No interaction between genetic variants and DNA methylation of the ferrochelatase gene in relation to antituberculosis drug-induced liver injury

Objective The pathogenic mechanisms of antituberculosis drug-induced liver injury (AT-DILI) remain unclear. Isoniazid and rifampicin may lead to hepatic accumulation of protoporphyrin IX in which heme synthesis ferrochelatase (FECH), a key rate-limiting enzyme, potentially plays an important role. This study aimed to investigate the combined effects of FECH gene polymorphisms and promoter methylation on AT-DILI risk in the Eastern Chinese population. Methods A 1 : 1 matched case-control study was conducted, detecting one CpG island in the FECH promoter and four single-nucleotide polymorphisms (SNPs). A multivariate conditional logistic regression was used to estimate the association between genotypes and the risk of AT-DILI by the odds ratios (OR) with 95% confidence intervals (CIs). Additive and multiplicative interactions between methylation status and SNPs were further analyzed: additive interactions via the relative excess risk due to interaction (RERI) with 95% CIs, and multiplicative interactions by incorporating methylation-SNP product terms into regression models. Results Overall, 182 cases and 182 controls were included. Neither FECH promoter methylation (adjusted OR: 0.978, 95% CI: 0.408–1.560, P = 0.509) nor the four SNPs showed individual associations with AT-DILI risk ( P > 0.05). Crossover analyses revealed no significant genotype–methylation interactions ( P > 0.05). Both additive (rs17063905 RERI: ‐0.556, P = 0.691) and multiplicative interaction models (rs17063905, OR: 0.723, P = 0.615) demonstrated no synergistic effects between methylation and polymorphisms. Conclusion This research finds no significant association between FECH promoter methylation status in the CpG island, polymorphisms, or their interactions and the risk of AT-DILI.