Polymorphism in the 5'-flanking region of human glutamate-cysteine ligase modifier subunit gene is associated with myocardial infarction.

Abstract

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.

• Authors: Shin-ichi Nakamura, Kiyotaka Kugiyama, Seigo Sugiyama, Shinji Miyamoto, Shun-ichi Koide, Hironobu Fukushima, Osamu Honda, Michihiro Yoshimura, Hisao Ogawa
• Journal: Circulation (Circulation) Vol. 105 Issue 25 Pg. 2968-73 (Jun 25 2002) ISSN: 1524-4539 [Electronic] United States
• PMID: 12081989 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Subunits
• RNA, Messenger
• Glutamate-Cysteine Ligase
• Glutathione

Topics

• 5' Flanking Region
• Cell Line
• Cells, Cultured
• Female
• Genetic Predisposition to Disease
• Genotype
• Glutamate-Cysteine Ligase (biosynthesis, genetics)
• Glutathione (blood)
• HeLa Cells
• Humans
• Macrophages (metabolism)
• Male
• Middle Aged
• Monocytes (metabolism)
• Myocardial Infarction (diagnosis, genetics, metabolism)
• Polymorphism, Genetic
• Promoter Regions, Genetic
• Protein Subunits
• RNA, Messenger (biosynthesis)
• Transcriptional Activation