NAT2 Polymorphism and Clinical Factors that Increase Antituberculosis Drug-Induced Hepatotoxicity

Abstract

Aim: Hepatotoxicity is a known adverse effect of antituberculosis drugs. The NAT2 gene polymorphism has been associated with an increased risk of antituberculosis drug-induced hepatotoxicity (ATDIH). Materials & methods: This study investigates the association of NAT2 polymorphism and clinical risk factors that may contribute to the development of ATDIH. The authors sequenced the NAT2 region of 33 tuberculosis patients who developed ATDIH and 100 tuberculosis patients who did not develop ATDIH during tuberculosis treatment. NAT2 haplotypes were inferred and NAT2 acetylator status was predicted from the combination of the inferred haplotypes. Multiple logistic regression was performed to identify possible factors that are associated with ATDIH. Results: The TT genotype of NAT2*13A and the AA genotype of NAT2*6B were found to be substantially linked with the risk of ATDIH, with odds ratios of 3.09 (95% CI: 1.37–6.95) and 3.07 (95% CI: 1.23–7.69), respectively. NAT2 slow acetylators are 3.39-times more likely to develop ATDIH. Factors that were associated with ATDIH include underlying diabetes mellitus (adjusted odds ratio [AOR]: 2.96; 95% CI: 1.05–8.37), pre-treatment serum bilirubin (AOR: 1.09; 95% CI: 1.02–1.16) and NAT2 slow acetylator (AOR: 3.77; 95% CI: 1.51–9.44). Conclusion: Underlying diabetes mellitus, having a higher baseline bilirubin and being a slow acetylator are identified as the risk factors associated with ATDIH among patients in Malaysia.

Keywords::

• antituberculosis
• hepatotoxicity
• Malaysia
• NAT2
• polymorphism
• risk factor

Author contributions

LK Teh, MZ Salleh, NFM Noor and MAM Zim designed the research study. NFM Noor, MAM Zim, ZA Bakar, NI Zakaria and MI Lailanor established cohort and collected the clinical data for patients. NFM Noor carried out genotyping. NFM Noor and MNF Noorizhab carried out data analysis and documented the findings. NFM Noor wrote the manuscript. LK Teh and MZ Salleh provided critical inputs to the manuscripts. The final version of the manuscript has been read and approved by all the authors.

Acknowledgments

We would like to thank the Director General of Health Malaysia for his permission to publish this article. Thank you to all staff from TB Management Unit from Institute of Respiratory Medicine and Selayang Hospital for their kindness, help and support.

Financial & competing interests disclosure

The authors acknowledge the research funding awarded by the Ministry of Higher Education Malaysia by grant no. 600-IRMI/LRGS 5/3 (0003/2016). 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.

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

Ethical conduct of research

This study was approved by the Research Ethics Committees Universiti Teknologi MARA (REC-715-19) and the Medical Research and Ethics Committee Ministry of Health Malaysia (KKM/NIHSEC/P19-2502). Written informed consent was obtained from every patient prior to participation in the study.

Additional information

Funding

The authors acknowledge the research funding awarded by the Ministry of Higher Education Malaysia by grant no. 600-IRMI/LRGS 5/3 (0003/2016). 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. No writing assistance was utilized in the production of this manuscript.