Glutathione S-Transferase T1 (GSTT1) Null Polymorphism, Smoking, and Their Interaction in Coronary Heart Disease: A Comprehensive Meta-Analysis

Background

The association between glutathione S-transferase T1 (GSTT1) null polymorphism and coronary heart disease (CHD) is inconsistent among studies, and data on the GSTT1 null genotype-smoking interplay in CHD is lacking. We conducted this meta-analysis to investigate the relationship between GSTT1 null polymorphism and CHD and to assess the potential interaction between GSTT1 null genotype and smoking.

Methods

PubMed and EMBASE databases were searched up to 27 January 2016 using the appropriate terms. Odds ratios were pooled using either fixed-effects or random-effects models.

Results

Twenty-nine articles including 31 studies with 15,004 cases and 35,597 controls were eligible. The random-effects model showed that the GSTT1 null genotype was associated with increased CHD risk (OR = 1.213, 95%CI: 1.004-1.467; I² = 90.4%). After excluding 10 studies detected by Galbraith plot, the fixed effects summary estimate also showed an increased risk of CHD (OR = 1.14, 95% CI: 1.06-1.22; I² = 27.7%). A case-only analysis including eight studies showed a statistically significant positive interaction between GSTT1 null polymorphism and smoking status on CHD (OR = 1.34, 95% CI: 1.09-1.64; I² = 0%). Sensitivity analyses further supported the associations. No publication bias was observed.

Conclusions

This meta-analysis suggests that GSTT1 null polymorphism is associated with the risk of CHD. To our knowledge, this is the first meta-analysis to prove a positive effect of the interaction between GSTT1 null genotype and smoking status on the risk of CHD. Future studies with detailed individual information are needed to confirm our findings.

Introduction

Coronary heart disease (CHD), which is the main cause of morbidity and mortality, is a major health problem worldwide. The interaction between predisposing genes and multiple environmental influences may contribute to the development of CHD [1], [2].

It is well known that cigarette smoking is one of the powerful environmental risk factors for CHD [3]. Multiple chemicals in tobacco smoke can cause excessive generation of reactive oxygen species (ROS) that results in smooth muscle cell proliferation, DNA damage, inflammation, and lipid peroxidation, which all lead to atherosclerosis and, hence, CHD [4], [5]. Moreover, mutagens in tobacco smoke can cause DNA adducts that have been detected in atherosclerotic plaques [6] and in severe CAD patients [7], suggesting they are involved in the underlying patho-physiological mechanisms of cardiovascular disease [8].

Glutathione S-transferases (GSTs) are a group of phase II detoxifying enzymes which play vital roles in protecting the cell against xenobiotics generated by smoking [9]. Glutathione S-transferases are usually regarded as antioxidants which are involved in detoxification reactions of electrophilic substrates in cigarette smoke through conjugation to glutathione [9], [10]. Furthermore, GSTs can protect DNA from genotoxic damage by modulating generation of DNA adducts [11].

Human GST enzymes are coded for at eight loci: GSTA(alpha), GSTK(kapa), GSTM(mu), GSTO(omega), GSTP(pi), GSTS(sigma), GSTT(theta) and GSTZ(zeta) genes [12]. Their expression and functional activities, possibly influenced by the genetic variants of GSTs, may be associated with susceptibility to CHD [13]. Among them, the glutathione S-transferase T1 (GSTT1) is located on chromosomes 22q11.2 and two alleles (GSTT1*0 and GSTT1*1) have been identified at GSTT1 locus. The null polymorphism of GSTT1 gene can lead to the lack of functional enzyme [14], and thus it was hypothesised to be associated with smoking-related CHD [15], [16], [17].

Numerous case-control studies have investigated the association between the GSTT1 null genotype and risk of CHD but have not reached unanimous conclusions [4], [5], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], and data on the interaction between the GSTT1 null genotype and smoking are lacking. Regarding the association between GSTT1 null genotype and CHD, two meta-analyses suggested that a non-significant association existed between GSTT1 null genotype and CHD risk [42], [43]. Several additional relevant studies examining GSTT1 have been published thereafter [20], [25], [27], [28], [41], and the multiplicative interaction between GSTT1 null polymorphism and smoking was not clear. Therefore, we conducted the present meta-analysis to investigate the relationship between GSTT1 null polymorphism and the risk of CHD, and to investigate the GSTT1 null genotype-smoking interplay.