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(Circulation. 2003;108:1425.)
© 2003 American Heart Association, Inc.

Brief Rapid Communications

Polymorphism in Glutamate-Cysteine Ligase Modifier Subunit Gene Is Associated With Impairment of Nitric Oxide–Mediated Coronary Vasomotor Function

Shin-ichi Nakamura, MD, PhD; Seigo Sugiyama, MD, PhD; Daisuke Fujioka, MD; Ken-ichi Kawabata, MD, PhD; Hisao Ogawa, MD, PhD; Kiyotaka Kugiyama, MD, PhD

From the 2nd Department of Internal Medicine (S.-i.N., D.F., K.-i.K., K.K.), Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan; and the Department of Cardiovascular Medicine (S.-i.N., S.S., H.O.), Graduate School of Medical Sciences, Kumamoto University, Japan.

Correspondence to Kiyotaka Kugiyama, MD, PhD, 2nd Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Nakakoma-gun, Yamanashi, 409-3898 Japan. E-mail kugiyama{at}yamanashi.ac.jp

Received June 4, 2003; revision received July 29, 2003; accepted July 30, 2003.

Background— The minor -588T allele of polymorphism -588C/T of a modifier subunit gene in glutamate-cysteine ligase (GCLM), a rate-limiting enzyme for glutathione (GSH) synthesis, was associated with lower plasma GSH levels and was a risk factor for myocardial infarction.

Methods and Results— We examined effects of the -588C/T polymorphism on coronary arterial diameter and blood flow responses to intracoronary infusion of acetylcholine in 157 consecutive subjects who had normal coronary angiograms. In multivariate linear regression analysis with covariates including traditional risk factors, the minor -588T allele had an independent association with impaired dilation or enhanced constriction of epicardial coronary arteries in response to acetylcholine, and it was independently associated with blunted increase in coronary flow response to acetylcholine. In a subgroup of 59 consecutive subjects, constrictor responses of epicardial coronary diameter to intracoronary infusion of N^G-monomethyl-L-arginine, reflecting the presence of coronary nitric oxide (NO) bioactivity, had an inverse and independent association with the -588T allele in multivariate analysis.

Conclusions— The -588T polymorphism of the GCLM gene causes a decrease in endothelial NO bioactivity, leading to impairment of endothelium-dependent vasomotor function in large and resistance coronary arteries. The GCL–GSH–NO axis may play a role in the defense system against coronary artery disease.

Key Words: antioxidants • genetics • nitric oxide • acetylcholine

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