Glutathione S transferase theta 1 gene (GSTT1) null genotype is associated with an increased risk for acquired aplastic anemia in children
Glutathione S transferase theta 1 gene (GSTT1) null genotype is associated with an increased risk for acquired aplastic anemia in children
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DOI：
10.1203/01.pdr.0000111201.56182.fe
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发表时间：
2004-03-01
影响因子：
3.6
通讯作者：
Burdach, S
中科院分区：
文献类型：
--
作者：
Dirksen, U;Moghadam, KA;Burdach, S
获得性再生障碍性贫血的发病机制涉及两个主要因素：环境因素和遗传易感性。由于生物转化酶的多态，个体代谢几种DNA损伤剂的能力各不相同。基因决定的这些酶表达的差异可以解释患获得性再生障碍性贫血的个体间风险。本研究旨在研究儿童获得性再生障碍性贫血(再障)患者的生物转化相(P450-细胞色素P450-细胞色素P4502E_1)和生物转化相II[微粒体环氧化物水解酶、谷胱甘肽S转移酶]酶的遗传多态性。GSTT1缺失型(两个等位基因缺失)与获得性再生障碍性贫血的风险显著增加相关(优势比，2.8；95%可信区间，0.15-5.7)。相比之下，P450-CYP2E1和meh基因的GSTM1缺失基因型或多态在患者组和对照组中没有显著差异。进行多变量分析，以评估这些酶是否与年龄、性别或治疗反应等其他变量一起与所测试的基因型别有任何显著的关联。没有发现上述参数的组合与获得性再生障碍性贫血有关。GST主要参与代谢血液毒性和诱变底物，如苯衍生物。GSTT1缺失基因可能调节外源性污染物或有毒中间体的代谢。缺乏GSTT1酶，导致对某些污染物的遗传易感性，可能决定儿童患获得性再生障碍性贫血的个体风险。
Two main factors have been implicated in the mechanism underlying the pathogenesis of acquired aplastic anemia: environmental factors and genetic susceptibility. Individuals vary in their ability to metabolize several DNA-damaging agents due to polymorphisms of biotransforming enzymes. Genetically determined differences in the expression of these enzymes could explain interindividual risks in developing acquired aplastic anemia. The aim of the study was to characterize the genetic polymorphism of biouransforming phase I (p450-cyp2E1) and phase II [microsomal epoxide hydrolase (mEh), glutathione S-transferase (GST)] enzymes in pediatric patients with acquired aplastic anemia. The GSTT1 null genotype (absence of both alleles) was associated with a significantly increased risk for acquired aplastic anemia (odds ratio, 2.8; 95% confidence interval, 0.15-5.7). In contrast, the GSTM1 null genotype or polymorphisms within the p450-cyp2E1 and mEh genes was not significantly different in patients and controls. Multivariate analysis was per-formed to assess whether the enzymes together or with other variables as age, gender, or response to therapy may have any significant association with the tested genotypes. In no combinations of the mentioned parameters was an association found with acquired aplastic anemia. GST are mainly involved in metabolizing hematotoxic and mutagenic substrates such as benzene derivatives. The GSTT1 null genotype may modulate the metabolism of exogenous pollutants or toxic intermediates. The absence of the GSTT1 enzyme, leading to genetic susceptibility toward certain pollutants, might determine the individual risk for development of acquired aplastic anemia in children.