Association of a synonymous GAT3 polymorphism with antiepileptic drug pharmacoresistance

Abstract

It would be likely that the genetic variants of the GTA3 gene encoding GAT-3, an astrocytic GABA transporter, may alter gammaaminobutyric 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 (n¼400) was used for the initial exploratory stage of the study and sample 2 (n¼435) was used for confirmation of the genetic association in the replication stage of the study. A GAT3 polymorphism (GAT3 c.1572 C4T, rs2272400) was nominally associated with AEDs pharmacoresistance (P CC vs P CT/TT ¼0.012, P allelic ¼0.01). The odds ratio (OR) for AED pharmacoresistance was 1.6 (95% confidence interval (CI), 1.11-2.24; P¼0.01) 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 ¼0.037, joint P-value of the replication¼0.001). 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.

Meta‐Analysis of Genetic Influences on Initial Alcohol Sensitivity

“…Suggestive loci localize to several genes of interest. For example, SLC6A11 is a GABA transporter preferentially expressed in brain (Fagerberg et al, 2014); variation in this gene has been associated with intellectual and behavioral aberrations (Dikow et al, 2014) and resistance to epilepsy pharmacotherapy (Kim et al, 2011). Given the role of the GABAergic system in alcohol response and sensitization (Camarini and Pautassi, 2016; Koob, 2013), the biological plausibility of SLC6A11 is compelling.…”

GAT‐1 (rs2697153) and GAT‐3 (rs2272400) polymorphisms are associated with febrile seizures and temporal lobe epilepsy

“…This study, together with the study of Carvill et al, suggests that SLC6A1 mutation-positive patients have a combination of intellectual disability, language delay and epilepsy, most frequently associated with MAE syndrome (Johannesen et al, 2018). Regarding GAT-3, the SNP with dbSNP identifier rs2272400 (GAT-3 c.1572 C>T, exon 12) has been associated with antiepileptic drug resistance in a Korean study (Kim et al, 2011). Structurally, the SNP rs2272400 is located in the coding region of GAT-3 on exon 12, however, this does not lead to amino acid changes.…”

“…In this association study, we analysed the rs2697153 SNP in the GAT-1 gene (SLC6A1) and the rs2272400 SNP in the GAT-3 gene (SLC6A11) in a well-circumscribed cohort of patients with drug-resistant TLE and matched healthy controls. The SNPs were selected based on relevant recent literature (Thoeringer et al, 2009;Kim et al, 2011;Carvill et al, 2015;Johannesen et al, 2018), however, the clinical significance of both SNPs is not yet reported in major databases (dbSNP, gnomAD and ExAC). We observed that the AA GAT-1 genotype was significantly more frequent in patients than in controls.…”

Regulation of Glutamate, GABA and Dopamine Transporter Uptake, Surface Mobility and Expression

“…Under these conditions, the reversal of GABA uptake could provide a useful mechanism to curtail seizure propagation. With some exceptions (Xie et al, 2017), single nucleotide polymorphisms in SLC6A11, the gene encoding human GAT3, have been detected in patients with antiepileptic drug resistance (Kim et al, 2011). It is possible that a dysfunction of GAT3 could alter both phasic and tonic GABAergic transmission in the epileptic brain.…”