Role of polymorphisms of γ-glutamylcysteine synthetase genes in pathogenesis of coronary spastic angina

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Human glutamate-cysteine ligase (GCL) is a rate-limiting enzyme for synthesis of glutathione (GSH) that plays a crucial role in antioxidant defense mechanisms in most mammalian cells, including vascular cells. GCL is a heterodimer composed of a heavy catalytic subunit (GCLC) and a light modifier subunit (GCLM). Oxidants transcriptionally upregulate GCL genes for GSH synthesis, providing a protective mechanism against oxidative stress-induced cellular dysfunction. We found a polymorphism (-588C/T) of GCLM gene and a polymorphism (-129C/T) of GCLC gene in which minor alleles showed lower promoter activity in response to oxidants in the luciferase reporter gene assay. The induction of GCLM mRNA expression in the cultured human monocytes-macrophages was less in the cells from subjects with the minor allele as compared with those without minor allele. Plasma GSH levels were significantly lower in subjects with the minor allele of GCLM polymorphism than those without the minor allele (2.1±0.3 versus 3.3±0.2 μmol/L; P=0.001). The frequency of each of the minor alleles was significantly higher in those with previous myocardial infarction than in the control. In multiple logistic regression analysis, each of the minor alleles of GCLC and GCLM genes was a risk factor for myocardial infarction independently of traditional coronary risk factors. Endothelium-dependent dilation of coronary arteries was impaired in the subjects with the minor allele of GCLC gene polymorphism as compared with the age-matched those without the minor allele. In conclusion the polymorphisms of GCLC and GCLM genes may suppress GCL genes induction response to an oxidant and it is implicated in coronary endothelial vasomotor dysfunction and myocardial infarction.