Interactive effect of the glutathione S-transferase genes and cigarette smoking on occurrence and severity of coronary artery risk

Abstract

Cardiovascular diseases and cancer are the main causes of death in developed countries. Mortality trends for these diseases suggest that they share common pathogenetic mechanisms. Glutathione S-transferase (GST) is a family of enzymes that detoxify reactive electrophiles, particularly present in tobacco smoke. Glutathione S-transferase null M1 and T1 (GSTM1 and GSTT1) genotypes have often been associated with increased risk of developing cancer. Our hypothesis was that the polymorphic GSTM1 and GSTT1 genes modulate the risk of smoking-coronary artery disease (CAD). We evaluated the distribution of GST genotypes in 430 angiographically defined patients (308 CAD and 122 non-CAD). The frequencies of GST null genotypes did not differ significantly between patients with CAD and without CAD. However, smokers with GSTM1 and GSTT1 null genotypes had a significantly higher risk of CAD than never-smokers with these genotypes present (OR 2.2 and 3.4 for smokers with null GSTM1 and GSTT1 genes, respectively). There was also evidence of multiple interaction between GSTM1 and GSTT1 deleted genotypes and smoking. In nonsmokers carrying both null genotypes the risk of CAD was 0.66. In smokers with both present genotypes the OR was 1.5 and was significantly increased in smokers with concurrent lack for GSTM1 and GSTT1 genes (OR=4.0). Moreover, smokers lacking GST genes had both more stenosed vessels and a higher Duke score than smokers expressing the genes. We also examined the levels of DNA damage in 66 men patients using the micronucleus test, a sensitive assay for evaluating chromosome damage. Micronucleus levels were higher in smokers with null genes than in smokers with present genes. These observations suggest that GST-null genotypes strengthen the effect of smoking on CAD risk by modulating the detoxification of genotoxic atherogens.

Glutathione-S-transferase P protects against endothelial dysfunction induced by exposure to tobacco smoke

“…The association between the GST genotype and lung cancer is less clear, because both positive and negative data have been reported (34,38). Similarly, in some studies, the GSTM-null phenotype was associated with an increase in coronary artery disease in smokers (33), whereas in others the null phenotype has been reported to be associated with a decrease in risk of myocardial infarction in smokers (46). Although GSTM participates in the metabolism of several PAHs present in CS, many of the small reactive carbonyls present in CS, such as acrolein and crotonaldehyde, are preferentially conjugated by GSTP (8).…”

Analysis of selected glutathione S-transferase gene polymorphisms in Malaysian type 2 diabetes mellitus patients with and without cardiovascular disease

“…It has been demonstrated that individuals carrying the null GSTM1 allele are more susceptible to inflammatory pathologies and at increased risk of some smoking-related cancers. Smokers that lack the GSTM1 gene develop both CHD and atherosclerosis at higher rates (Salama et al, 2002;Masetti et al, 2003). Conversely, this hypothesis has been rejected in other studies, in which the null GSTM1 genotype has been associated with lower risk of myocardial infarction and peripheral vascular disease (Wilson et al, , 2003.…”

“…Pemble et al (1994) reported that approximately 20% of the white population is homozygous for a null variant of GSTT1, which is consistent with our findings (17.3 to 28.3%). The role of GSTT1 in deactivating the epoxides in cigarette smoke, together with its absence in smoking-related cancers, suggests that individuals homozygous for the null allele may be at higher risk of cancer (Salama et al, 2002;Masetti et al, 2003). However, other studies suggest that the absence of this gene is associated with a lower risk of damage and disease (Li et al, 2000;Olshan et al, 2003).…”

Effect of the GSTM1 genotype on the biomarkers of exposure to polycyclic aromatic hydrocarbons: Meta-analysis

“…Because of the high heterogeneity, 3 articles [58][59][60] were excluded from the analysis, after which the heterogeneity decreased significantly to 41% (p = 0.1) for the remaining studies. However, the effect of the GSTM1 genotype on the micronucleus frequency was still evident, with a SMD = -0.33 (95% CI: -0.5-(-0.17), p < 0.0001) (Table 10).…”