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

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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.

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Abbreviations

CAD :

Coronary artery disease

CI :

Confidence interval

GST :

Glutathione S-transferase

MN :

Micronucleus

OR :

Odds ratios

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Authors and Affiliations

  1. CNR Institute of Clinical Physiology, G. Pasquinucci Hospital, via Aurelia Sud-Montepepe, 54100, Massa, Italy

    Samantha Manfredi, Maria Giovanna Colombo, Antonio Rizza, Cristina Vassalle, Aldo Clerico, Andrea Biagini & Maria Grazia Andreassi

  2. Sant'Anna School, Pisa, Italy

    Serena Masetti & Nicoletta Botto

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  1. Serena Masetti
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  2. Nicoletta Botto
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  3. Samantha Manfredi
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  4. Maria Giovanna Colombo
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  5. Antonio Rizza
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  6. Cristina Vassalle
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  7. Aldo Clerico
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  8. Andrea Biagini
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  9. Maria Grazia Andreassi
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Correspondence to Maria Grazia Andreassi.

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Masetti, S., Botto, N., Manfredi, S. et al. Interactive effect of the glutathione S-transferase genes and cigarette smoking on occurrence and severity of coronary artery risk. J Mol Med 81, 488–494 (2003). https://doi.org/10.1007/s00109-003-0448-5

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  • DOI: https://doi.org/10.1007/s00109-003-0448-5

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