Genetic Basis of Anti-Tuberculosis Drug-Induced Liver Injury (AT-DILI)

Abstract

Anti-tuberculosis drug-induced liver injury (AT-DILI) is a severe adverse drug reaction associated with using anti-tuberculosis medications. Isoniazid, rifampicin, and pyrazinamide are potentially hepatotoxic drugs used in TB treatment. The rate of AT-DILI ranges from 2 to 28%, and this is also attributed to genetic factors. Drug metabolism genes are the major targets for association studies with AT-DILI. Some of the major genes that have been reported to be associated with DILI are N-acetyltransferase 2 (NAT2), glutathione S-transferase gene (GSTM1, GSTT1), Pregnane X receptor (PXR) etc. The present study aims to determine the prevalent genotypes of NAT2, PXR, ABCB1, GSTs, and their association with AT-DILI in the Manipuri population of India. About 450 individuals, including both controls and cases, were recruited, and genotyping of NAT2, PXR, ABCB1, and GST genes was performed using the Taqman allelic discrimination assay. Liver function tests (LFT) were also conducted to assess the liver injuries. Ten genotypes of NAT2 were observed in the population. About 51.2% of the population were of the intermediate acetylator genotype of NAT2, and the variant allele `T' of the PXR and ABCB1 genes were observed to be 21.0% and 58%, respectively. The null genotypes of GSTT1 and GSTM1 were found to be 37.8% and 68.0%, respectively. LFT analysis in 32 follow-up patients showed that about 75% of patients developed mild AT-DILI after two months of TB treatment. Case-control analysis showed that the null genotypes of GSTT1 and GSTM1, and the slow acetylator genotype of NAT2 were associated with AT-DILI. The study revealed that most Indian Manipuri populations were carriers of ancestral alleles for NAT2, PXR, and ABCB1. However, the null mutation of the GSTT1 and GSTM1 genes was highly prevalent in the population, and they could be significant contributors to AT-DILI in TB patients along with the slow acetylator genotype of NAT2.