N-乙酰化转移酶2基因多态性与抗结核药物所致肝损伤的相关性

The relationship between polymorphisms of N-acetyltransferase 2 genes and anti-tuberculosis drug induced hepatic-injury

目的探讨N-乙酰化转移酶2（NAT2）基因多态性与抗结核药致肝损伤（ADIH）的相关性。方法以抗结核治疗3个月内出现肝损伤的106例结核患者为病例组，未出现肝损伤的106例结核患者为配对对照。采用1：1匹配的病例对照研究和聚合酶链反应限制性片段长度多态性分析（PCRRFI，P）技术，检测106对结核患者的NAT2基因481C／T、590G／A、857G／A位点多态性情况，并对主要环境影响因素和基因型进行单因素和多因素条件Logistic回归分析。结果病例组NAT2基因的481C／T、590G／A、8576／A位点的T、A、A等位基因频率分别为7．5％、28．8％、17．9％，对照组分别为6．6％、18．9％、17．5％。病例组NAT2慢速乙酰化型的频率明显高于对照组，粗OR值为2．250（95％CI为1．140～4．441）。对文化程度、职业、体质指数（BMI）、吸烟、饮酒和结核类型6个可疑危险因素进行了单因素分析，仅低BMI和饮酒为ADIH发生的危险因素。在多因素分析中调整BMI、饮酒两个因素后，NAT2乙酰化程度仍与ADIH的发生显著相关，调整OR值为2．246（95％CI为1．086～4．644）。结论NAT2基因慢速乙酰化型可能与ADIH的发生有关。

Objective To investigate the relationship between polymorphisms of N acetyltransferase 2 （NAT2） genes and anti tuberculosis drug induced hepatic-injury （ADIH）. Methods A 1 ： 1 matched case-control study was conducted. One hundred and six cases fulfilling the criteria of ADIH were selected as ADIH group from the patients who received anti-tuberculosis therapy, whereas those patients without any hepatic injury related clinical symptoms during three months of follow-up period were selected as control. The genetic polymorphisms of the loci, NAT2- 481C/T, NAT2-590G/A and NAT2 857G/A, were determined by polymerase chain reaction and restriction fragment length polymorphism technique （PCR RFLP） in patients who received anti tuberculosis therapy. The major environmental factors and genotypes were analyzed by univariate and rnuhivariate conditional Logistic analyses. Results The T, A, A allele frequencies of NAT2-481C/T, NAT2-590G/A and NAT2-857G/A were 7.5 ~//00, 28.8~ and 17.9~ respectively in ADIH group, and 6.6~/oo ,18.9~ and 17. 5o//oo, respectively in the control group. Univariate analysis demonstrated that the frequency of NAT2 slow acetylation genotype in ADIH group was significantly higher than that in control group with a crudeOR （95%CI） of 2. 250 （1.140-4.441）. Among 6 potential risk factors, i.e. education level, occupation, body mass index （BMI）, smoking, drinking and tile type of tuberculosis, the low BMI and drinking were two risk factors for ADIH. In multivariate analysis, ADIH remained associated with acetylation gcnotype after adjusting for BMI and drinking status. The adjusted OR（95%CI）was 2.246（1. 086-4. 644）. Conclusion NAT2 slow aeetylation genotype may be associated with the occurrence of ADIH.