Null genotypes of GSTM1 and GSTT1 contribute to increased risk of diabetes mellitus: A meta-analysis

Abstract

Diabetes mellitus (DM) is a common disease which results from various causes including genetic and environmental factors. Glutathione S-Transferase M1 (GSTM1) and Glutathione S-Transferase T1 (GSTT1) genes are polymorphic in human and the null genotypes lead to the absence of enzyme function. Many studies assessed the associations between GSTM1/GSTT1 null genotypes and DM risk but reported conflicting results. In order to get a more precise estimate of the associations of GSTM1/GSTT1 null genotypes with DM risk, we performed this meta-analysis. Published literature from PubMed, Embase and China Biology Medicine (CBM) databases was searched for eligible studies. Pooled odds ratios (OR) and corresponding 95% confidence intervals (95%CI) were calculated using a fixed- or random-effects model. 11 publications (a total of 2577 cases and 4572 controls) were finally included into this meta-analysis. Meta-analyses indicated that null genotypes of GSTM1/GSTT1 and dual null genotype of GSTM1–GSTT1 were all associated with increased risk of DM (GSTM1: OR _{random-effects} = 1.60, 95%CI 1.10–2.34, P_OR = 0.014; GSTT1: OR _{random-effects} = 1.47, 95%CI 1.12–1.92, P_OR = 0.005; GSTM1–GSTT1: OR _{fixed-effects} = 1.83, 95%CI 1.30–2.59, P_OR = 0.001). Subgroup by ethnicity suggested significant associations between null genotypes of GSTM1 and GSTT1 and DM risk among Asians (GSTM1: OR _{random-effects} = 1.77, 95%CI 1.24–2.53, P_OR = 0.002; GSTT1: OR _{random-effects} = 1.58, 95%CI 1.09–2.27, P_OR = 0.015). This meta-analysis suggests null genotypes of GSTM1/GSTT1 and dual null genotype of GSTM1–GSTT1 are all associated with increased risk of DM, and null genotypes of GSTM1/GSTT1 and dual null genotype of GSTM1–GSTT1 are potential biomarkers of DM.

Introduction

Diabetes mellitus (DM), which is estimated that 347 (314–382) million adults are suffering from (Danaei et al., 2011), has become an important cause of mortality and morbidity worldwide, through both direct clinical sequelae and increased mortality from cardiovascular and kidney diseases (Danaei et al., 2006, Khaw et al., 2004, Lawes et al., 2004, Nakagami, 2004). DM results from body's ineffective use of insulin, which is determined by several different genes and environmental factors. Causes of the DM are both various and complex, and one of these causes is oxidative stress, arising as a result of an imbalance between free radicals and antioxidant defenses (West, 2000). As β-cells are very sensitive to cytotoxic stress because of their little expression of the antioxidant enzymes, they are susceptible to the oxidative stress attack, and the dysfunction of β-cells after oxidative stress attack may further result in the development of DM (Tiedge et al., 1997).

Glutathione S-Transferases (GSTs) are the most important family of phase II isoenzymes known to detoxify a variety of electrophilic compounds, including carcinogens, chemotherapeutic drugs, environmental toxins, and DNA products generated by reactive oxygen species damage to intracellular molecules, chiefly by conjugating them with glutathione (Hayes et al., 2005). GSTs play a major role in cellular antimutagen and antioxidant defense mechanisms (Baiocco et al., 2006). Glutathione S-Transferase M1 (GSTM1) and Glutathione S-Transferase T1 (GSTT1) genes are polymorphic in human and the null genotypes result in the absence of enzyme function, contributing to interindividual differences in response to xenobiotics (Binkova et al., 2007). In recent years many studies have assessed the associations between DM and GSTM1 and/or GSTT1 polymorphisms (Amer et al., 2011, Bekris et al., 2005, Bid et al., 2010, Datta et al., 2010, Hori et al., 2007, Hayek et al., 2006, Ramprasath et al., 2011, Wu et al., 2006, Wang et al., 2006, Yalin et al., 2007). Ramprasath T's study demonstrated significant associations between GSTM1/GSTT1 null genotypes and DM risk (Ramprasath et al., 2011), and similar results were also reported in other studies (Amer et al., 2011). However, some studies reported different conclusions and showed that there were no obvious associations between GSTM/GSTT1 null genotypes and DM risk (Bekris et al., 2005, Datta et al., 2010, Hori et al., 2007, Wu et al., 2006), or either GSTM1 or GSTT1 caught the associations (Bid et al., 2010, Hayek et al., 2006, Wang et al., 2006, Yalin et al., 2007). Thus, it remains unclear whether there are significant associations between GSTM1 and GSTT1 polymorphisms and DM risk.

Small genetic association studies have various designs, different methodology and insufficient power, and could inevitably increase the risk that chance could be responsible for their conclusions, while combining data from all eligible studies by meta-analysis has the advantage of reducing random error and obtaining precise estimates for some potential genetic associations. Therefore, there is a role for meta-analysis in pooling these studies, particularly to clarify the effects of GSTM1 and GSTT1 polymorphisms on DM risk. Hence, to address this controversial issue and get a more precise estimate of the associations of GSTM1/GSTT1 null genotypes with DM risk, we performed a meta-analysis of published data from available studies.