CYP450、GSTs、UGT基因多态性与抗结核药物肝损伤的关系

摘要

目的 探讨细胞色素P450(CYP450)、谷胱甘肽转移酶(GSTs)、尿苷二磷酸葡萄糖醛酸转移酶(UGT)基因多态性及其交互作用与抗结核药物性肝损伤(ADLI)发生的关系.方法 选择接受抗结核化疗6个月内出现肝损伤的汉族结核病患者207例纳入病例组,以同期治疗中未出现肝功能异常的结核病患者207例为对照组.采用聚合酶链反应-限制性片段长度多态性法观察CYP1A2734C/A、CYP3A418B-20232G/A、CYP3A53-6986A/G、CYP2C19681G/A、GSTA1-69C/T、GSTM3缺失突变、UGT2B7-268A/G、UGT2B7802C/T位点的多态性.采用单因素、多因素Logistics回归分析法分析CYP450、GSTs、UGT基因多态性与ADLI发生的关系.采用多因子降维法分析CYP450、GSTs、UGT基因多态性位点之间的交互作用与ADLI发生的关系.结果 CYP1A2734C/A的AA基因型、CYP3A418B-20232G/A的GA基因型、UGT2B7-268A/G的AG基因型、UGT2B7802C/T的TT基因型是ADLI的保护基因型,而CYP3A53-6986A/G的AG及GG基因型、GSTA1-69C/T的TT基因型则是ADLI的危险基因型.调整其他基因多态性的影响后,发现CYP3A418B-20232G/A、CYP3A53-6986A/G、UGT2B7-268A/G和UGT2B7802C/T位点基因多态性与ADLI的发生有关.多因子降维法分析得到UGT2B7-268A/G、CYP3A418B-20232G、CYP3A53-6986G组成的3因素模型为最佳模型,检验样本准确度为61.29%,交叉验证一致性为10/10.最佳模型的估计结果显示,与低危基因型组合相比,高危基因型组合显著增加ADLI的发病风险.结论 CYP3A418B-20232G/A、CYP3A53-6986A/G、UGT2B7-268A/G、UGT2B7802C/T位点基因多态性与ADLI的发生有关,且基因位点之间存在交互作用,其中UGT2B7-268A/G、CYP3A418B-20232G、CYP3A53-6986G组合将显著增加ADLI的发生风险.%Objective To investigate the correlations of drug metabolic enzymes cytochrome P450 (CYP450),gluta-thione S-transferases (GSTs),and uridine diphosphate glycosyltransferase (UGT)gene single nucleotide polymorphisms (SNPs)with anti-tuberculosis drug-induced liver injury (ADLI). Methods We selected 207 cases of Han tuberculosis (TB)patients who experienced liver injury within 6 months of anti-TB chemotherapy treatment as the case group and 207 cases of TB patients with no abnormal liver function as the control group. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP)was employed to identify the SNPs of CYP1A2734C/ A,CYP3A418B-20232G/ A, CYP3A53-6986A/ G,CYP2C19681G/ A,GSTA1 -69C/ T,and GSTM3 deletion mutation,and UGT2B7-268A/ G and UGT2B7802C/ T. We adopted univariate and multivariate logistic regression methods to discuss the relationships of CYP450,GSTs,and UGT gene SNPs with ADLI. Multifactor dimensionality reduction (MDR)method was used to explore the interaction between ADLI and SNPs. Results Univariate and multivariate logistic regression analysis showed that the genotype AA of CYP1A2734C/ A,the genotype GA of CYP3A418B-20232G/ A,the genotype AG of UGT2B7-268A/ G,and the genotype TT of UGT2B7802C/ T were the protective genotypes of ADLI,and the mutant genotypes AG and GG of CYP3A53-6986A/ G and the genotype TT of GSTA1-69C/ T were the risk genotypes of ADLI. After adjusting the effects of other gene SNPs,we found that CYP3A418B-20232G/ A,CYP3A53-6986A/ G,UGT2B7-268A/ G,and UGT2B7802C/ T were related to the occurrence of ADLI. A best model consisted of three factors UGT2B7 -268A/ G,CYP3A418B-20232G,and CYP3A53-6986G,with the sample accuracy of 61. 29% and the cross-validation consistency of 10 / 10,was obtained by MDR,and the high risk genotype combination could increase risk of ADLI. Conclusions CYP3A418B-20232G/ A,CYP3A53-6986A/ G,UGT2B7-268A/ G,and UGT2B7802C/ T gene SNPs are related to the occurrence of ADLI. Multifactor dimensionality reduction analysis shows that there are gene-gene interactions and the combination of UGT2B7-268A/ G,CYP3A418B-20232G/ A,and CYP3A53-6986A/ G can increase the risk of ADLI.