中国人细胞色素P450 2E1基因多态性与抗结核药物性肝损害关系的Meta分析

Association between Chinese CYP2E1 polymorphisms and anti-tuberculosis drug-induced liver injury: a Meta analysis

目的收集发表过的关于中国人群细胞色素P450 2E1(CYP2E1)基因多态性与抗结核药物性肝损害(ATLI)关系的病例对照研究进行Meta分析,明确两者的关系。方法通过Medline、Pub Med、EMBASE、ISI Web of Science、CNKI和万方数据库检索相关文献,检索词包括:药物代谢酶/drug-metabolizing enzymes,抗结核药/antitubercular agents,药物性肝毒性/drug-induced hepatotoxicity,药物性肝损害/drug-induced liver injury,基因多态性/genetic polymorphism,细胞色素酶2E1/cytochrome2E1,遗传易感性/genetic susceptibility等。纳入2000年1月1日至2016年10月31日研究中国人群CYP2E1基因多态性与ATLT风险关系的相关文献,由2名研究者独立进行文献筛选和数据提取,并进行质量评价。CYP2E1与ATLI之间关联强度用OR值和95%可信区间(95%CI)表示。采用χ2检验和I2检验对同类研究间的异质性进行评价。结果最终纳入符合标准的相关文献共8篇,含病例组1 071例,对照组3 720例。Meta分析结果显示:性别与ATLI风险关系OR=1.05,95%CI:0.80~1.39;CYP2E1 c1/c1与ATLI风险关系OR=1.32,95%CI:0.93~1.89;氮乙酰转移酶2(N-acetyltransferase2,NAT2)慢乙酰化表型与ATLI风险关系OR=2.57,95%CI:1.77~3.71;NAT2慢乙酰化表型联合CYP2E1 c1/c1与ATLI风险关系OR=3.53,95%CI:2.05~6.07。结论中国人群中NAT2慢乙酰化表型可以增加ATLI的发生风险;虽然CYP2E1 c1/c1与ATLI之间关系无统计学意义,但当其与NAT2慢乙酰化表型同时存在时,更易导致抗结核药物性肝损害的发生。

Objective To clarify the association between CYP450 2E1 polymorphism and anti-tuberculosis drug-induced liver injury among Chinese. Methods Medline, Pub Med, EMBASE, ISI Web of Science, CNKI and Wan Fang database were searched to identify relevant studies including the words: drug-metabolizing enzymes, antitubercular agents, drug-induced hepatotoxicity, drug-induced liver injury, genetic polymorphism, cytochrome 2E1, genetic susceptibility. The time for retrieving was from January 1, 2000 to October 31, 2016, literatures on association between Chinese CYP2E1 polymorphisms and anti-tuberculosis drug-induced liver injury were retrieved, and data was analyzed and evaluated by 2 independent researchers. Odds ratios(OR) and 95% confidence intervals(95% CI) were calculated. The heterogeneity was analyzed by χ~2 test and I2 test. Results Eight literatures involving a total of 1 071 cases and 3 720 controls were finally enrolled in this study. The results of Meta analysis showed: compared with the gender, the OR of ATLI was 1.05(95% CI: 0.80-1.39). Compared with the wild genotype(c1/c1), the OR of ATLI was 1.32(95% CI: 0.93-1.89) for the PstⅠ/RsaⅠ polymorphism. The summary OR of the NAT2 slow acetylator genotype for ATLI was 2.57(95% CI: 1.77-3.71). The summary OR of the NAT2 slow acetylator combine with CYP2E1 c1/c1 genotype for ATLI was 3.53(95% CI: 2.05-6.07). Conclusions The present Meta-analysis indicates that the NAT2 genotype is significantly associated with anti-tuberculosis drug-induced liver injury. Although there is no statistically significant association between Chinese CYP2E1 c1/c1 and anti-tuberculosis drug-induced liver injury, the NAT2 slow acetylator combine with CYP2E1 c1/c1 genotype may further increase the risk of ATLI.