Association of EPHX1 polymorphisms with plasma concentration of carbamazepine in epileptic patients: Systematic review and meta-analysis

Background: Carbamazepine (CBZ) is a wildly used anti-epileptic drug (AED). Increasing evidence suggested that polymorphisms in Epoxide Hydrolase1 (EPHX1) gene are associated with the pharmacokinetics (PK) and pharmacodynamics (PD) of CBZ, albeit the results were inconsistent.

Methods: A literature search on PubMed, Embase, and Cochrane Library was conducted to identify eligible studies published between 1974 and 2020. A meta-analysis was performed and the standardized mean difference (SMD) and 95% confidence interval (95% CI) were estimated using a random-effects model. The heterogeneity and leave-one-study-out sensitivity analyses of each article and the publication bias were also performed. All the statistical analyses were performed using STATA 14.0.

Results: A total of 6 articles with 1746 subjects were included in this meta-analysis. A significant correlation was detected between EPHX1 rs1051740 T > C polymorphisms and decreased plasma concentration of CBZ (TT vs CC: SMD = 0.34, P < 0.001; TC vs CC: SMD = 0.35, P = 0.009). However, similar results were not detected in the comparison of TT vs. TC in the EPHX1 rs1051740 T > C variation (P = 0.637), while subgroup analyses showed an association with plasma CBZ concentration in the non-Asian group (P < 0.001, I² = 0.0%, Ph = 0.400). Although the association of EPHX1 rs2234922 A > G polymorphisms with plasma CBZ concentration was not detected (AA vs GG:SMD = 0.54, P = 0.102; AA vs AG:SMD = -0.05, P = 0.670; AG vs GG: SMD = 0.86, P = 0.107), subgroup analyses showed that the GG genotype EPHX1 rs2234922 was associated with increased plasma CBZ concentration in the Asian group (P = 0.005, I² = 48.6%, Ph = 0.143).

Conclusion: EPHX1 rs1051740 T > C and rs2234922 A > G are important genetic variants associated with plasma CBZ concentration. The role of EPHX1 polymorphisms in the interindividual variability of plasma CBZ concentration varied significantly among different ethnic groups, which should be considered during clinical validation and in future studies.