Association of CYP2B6 gene polymorphisms and anti-tuberculosis drug-induced hepatotoxicity in a Chinese population

Wang, Yu; Xiang, Xi; Wu, Shouquan; Guo, Cheng; Zhang, Miaomiao; Wang, Minggui; Wang, Fengjuan; Sandford, Andrew J.; He, Jian-Qing

doi:10.1016/j.meegid.2017.04.001

Cited by 8 publications

(8 citation statements)

References 38 publications

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“…ATP binding cassette subfamily B member 1 in Brazilians or human leukocyte antigen in Indians 13,14 . In our previous study, we observed cytochrome P450 2B6 variants may associate with susceptibility to ATDH but only in males 15 . However, the findings to date may only represent a small minority of the genetic variants relevant to ATDH and a more reliable biomarker is needed for predicting ATDH.…”

Section: Introductionmentioning

confidence: 81%

“…Genetic polymorphisms of NAT2 , CYP2E1 and the GST family are the most studied in relation to ATDH, for they may affect the metabolism and elimination of isoniazid, or are involved in oxidant-antioxidant balance in liver cells after exposure to anti-TB drugs 12 . We previously demonstrated that CYP2E1, GSTP1 and CYP2B6 were associated with susceptibility to ATDH by a meta-analysis and a case-control study 15,30,31 . Moreover, NAT2 mediates isoniazid biotransformation to form acetylhydrazine, which then undergoes oxidization by CYP2E1 to form a hepatotoxic substance 32 , but there is little evidence to implicate these enzymes in the metabolism of other anti-TB drugs such as pyrazinamide, which account for approximately 60% of ATDH 33 .…”

Section: Discussionmentioning

confidence: 98%

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Association of PXR and CAR Polymorphisms and Antituberculosis Drug-Induced Hepatotoxicity

Wang

Xiang

Huang

et al. 2019

Sci Rep

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A combination therapy of multiple drugs including isoniazid, rifampicin, ethambutol and pyrazinamide has been proven to be an effective option for the vast majority of tuberculosis (TB) patients. However, various adverse drug reactions (ADRs) limit its merit, with anti-TB drug-induced hepatotoxicity (ATDH) being a common and sometimes severe ADR. This study aimed to investigate the association between polymorphisms in two nuclear receptor genes, pregnane X receptor (PXR) and constitutive androstane receptor (CAR), and the risk of ATDH in a Chinese population. Subjects with or without hepatotoxicity during anti-TB treatment were recruited. DNA was extracted from peripheral blood and genotypes of the selected single nucleotide polymorphisms (SNPs) were determined by using the improved multiplex ligation detection reaction technique. Three genetic models (additive, dominant, and recessive) as well as haplotype, SNP-SNP interaction analyses were used to evaluate the genetic risk of ATDH. A total of 502 subjects (203 ATDH and 299 non-ATDH) were enrolled. The results showed that the minor allele of rs7643645 and the H0010001 haplotype in PXR were associated with decreased risk of ATDH, suggesting that drug-metabolizing enzymes regulated by PXR are involved in the pathogenesis of ATDH. More studies are required to verify this result.

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Section: Introductionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 98%

Association of PXR and CAR Polymorphisms and Antituberculosis Drug-Induced Hepatotoxicity

Wang

Xiang

Huang

et al. 2019

Sci Rep

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“…At present, WHO still recommends the combination of isoniazid, rifampicin, pyrazinamide and streptomycin as the first-line treatment protocol [1]. Although effective, the side effects of the combination protocol cannot be ignored, and anti-tuberculosis drug-induced liver injury (ATDILI) is the most common side effect, with an incidence of 2.0–28.0%[2]. The early symptoms of ATDILI are atypical and the diagnostic criteria lack specificity, which can cause a missed diagnosis or misdiagnosis, delaying treatment and resulting in adverse consequences.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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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.

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“…A review by Klein et al (2016) suggests that INH dose reduction in slow acetylators relative to rapid acetylators does not reduce anti-TB efficacy while likely reducing liver toxicity. Another recent study has reported an association between anti-TB drugs and CYP2B6 polymorphisms and the risk of ATDH in a Chinese population (Wang et al, 2017). In their review of pharmacokinetics and pharmacogenetics of anti-TB drugs, Motta et al (2018) suggest that increasing the RFP doses in individuals with SLCO1B1 loss of function alleles is a promising strategy-SLCO1B1 is a transporter of drugs into hepatic cells.…”

Section: Do Genetic Variants Of the Host Influence Tb Drug Efficacy mentioning

confidence: 99%

Challenges of Immune Response Diversity in the Human Population Concerning New Tuberculosis Diagnostics, Therapies, and Vaccines

Azad

Lloyd

Sadée

et al. 2020

Front. Cell. Infect. Microbiol.

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Universal approaches to the prevention and treatment of human diseases fail to take into account profound immune diversity resulting from genetic variations across populations. Personalized or precision medicine takes into account individual lifestyle, environment, and biology (genetics and immune status) and is being adopted in several disease intervention strategies such as cancer and heart disease. However, its application in infectious diseases, particularly global diseases such as tuberculosis (TB), is far more complex and in a state of infancy. Here, we discuss the impact of human genetic variations on immune responses and how they relate to failures seen in current TB diagnostic, therapy, and vaccine approaches across populations. We offer our perspective on the challenges and potential for more refined approaches going forward.

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Association of CYP2B6 gene polymorphisms and anti-tuberculosis drug-induced hepatotoxicity in a Chinese population

Cited by 8 publications

References 38 publications

Association of PXR and CAR Polymorphisms and Antituberculosis Drug-Induced Hepatotoxicity

Association of PXR and CAR Polymorphisms and Antituberculosis Drug-Induced Hepatotoxicity

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

Challenges of Immune Response Diversity in the Human Population Concerning New Tuberculosis Diagnostics, Therapies, and Vaccines

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