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Genetic polymorphisms of and susceptibility to anti-tuberculosis drug-induced liver: A RUCAM-based case–control study.

ABSTRACT: Uridine 5’-diphospho-glucuronosyl-transferase 1A1 (UGT1A1) plays an important role in the biliary excretion of bilirubin, suggesting genetic polymorphisms of may have an impact on bile acid metabolism, which may be related to the development of anti-tuberculosis drug-induced liver injury (ATLI). This study explores the associations between genetic polymorphisms of and ATLI in a Chinese anti-tuberculosis population. A 1:2 matched case–control study was conducted among 290 ATLI cases and 580 controls, of which causality assessment of ATLI cases was based on the updated Roussel Uclaf Causality Assessment Method (RUCAM). Conditional logistic regression was applied to calculate odds ratio (OR) and 95% confidence intervals (CIs), with weight and use of hepatoprotectant as covariates. The Bonferroni correction was used to adjust values for multiple testing. Compared with those carrying rs6719561 TT genotype, patients with TC genotype had lower risk of ATLI (adjusted OR = 0.723, 95% CI: 0.531–0.985, = 0.040). The haplotype TAG (rs3755319-rs2003569-rs4148323) could marginally significantly increase the risk of ATLI (adjusted OR = 5.071, 95% CI: 1.007–25.531, = 0.049), while haplotype TC (rs4148329-rs6719561) could reduce the risk of ATLI (adjusted OR = 0.719, 95% CI: 0.527–0.982, = 0.038). Patients with polymorphisms at rs4148328 or rs3755319 were at a reduced risk of moderate and severe liver injury under different genetic models. Based on this case–control study, genetic polymorphisms of may be associated with susceptibility to ATLI in the Chinese anti-tuberculosis population.

SUBMITTER: Tao B

PROVIDER: S-EPMC6299304 | biostudies-other | 2018 Mar-Dec

REPOSITORIES: biostudies-other

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Project description:BACKGROUND:Pregnane X receptor (PXR) regulates the expression of drug-metabolizing enzymes and transport enzymes. NF-?B 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-?B1 genetic polymorphisms and adverse drug reactions, we explored the association between PXR and NF-?B1 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-?B1) 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-?B1 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-?B1 are associated with susceptibility to ATDILI caused by first-line anti-tuberculosis combination treatment in the Han Chinese population.

Project description:BackgroundAnti-tuberculosis drug-induced hepatotoxicity (ATDH) is one of the most common adverse effects associated with tuberculosis (TB) therapy. Animal studies have demonstrated important roles of glutathione S-transferases in the prevention of chemical-induced hepatotoxicity. The aim of this study was to investigate the relationship between single nucleotide polymorphisms (SNPs) of glutathione S-transferase P1 (GSTP1) and ATDH in TB patients.MethodsWe used two independent samples for this genetic association study. In the initial prospective study, 322 newly diagnosed TB patients were followed up for three months after initiating anti-TB therapy. In an independent retrospective study, 115 ATDH patients and 116 patients without ATDH were selected to verify the results of the prospective study. Tag-SNPs of GSTP1 were genotyped either with the MassARRAY platform or the improved multiple ligase detection reaction (iMLDR) method. The associations between SNPs and ATDH were analyzed by logistic regression analysis adjusting for confounding factors.ResultsOf the 322 patients recruited in the prospective cohort, 35 were excluded during the 3 months of follow-up, and 30 were diagnosed with ATDH and were considered as the ATDH group. The remaining 257 subjects without ATDH were considered as the non-ATDH group. After correction for potential confounding factors, significant differences were found for rs1695 (A>G) under an allelic model (OR = 3.876, 95%CI: 1.258011.905; P = 0.018). In the retrospective study, rs1695 allele A also had a higher risk of ATDH (OR = 2.10, 95%CI: 1.17-3.76; P = 0.012). We only found rs4147581AA genotype under a dominant model was related to ATDH in the prospective study (OR = 2.578, 95%CI: 1.076-6.173; P = 0.034).ConclusionsThis is the first study to suggest that GSTP1 genotyping can be an important tool for identifying patients who are susceptible to ATDH. This result should be verified in independent large sample studies and also in other ethnic populations.

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Genetic polymorphisms of and susceptibility to anti-tuberculosis drug-induced liver: A RUCAM-based case–control study.

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