CYP450、GSTs、UGT基因多态性与抗结核药物肝损伤的关系

发布时间：2018-03-06 15:40

本文选题：结核病　切入点：抗结核药　出处：《山东医药》2017年39期 　论文类型：期刊论文

【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CYP1A2 734C/A、CYP3A4 18B-20232G/A、CYP3A5 3-6986A/G、CYP2C19 681G/A、GSTA1-69C/T、GSTM3缺失突变、UGT2B7-268A/G、UGT2B7 802C/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 CYP1A2 734C/A的AA基因型、CYP3A4 18B-20232G/A的GA基因型、UGT2B7-268A/G的AG基因型、UGT2B7 802C/T的TT基因型是ADLI的保护基因型,而CYP3A5 3-6986A/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、CYP3A4 18B-20232G、CYP3A5 3-6986G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、UGT2B7 802C/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、CYP3A4 18B-20232G、CYP3A5 3-6986G组合将显著增加ADLI的发生风险。
[Abstract]:Objective to investigate the relationship between cytochrome P450 (CYP450), glutathione transferase (GSTs), uridine diphosphate glucuronyltransferase (UGTT) gene polymorphism and the occurrence of anti-tuberculosis drug induced liver injury (ADLI). 207 patients with tuberculosis in Han nationality who had liver injury within 6 months were included in the case group. A total of 207 patients with tuberculosis without liver dysfunction were selected as control group. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to observe the polymorphism of CYP3A5 3-6986A / CYP2C19 681G / TGSTM3 deletion mutation UGT2B7-268A / GUGT2B7 802CT locus in CYP1A2 734C / ACYP3A4 18B-20232Gr / ACYP3A53-6986A / GG / CYP2C19 681 GSTM3 deletion mutation UGT2B7-268A / GUGT2B7 802CT. Multivariate Logistics regression analysis was used to analyze the relationship between the polymorphism of CYP450 GSTsUGT gene and the occurrence of ADLI. The interaction between the polymorphism loci of CYP450 GSTsUGT gene and the occurrence of ADLI was analyzed by using multivariate dimensionality reduction method. Results the AA genotype of CYP1A2 734C / A was CYP3A4 18B-20232 GPA. The TT genotype of UGT2B7 802C / T is the protective genotype of ADLI, and the AG genotype of UGT2B7-268 A / G is the TT genotype of UGT2B7 802C / T. The AG and GG genotype of CYP3A5 3-6986A / G and the TT genotype of GSTA1-69C / T were risk genotypes of ADLI. It was found that the polymorphism of CYP3A53-6986A / G / UGT2B7-268AG and UGT2B7802C/T locus was associated with the occurrence of ADLI. The three factor models consisting of CYP3A4 18B-20232G / CYP3A418B-20232G / CYP3A53-6986G were obtained by multivariate dimensionality reduction method. Compared with low risk genotypes, high risk genotypes significantly increased the risk of ADLI. Conclusion CYP3A4 (18B-20232G / AV) 3-6986A / G / G UGT2B7-268A / GUGT2B7 802CT / T polymorphism is associated with the occurrence of ADLI, and there is interaction between the gene loci. The combination of CYP3A4 18B-20232G, CYP3A5 3-6986G, UGT2B7-268A / P, will significantly increase the risk of ADLI.
【作者单位】：华北理工大学;
【基金】：国家自然科学基金项目(81041096)
【分类号】：R52;R575

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