Abstract
ObjectiveGlutathione-S-transferases (GSTs) play an important role in tobacco smoke detoxification, interestingly approximately 50% of individuals in most human populations lack the gene GSTM1 due to copy number variation (CNV). We aimed to investigate GSTM1 CNV in Rheumatoid Arthritis (RA) in relation to smoking and HLA-DRB1 shared epitope; the two best known risk factors for RA and in addition, to perform subanalyses in patients where relations between variations in GSTM1 and RA have previously been described.MethodsqPCR was performed using TaqMan Copy Number assays (Applied Biosystems) for 2426 incident RA cases and 1257 controls from the Swedish EIRA. Odds ratio (OR) together with 95% confidence intervals (CI) was calculated and used as a measure of the relative risk of developing RA.ResultsNo association between RA and GSTM1 CNV was observed when analyzing whole EIRA. However, ≥1 copy of GSTM1 appears to be a significant risk factor for autoantibody positive RA in non-smoking females ≥60 years (OR: 2.00 95% CI: 1.07–3.74), a population where such relationships have previously been described. Our data further suggest a protective effect of GSTM1 in ACPA-negative smoking men (OR: 0.56 95% CI: 0.35–0.90).ConclusionWe assessed the exact number of GSTM1 gene copies in relation to development and severity of RA. Our data provide support for the notion that variations in copy numbers of GSTM1 may influence risk in certain subsets of RA, but do not support a role for GSTM1 CNV as a factor that more generally modifies the influence of smoking on RA.
Highlights
Rheumatoid arthritis (RA) is characterized by chronic inflammation of synovial joints, resulting in progressive destruction of cartilage and bone
No significant association was detected with development of RA, neither alone (OR: 0.93 95% confidence intervals (CI): 0.81–1.06) or after stratification by smoking status (ORever smoker: 0.92 95% CI: 0.76–1.11) (ORnever smoker: 0.93 95% CI: 0.72–1.21) or by the shared epitope alleles (SE) alleles (ORno SE: 0.93 95% CI: 0.74–1.16) (ORyes SE: 0.91 95% CI: 0.76–1.09) (Table 1)
We compared individuals with no copies of Glutathione S-transferase M1 (GSTM1) with individuals with $2 copies and found similar results; GSTM1 copy number variation (CNV) and development of RA Odds ratio (OR): 0.95 95% CI: 0.74–1.24, smoking (ORever smoker: 0.94 95% CI: 0.66–1.36) (ORnever smoker: 1.02 95% CI: 0.64–1.65) and SE (ORno SE: 1.06 95% CI: 0.68–1.65) (ORyes SE: 0.84 95% CI: 0.60–1.17)
Summary
Rheumatoid arthritis (RA) is characterized by chronic inflammation of synovial joints, resulting in progressive destruction of cartilage and bone. ROS are produced by phagocytes in the synovial fluid and pannus and by synovial endothelial cells during hypoxia-reperfusion events This means that variations in host effectiveness in detoxification of products of ROS activity might be important and there is growing evidence that ROS and their by-products may play a direct role in the development of RA [8,9]. An alternative view on oxidative mechanisms was developed when upregulation of NcfI in a rat model for arthritis was shown to be protective [10] These data indicate that genetic differences in oxidative events may modulate the risk and/or severity of RA, and that several mechanisms may be involved, some even working in opposite directions. Since genetic polymorphisms of enzymes such as glutathione S-transferases (GSTs) have been shown to have an important role in detoxifying foreign substances from tobacco smoke, influencing susceptibility to both lung and colon cancer [11,12] it is tempting to speculate that such polymorphisms may be of importance for the development of RA, and that such influences may be very complex [13]
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