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CLINICAL STUDY: MYOCARDIAL INFARCTION

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

Shun-ichi Koide, MD^*, Kiyotaka Kugiyama, MD, PhD^*,*, Seigo Sugiyama, MD, PhD^*, Shin-ichi Nakamura, MD^*, Hironobu Fukushima, MD^*, Osamu Honda, MD^*, Michihiro Yoshimura, MD, PhD^* and Hisao Ogawa, MD, PhD^*

^* Department of Cardiovascular Medicine, Kumamoto University School of Medicine, Kumamoto, Japan
Second Department of Internal Medicine, Yamanashi University School of Medicine, Yamanashi, Japan

Manuscript received May 20, 2002; revised manuscript received August 6, 2002, accepted September 6, 2002.

^* Reprint requests and correspondence: Dr. Kiyotaka Kugiyama, Second Department of Internal Medicine, Yamanashi Medical University, 1110 Shimokato, Tamaho, Nakakomegun, Yamanashi, 409-3898, Japan.
kugiyama{at}res.yamanashi-med.ac.jp

OBJECTIVES: 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).

BACKGROUND: 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 GCLC gene for GSH synthesis, providing a protective mechanism against oxidant-induced endothelial dysfunction or activation, which plays a pathogenetic role in cardiovascular diseases.

METHODS: 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.

RESULTS: 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 H₂O₂ in 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).

CONCLUSIONS: The –129T polymorphism of the GCLC gene may suppress the GCLC gene induction response to an oxidant, and it is implicated in coronary endothelial vasomotor dysfunction and MI.

Abbreviations and Acronyms   ACh   acetylcholine   bp   basepair   DNA   deoxyribonucleic acid   GCL   glutamate-cysteine ligase   GCLC   glutamate-cysteine ligase-catalytic subunit   GCLR   glutamate-cysteine ligase-regulatory subunit   GSH   reduced glutathione   HUVECs   human umbilical vein endothelial cells   MI   myocardial infarction   PBS   phosphate-buffered saline   PCR   polymerase chain reaction

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