Impact of Shared Epitope Genes and Smoking on Risk of Seropositive RA Development
Both cigarette smoking and the shared epitope of RA, an inherited sequence of amino acids from codons 67 to 74 of the DRB1 chain (component of some MHC class II molecules such as DR4 and DR1) are associated with an increased risk of developing RA. Here, Padyukov et al (Arthritis Rheum 50(10):3085, 2004) define an interaction between cigarette smoking and the shared epitope associated with an increased risk of developing RF-seropositive RA.
Methods: Randomly selected subjects from the Swedish national population register were matched based on age, sex, and residential area to RA patients enrolled in an early arthritis cohort from middle and southern Sweden from May 1996 to February 2001. Cigarette smoking status (current or never) was obtained by questionnaire for all subjects. HLA-DRB1 genotyping was performed on all subjects submitting blood samples (98% of cases and 60% of controls). RF status was determined in RA subjects. The index year for the onset of RA was defined as the time point of the initial appearance of symptoms indicative of RA. For the analysis, genotype and smoking status were compared with regard to the incidence of RA.
Results: Of the 900 identified RA patients, 858 (612 women and 246 men) completed questionnaires concerning smoking habits. 66% of RA patients were seropositive for RF near the time of diagnosis. 1,048 controls (736 women and 312 men) completed questionnaires concerning smoking habits. 97% of all patients were Caucasian; most born in Sweden.
Current smokers demonstrated an increased risk of developing RF-seropositive RA compared to never smokers (RR 2.2, 95% CI 1.7 3.0). Current smoking was not a risk factor for developing seronegative RA.
Subjects possessing one shared epitope gene demonstrated an increased for developing RF-seropositive RA (RR 2.5, 95% CI 1.9 3.3) compared to subjects with no shared epitope genes. The risk was higher for subjects with two inherited shared epitope genes (RR 6.0, 95% CI 4.2 8.5). Shared epitope gene inheritance was not a risk factor for seronegative RA.
Current smokers with shared epitope genes demonstrated an even greater risk of developing RF-seropositive RA compared to never smokers without shared epitope genes (RR 5.5, 95% CI 3.0 -10.0 for single shared epitope genes, RR 15.7, 95% CI 7.2 34.2 for double shared epitope genes). Neither smoking, shared epitope genes, nor the combination of these conveyed an increased risk of RF-seronegative RA.
Conclusion: The combination of cigarette smoking the inheritance of shared epitope genes increases the risk of RF-seropositive RA in a dose dependent fashion.
Editorial Comment: This investigation identifies a striking interaction between genetic inheritance and an environmental exposure on the risk of developing seropositive (but not seronegative) RA. In particular, the 15 times higher risk associated with double inheritance of shared epitope genes and smoking is quite dramatic.
The physiologic basis behind this risk is not known. Many potential mechanisms are possible; including the possibility that chemicals in cigarette smoke may promote citrullination of some peptides that, in turn, unmask neoepitopes that are antigenic in the context of MHC Class II molecules containing the shared epitope, leading to the clonal expansion of autoreactive T cells. It would have been interesting in this regard if the investigators had tested for anti-CCP antibody status in addition to RF status.
The relative risk for incident RA risk conferred by HLA-DRB1 alleles differs for different populations. In addition, loci in the MHC other than HLA-DRB1 that encode shared epitope alleles (eg HLA-DQ), and other non-HLA genes such as those coding for tumor necrosis factor (TNF), may also play a role in disease susceptibility. Therefore, these results will require confirmation in populations outside of Scandinavia before they can be generalized.