Lack of association between genetic polymorphisms of CYP3A4, CYP2C9 and CYP2C19 and antituberculosis drug-induced liver injury in a community-based Chinese population
Lack of association between genetic polymorphisms of CYP3A4, CYP2C9 and CYP2C19 and antituberculosis drug-induced liver injury in a community-based Chinese population
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中国社区人群中 CYP3A4、CYP2C9 和 CYP2C19 基因多态性与抗结核药物性肝损伤之间缺乏关联
DOI：
10.1111/1440-1681.12074
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发表时间：
2013-05-01
影响因子：
2.9
通讯作者：
Zhan, Si-Yan
中科院分区：
文献类型：
--
作者：
Tang, Shao-Wen;Lv, Xiao-Zhen;Zhan, Si-Yan
抗结核（抗结核）药物引起的肝损伤（ATLI）的确切致病机制尚不清楚。它可能与药物代谢酶有关，例如细胞色素 P450 (CYP) 3A4、CYP2C9 和 CYP2C19。本研究的目的是探讨标记 CYP3A4、CYP2C9 和 CYP2C19 的单核苷酸多态性 (tSNP) 在基于人群的抗结核治疗队列中 ATLI 风险中的作用。设计了一项巢式病例对照研究。根据年龄、性别、治疗史、疾病严重程度和药物剂量，将每个 ATLI 病例与对照组进行 1:4 匹配。基于北京汉族HapMap数据库，利用Haploview 4.2筛选tSNP，并通过TaqMan等位基因判别技术进行基因分型。该研究包括 89 名 ATLI 患者和 356 名对照者。选择 CYP3A4 中的 1 个 tSNP (rs12333983)、CYP2C9 中的 2 个 (rs4918758、rs9332098) 和 CYP2C19 中的 2 个 (rs11568732、rs4986894) 进行基因分型。患者中rs12333983、rs4918758、rs9332098、rs11568732和rs4986894的次要等位基因频率分别为36.0%、41.4%、1.1%、5.7%和35.7%，而对照组为31.7%、42.9%。对照组分别为 3.4%、8.9% 和 35.1%。两组之间 5 个 tSNP 的基因型或等位基因频率没有观察到显着差异，并且 CYP2C9 或 CYP2C19 单倍型均未与 ATLI 的发生显着相关。基于中国抗结核治疗队列，我们没有发现 ATLI 风险与 CYP3A4、CYP2C9 和 CYP2C19 基因多态性之间存在显着关联。在中国结核病人群中，没有一个单倍型与 ATLI 的发展存在显着关联。
The precise pathogenic mechanism of antituberculosis (anti-TB) drug-induced liver injury (ATLI) is poorly understood. It may be associated with drug-metabolizing enzymes, such as cytochrome P450 (CYP) 3A4, CYP2C9 and CYP2C19. The aim of the present study was to explore the role of tagging single nucleotide polymorphisms (tSNPs) of CYP3A4, CYP2C9 and CYP2C19 in the risk of ATLI in a population-based anti-TB treatment cohort. A nested casecontrol study was designed. Each ATLI case was matched 1:4 with controls on the basis of age, gender, treatment history, disease severity and drug dosage. The tSNPs were selected using Haploview 4.2 based on the HapMap database of Han Chinese in Beijing and genotyped by TaqMan allelic discrimination technology. Eighty-nine patients with ATLI and 356 controls were included in the study. One tSNP in CYP3A4 (rs12333983), two in CYP2C9 (rs4918758, rs9332098) and two in CYP2C19 (rs11568732, rs4986894) were selected and genotyped. The minor allele frequencies of rs12333983, rs4918758, rs9332098, rs11568732 and rs4986894 were 36.0%, 41.4%, 1.1%, 5.7% and 35.7%, respectively, in the patients, compared with 31.7%, 42.9%, 3.4%, 8.9% and 35.1%, respectively, in the controls. No significant differences were observed in genotypes or allele frequencies of the five tSNPs between the two groups and none of the CYP2C9 or CYP2C19 haplotypes was significantly associated with the development of ATLI. Based on the Chinese anti-TB treatment cohort, we did not find a significant association between the risk of ATLI and genetic polymorphisms of CYP3A4, CYP2C9 and CYP2C19. None of the haplotypes exhibited a significant association with the development of ATLI in a Chinese tuberculosis population.