| Objectives:Epilepsy,one of the most common chronic neurological disorder,affects more than 70 million people worldwide.Carbamazepine(CBZ)is prescribed worldwide as a first-line treatment for simple partial,complex partial,and generalized tonic-clonic seizures,but the large interindividual variabilities in the CBZ metabolism and therapeutic efficacy of epileptic patients were reported.With the development of pharmacogenomics,CYP3A4(rs2242480),CYP3A5(rs776746),EPHX1(rs1051740 and rs2234922)and SCN1A(rs3812718 and rs2298771)gene polymorphisms were previously indicated to be associated with CBZ metabolism and resistance in epilepsy.However,previous studies regarding the effects of these polymorphisms still remain controversial.Therefore,we performed a meta-analysis to evaluate whether the six polymorphisms are associated with CBZ metabolism and resistance in epilepsy.Therefore,it is necessary to comprehensively evaluate the associations of the abovementioned polymorphisms in CYP3A4,CYP3A5,EPHX1 and SCN1A genes with CBZ metabolism and resistance to achieve a more rational and individualized use of CBZ in epileptic treatment.In this regard,we performed a systematic meta-analysis to evaluate whether the six polymorphisms are associated with CBZ metabolism and resistance in epilepsy.Methods:The PubMed,EMBASE,Cochrane library,Chinese National Knowledge Infrastructure,Chinese Science and Technique Journals Database,China Biology Medicine disc and Wan fang Database were searched up to May 2020 for appropriate studies regarding the association of CYP3A4(rs2242480),CYP3A5(rs776746),EPHX1(rs1051740 and rs2234922)and SCN1A(rs3812718 and rs2298771)gene polymorphisms with metabolism and resistance to CBZ.The meta-analysis was conducted by Review Manager 5.3 software.Comparisons of the dichotomous variables were performed using risk ratio(RR)with 95%confidence interval(CI).For continuous variables,the mean differences(MD)or standard mean differences(SMD)with 95%CI were used in the meta-analysis.The statistical significance was determined by Z test,and P-value<0.05 was considered as statistically significant.Heterogeneity was tested using the Cochran's Q test and measured inconsistency by I2.Data with low heterogeneity(P>0.10 and I2?50%)were analyzed by a fixed-effects model while a random-effect model was used for data with high heterogeneity(P?0.10 and I2>50%).Results:(1)Meta-analysis of the associations between CYP3A4 rs2242480 and CYP3A5 rs776746 polymorphisms and CBZ metabolism and resistance.Eleven studies involving 1264 related epilepsy patients were included.Meta-analysis showed that the CYP3A4 rs2242480 and CYP3A5 rs776746 polymorphisms were significantly associated with plasma concentration of CBZ.For rs2242480,the results showed that patients carryied the mutant genotype reduced plasma concentration of CBZ compared with the wild-type genotypes.For rs776746,the results showed that patients carryied the mutant genotypes had significantly higher plasma CBZ concentration than those carryied the wild-type genotypes.However,no association was observed between these polymorphisms and resistance to CBZ.(2)Meta-analysis of the associations between EPHX1 rs 1051740 and rs2234922 polymorphisms and CBZ metabolism and resistanceSeven studies involving 1118 related epilepsy patients were included Meta-analysis showed that the EPHX1 rs1051740 polymorphism was significantly associated with plasma concentration of CBZ.The CC genotype of rs1011740 was associated with a reduction in plasma concentration of CBZ when compared to the TT and CT+TT genotypes.Furthermore,EPHX1 rs2234922 polymorphism was also observed to be significantly associated with plasma concentration of CBZD and CBZD:CBZE ratio.The results showed that patients with the GG genotype of rs2234922 decreased plasma concentration of CBZD and CBZD:CBZE ratio when compared to those with the wild-type genotypes.Nevertheless,the pooled analysis showed that the EPHX1 polymorphisms had no significant effect on CBZ resistance.(3)Meta-analysis of the associations between SCN1A rs3812718 and rs2298771 polymorphisms and CBZ metabolism and resistance.Nine studies involving 1559 related epilepsy patients were included.Meta-analysis showed that the SCN1A rs3812718 polymorphism was significantly associated with plasma concentration of CBZ and CBZE:CBZ ratio.The results showed that patients carryied the mutant genotypes of rs3812718 had significantly lower plasma CBZ concentrations and higher CBZE:CBZ ratio than those carryied the wild-type genotypes.Additionally,meta-analysis showed that the SCN1A rs3812718 polymorphism was significantly associated with CBZ resistance.The patients carryied mutant genotypes of rs3812718 had significantly higher CBZ resistance than those carryied the wild-type genotypes.However,no association was observed between SCN1A rs2298771 polymorphism and metabolism and resistance to CBZ.Conclusions:(1)The CYP3A4 rs2242480 and CYP3A5 rs776746 polymorphisms were able to affect the CBZ metabolism,while no associations between these polymorphisms and CBZ resistance for epilepsy patients.(2)The EPHX1 rs1051740 and rs2234922 polymorphisms may affect the CBZ metabolism,but CBZ resistance was not related to any of the single nucleotide polymorphisms investigated.(3)The SCN1A rs3812718 polymorphism may play an important role in metabolism and resistance to CBZ,while the SCN1A rs2298771 polymorphism is not associated with CBZ in epilepsy.These findings would improve the individualized therapy of epileptic patients in clinics. |
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