Association of polymorphism in glutamate-cysteine ligase catalytic subunit gene with coronary vasomotor dysfunction and myocardial infarction

• Published in: Journal of the American College of Cardiology 2003-02, Vol.41 (4), p.539-545
• Main Authors: Koide, Shun-ichi, Kugiyama, Kiyotaka, Sugiyama, Seigo, Nakamura, Shin-ichi, Fukushima, Hironobu, Honda, Osamu, Yoshimura, Michihiro, Ogawa, Hisao
• Format: Article
• Language: English
• Subjects: Adult; Age; Aged; Aged, 80 and over; Antioxidants; Autonomic Nervous System Diseases - genetics; Autonomic Nervous System Diseases - physiopathology; Biological and medical sciences; Body mass index; Cardiology; Cardiology. Vascular system; Cardiovascular disease; Cardiovascular Diseases - genetics; Cardiovascular Diseases - physiopathology; Catalytic Domain - genetics; Confidence intervals; Coronary heart disease; Coronary vessels; Coronary Vessels - physiopathology; Deoxyribonucleic acid; Diabetes; DNA; Endothelium, Vascular - physiopathology; Gene expression; Genotype & phenotype; Glutamate-Cysteine Ligase - genetics; Health risk assessment; Heart; Heart attacks; Humans; Hypertension; Male; Medical imaging; Medical sciences; Middle Aged; Myocardial Infarction - genetics; Myocardial Infarction - physiopathology; Oxidative stress; Pathogenesis; Polymorphism, Genetic - genetics; Promoter Regions, Genetic - genetics; Risk factors; Rodents; Smoking; Vasomotor System - physiopathology
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/S0735-1097(02)02866-8

The purpose of this study was to test the hypothesis that polymorphisms in the promoter region of the glutamate-cysteine ligase catalytic subunit (GCLC)gene may be associated with coronary endothelial vasomotor dysfunction and myocardial infarction (MI). Glutamate-cysteine ligase is a rate-limiting enzyme for synthesis of glutathione (GSH) that plays a crucial role in the intracellular antioxidant defense systems. Oxidants transcriptionally upregulate the GCLCgene for GSH synthesis, providing a protective mechanism against oxidant-induced endothelial dysfunction or activation, which plays a pathogenetic role in cardiovascular diseases. The association of the possible polymorphisms with coronary arterial diameter responses to acetylcholine was determined in 62 male subjects. The frequency of polymorphisms was compared between 255 male patients with MI and 179 male control subjects. We found a polymorphism (−129C/T) in which the T allele showed lower promoter activity (50% to 60% of the activity of the C allele) in response to H2O2in human endothelial cells. Endothelium-dependent dilation of coronary arteries was impaired in subjects with the −129T allele (n = 31), as compared with the age-matched subjects without the −129T allele (n = 31). The T allele was highly frequent in patients with MI as compared with control subjects, and it was a significant risk factor for MI, independent of traditional coronary risk factors (odds ratio [OR] 1.81, 95% confidence interval [CI] 1.08 to 3.03; p = 0.03). The −129T polymorphism of the GCLCgene may suppress the GCLCgene induction response to an oxidant, and it is implicated in coronary endothelial vasomotor dysfunction and MI.