Published Online
on June 17, 2002

A more recent version of this article appeared on June 25, 2002

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Submitted on March 20, 2002
Revised on April 11, 2002
Accepted on April 12, 2002

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

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

From the Department of Cardiovascular Medicine, Kumamoto University School of Medicine, Kumamoto City (S.-i.N., K.K., S.S., S.-i.K., H.F., O.H., M.Y., H.O.); the Second Department of Internal Medicine, Yamanashi Medical University, Yamanashi (K.K.), and the Department of Pharmacy, Kumamoto University Hospital, Kumamoto City, Japan (S.M.).

^* To whom correspondence should be addressed. E-mail: kugiyama{at}res.yamanashi-med.ac.jp.

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.

Key words: antioxidants • genes • myocardial infarction • risk factors

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