This Article Full Text Full Text (PDF) All Versions of this Article: 105/25/2968    most recent 01.CIR.0000019739.66514.1Ev1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nakamura, S.-i. Articles by Ogawa, H. Search for Related Content PubMed PubMed Citation Articles by Nakamura, S.-i. Articles by Ogawa, H. Related Collections Clinical genetics

(Circulation. 2002;105:2968.)
© 2002 American Heart Association, Inc.

Clinical Investigation and Reports

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; 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.).

Correspondence to Kiyotaka Kugiyama, MD, PhD, the Second Department of Internal Medicine, Yamanashi Medical University, 1110 Shimokato, Tamaho, Nakakomagun, Yamanashi, 409-3898 Japan. 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

This article has been cited by other articles:

				M. Siedlinski, D. S. Postma, C. C. van Diemen, A. Blokstra, H. A. Smit, and H. M. Boezen Lung Function Loss, Smoking, Vitamin C Intake, and Polymorphisms of the Glutamate-Cysteine Ligase Genes Am. J. Respir. Crit. Care Med., July 1, 2008; 178(1): 13 - 19. [Abstract] [Full Text] [PDF]

				A.-L. Levonen, E. Vahakangas, J. K. Koponen, and S. Yla-Herttuala Antioxidant Gene Therapy for Cardiovascular Disease: Current Status and Future Perspectives Circulation, April 22, 2008; 117(16): 2142 - 2150. [Abstract] [Full Text] [PDF]

				G. Giordano, C. C. White, I. Mohar, T. J. Kavanagh, and L. G. Costa Glutathione Levels Modulate Domoic Acid Induced Apoptosis in Mouse Cerebellar Granule Cells Toxicol. Sci., December 1, 2007; 100(2): 433 - 444. [Abstract] [Full Text] [PDF]

				L. A. McConnachie, I. Mohar, F. N. Hudson, C. B. Ware, W. C. Ladiges, C. Fernandez, S. Chatterton-Kirchmeier, C. C. White, R. H. Pierce, and T. J. Kavanagh Glutamate Cysteine Ligase Modifier Subunit Deficiency and Gender as Determinants of Acetaminophen-Induced Hepatotoxicity in Mice Toxicol. Sci., October 1, 2007; 99(2): 628 - 636. [Abstract] [Full Text] [PDF]

				G. Dai, S. Vaughn, Y. Zhang, E. T. Wang, G. Garcia-Cardena, and M. A. Gimbrone Jr Biomechanical Forces in Atherosclerosis-Resistant Vascular Regions Regulate Endothelial Redox Balance via Phosphoinositol 3-Kinase/Akt-Dependent Activation of Nrf2 Circ. Res., September 28, 2007; 101(7): 723 - 733. [Abstract] [Full Text] [PDF]

				M. Tsai-Turton, B. N Nakamura, and U. Luderer Induction of Apoptosis by 9,10-Dimethyl-1,2-Benzanthracene in Cultured Preovulatory Rat Follicles Is Preceded by a Rise in Reactive Oxygen Species and Is Prevented by Glutathione Biol Reprod, September 1, 2007; 77(3): 442 - 451. [Abstract] [Full Text] [PDF]

				L. Baum, Xiangyan Chen, Wing Sze Cheung, C. K. A. Cheung, Lap Woon Cheung, K. F. P. Chiu, Hong Mei Wen, P. Poon, Kam Sang Woo, Ho Keung Ng, et al. Polymorphisms and Vascular Cognitive Impairment After Ischemic Stroke J Geriatr Psychiatry Neurol, June 1, 2007; 20(2): 93 - 99. [Abstract] [PDF]

				G. Giordano, C. C. White, L. A. McConnachie, C. Fernandez, T. J. Kavanagh, and L. G. Costa Neurotoxicity of Domoic Acid in Cerebellar Granule Neurons in a Genetic Model of Glutathione Deficiency Mol. Pharmacol., December 1, 2006; 70(6): 2116 - 2126. [Abstract] [Full Text] [PDF]

				D. Botta, S. Shi, C. C. White, M. J. Dabrowski, C. L. Keener, S. L. Srinouanprachanh, F. M. Farin, C. B. Ware, W. C. Ladiges, R. H. Pierce, et al. Acetaminophen-induced Liver Injury Is Attenuated in Male Glutamate-cysteine Ligase Transgenic Mice J. Biol. Chem., September 29, 2006; 281(39): 28865 - 28875. [Abstract] [Full Text] [PDF]

				Y. Chen, H. G. Shertzer, S. N. Schneider, D. W. Nebert, and T. P. Dalton Glutamate Cysteine Ligase Catalysis: DEPENDENCE ON ATP AND MODIFIER SUBUNIT FOR REGULATION OF TISSUE GLUTATHIONE LEVELS J. Biol. Chem., October 7, 2005; 280(40): 33766 - 33774. [Abstract] [Full Text] [PDF]

				S. Kann, C. Estes, J. F. Reichard, M.-y. Huang, M. A. Sartor, S. Schwemberger, Y. Chen, T. P. Dalton, H. G. Shertzer, Y. Xia, et al. Butylhydroquinone Protects Cells Genetically Deficient in Glutathione Biosynthesis from Arsenite-Induced Apoptosis Without Significantly Changing Their Prooxidant Status Toxicol. Sci., October 1, 2005; 87(2): 365 - 384. [Abstract] [Full Text] [PDF]

				S. Sugiyama, K. Kugiyama, M. Aikawa, S. Nakamura, H. Ogawa, and P. Libby Hypochlorous Acid, a Macrophage Product, Induces Endothelial Apoptosis and Tissue Factor Expression: Involvement of Myeloperoxidase-Mediated Oxidant in Plaque Erosion and Thrombogenesis Arterioscler. Thromb. Vasc. Biol., July 1, 2004; 24(7): 1309 - 1314. [Abstract] [Full Text] [PDF]

				T. L'Ecuyer, Z. Allebban, R. Thomas, and R. Vander Heide Glutathione S-transferase overexpression protects against anthracycline-induced H9C2 cell death Am J Physiol Heart Circ Physiol, June 1, 2004; 286(6): H2057 - H2064. [Abstract] [Full Text] [PDF]

				S.-i. Nakamura, S. Sugiyama, D. Fujioka, K.-i. Kawabata, H. Ogawa, and K. Kugiyama Polymorphism in Glutamate-Cysteine Ligase Modifier Subunit Gene Is Associated With Impairment of Nitric Oxide-Mediated Coronary Vasomotor Function Circulation, September 23, 2003; 108(12): 1425 - 1427. [Abstract] [Full Text] [PDF]

				A. C. Walsh Regulation of Nrf2-Mediated Induction of Glutamate Cysteine Ligase Modulatory Gene (GCLM) Expression: Considerations for Future Studies Toxicol. Sci., May 1, 2003; 73(1): 1 - 3. [Abstract] [Full Text] [PDF]

				F. Bea, F. N. Hudson, A. Chait, T. J. Kavanagh, and M. E. Rosenfeld Induction of Glutathione Synthesis in Macrophages by Oxidized Low-Density Lipoproteins Is Mediated by Consensus Antioxidant Response Elements Circ. Res., March 7, 2003; 92(4): 386 - 393. [Abstract] [Full Text] [PDF]

				Y. Yang, M. Z. Dieter, Y. Chen, H. G. Shertzer, D. W. Nebert, and T. P. Dalton Initial Characterization of the Glutamate-Cysteine Ligase Modifier Subunit Gclm(-/-) Knockout Mouse. NOVEL MODEL SYSTEM FOR A SEVERELY COMPROMISED OXIDATIVE STRESS RESPONSE J. Biol. Chem., December 13, 2002; 277(51): 49446 - 49452. [Abstract] [Full Text] [PDF]

				Glutamate-Cysteine Ligase Modifier Knockout Mice Sci. Aging Knowl. Environ., November 6, 2002; 2002(44): tg12 - 12. [Full Text]