Pharmacogenetics and genomics · 2025
No interaction between genetic variants and DNA methylation of the ferrochelatase gene in relation to antituberculosis drug-induced liver injury.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Wang Fei, Zhang Meiling, Wu Yu, Cheng Jingru, Chen Ruina, Pan Hongqiu, Lu Lihuan, He Xiaomin, Yi Honggang, Tang Shaowen
Аннотация
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.
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.