Evidence for epistatic interactions in antiepileptic drug resistance

Abstract

To investigate the epistatic interactions involved in antiepileptic drug (AED) resistance, 26 coding single-nucleotide polymorphisms (SNPs) were selected from 16 candidate genes. A total of 200 patients with drug-resistant localization-related epilepsy and 200 patients with drug-responsive localization-related epilepsy were genotyped individually for the SNPs. Rather than using the traditional parametric statistical method, a new statistical method, multifactor dimensionality reduction (MDR), was used to determine whether gene–gene interactions increase the risk of AED resistance. The MDR method indicated that a combination of four SNPs (rs12658835 and rs35166395 from GABRA1, rs2228622 from EAAT3 and rs2304725 from GAT3) was the best model for predicting susceptibility to AED resistance with a statistically significant testing accuracy of 0.625 (P<0.001) and cross-validation consistency of 10/10. This best model had an odds ratio of 3.68 with a significant 95% confidence interval of 2.32–5.85 (P<0.0001). Our results may provide meaningful information on the mechanism underlying AED resistance and, to the best of our knowledge, this is the first report of evidence for gene–gene interactions underlying AED resistance.