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


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.
Nakamura
Shin-ichi
S
Department of Cardiovascular Medicine, Kumamoto University School of Medicine, Kumamoto City, Japan.
Kugiyama
Kiyotaka
K
Sugiyama
Seigo
S
Miyamoto
Shinji
S
Koide
Shun-ichi
S
Fukushima
Hironobu
H
Honda
Osamu
O
Yoshimura
Michihiro
M
Ogawa
Hisao
H
D024506:5' Flanking Region; D002460:Cell Line; D002478:Cells, Cultured; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005721:Glutamate-Cysteine Ligase / Q000096:biosynthesis / Q000235:genetics*; D005978:Glutathione / Q000097:blood; D006367:HeLa Cells; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D009203:Myocardial Infarction / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D021122:Protein Subunits; D012333:RNA, Messenger / Q000096:biosynthesis; D015533:Transcriptional Activation
D021122:Protein Subunits; D012333:RNA, Messenger; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione