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

• Published in: Circulation (New York, N.Y.) Vol. 105; no. 25; pp. 2968 - 2973
• Main Authors: Nakamura, Shin-ichi, Kugiyama, Kiyotaka, Sugiyama, Seigo, Miyamoto, Shinji, Koide, Shun-ichi, Fukushima, Hironobu, Honda, Osamu, Yoshimura, Michihiro, Ogawa, Hisao
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 25.06.2002; American Heart Association, Inc
• Subjects: 5' Flanking Region; Biological and medical sciences; Cardiology. Vascular system; Cell Line; Cells, Cultured; Coronary heart disease; Female; Genetic Predisposition to Disease; Genotype; Glutamate-Cysteine Ligase - biosynthesis; Glutamate-Cysteine Ligase - genetics; Glutathione - blood; Heart; HeLa Cells; Humans; Macrophages - metabolism; Male; Medical sciences; Middle Aged; Monocytes - metabolism; Myocardial Infarction - diagnosis; Myocardial Infarction - genetics; Myocardial Infarction - metabolism; Polymorphism, Genetic; Promoter Regions, Genetic; Protein Subunits; RNA, Messenger - biosynthesis; Transcriptional Activation; Glutamate-cysteine ligase; Human; Oxidative stress; Carbon-nitrogen ligases; Infarct; Enzyme; Pathogenesis; Cardiovascular disease; Genotype; Coronary heart disease; Myocardial disease; Genetic determinism; Phenotype; Gene; Ligases; Risk factor; Myocardium; Polymorphism
• ISSN: 0009-7322; 1524-4539; 1524-4539
• DOI: 10.1161/01.CIR.0000019739.66514.1E

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 429 patients with MI and 428 control subjects (as defined by angiography) in Kumamoto Prefecture, Japan. The frequency of the T polymorphism was significantly higher in the MI group than in the control group (CT and TT genotypes: 31.5% in MI group versus 19.2% in control group; P <0.001). In multiple logistic regression analysis, the T polymorphism was a risk factor for MI independent of traditional coronary artery disease risk factors (odds ratio, 1.98; 95% confidence interval, 1.38 to 2.83; P <0.001). Conclusions — These findings suggest that the −588T polymorphism of the GCLM gene may suppress GCLM gene induction in response to oxidants and that it is a genetic risk factor for MI.