药物代谢酶CYP2E1、GSTM1基因启动子区甲基化与抗结核药物性肝损伤的相关性研究

Anti-tuberculosis drug-induced liver injury correlated with the methylation in the promoter regions of CYP2E1 and GSTM1

目的药物代谢酶基因异常甲基化是否与抗结核药物性肝损伤(ATLI)发生有关尚未见报道。文中旨在探讨蒙古族结核病患者细胞色素P4502E1(CYP2E1)和谷胱甘肽S-转移酶M1(GSTM1)基因启动子区CpG岛甲基化水平与ATLI之间的关系。方法选取2016年9月至2018年12月在内蒙古自治区通辽市结核病防治所已确诊并进行治疗的93例蒙古族肺结核患者资料。肝损伤组(选择接受抗结核药物治疗6个月内发生ATLI的蒙古族结核病患者,n=31)、对照组(与肝损伤组同性别、年龄相差≤5岁、接受抗结核药物治疗6个月内未发生ATLI的蒙古族结核病患者,n=62)。分析比较2组CYP2E1和GSTM1基因甲基化水平及结核病患者ATLI发生的影响因素。结果肝损伤组和对照组CYP2E1基因启动子区总体甲基化水平([0.694±0.091)、(0.759±0.066)],及GSTM1基因启动子区总体甲基化水平([0.187±0.092)、(0.207±0.093)]差异有统计学意义(P<0.05)。多因素Logistic回归分析显示:饮酒(OR=5.329,95%CI:1.442~19.697)、CYP2E1基因启动子区甲基化(OR=0.312,95%CI:0.165~0.591)是蒙古族结核病患者ATLI发生的影响因素(P<0.05)。结论蒙古族结核病患者ATLI与CYP2E1基因启动子区甲基化水平有关。提示CYP2E1基因甲基化可作为ATLI发生的生物标志物应用于结核病患者ATLI的预防和控制。

Objective No study has been reported on the association between the abnormal methylation of drug metabolic enzymes and anti-tuberculosis drug-induced liver injury(ATLI). This article aimed to investigate the relationship of ATLI with the methylation of the CpG islands in the promoter regions of cytochrome P450 2E1(CYP2E1)and glutathione s-transferase M1(GSTM1)in Chinese Mongolian patients with tuberculosis (TB). Methods This retrospective study included 93 cases of TB diagnosed and treated in the TB prevention and treatment institutions of Tongliao,Inner Mongolia,between September 2016 and December 2017,which were divided into an ATLI(n = 31)and a non-ATLI group(n = 62), the former with and the latter without ATLI within 6 months after anti-TB medication. We compared the methylation levels of the CYP2E1 and GSTM1 genes between the two groups of patients and analyzed the risk factors of ATLI. Results In comparison with the non-ATLI controls,the patients of the ATLI group showed significantly lower methylation levels in the promoter regions of CYP2E1(0.759 ± 0.066 vs 0.694 ± 0.091,P < 0.05)and GSTM1(0.207 ± 0.093 vs 0.187 ± 0.092,P < 0.05). Multivariate logistic regression analysis revealed that the main risk factors of ATLI included alcohol consumption(OR = 5.329,95% CI:1.442-19.697,P < 0.05)and methylation in the CYP2E1 promoter region(OR = 0.312,95% CI: 0.165-0.591,P < 0.05)in the TB patients. Conclusion ATLI is associated with the methylation level in the promoter region of the CYP2E1 gene in Chinese Mongolian patients with tuberculosis,indicating that the methylation of CYP2E1 could be used as a biomarker in the prevention and control of ATLI.