Dataset Information

Clinical and Genetic Risk Factors for Drug-Induced Liver Injury Associated with Anti-Tuberculosis Treatment-A Study from Patients of Portuguese Health Centers.

ABSTRACT: Drug-induced liver injury (DILI) is an unpredictable and feared side effect of antituberculosis treatment (AT). The present study aimed to identify clinical and genetic variables associated with susceptibility to AT-associated hepatotoxicity in patients with pulmonary tuberculosis treated with a standard protocol. Of 233 patients enrolled, 90% prospectively, 103 developed liver injury: 37 with mild and 66 with severe phenotype (DILI). All patients with mild hepatitis had a RUCAM score ≥4 and all patients with DILI had a RUCAM score ≥ 6. Eight clinical variables and variants in six candidate genes were assessed. A logistic multivariate regression analysis identified four risk factors for AT-DILI: age ≥ 55 years (OR:3.67; 95% CI:1.82-7.41; p < 0.001), concomitant medication with other hepatotoxic drugs (OR:2.54; 95% CI:1.23-5.26; p = 0.012), NAT2 slow acetylator status (OR:2.46; 95% CI:1.25-4.84; p = 0.009), and carriers of p.Val444Ala variant for ABCB11 gene (OR:2.06; 95%CI:1.02-4.17; p = 0.044). The statistical model explains 24.9% of the susceptibility to AT-DILI, with an 8.9 times difference between patients in the highest and in the lowest quartiles of risk scores. This study sustains the complex architecture of AT-DILI. Prospective studies should evaluate the benefit of NAT2 and ABCB11 genotyping in AT personalization, particularly in patients over 55 years.

SUBMITTER: Cavaco MJ

PROVIDER: S-EPMC9144180 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Clinical and Genetic Risk Factors for Drug-Induced Liver Injury Associated with Anti-Tuberculosis Treatment-A Study from Patients of Portuguese Health Centers.

Cavaco Maria João MJ Alcobia Celeste C Oliveiros Bárbara B Mesquita Luís Alcides LA Carvalho Aurora A Matos Fernando F Carvalho José Miguel JM Villar Miguel M Duarte Raquel R Mendes João J Ribeiro Carolina C Cordeiro Carlos Robalo CR Regateiro Fernando F Silva Henriqueta Coimbra HC

Journal of personalized medicine 20220513 5

Drug-induced liver injury (DILI) is an unpredictable and feared side effect of antituberculosis treatment (AT). The present study aimed to identify clinical and genetic variables associated with susceptibility to AT-associated hepatotoxicity in patients with pulmonary tuberculosis treated with a standard protocol. Of 233 patients enrolled, 90% prospectively, 103 developed liver injury: 37 with mild and 66 with severe phenotype (DILI). All patients with mild hepatitis had a RUCAM score ≥4 and all ...[more]

PMID: 35629211

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Project description: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.

Project description:Although many genetic variants related to anti-tuberculosis drug induced liver injury (ATDILI) have been identified, the prediction and personalized treatment of ATDILI have failed to achieve, indicating there remains an area for further exploration. This study aimed to explore the influence of single nucleotide polymorphisms (SNPs) in Bradykinin receptor B2 (BDKRB2), Teneurin transmembrane protein 2 (TENM2), transforming growth factor beta 2 (TGFB2), and solute carrier family 2 member 13 (SLC2A13) on the risk of ATDILI.The subjects comprised 746 Chinese tuberculosis (TB) patients. Custom-by-design 2x48-Plex SNPscanTM kit was employed to genotype 28 selected SNPs. The associations of SNPs with ATDILI risk and clinical phenotypes were analyzed according to the distributions of allelic and genotypic frequencies and different genetic models. The odds ratio (OR) with corresponding 95% confidence interval (CI) was calculated.Among subjects with successfully genotyped, 107 participants suffered from ATDILI during follow-up. In BDKRB2, patients with rs79280755 G allele or rs117806152 C allele were more vulnerable to ATDILI (PBonferronicorrection = .002 and .03, respectively). Rs79280755 increased the risk of ATDILI significantly whether in additive (OR = 3.218, 95% CI: 1.686-6.139, PBonferroni correction = .003) or dominant model (PBonferroni correction = .003), as well as rs117806152 (Additive model: PBonferroni correction = .05; dominant model: PBonferroni correction = .03). For TENM2, rs80003210 G allele contributed to the decreased risk of ATDILI (PBonferroni correction = .02), while rs2617972 A allele conferred susceptibility to ATDILI (PBonferroni correction = .01). Regarding rs2617972, significant findings were also observed in both additive (OR = 3.203, 95% CI: 1.487-6.896, PBonferroni correction = .02) and dominant model (PBonferroni correction = .02). Moreover, rs79280755 and rs117806152 in BDKRB2 significantly affected some laboratory indicators. However, no meaningful SNPs were observed in TGFB2 and SLC2A13.Our study revealed that both BDKRB2 and TENM2 genetic polymorphisms were interrogated in relation to ATDILI susceptibility and some laboratory indicators in the Western Chinese Han population, shedding a new light on exploring novel biomarkers and targets for ATDILI.

Project description:Background: Anti-tuberculosis drug-induced liver injury (ATB-DILI) is an adverse reaction with a high incidence and the greatest impact on tuberculosis treatment. However, there is a lack of effective biomarkers for the early prediction of ATB-DILI. Herein, this study uses UPLC‒MS/MS to reveal the plasma metabolic profile and lipid profile of ATB-DILI patients before drug administration and screen new biomarkers for predicting ATB-DILI. Methods: A total of 60 TB patients were enrolled, and plasma was collected before antituberculosis drug administration. The untargeted metabolomics and lipidomics analyses were performed using UPLC‒MS/MS, and the high-resolution mass spectrometer Q Exactive was used for data acquisition in both positive and negative ion modes. The random forest package of R software was used for data screening and model building. Results: A total of 60 TB patients, including 30 ATB-DILI patients and 30 non-ATB-DILI subjects, were enrolled. There were no significant differences between the ATB-DILI and control groups in age, sex, smoking, drinking or body mass index (p > 0.05). Twenty-two differential metabolites were selected. According to KEGG pathway analysis, 9 significantly enriched metabolic pathways were found, and both drug metabolism-other enzymes and niacin and nicotinamide metabolic pathways were found in both positive and negative ion models. A total of 7 differential lipid molecules were identified between the two groups. Ferroptosis and biosynthesis of unsaturated fatty acids were involved in the occurrence of ATB-DILI. Random forest analysis showed that the model built with the top 30 important variables had an area under the ROC curve of 0.79 (0.65-0.93) for the training set and 0.79 (0.55-1.00) for the validation set. Conclusion: This study demonstrated that potential markers for the early prediction of ATB-DILI can be found through plasma metabolomics and lipidomics. The random forest model showed good clinical predictive value for ATB-DILI.

Dataset Information

Clinical and Genetic Risk Factors for Drug-Induced Liver Injury Associated with Anti-Tuberculosis Treatment-A Study from Patients of Portuguese Health Centers.

Publications

Clinical and Genetic Risk Factors for Drug-Induced Liver Injury Associated with Anti-Tuberculosis Treatment-A Study from Patients of Portuguese Health Centers.

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