Uridine 5’-diphospho-glucuronosyl-transferase 1A1 (UGT1A1) plays an important
role in the biliary excretion of bilirubin, suggesting genetic polymorphisms of
UGT1A1 may have an impact on bile acid metabolism, which
may be related to the development of anti-tuberculosis drug-induced liver injury
(ATLI). This study explores the associations between genetic polymorphisms of
UGT1A1 and ATLI in a Chinese anti-tuberculosis population.
A 1:2 matched case–control study was conducted among 290 ATLI cases and 580
controls, of which causality assessment of ATLI cases was based on the updated
Roussel Uclaf Causality Assessment Method (RUCAM). Conditional logistic
regression was applied to calculate odds ratio (OR) and 95% confidence intervals
(CIs), with weight and use of hepatoprotectant as covariates. The Bonferroni
correction was used to adjust P values for multiple testing.
Compared with those carrying rs6719561 TT genotype, patients with TC genotype
had lower risk of ATLI (adjusted OR = 0.723, 95% CI: 0.531–0.985,
P = 0.040). The haplotype TAG
(rs3755319-rs2003569-rs4148323) could marginally significantly increase the risk
of ATLI (adjusted OR = 5.071, 95% CI: 1.007–25.531, P = 0.049),
while haplotype TC (rs4148329-rs6719561) could reduce the risk of ATLI (adjusted
OR = 0.719, 95% CI: 0.527–0.982, P = 0.038). Patients with
polymorphisms at rs4148328 or rs3755319 were at a reduced risk of moderate and
severe liver injury under different genetic models. Based on this case–control
study, genetic polymorphisms of UGT1A1 may be associated with
susceptibility to ATLI in the Chinese anti-tuberculosis population.
Summary
What is known and objective
Reactive metabolites from anti‐tuberculosis (anti‐TB) drugs can result in abnormal accumulation of reactive oxygen species (ROS), which plays an important role in anti‐TB drug‐induced liver injury (ATLI). Liver cells could keep the production of ROS in balance by antioxidant activities. The heme oxygenase 1, encoded by the HMOX1 gene and NADH:quinone oxidoreductase 1, encoded by the NQO1 gene are crucial mediators of cellular defense against ROS. The present study aimed to investigate the associations between HMOX1 and NQO1 polymorphisms and ATLI in Chinese anti‐TB treatment population.
Methods
A matched case‐control study was conducted using 314 ATLI cases and 628 controls. Multivariate conditional logistic regression analysis was used to estimate the association between genotypes and risk of ATLI by the odds ratios (ORs) with 95% confidence intervals (CIs), with weight and use of hepatoprotectant as covariates.
Results and discussion
Patients carrying the GG genotype at rs2071748 in HMOX1 were at a higher risk of ATLI than those with the AA genotype (adjusted OR = 1.503, 95% CI: 1.005‐2.249, P = 0.047), and significant differences were also found under the recessive (P = 0.015) and additive (P = 0.045) models. Subgroup analysis confirmed the relationship in mild hepatotoxicity cases under the recessive and additive models (adjusted OR = 1.714, 95% CI: 1.169‐2.513, P = 0.006; adjusted OR = 1.287, 95% CI: 1.015‐1.631, P = 0.037, respectively).
What is new and conclusion
This is the first study to explore the relationship between HMOX1, NQO1 polymorphisms and ATLI in Chinese anti‐TB treatment population. Based on a matched case‐control study, genetic polymorphisms of HMOX1 may be associated with susceptibility to ATLI in the Chinese population.
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