NAT2 rs1495741 and anti-tuberculosis drug-induced liver injury in children: genetic association and risk prediction.

BACKGROUND: Anti-tuberculosis drug-induced liver injury (ATB-DILI) is a major adverse event in children receiving anti-tuberculosis therapy, but pediatric pharmacogenetic evidence remains limited.

METHODS: We studied 192 children receiving anti-tuberculosis treatment, including 31 with ATB-DILI and 161 without DILI. After quality control, 86 single-nucleotide polymorphisms were tested for association with ATB-DILI. Based on three available NAT2 variants, NAT2 diplotypes were inferred from the genotype data, and acetylator phenotypes were determined. The relationship of rs1495741 with 2-h plasma isoniazid concentration and ATB-DILI was further evaluated, and prediction models integrating genetic and clinical variables were developed.

RESULTS: After Bonferroni correction, only NAT2 rs1495741 remained significantly associated with ATB-DILI (= 0.013). Under the recessive model, the AA genotype was associated with a 7.29-fold higher risk of ATB-DILI than the GG/AG genotypes (95% CI: 3.22-17.52;< 0.001). In the NAT2 analysis, slow acetylator phenotypes were more frequent in the ATB-DILI group than in the non-DILI group (64.52% vs. 21.12%). Rs1495741 showed high concordance with inferred NAT2 acetylator phenotypes (Cohen's kappa = 0.89,< 0.001). Measured 2-h plasma isoniazid concentrations increased across rs1495741 genotypes, and the AA genotype was strongly associated with high isoniazid concentration (>6&#xa0;&#x3bc;g/mL; OR = 11.23, 95% CI: 6.62-19.07;< 0.001). The best predictive model achieved an AUC of 0.874.

CONCLUSION: NAT2 rs1495741 was strongly associated with pediatric ATB-DILI risk and showed high concordance with inferred NAT2 acetylator phenotypes. This association was not significantly mediated by the measured single 2-h plasma isoniazid concentration in this dataset. Incorporating rs1495741 may improve risk stratification in children.