Association of a synonymous GAT3 polymorphism with antiepileptic drug pharmacoresistance

It would be likely that the genetic variants of the GTA3 gene encoding GAT-3, an astrocytic GABA transporter, may alter gamma-aminobutyric acid (GABA) neurotransmission in the synaptic cleft in the epileptic brain and cause antiepileptic drugs (AEDs) pharmacoresistance. A candidate gene association analysis with fine mapping was performed to dissect the genetic contributions of GAT3 to AEDs pharmacoresistance. Two independent case sample sets were recruited (Samples 1 and 2), and each set was divided into two groups (drug-resistant and drug-responsive) according to the treatment outcomes with AEDs. Sample1 (n=400) was used for the initial exploratory stage of the study and sample 2 (n=435) was used for confirmation of the genetic association in the replication stage of the study. A GAT3 polymorphism (GAT3 c.1572 C>T, rs2272400) was nominally associated with AEDs pharmacoresistance (P(CC) vs P(CT/TT)=0.012, P(allelic)=0.01). The odds ratio (OR) for AED pharmacoresistance was 1.6 (95% confidence interval (CI), 1.11-2.24; P=0.01) in the additive models of inheritance. The statistical significance remained after we adjusted for a confounding factor, the etiology of epilepsy, at 0.012 (adjusted OR: 1.73, 95% CI: 1.13-2.67) and used Bonferroni's correction for multiple comparisons at 0.048. Importantly, the positive association of c.1572 T was reproduced in the replication stage (P(allelic)=0.037, joint P-value of the replication=0.001). The results suggest that GAT3 c.1572T may be one of the contributing factors with a modest effect on AEDs pharmacoresistance in the epileptic brain, shed light on a better understanding of the underlying mechanisms and serve as an impetus for new avenues of treatment for AEDs pharmacoresistance.