PXR 和 NF-κB1 基因多态性影响抗结核药物性肝损伤易感性。
Genetic polymorphisms in PXR and NF-κB1 influence susceptibility to anti-tuberculosis drug-induced liver injury.
机构信息
Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China.
West China School of Medicine, Sichuan University, Chengdu, China.
出版信息
PLoS One. 2019 Sep 6;14(9):e0222033. doi: 10.1371/journal.pone.0222033. eCollection 2019.
BACKGROUND
Pregnane X receptor (PXR) regulates the expression of drug-metabolizing enzymes and transport enzymes. NF-κB not only plays a role in liver homeostasis and injury-healing processes by regulating inflammatory responses but may also regulate the transcription of PXR. Currently, genetic polymorphisms in PXR are associated with adverse drug effects. Because little is known about the association between NF-κB1 genetic polymorphisms and adverse drug reactions, we explored the association between PXR and NF-κB1 single nucleotide polymorphisms (SNPs) and susceptibility to anti-tuberculosis drug-induced liver injury (ATDILI).
MATERIALS AND METHODS
A total of 746 tuberculosis patients (118 with ATDILI and 628 without ATDILI) were prospectively enrolled at West China Hospital between December 2014 and April 2018. Nine selected SNPs (rs3814055, rs13059232, rs7643645 and rs3732360 in PXR and rs78872571, rs4647992, rs60371688, rs1598861 and rs3774959 in NF-κB1) were genotyped with a custom-designed 2x48-plex SNP Scan TM Kit. The frequencies of the alleles, genotypes and genetic models of the variants were compared between patients with or without ATDILI, while joint effect analysis of the SNP-SNP interactions was performed using multiplicative and additive models. The odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were calculated.
RESULTS
The T allele of rs3814055 in PXR was associated with a decreased risk for ATDILI (OR 0.61; 95% CI: 0.42-0.89, p = 0.0098). The T alleles of rs78872571 and rs4647992 in NF-κB1 were significantly associated with an increased risk for ATDILI (OR 1.91; 95% CI: 1.06-3.43, p = 0.028 and OR 1.81; 1.06-3.10, p = 0.029, respectively). The allele, genotype and genetic model frequencies were similar in the two groups for the other six SNPs (all P>0.05). There were no multiplicative or additive interactions between the SNPs.
CONCLUSION
Our study is the first to reveal that rs3814055 variants in PXR and rs78872571 and rs4647992 variants in NF-κB1 are associated with susceptibility to ATDILI caused by first-line anti-tuberculosis combination treatment in the Han Chinese population.
背景
pregnane X 受体 (PXR) 调节药物代谢酶和转运酶的表达。NF-κB 不仅通过调节炎症反应在肝脏稳态和损伤修复过程中发挥作用，还可能调节 PXR 的转录。目前，PXR 的遗传多态性与药物不良反应有关。由于人们对 NF-κB1 遗传多态性与药物不良反应之间的关系知之甚少，因此我们探讨了 PXR 和 NF-κB1 单核苷酸多态性 (SNP) 与抗结核药物性肝损伤 (ATDILI) 易感性之间的关系。
材料和方法
2014 年 12 月至 2018 年 4 月，我们前瞻性纳入了在华西医院接受治疗的 746 例结核病患者（118 例发生 ATDILI，628 例未发生 ATDILI）。选择了 9 个候选 SNP（PXR 中的 rs3814055、rs13059232、rs7643645 和 rs3732360，以及 NF-κB1 中的 rs78872571、rs4647992、rs60371688、rs1598861 和 rs3774959），采用定制的 2x48-plex SNP Scan TM 试剂盒进行基因分型。比较了患者中 SNP 等位基因、基因型和遗传模型的频率，同时采用乘法和加法模型进行 SNP-SNP 相互作用的联合效应分析。计算了比值比 (OR) 和相应的 95%置信区间 (CI)。
结果
PXR 中的 rs3814055 的 T 等位基因与 ATDILI 的风险降低相关（OR 0.61；95%CI：0.42-0.89，p = 0.0098）。NF-κB1 中的 rs78872571 和 rs4647992 的 T 等位基因与 ATDILI 的风险增加显著相关（OR 1.91；95%CI：1.06-3.43，p = 0.028 和 OR 1.81；1.06-3.10，p = 0.029，分别）。两组中其他六个 SNP 的等位基因、基因型和遗传模型频率均相似（均 p＞0.05）。SNP 之间没有乘法或加法相互作用。
结论
我们的研究首次揭示了 PXR 中的 rs3814055 变异体和 NF-κB1 中的 rs78872571 和 rs4647992 变异体与汉族人群一线抗结核联合治疗引起的 ATDILI 易感性相关。
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