N-乙酰基转移酶2及谷胱甘肽S转移酶M1基因多态性与抗结核药物性肝损伤的关系研究

doi:10.3969/j.issn.1000-6621.2014.01.004

摘要/Abstract

摘要： 目的研究药物代谢酶NAT2、GSTM1、GSTT1的基因多态性与抗结核药物肝损伤的关系，阐明抗结核药物性肝损伤(antituberculosis drug-induced liver injury，ATDILI)的分子机制。方法解放军第三〇九医院结核科2008—2009年度住院初治结核病患者208例，具有明确抗结核药物性肝损伤发生的患者为肝损伤组（共101例），无抗结核药物性肝损伤发生的患者为对照组（共107例），通过PCR扩增产物直接测序的方法分析两组的NAT2基因多态性并分型。通过多重PCR方法检测两组患者GSTM1、GSTT1是否存在基因型缺失。以SPSS 12.0软件进行χ²检验处理，比较两组之间各基因型分布频率的差异，并计算各基因型风险系数（odds ratio，OR值）及95％可信区间（95%CI），分析疾病与基因的关联强度。结果（1）肝损伤组患者中，39.6％（40/101）为NAT2慢乙酰化基因型；对照组中，12.2％（13/107）为NAT2慢乙酰化基因型。NAT2慢乙酰化基因型者发生抗结核药物性肝损伤的风险系数（OR值）为4.74（95％CI＝2.42～9.28；χ²=20.62，P<0.05）。（2）肝损伤组中，GSTM1缺失基因型占63.4％(64/101)，对照组GSTM1缺失基因型占51.4％(55/107)；两组比较GSTM1缺失基因型发生药物性肝损伤的OR值偏高（但无统计学意义），为1.64（95％CI=0.94～2.84，χ²=3.038，P>0.05）。肝损伤组中，GSTT1缺失基因型占47.5％(48/101)，对照组GSTT1缺失基因型占45.8％(49/107)，两组比较OR值接近，为1.07（95%CI=0.62～1.85，χ²=0.063，P>0.05）。（3）肝损伤组中同时具有NAT2慢乙酰化基因型及GSTM1缺失基因型的患者29例，对照组5例，发生抗结核药物性肝损伤的风险系数OR值高达10.21（95%CI=3.87～26.96，χ²=20.62，P<0.005）。结论基因的慢乙酰化基因型及GSTM1缺失基因型可能与ATDILT有关。

关键词: 抗结核药, 肝炎, 中毒性, 芳基胺N-乙酰转移酶, 谷胱甘肽转移酶, 多态现象, 遗传

Abstract: Objective To study the relationship between the antituberculosis drug-induced liver injury （ATDILI）and genetic polymorphism of drug metabolizing emzymes (DME)，including NAT2, GSTM1, GSTT1，and to illuminate the molecular mechanism of ATDILI. Methods Of 208 inpatients in the initial treament of tuberculosis were admitted to the department of tuberculosis research, 309th Clinical Division of Chinese PLA, Amomg these patients 101 cases were with ATDILI while the other 107 cases without ATDILI were used as control. Polymorphisms of NAT2 were determined by polymerase chain reaction-direct sequencing(PCR-DS). The deletion in GSTM1 and GSTT1 genes was determined by multiplex PCR. Genotype frequencies were compared between cases and controls byχ² test using SPSS 12.0 software,Odds ratio (OR) and 95% confidence interval(95%CI) were calculated to analyze the relationship between genotypes and ATDILI. Results （1）There were 40 patients with slow acetylator (39.6％) in 101 cases with hepatotoxicity and 13 with slow acetylator (12.2％）in 107 controls without hepatotoxicity. Patients with slow acetylator genotype (OR＝4.74, 95%CI:2.42-9.28; χ²=20.62, P<0.05) had a significantly higher risk of antituberculosis drug-induced hepatotoxicity than those with rapid or intermediate acetylator genotypes. (2) There were 64 patients with GSTM1 null genotype(63.4％) in cases with hepatotoxicity and 55 with GSTM1 null genotype (51.4％）in controls without hepatotoxicity. The GSTM1 null genotype (OR=1.64, 95％CI=0.94-2.84,χ²=3.038，P>0.05) had higher risk of ATDILI than GSTM1 non-null genotype no statistical significance).There were 48 patients with slow acetylator (47.5％) in cases with hepatotoxicity and 49 with slow acetylator (45.8％）in controls without hepatotoxicity, (OR=1.07, 95％CI=0.62-1.85,χ²=0.063，P>0.05). (3) The patients with slow acetylator genotype of NAT2 combined with GSTM1 null genotype(OR=10.21, 95%CI=3.87-26.96，χ²=20.62，P<0.005) had higher risk of ATDILI than those only with slow acetylator genotype (OR=4.74, P=0.000) or with GSTM1 null genotype (OR=1.64, P>0.05). Conclusion The slow acetylators of NAT2 and the GSTM1 null genotype might be associated with ATDILI.

安慧茹，吴雪琼，王仲元. N-乙酰基转移酶2及谷胱甘肽S转移酶M1基因多态性与抗结核药物性肝损伤的关系研究[J]. 中国防痨杂志, 2014, 36(1): 14-20. doi: 10.3969/j.issn.1000-6621.2014.01.004

AN Hui-ru, WU Xue-qiong, WANG Zhong-yuan. The relationship between genetic polymorphism of NAT2, GSTM1, and antituberculosis drug-induced liver injury[J]. Chinese Journal of Antituberculosis, 2014, 36(1): 14-20. doi: 10.3969/j.issn.1000-6621.2014.01.004

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