A study of N-acetyltransferase 2 gene polymorphisms in the Indian population and its relationship with serum isoniazid concentrations in a cohort of tuberculosis patients

The N-acetyltransferase 2 (NAT2) gene exhibits substantial genetic diversity, leading to distinct acetylator phenotypes among individuals. In this study, we determine NAT2 gene polymorphisms in tuberculosis (TB) patients and analyze serum isoniazid (INH) concentrations across the various genotypes. An observational prospective cohort study involving 217 patients with pulmonary or extrapulmonary TB was carried out. The NAT2 genotypes were identified using real-time polymerase chain reaction technology. INH concentrations at baseline and 2 hours post-dosing were estimated using high-performance liquid chromatography. The association between the acetylator status and INH concentrations was evaluated using odds ratios (OR), and the occurrence of adverse events across the different patient genotypes was also assessed. The genotype frequency of fast, intermediate, and slow acetylators was 7.37%, 39.17%, and 53.46%, respectively, while allele frequency was 27% for fast acetylators and 73% for slow acetylators. All the alleles followed the Hardy-Weinberg equilibrium. Patients with slow acetylator status had significantly increased serum INH concentrations 2 hours post-drug administration, followed by intermediate acetylators, as compared to fast acetylators. 69 (31.8%) patients developed adverse drug reactions post-therapy. Patients with slow acetylator status had the highest (OR: 9.66) risk of developing drug-induced hepatotoxicity, especially those with raised serum INH concentrations (OR: 1.34). Understanding the correlation between genetics and serum antitubercular drug levels in antitubercular drug-induced hepatotoxicity will provide valuable information to the medical community, minimizing the risk of adverse reactions and hospitalizations.