to RF-positive RA (8), and since the presence of anticitrulline antibodies correlates with, 44 KLARESKOG ET AL”
Calculating measures of biological interaction (2005, background): “The example investigates the possible biological interaction between one gene and smoking in relation to rheumatoid arthritis [7].”
Management of Rheumatoid Arthritis: An Overview (2021, background): “Moreover, the risk of developing ACPA-positive RA is much higher in smokers who carry HLA-DR Beta 1 shared epitope alleles [52].”