Elsevier

Gene

Volume 521, Issue 1, 25 May 2013, Pages 155-159
Gene

Association between the polymorphisms of glutathione S-transferase genes and rheumatoid arthritis: A meta-analysis

https://doi.org/10.1016/j.gene.2013.03.023Get rights and content

Abstract

The glutathione S-transferases (GSTs) are a family of phase II xenobiotic metabolizing enzymes known to be involved in the detoxification and elimination of reactive oxygen species (ROS), thus defending tissues against oxidative stress. Recently, several studies have examined the potential contributions of GSTM1 and GSTT1 gene polymorphisms toward susceptibility to rheumatoid arthritis (RA), but these studies have produced diverse results. To verify the association between GSTM1 and GSTT1 gene polymorphisms and susceptibility to RA, we conducted a meta-analysis of all relevant reports cited in MEDLINE/PubMed before April 2012. A meta-analysis on the association between the GSTM1 polymorphism and RA was performed for 4636 patients with RA and 3916 controls from 8 published studies. In addition, a total of 5 studies involving 3174 RA patients and 2958 controls were considered in the meta-analysis of the association between the GSTT1 polymorphism and RA. No significant association was found between the GSTM1 null genotype and RA susceptibility in all subjects; however, a significant increased risk was found in East Asians. The GSTT1 null genotype was not associated with susceptibility to RA in any study subject. No apparent effect of smoking was found in stratified analysis. The results of our meta-analysis indicated that the GSTM1 null genotype is significantly associated with RA in East Asians alone, indicating that GSTM1 is another non-human leukocyte antigen (non-HLA) susceptibility gene for RA in East Asian populations.

Introduction

Rheumatoid arthritis (RA) is a common autoimmune disease characterized by chronic inflammation of synovial joints, which leads to progressive destruction of cartilage and bone. The precise etiology of RA is not completely known, but previous genetic and family studies have indicated that a number of genetic predisposing factors contribute to its development (de Vries et al., 2011; Kochi et al., 2009; McInnes and Schett, 2011). The contribution of genetic components to RA susceptibility was previously estimated to be approximately 60% (MacGregor et al., 2000). Among the genes involved in RA susceptibility, the human leukocyte antigen (HLA) class II genes have been identified as the most significant, with a contribution to the genetic susceptibility of RA that has been estimated to be approximately 37% (Deighton et al., 1989). In addition to HLA class II genes, about 30 non-HLA loci contributing to RA susceptibility have been identified, and their contribution to genetic susceptibility may be approximately 5% (Stahl et al., 2010). Therefore, known genetic factors explain about 40% of the genetic susceptibility of RA, indicating that additional genetic risk factors remain to be identified (de Vries et al., 2011, Stahl et al., 2010). As with most autoimmune diseases, environmental factors trigger the development of RA in the genetically predisposed individuals. Cigarette smoking appears to be the most well-established environmental factor for modifying RA, and has been associated with both susceptibility to and severity of RA (Costenbader et al., 2006, Karlson et al., 1999, Saag et al., 1997).

Glutathione S-transferases (GST) are a family of phase II xenobiotic metabolizing enzymes known to catalyze the conjugation of glutathione to electrophilic compounds including carcinogens, environmental toxins, and reactive oxygen species (ROS) (Hayes and Pulford, 1995, Strange et al., 2001). GSTs are involved in the detoxification and elimination of ROS, and thus in defending tissues against oxidative stress (Minelli et al., 2011). In humans, 8 distinct gene families encode these GSTs, including alpha on chromosome 6, mu on chromosome 1, theta on chromosome 22, pi on chromosome 11, zeta on chromosome 14, sigma on chromosome 4, kappa (chromosomal location not known), and chi (also called omega) on chromosome 10, and several polymorphisms have been identified in the genes of these families (Strange et al., 2001). The most common polymorphism in GSTM1 is a deletion of the whole gene (null genotype), resulting in no functional activity of the enzyme (Hayes and Strange, 2000, Rebbeck, 1997). A homozygous deletion in GSTT1 has also been reported. These 2 common deletion polymorphisms of GSTM1 and GSTT1 may be associated with increased sensitivity to toxic compounds such as ROS and the decreased function of GSTM1 and GSTT1 resulting from these polymorphisms may be associated with an increased susceptibility to certain diseases influenced by endogenous and exogenous toxic compounds, such as tobacco-associated cancers, colorectal cancer, asthma, and chronic obstructive pulmonary disease (COPD) (Carlsten et al., 2008, Cotton et al., 2000, Minelli et al., 2011, Xue et al., 2012, Zhang et al., 2011). Several lines of evidence suggest that ROS are involved in the pathogenesis of RA (Griffiths, 2008, Hitchon and El-Gabalawy, 2004). Therefore, it has been proposed that increased susceptibility to RA may be expected in individuals with decreased elimination of ROS due to deletion polymorphisms of GSTM1 and GSTT1 genes. A number of studies have examined the contributions made by GSTM1 and GSTT1 polymorphisms to RA susceptibility but have generated inconsistent results (Criswell et al., 2006, Ghelani et al., 2011, Keenan et al., 2010, Lundstrom et al., 2011, Mattey et al., 1999, Mikuls et al., 2012, Morinobu et al., 2006, Yun et al., 2005). Therefore, we performed a meta-analysis on the published studies to clarify whether the deletion polymorphisms of GSTM1 or GSTT1 genes increase the risk of RA.

Section snippets

Data collection

We have included studies on the association between GSTM1 and GSTT1 polymorphisms and RA published before April 2012 searched in PubMed using a combination of keywords such as “GSTM1” and “Rheumatoid arthritis” or “GSTT1” and “Rheumatoid arthritis” without restriction on the language. We also tried to identify additional studies by hand-searching references of original articles or review articles on this topic. From the literature search we identified 8 publications for meta-analysis on the

Characteristics of included studies

Nineteen relevant studies, which investigated the association between GSTM1 and RA or the association between GSTT1 and RA, were identified using PubMed. Based on title and abstract details, 8 studies were selected for the meta-analysis on the association between GSTM1 gene polymorphism and RA and 5 studies were selected for the meta-analysis on the association between GSTT1 gene polymorphism and RA. Detailed characteristics of each selected study are described in Table 1. One study on the

Discussion

In this study, we addressed the association between GSTM1 and GSTT1 gene polymorphisms and susceptibility to RA. To the best of our knowledge, this is the first meta-analysis to investigate the association of GSTM1 and GSTT1 gene polymorphisms with RA, and the influence of these gene polymorphisms on RA susceptibility in different ethnic populations. Meta-analysis of the GSTM1 polymorphism showed no association with RA in the overall study populations or in Caucasians but detected a significant

Conflict of interest statement

The authors declare no conflicts of interest.

Acknowledgment

This study was supported by a Korea University grant.

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