Polymorphism of CYP3A4*18 is associated with anti-tuberculosis drug-induced hepatotoxicity

Abstract

Aim: The association between cytochrome P450 (CYP) gene polymorphisms and anti-tuberculosis drug-induced hepatotoxicity (ATDH) was investigated in patients with or without pre-existing liver diseases (PLD). Materials & methods: We followed 164 tuberculosis subjects, 58 with PLD and 106 without PLD. Polymorphisms in CYP2D6, CYP2C9, CYP2C19, CYP3A4 and CYP3A5 were analyzed using the TaqMan^® SNP genotyping assay. Results: The CYP3A4*18 heterozygous genotype was associated with ATDH (OR: 3.24, 95% CI: 1.06–9.86) regardless of PLD presence. Among subjects without PLD, CYP3A4*18 heterozygotes had significantly higher ATDH risk (OR: 9.10, 95% CI: 1.56–53.16). Conversely, in the PLD group, CYP3A4*18 heterozygotes had lower ATDH risk (OR: 0.21, 95% CI: 0.05–0.98). Conclusion: CYP3A4*18 genotype is linked to ATDH in tuberculosis patients, with differential effects based on PLD presence.

Summary points

• First-line anti- tuberculosis drugs like isoniazid, rifampicin and pyrazinamide are used a lot, but they can give some patients drug-induced hepatitis.

• Pre-existing liver diseases are the important risk for anti-tuberculosis drug-induced hepatotoxicity (ATDH).

• In Taiwan, liver disease is more common. Previous pharmacogenetic studies on ATDH typically focused only on patients without pre-existing liver diseases.

• In individuals without pre-existing liver diseases, we found a significant association between the CYP3A418 heterozygous genotype and an elevated risk of ATDH. However, among those with pre-existing liver diseases, individuals with the CYP3A4*18 heterozygous genotype had a reduced risk of ATDH.

• When investigating or applying the association between CYP genetic polymorphisms and ATDH in clinical settings, the presence of pre-existing liver diseases should be carefully considered.

Keywords: :

• anti-tuberculosis drugs
• cytochrome P450 genes
• hepatotoxicity

Acknowledgments

We thank all the participants in this research for their generous and continued support. Additionally, we thank the Laboratory Medicine Department personnel at Taoyuan General Hospital for their support during the conduct of the study.

Author contributions

Conceptualization: SW Lee and LS Wu; methodology: LS Wu and CW Liu; laboratory analysis: PT Chen and YH Lee; investigation: SW Lee, PT Chen, CW Lee, YH Lee and LS Wu; data curation: PT Chen and LS Wu; writing— original draft preparation: CW Liu and LS Wu; writing—review and editing: all authors; All authors have read and agreed to the published version of the manuscript.

Financial disclosure

This work was supported by the Taoyuan General Hospital, Taiwan (PTH10001). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

Written informed consent was obtained from each subject enrolled in this study. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki, and was approved by the Ethics Committee of Taoyuan General Hospital (TYGH99040).

Data sharing statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy and ethical restrictions.

Additional information

Funding

This work was supported by the Taoyuan General Hospital, Taiwan (PTH10001).