Effects of GSTM1 in Rheumatoid Arthritis; Results from the Swedish EIRA study

PLOS ONE, Mar 2011

Objective Glutathione-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. Methods qPCR 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. Results No 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). Conclusion We 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.

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Effects of GSTM1 in Rheumatoid Arthritis; Results from the Swedish EIRA study

Results from the Swedish EIRA study. PLoS ONE 6(3): e17880. doi:10.1371/journal.pone.0017880 Effects of GSTM1 in Rheumatoid Arthritis; Results from the Swedish EIRA study Emeli Lundstro m 0 Toinette Hartshorne 0 Kelly Li 0 Staffan Lindblad 0 Marius C. Wick 0 Camilla Bengtsson 0 Lars Alfredsson 0 Lars Klareskog 0 Leonid Padyukov 0 Yehuda Shoenfeld, Sheba Medical Center, Israel 0 1 Department of Rheumatology, Karolinska Institutet, Stockholm, Sweden , 2 Applied Biosystems, Foster City , California, United States of America, 3 Department of Radiology, Innsbruck Medical University , Innsbruck , Austria , 4 Institute of Environmental Medicine, Karolinska Institutet , Stockholm , Sweden Objective: Glutathione-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. Methods: qPCR 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. Results: No 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). Conclusion: We 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. - Funding: This study was supported in part by the Swedish Research Council, the Swedish Rheumatism Foundation, the AFA insurance company, the Swedish Combine program, and the EUFp6 funded Autocure program. LP is supported by the Swedish Research Council grant 521-2006-5752. Applied Biosystems provided reagents for genotyping of GSTM1 for this study. No additional external funding was received for this study. Competing Interests: Applied Biosystems (AB) provided reagents for genotyping of GSTM1 for this study. Toinette Hartshorne and Kelly Li are employed by AB. Neither AB nor any of its employees had a role in study design, data collection and analysis, decision to publish. Toinette Hartshorne and Kelly Li were involved in preparation of the manuscripts and are co-authors for this paper. This does not alter the authors adherence to all the PLoS ONE policies on sharing data and materials. Rheumatoid arthritis (RA) is characterized by chronic inflammation of synovial joints, resulting in progressive destruction of cartilage and bone. Increasing evidence exist that genes and environment interact in the development of the disease, and also that two major subsets of RA exists defined by presence/absence of antibodies to citrullinated protein antigens (ACPAs) [1]. In particular, a smoking history together with the shared epitope alleles (SE) of the HLA-DRB1 locus in the major histocompatibility complex have repeatedly been found to strongly increase the risk of developing RA, in ACPA-positive RA [2,3,4,5,6,7]. A central feature of RA is inflammation with the resulting reactive oxygen species (ROS), which causes oxidation of macromolecules giving rise to a variety of cytotoxic products. 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 (...truncated)


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Emeli Lundström, Toinette Hartshorne, Kelly Li, Staffan Lindblad, Marius C. Wick, Camilla Bengtsson, Lars Alfredsson, Lars Klareskog, Leonid Padyukov. Effects of GSTM1 in Rheumatoid Arthritis; Results from the Swedish EIRA study, PLOS ONE, 2011, 3, DOI: 10.1371/journal.pone.0017880