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.
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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)