Association Of Metabolism, Transport And Effect Pathway Related Gene Polymorphism And Valproic Acid Therapy In Epilepsy

Objectives:Epilepsy has matured therapeutic drugs and treatment protocols, but approximately one-third of the patients do not respond adequately to anti-epileptic drugs. Such interindividual variations in drug response are believed to result from genetic variations in candidate genes belonging to multiple pathways. Valproic acid is a commonly used first-line drug for treatment of epilepsy. But its clinical efficacy in individual is different. The aim of this study was to investigate whether gene polymorphisms of metabolism, transport and effect pathway affect the therapeutic response to Valproic acid in epilepsy patients.Methods:A total of201epilepsy patients were enrolled, in which70were diagnosed as multiple drug-resistant epilepsy and131patients were diagnosed as having drug-responsive epilepsy. Valproic acid responsivness was defined as freedom from seizures for more than12months. We selected a total of24SNPs in11candidate genes belonging to metabolism, transport and effect pathway. These SNPs were included in ABCB1, CYP2C19, UGT2B7, GRIN2B, SCN1A, SCN2A, GABRA1, GABRG2, GABRA6, ALDH5A1and ABAT. Genotyping was performed by using MassARRAY(?) iPlEX Gold method. Statistical analyses were performed by binary logistic regression, T test, Pearson’s χ2and Multifactor Dimensionality Reduction (MDR).Results:The genetic polymorphisms of24SNPs were consistent with Hardy-Weinberg equilibrium. In transport pathway, ABAT rs1731017C>T polymorphism, genotype TT was associated with drug-resistant phenotype in epilepsy patients (P=0.048, OR=0.271,95%CI=0.108-0.682). In effect pathway, SCN2A rs2304016A>G polymorphism showed a marginal significant difference between drug resistance and drug-responsive patients for the AG genotype (P=0.09; OR=3.495,95%CI=1.418-8.618). We also detected gene-gene interaction by using the application of maltifactor dimensionality reduction and got the best SNP combination of ABAT rs1731017with SCN2A rs2304016(P<0.0001, OR=3.6892,95%CI=1.9347-7.0347).Conclusions:ABAT rs1731017polymorphism was significantly associated with Valproic acid-resistant in Chinese patients with epilepsy. SCN2A rs2304016A>G polymorphism showed a marginal significant difference between drug resistance and drug-responsive patients. We also observed ABAT rs1731017and SCN2A rs2304016has a gene-gene interaction.