Genetic polymorphisms in PXR and NF-κB1 influence susceptibility to anti-tuberculosis drug-induced liver injury

Abstract

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.

NR1I2 genetic polymorphisms and the risk of anti‐tuberculosis drug‐induced hepatotoxicity: A systematic review and meta‐analysis

“…and ATDH susceptibility. [20][21][22][23][24] Using the fixed-effects model, the pooled estimates of the five included studies did not show a significant association between SNP rs3814055 and the risk of ATDH (dominant model, OR = 1.00, 95% CI: 0.82-1.22, P = 1.00, Figure 2;…”

“…No further significant association was observed between these SNP polymorphisms and ATDH susceptibility ( Table 2, Figure S1-S8). The remaining 8 SNPs (ie, rs12488820, rs1523127, rs2276707, rs2461825, rs2472677, rs2472682, rs3732357, and rs3732360) reported only in a single original study were all from Chinese patients, 20,[22][23][24] and no genotypes were found to be significantly related to ATDH, except one SNP, rs2276707, under the recessive model (OR = 0.600, 95% CI: 0.364-0.988, P = .045). 24 Additionally, there was no evidence for a significant association between six SNPs (ie, rs3814055, rs7643645, rs13059232, rs2461823, rs3814057, and rs6785049) and the risk of ATDH in the allele comparison model (Table 3).…”

“…A total of 106 relevant articles were identified after an initial screening, and 5 case-control studies, which consisted of 572 ATDH cases and 1867 controls, were included. [20][21][22][23][24] The flow chart of the included and excluded studies is shown in Figure 1. There were 14 SNPs in the NR1I2 gene that have been reported previously (ie, rs3814055, rs7643645, rs13059232, rs2461823, rs3814057, rs6785049, rs12488820, rs1523127, rs2276707, rs2461825, rs2472677, rs2472682, rs3732357, and rs3732360), and the most heavily studied SNPs were rs3814055 and rs7643645.…”

“…Four studies with 537 cases and 1796 controls investigated the effect of SNP rs7643645 on the risk of developing ATDH, 20,[22][23][24] and all patients were Chinese. Using the random-effect model, the pooled estimates of four included studies also did not indicate a significant association between SNP rs7643645 and the risk of ATDH (dominant model, OR = 1.04, 95% CI: 0.64-1.68, P = .89, Figure 4;…”

“…19 To date, a number of studies have been conducted to investigate the potential association between NR1I2 genetic polymorphisms and the risk of ATDH, with inconsistent results being obtained. [20][21][22][23][24] For example, earlier studies from Indonesia showed that patients with the TT genotype at rs3814055 had a significantly increased risk of ATDH, 21 but another study from China reached the opposite conclusion, namely, the T allele of rs3814055 was associated with a decreased risk for ATDH. 20 However, a systematic review and meta-analysis can be used to pool results from different studies, thereby enhancing the precision of estimates of treatment effects.…”