Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Centre, Beijing, China.
J Clin Pharm Ther. 2012 Oct;37(5):588-93. doi: 10.1111/j.1365-2710.2012.01334.x. Epub 2012 Feb 15.
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 case-control study nested in a population-based prospective antituberculosis treatment cohort.
A total of 4304 patients with smear-positive tuberculosis (TB) who received standard short-course chemotherapy were monitored for 6-9 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 PCR-RFLP 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.
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:0·62-1·59; OR = 1·13, 95% CI: 0·40-3·20, 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: 0·76-1·96; OR = 0·96, 95% CI: 0·60-1·52, respectively) compared with non-null genotypes.
This is the first study of the involvement of CYP2E1, GSTM1 and GSTT1 genetic polymorphisms in ATDH using a nested case-control 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.
抗结核药物性肝毒性（ATDH）的致病机制被认为涉及包括 N-乙酰基转移酶 2（NAT2）、细胞色素 P4502E1（CYP2E1）和谷胱甘肽 S-转移酶（GST）M1、T1 在内的药物代谢酶。已经报道了这些基因的遗传多态性与 ATDH 之间的关联，但结果不一致。此外，大多数研究都是基于医院的回顾性研究，而不是前瞻性研究。我们旨在使用基于人群的前瞻性抗结核治疗队列中嵌套的更稳健的病例对照研究来研究 CYP2E1、GSTM1 和 GSTT1 遗传多态性与 ATDH 之间的可能关联。
对 4304 例痰涂片阳性肺结核（TB）患者进行了为期 6-9 个月的标准短程化疗监测。采用发生率密度抽样法选择对照者，并按年龄（±5 岁）、性别、治疗史、疾病严重程度和药物剂量与每个 ATDH 病例以 4：1 配对。采用 PCR-RFLP 和多重 PCR 方法对 CYP2E1、GSTM1 和 GSTT1 多态性进行基因分型。使用条件逻辑回归模型计算比值比（OR）和 95%置信区间（CI）以及相应的 P 值。
本研究共纳入 89 例 ATDH 病例和 356 例对照者。与 CYP2E1 RsaI c1/c1 基因型或 DraI C/C 基因型相比，CYP2E1 RsaI c1/c2 或 c2/c2 基因型或 DraI D/D 基因型与 ATDH 之间无统计学显著关联（OR=0.99，95%CI：0.62-1.59；OR=1.13，95%CI：0.40-3.20），与 GSTM1/GSTT1 缺失基因型与 ATDH 之间也无统计学显著关联（OR=1.22，95%CI：0.76-1.96；OR=0.96，95%CI：0.60-1.52）。
这是使用基于人群的嵌套病例对照前瞻性队列设计研究 CYP2E1、GSTM1 和 GSTT1 遗传多态性与 ATDH 关系的第一项研究。我们不能证实 CYP2E1 RsaI、CYP2E1 DraI、GSTM1 缺失和 GSTT1 缺失的遗传多态性与中国结核病人群中各种报道的 ATDH 之间存在阳性关联。
