Smoking and disease severity in rheumatoid arthritis: Association with polymorphism at the glutathione S-transferase M1 locus

Staffordshire Rheumatology Centre, Stoke-on-Trent, UK.
Arthritis & Rheumatology (Impact Factor: 7.76). 03/2002; 46(3):640-6. DOI: 10.1002/art.10174
Source: PubMed

ABSTRACT To determine whether the relationship between smoking and disease severity in women with rheumatoid arthritis (RA) is associated with polymorphism at the glutathione S-transferase (GST) M1 locus.
Genotyping for GSTM1 was carried out using polymerase chain reaction methodology on 164 women with established RA. Smoking history was obtained on each patient. Radiographic damage was measured by the Larsen score, and functional outcome was assessed by the Health Assessment Questionnaire (HAQ). Data were analyzed by multiple regression analyses, with correction for age and disease duration.
Ever having smoked was associated with a worse radiographic and functional outcome than was never having smoked. Both past and current smoking were associated with increased disease severity. Stratification by GSTM1 status revealed that polymorphism at this locus affected the relationship between smoking and disease outcome measures. Patients who lacked the GSTM1 gene and had ever smoked had significantly higher Larsen and HAQ scores than did those who lacked the gene and had never smoked. Radiographic outcome in these patients was worse than that in patients who had the GSTM1 gene and who had smoked. The associations were not affected by correction for socioeconomic status. Rheumatoid factor (RF) production was found to be associated with smoking in only the GSTM1-null patients.
Our data suggest that disease outcome in female RA patients with a history of smoking is significantly worse than in those who have never smoked. Smoking was associated with the most severe disease in patients who carried the GSTM1-null polymorphism. This association may be due in part to a relationship between the GSTM1 polymorphism and RF production in smokers.

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Available from: Derek Mattey, Oct 15, 2014
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    • "Epidemiological studies suggest that smoking is an independent risk factor for RA, particularly in rheumatoid factor-positive individuals [27] [28]. Smokers with RA also appear likely to have more severe disease [29] [30]. A possible mechanism is that long-term exposure to cigarette smoke induces mechanisms that accelerate deimination of arginine to citrulline in pulmonary autoantigens, possibly via up-regulation of peptidylarginine–deiminase activity in macrophages [31]. "
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    ABSTRACT: The immune system must be able to discriminate between self and non-self. However, mechanisms of doing so sometimes fail, causing the activation and clonal expansion of autoreactive lymphocytes and the development of autoimmune conditions. Although some autoimmune diseases have heritable components, these components are not sufficient to develop an autoimmune condition. A variety of environmental factors have been described as possible triggers of autoimmune diseases, including drugs, infectious agents, smoking, vaccination and adjuvants. The aim of this chapter is to review the most common environmental factors associated with autoimmune diseases.
    Best practice & research. Clinical rheumatology 02/2012; 26(1):5-11. DOI:10.1016/j.berh.2012.01.010 · 2.60 Impact Factor
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    • "The absence of GSTM1 was previously found to be a risk factor for RA and a factor contributing to disease severity [16], [17]. Thus, our new findings do not confirm some of the previous studies in relation to possible effect of GSTM1 CNV. "
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    ABSTRACT: 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. 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. 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). 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.
    PLoS ONE 03/2011; 6(3):e17880. DOI:10.1371/journal.pone.0017880 · 3.23 Impact Factor
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    • "Associations of glutathione S-transferase polymorphisms with RA have been the subject of several other investigations [12-15,38,39], although none of these have examined the association of GSTM1 status with ACPA-positive disease. This study is the first to show that the GSTM1-null genotype, present in approximately one half of all individuals of European ancestry, shows a significant biologic interaction with HLA-DRB1 SE-containing alleles with reference to the risk of ACPA positivity in RA. "
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    ABSTRACT: A deletion polymorphism in glutathione S-transferase Mu-1 (GSTM1-null) has previously been implicated to play a role in rheumatoid arthritis (RA) risk and progression, although no prior investigations have examined its associations with anticitrullinated protein antibody (ACPA) positivity. The purpose of this study was to examine the associations of GSTM1-null with ACPA positivity in RA and to assess for evidence of interaction between GSTM1 and HLA-DRB1 shared epitope (SE). Associations of GSTM1-null with ACPA positivity were examined separately in two RA cohorts, the Veterans Affairs Rheumatoid Arthritis (VARA) registry (n = 703) and the Study of New-Onset RA (SONORA; n = 610). Interactions were examined by calculating an attributable proportion (AP) due to interaction. A majority of patients in the VARA registry (76%) and SONORA (69%) were positive for ACPA with a similar frequency of GSTM1-null (53% and 52%, respectively) and HLA-DRB1 SE positivity (76% and 71%, respectively). The parameter of patients who had ever smoked was more common in the VARA registry (80%) than in SONORA (65%). GSTM1-null was significantly associated with ACPA positivity in the VARA registry (odds ratio (OR), 1.45; 95% confidence interval (CI), 1.02 to 2.05), but not in SONORA (OR, 1.00; 95% CI, 0.71 to 1.42). There were significant additive interactions between GSTM1 and HLA-DRB1 SE in the VARA registry (AP, 0.49; 95% CI, 0.21 to 0.77; P < 0.001) in ACPA positivity, an interaction replicated in SONORA (AP, 0.38; 95% CI, 0.00 to 0.76; P = 0.050). This study is the first to show that the GSTM1-null genotype, a common genetic variant, exerts significant additive interaction with HLA-DRB1 SE on the risk of ACPA positivity in RA. Since GSTM1 has known antioxidant functions, these data suggest that oxidative stress may be important in the development of RA-specific autoimmunity in genetically susceptible individuals.
    Arthritis research & therapy 11/2010; 12(6):R213. DOI:10.1186/ar3190 · 3.75 Impact Factor
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