Genetic Variations of NAT2 and CYP2E1 and Isoniazid Hepatotoxicity in a Diverse Population

Abstract

Aims: TB is a serious global public health problem. Isoniazid, a key drug used to treat latent TB, can cause hepatotoxicity in some patients. This pilot study investigated the effects of genetic variation in NAT2 and CYP2E1 on isoniazid-induced hepatotoxicity in TB contacts in British Columbia, Canada. Materials & methods: DNA re-sequencing was used to establish the spectrum of genetic variation in the exons, promoter and conserved regions of NAT2 in all subjects. For CYP2E1, the CYP2E1*1C polymorphism was genotyped by PCR-RFLP. Association tests of NAT2 variants and haplotypes, as well acetylator types were performed. Results: We enrolled 170 subjects on isoniazid treatment (23 cases and 147 controls). Systematic re-sequencing of NAT2 revealed 18 known and 10 novel variants. Conclusion: No single genetic variant of NAT2 and CYP2E1 showed a significant association with isoniazid-induced hepatotoxicity in this highly heterogeneous population. There was evidence of a trend for increasing hepatotoxicity risk across the rapid, intermediate and slow acetylator groups (p = 0.08).

KEYWORDS::

• CYP2E1
• hepatotoxicity
• isoniazid
• NAT2
• SNP
• TB

Acknowledgements

The authors would like to thank Diana Palmquist and Peter Huang for help assembling DNA sequences.

Financial & competing interests disclosure

This study was funded by the BC Lung Association. Angela Brooks-Wilson is a Senior Scholar of the Michael Smith Foundation for Health Research. Victoria J Cook is supported in part by in it for life, Vancouver Coastal Health Research Institute. J Mark Fitzgerald is a recipient of a Michel Smith Distinguished Scholar Award and a CIHR/BC Lung Scientist Award. So Yamada was supported in part by a Ritsumeikan University International Research Fellowship. 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

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

This study was funded by the BC Lung Association. Angela Brooks-Wilson is a Senior Scholar of the Michael Smith Foundation for Health Research. Victoria J Cook is supported in part by in it for life, Vancouver Coastal Health Research Institute. J Mark Fitzgerald is a recipient of a Michel Smith Distinguished Scholar Award and a CIHR/BC Lung Scientist Award. So Yamada was supported in part by a Ritsumeikan University International Research Fellowship. 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.