蒙古族结核病患者CYP2E1基因多态性及其启动子区甲基化水平与抗结核药物致肝损伤的关系

Study on CYP2E1 gene polymorphism and the relationship between methylation level of its promoter region and liver injury induced by anti⁃tuberculosis drugs in Mongolian tuberculosis patients in Inner Mongolia

目的抗结核药物致肝损伤(ADIH)的发生与CYP2E1基因多态性及甲基化水平是否相关的研究甚少。文中旨在探讨蒙古族结核病患者CYP2E1基因多态性及启动子区甲基化水平与ADIH的关系。方法选取2015年11月至2018年6月于内蒙古通辽市结核病防治所标准化治疗的135例蒙古族结核病患者。根据ADIH判定标准选取发生肝损伤的蒙古族结核病患者为ADIH组(n=45),按照1∶2比例匹配未发生肝损伤的蒙古族结核病患者为对照组(n=90)。进行DNA提取,聚合酶链反应(PCR)扩增CYP2E1基因,确定CYP2E1 rs2031920基因型,分析CYP2E1基因多态性及启动子区甲基化水平与ADIH之间的关系。结果CYP2E1 rs2031920基因型、C1和C2基因频率在ADIH组和对照组中分布差异无统计学意义(P>0.05)。ADIH组CYP2E1基因启动子区总体甲基化水平较对照组明显降低[(0.711±0.085)vs(0.759±0.062)],差异有统计学意义(P<0.05)。Logistic回归显示CYP2E1基因启动子区总体甲基化水平是ADIH发生的影响因素(P<0.005),甲基化水平每升高0.1个单位,ADIH发生风险降低0.388倍,其OR(95%CI)值为0.388(0.204~0.739)。结论蒙古族ADIH患者的CYP2E1基因启动子区总体甲基化水平降低,但CYP2E1基因多态性与ADIH的发生无关,提示CYP2E1基因甲基化可应用于结核病患者ADIH的预防和治疗。

Objective There are few studies on whether the occurrence of anti⁃tuberculosis drug⁃induced liver injury(ADIH)is associated with the polymorphism of CYP2E gene and methylation level.This study aims to CYP2E1 gene polymorphism and the relationship between the methylation level of the promoter region and ADIH in Mongolian tuberculosis(TB)patients.Methods A total of 135 Mongolian TB patients who received standardized treatment at the Tuberculosis Research Institute of Tongliao City,Inner Mongolia from November 2015 to June 2018 were selected.According to the ADIH criteria,TB patients with liver injury were selected as the ADIH group(n=45),and TB patients without liver injury were matched as the control group based on a ratio of 1∶2(n=90).DNA extraction and polymerase chain reaction(PCR)were performed to amplify the CYP2E1 gene to determine the CYP2E1 rs2031920 genotype,and to analyze the CYP2E1 gene polymorphism and relationship between ADIH and promoter methylation level.Results There were no significant differences in the distribution of CYP2E1 rs2031920 genotype,C1 and C2 gene frequencies between the ADIH group and the control group(P>0.05).The overall methylation level in the promoter region of CYP2E1 gene in ADIH group(0.711±0.085)was significantly lower than that of the control group(0.759±0.062).Results of Logistic regression showed that the overall methylation level in the promoter region of CYP2E1 gene was the influencing factor for the occurrence of ADIH(P<0.005).For each 0.1 unit increase of methylation level,the risk of ADIH oc⁃currence reduced by 0.388 times,and the OR(95%CI)value was 0.388(between 0.204 and 0.739).Conclusion The overall methylation level in the promoter region of CYP2E1 gene was reduced in Mongolian ADIH patients,but the polymorphism of CYP2E1 gene was not related to the occurrence of ADIH.These results suggested that CYP2E1 methylation could be applied to the prevention and treatment of ADIH in patients with tuberculosis.