Original ArticleGlutathione S-Transferase T1 (GSTT1) Null Polymorphism, Smoking, and Their Interaction in Coronary Heart Disease: A Comprehensive Meta-Analysis
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.
Section snippets
Search Strategy
A comprehensive search was conducted to identify all articles published before 27 January 2016 that investigated the association between GSTT1 null polymorphism and the risk of CHD. PubMed and MBASE databases were searched using the following terms: glutathione S-transferase, GST, GSTT1; genetic, polymorphism, variant; and coronary heart disease, CHD, coronary artery disease, myocardial infarction, ischaemic heart disease. We included the study with the largest sample subjects in case of
Identifying Studies and Study Characteristics
Figure 1 shows a flowchart presenting the study selection. With the search criterion, 217 articles were found, and 29 articles met the criteria for entering our study. One article [33] included three studies. Table 1 summarises the main study characteristics.
Smoking
There are 23 studies with 8,987 CHD cases and 12,462 controls concerning smoking and CHD risk [4], [5], [15], [16], [17], [18], [19], [20], [21], [23], [24], [25], [26], [28], [29], [30], [31], [32], [34], [37], [38], [39], [41]. There was
Discussion
In the present meta-analyses, we investigated the associations between GSTT1 null polymorphism, smoking, and CHD risk and evaluated the multiplicative interaction between GSTT1 null polymorphism and smoking. Our meta-analysis of 31 studies [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] with 15,004 CHD cases and 35,597 controls showed that the GSTT1 null genotype slightly
Conclusion
In conclusion, the present meta-analysis suggests that the null genotype of GSTT1 was associated with an increased 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. The results of present meta-analysis may have clinical impact in identifying people more prone to developing CHD and take timely, preventive and therapeutic measures. Future studies with detailed individual
Conflict of Interest
None declared.
Acknowledgements
We appreciate the contribution of all the members participating in this study.
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