Genetic and non-genetic factors influencing the therapeutic response of valproic acid in pediatric epileptic patients.

Abstract

Aims: Considerable inter-individual variability in the efficacy of valproic acid (VPA) has been reported, with approximately 20-45% of patients failing to achieve satisfactory seizure control after VPA monotherapy. The aim of this study was to investigate the influence of non-genetic and genetic factors on 12-month VPA-response in a cohort of 194 pediatric patients.

Materials & methods: Trough concentrations were determined, and a panel of 48 variants located in pharmacokinetic and pharmacodynamic gene were genotyped.

Results: Aetiology was highlighted as a significant factor for the response to VPA. Specifically, patients with idiopathic epilepsy demonstrated poorer 12-month outcomes (p < 0.001). Trough VPA concentrations did not significantly affect outcomes. Marginal association was found between VPA efficacy and the following genetic variants: GABRA1 rs10068980 (p = 0.02), SLC16A1 rs7169 (p = 0.02), ABCC2 rs1885301 (p = 0.092), ACADM rs1251079 (p = 0.061) and GABRA1 rs6883877 (p = 0.085), as indicated by Fisher's exact test. A significant cumulative effect of two genetic factors (GABRA1 rs10068980 and SLC16A1 rs7169) was observed after a multiple logistic analysis, with ORs of 2.828 (1.213, 6.594) and 4.066 (1.148,14.398), respectively.

Conclusion: Our study indicated that GABRA1 rs10068980 and SLC16A1 rs7169 might serve as potential biomarkers for predicting the 12-month VPA treatment outcomes in pediatric patients with epilepsy.