Polymorphism in the 5′-Flanking Region of Human Glutamate-Cysteine Ligase Modifier Subunit Gene Is Associated With Myocardial Infarction

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Abstract
Background— Human glutamate-cysteine ligase (GCL) is a rate-limiting enzyme for the synthesis of glutathione that plays a crucial role in antioxidant defense mechanisms in most mammalian cells, including vascular cells. Oxidants transcriptionally upregulate GCL genes for glutathione synthesis, providing a protective mechanism against oxidative stress-induced cellular dysfunction. This study examined the hypothesis that variation in the GCL genes may be associated with coronary artery disease in which oxidative stress plays a pathogenetic role. Methods and Results— We searched for the common variants in the 5′-flanking region of the GCL modifier subunit (GCLM) gene in patients with myocardial infarction (MI). We found a polymorphism (−588C/T) in which the T allele showed lower promoter activity (40% to 50% of C allele) in response to oxidants in the luciferase reporter gene assay. Allele frequencies were determined by polymerase chain reaction-based analysis of restriction fragment length polymorphism in 4...

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