抗结核药物所致肝损伤与孕烷X受体基因多态性的关联性

Association between pregnane X receptor gene polymorphism and antituberculosis-drug-induced liver damage

目的探讨肺结核患者抗结核治疗所致肝损伤与孕烷X受体(PXR)基因的关联性。方法选择武汉市金银潭医院感染科2018年2月-2020年2月肺结核患者136例作为研究对象,根据患者治疗6个月内是否发生肝损伤分为肝损伤组(n=71)和无肝损伤组(n=65)。针对PXR基因-25385C/T位点设计特异性引物,采用SNPscanTM多重荧光单核苷酸多态性分型技术对该位点多态性进行检测。检测血清丙氨酸转氨酶(ALT)、天冬氨酸氨基转移酶(AST)、总胆红素(TBIL)、碱性磷酸酶(ALP)水平,计算药物性肝损伤(RUCAM)评分。结果肝损伤组患者PXR基因-25385C/T位点TT基因型、T等位基因频率(40.85%、58.45%)高于无肝损伤组(P<0.05);校正混杂因素后,多元Logistic回归分析结果显示,本地区肺结核患者PXR基因-25385C/T位点携带TT基因型、T等位基因是发生肝损伤的独立危险因素,以CC基因型为参考,携带TT基因型校正OR值为4.342,以C等位基因为参考,携带T等位基因校正OR值为2.403;在显性模型、隐形模型和加性模型下,PXR基因-25385C/T位点T等位基因突变可明显增加肝损伤的风险(OR值=1.895、1.533、3.159,P均<0.05);携带TT型患者ALT、TBIL、AST、ALP及RUCAM评分高于CC/CT型患者(P<0.05)。结论PXR基因-25385C/T位点突变能增加肺结核患者抗结核治疗所致肝损伤的风险,可据此进行针对性预防,改善患者预后。

OBJECTIVE To investigate the relationship between pregnane X receptor(PXR)gene and liver injury caused by anti-tuberculosis treatment in pulmonary tuberculosis patients.METHODS Totally 136cases of pulmonary tuberculosis patients from the department of infectious diseases of our hospital from Feb.2018to Feb.2020 were selected as the research subjects,and were divided into liver injury group(n=71)and non-liver injury group(n=65)according to whether the patients had liver injury within 6months of treatment.Specific primers for the PXR gene-25385C/T site were designed,and SNPscanTM multiple fluorescent SNP typing technology was used to detect the site polymorphism.Serum alanine aminotransferase(ALT),aspartate aminotransferase(AST),total bilirubin(TBIL),alkaline phosphatase(Alkaline phosphatase),(ALP)level were detected,and the Russel Uclaf Causality(RUCAM)score for drug-induced liver injury was calculated.RESULTS The TT genotype and T allele frequencies(40.85%,58.45%)of the PXR gene at-25385C/T in the liver injury group were significantly higher than those in the non-hepatic injury group(P<0.05).After adjusting for the above confounding factors,the re-sults of multivariate logistic regression analysis showed that the TT genotype,and the T allele carried at the-25385C/T site of PXR gene in tuberculosis patients in this region were independent risk factor for liver injury.Taking the CC genotype as a reference,the corrected OR value for carrying the TT gene was 4.324,and with the C allele as a reference,the corrected OR value for carrying the T allele was 2.403;in the dominant model,recessive model and additive model,mutations in the T allele at the-25385C/T locus of PXR gene can significantly increase the risk of liver injury(OR value=1.895,1.533,3.159,all P<0.05).The ALT,TBIL,AST,ALP and RUCAM scores of TT patients were significantly higher than those of CC/CT type patients(P<0.05).CONCLUSIONPXR gene-25385C/T mutation significantly increases the risk of liver damage caused by anti-tuberculosis treatment in pulmonary tuberculosis patients,which can be used for targeted prevention and improve patient prognosis.