The role of NAT2 genetic variants in anti-tuberculosis drug-induced liver injury (AT-DILI): a meta-analysis

Background Anti-tuberculosis drug-induced liver injury (AT-DILI) is one of the significant adverse effects of first-line tuberculosis therapy, frequently resulting in treatment discontinuation. Genetic polymorphisms in N-acetyltransferase 2 ( NAT2 ), a key enzyme in the metabolism of isoniazid (an anti-TB drug), are suggested to influence AT-DILI susceptibility. Methods A meta-analysis of published studies was conducted to evaluate the association between NAT2 polymorphisms and the risk of AT-DILI. Literature searches were conducted in PubMed, Web of Science, Wiley, ScienceDirect, and Medline up to December 2024. A total of 48 studies comprising 11,035 patients were included. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Subgroup analyses were conducted based on region, study design, genotyping method, hepatotoxicity definitions, and NAT2 genetic variants. Heterogeneity, publication bias, quality assessment, and sensitivity analysis were assessed using the I 2 statistic, Egger's test, the Newcastle-Ottawa Scale (NOS), and the leave-one-out method, respectively. Results Slow acetylator genotypes were significantly associated with an increased risk of AT-DILI (pooled OR = 3.02; 95% CI = 2.50-3.64; p 2 = 58.74%). No significant publication bias was observed ( p = 0.199). Conclusion NAT2 acetylator status was significantly associated with the likelihood of experiencing hepatotoxicity related to anti-tuberculosis drugs.