Genetic variations of NAT2 and CYP2E1 and isoniazid hepatotoxicity in a diverse population

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).