Polymorphism in the 5′-Franking Region of Human Glutamate-Cysteine Ligase Modifier Subunit Gene Is Associated With Myocardial Infarction
Polymorphism in the 5′-Franking Region of Human Glutamate-Cysteine Ligase Modifier Subunit Gene Is Associated With Myocardial Infarction
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人谷氨酸-半胱氨酸连接酶修饰子基因5′-Franking区多态性与心肌梗塞相关
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发表时间：
2002
期刊：
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通讯作者：
H. Ogawa
中科院分区：
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作者：
Shin;K. Kugiyama;S. Sugiyama;S. Miyamoto;S. Koide;H. Fukushima;O. Honda;M. Yoshimura;H. Ogawa
背景-人谷氨酸-半胱氨酸连接酶（GCL）是谷胱甘肽合成的限速酶，在大多数哺乳动物细胞（包括血管细胞）的抗氧化防御机制中起着至关重要的作用。氧化剂转录上调谷胱甘肽合成的GCL基因，为氧化应激诱导的细胞功能障碍提供保护机制。本研究检验了GCL基因变异可能与冠状动脉疾病相关的假设，在冠状动脉疾病中氧化应激起着致病作用。方法和结果-我们寻找心肌梗死（MI）患者GCL修饰亚基（GCLM）基因5′-侧翼区的常见变异。我们发现了一种多态性（− 588 C/T），其中T等位基因在荧光素酶报告基因测定中对氧化剂的反应中显示出较低的启动子活性（C等位基因的40%至50%）。在日本熊本县的429例MI患者和428例对照组（通过血管造影定义）中，通过基于聚合酶链反应的限制性片段长度多态性分析确定等位基因频率。MI组T基因多态性频率显著高于对照组（CT和TT基因型：MI组31.5%，对照组19.2%，P <0.001）。在多元Logistic回归分析中，T基因多态性是MI的危险因素，独立于传统的冠状动脉疾病危险因素（比值比，1.98; 95%可信区间，1.38 - 2.83;P <0.001）。结论-这些发现表明GCLM基因的− 588 T多态性可能抑制GCLM基因对氧化剂的诱导，并且是MI的遗传危险因素。
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′-franking 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.