Polymorphism in the 5′-flanking region of human glutamate-cysteine ligase modifier subunit gene is associated with myocardial infarction
Polymorphism in the 5′-flanking region of human glutamate-cysteine ligase modifier subunit gene is associated with myocardial infarction
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DOI：
10.1161/01.cir.0000019739.66514.1e
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发表时间：
2002-06-25
期刊：
影响因子：
37.8
通讯作者：
Ogawa, H
中科院分区：
文献类型：
--
作者：
Nakamura, S;Kugiyama, K;Ogawa, H
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。本研究探讨的假设，GCL基因的变化可能与冠状动脉疾病，其中氧化应激起着致病作用的role.Methods和Results-We搜索的常见变异体在5 '-侧翼区的GCL修饰亚基（GCLM）基因在心肌梗死（MI）患者。我们发现了一个多态性（-588C/T），其中T等位基因在荧光素酶报告基因试验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%vs19.2%，P
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