CYP2E1, GSTM1 and GSTT1 genetic polymorphisms and susceptibility to antituberculosis drug-induced hepatotoxicity: a nested case-control study
CYP2E1, GSTM1 and GSTT1 genetic polymorphisms and susceptibility to antituberculosis drug-induced hepatotoxicity: a nested case-control study
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DOI：
10.1111/j.1365-2710.2012.01334.x
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发表时间：
2012-10-01
影响因子：
2
通讯作者：
Zhan, S. -Y.
中科院分区：
文献类型：
--
作者：
Tang, S. -W.;Lv, X. -Z.;Zhan, S. -Y.
已知和客观：抗结核药物肝毒性（ATDH）的发病机制与药物代谢酶N-乙酰基转移酶2（NAT 2）、细胞色素P4502 E1（CYP 2 E1）和谷胱甘肽S-转移酶（GST）M1、T1有关。这些基因的遗传多态性与ATDH之间的关联已被报道，但结果不一致。此外，大多数研究是基于医院的回顾性研究，而不是前瞻性研究。我们的目的是调查可能的关联CYP 2 E1，GSTM 1和GSTT 1基因多态性与ATDH使用一个更强大的病例对照研究嵌套在人群为基础的前瞻性抗结核治疗队列。方法：对4304例接受标准短程化疗的涂阳肺结核患者进行为期69个月的监测。采用发病密度抽样方法，按年龄（± 5岁）、性别、治疗史、病情严重程度和药物剂量选择对照组和与每个ATDH病例4：1匹配的病例。采用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）和多重聚合酶链反应（PCR）方法对CYP 2 E1、GSTM 1和GSTT 1基因多态性进行分型。采用条件Logistic回归模型计算比值比（OR）和95%置信区间（CI），以及相应的P值。结果和讨论：本研究共纳入89例ATDH病例和356例对照。CYP 2 E1 RsaI c1/c1基因型和DraI C/C基因型与ATDH无统计学意义（OR = 0.99，95% CI：0.621.59; OR = 1.13，95% CI：与CYP 2 E1 RsaI c1/c2或c2/c2基因型或DraI D/D基因型或GSTM 1/GSTT 1缺失基因型与ATDH基因型比较，OR = 1.22，95%CI：0.761.96; OR = 0.96，95%CI：0.601.52）。什么是新的和结论：这是第一个研究参与CYP 2 E1，GSTM 1和GSTT 1基因多态性在ATDH使用巢式病例对照人群为基础的前瞻性队列设计。在中国结核病人群中，我们不能证实CYP 2 E1 RsaI、CYP 2 E1 DraI、GSTM 1 null和GSTT 1 null基因多态性与ATDH的正相关性。
What is Known and Objective: The pathogenic mechanism of antituberculosis drug-induced hepatotoxicity (ATDH) is thought to involve drug-metabolizing enzymes including N-acetyl transferase2 (NAT2), cytochrome P4502E1 (CYP2E1) and glutathione S-transferase (GST) M1, T1. The associations between genetic polymorphisms of those genes and ATDH have been reported but with inconsistent results. Moreover, most studies were hospital-based retrospective studies and not prospective. We aimed to investigate possible associations of CYP2E1, GSTM1 and GSTT1 genetic polymorphisms with ATDH using a more robust casecontrol study nested in a population-based prospective antituberculosis treatment cohort. Methods: A total of 4304 patients with smear-positive tuberculosis (TB) who received standard short-course chemotherapy were monitored for 69 months. Incidence density sampling method was adopted to select controls and 4 : 1 matched with each ATDH cases by age (+/- 5 years), sex, treatment history, disease severity and drug dosage. The CYP2E1, GSTM1 and GSTT1 polymorphisms were genotyped using PCRRFLP and multiplex PCR methods. Conditional logistic regression model was used to calculate odds ratio (OR) and 95% confidence interval (CI), as well as corresponding P-values. Results and Discussion: A total of 89 ATDH cases and 356 controls were included in this study. There was no statistically significant association between CYP2E1 RsaI c1/c1 genotype or DraI C/C genotype and ATDH (OR = 0.99, 95% CI:0.621.59; OR = 1.13, 95% CI: 0.403.20, respectively) compared with CYP2E1 RsaI c1/c2 or c2/c2 genotypes or DraI D/D genotype, or between GSTM1/GSTT1 null genotypes and ATDH (OR = 1.22, 95% CI: 0.761.96; OR = 0.96, 95% CI: 0.601.52, respectively) compared with non-null genotypes. What is new and Conclusion: This is the first study of the involvement of CYP2E1, GSTM1 and GSTT1 genetic polymorphisms in ATDH using a nested casecontrol population-based prospective cohort design. We could not confirm positive associations of genetic polymorphisms of CYP2E1 RsaI, CYP2E1 DraI, GSTM1 null and GSTT1 null with ATDH reported by various groups, in our Chinese TB population.