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

ABSTRACT: Anti-tuberculosis drug-induced hepatotoxicity (ATDH) is a serious adverse drug reaction. Conflicting results have been obtained regarding the associations of nuclear receptor subfamily 1 group I member 2 (NR1I2) gene polymorphisms on susceptibility to ATDH. Therefore, we aimed to evaluate the associations using a systematic review/meta-analysis approach. PubMed, Medline, Cochrane Library, Web of Science and SinoMed databases were searched for all eligible studies from inception to June 10, 2020. Pooled adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were employed to evaluate the strength of the association between the NR1I2 polymorphisms and the risk of ATDH. Subgroup analysis was performed by region of origin, and meta-regression were performed to detect potential sources of heterogeneity. A total of five case-control studies involving 572 cases and 1867 controls were identified. Fourteen SNPs in the NR1I2 gene have been reported, and the most heavily studied SNPs were rs3814055 and rs7643645. The pooled estimates did not exhibit any significant associations between SNPs rs3814055 and rs7643645 and the risk of ATDH (rs3814055: dominant model, OR = 1.00, 95% CI: 0.82-1.22, P = 1.00; recessive model, OR = 1.17, 95% CI: 0.76-1.78, P = .48; rs7643645: dominant model, OR = 1.04, 95% CI: 0.64-1.68, P = .89; recessive model, OR = 0.98, 95% CI: 0.65-1.49, P = .93). Subgroup analysis obtained similar negative results in Chinese patients, and the diagnostic criteria of ATDH may be the source of heterogeneity. Based on the meta-analysis described in this report, we did not observe any association between NR1I2 gene polymorphisms and ATDH susceptibility. However, this conclusion should be interpreted with caution due to the low number of studies and the relatively small sample size.

SUBMITTER: Yang M

PROVIDER: S-EPMC7726956 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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

Yang Miaomiao M Qiu Yunliang Y Jin Yanyu Y Liu Wenpei W Wang Qingliang Q Yi Honggang H Tang Shaowen S

Pharmacology research & perspectives 20201201 6

Anti-tuberculosis drug-induced hepatotoxicity (ATDH) is a serious adverse drug reaction. Conflicting results have been obtained regarding the associations of nuclear receptor subfamily 1 group I member 2 (NR1I2) gene polymorphisms on susceptibility to ATDH. Therefore, we aimed to evaluate the associations using a systematic review/meta-analysis approach. PubMed, Medline, Cochrane Library, Web of Science and SinoMed databases were searched for all eligible studies from inception to June 10, 2020. ...[more]

PMID: 33300686

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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.

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.

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

Publications

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

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