title: 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 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.
authors.affiliation: Department of Medical Science, Chonnam National University Graduate School, Gwangju, Korea.
authors.forename: Dong-Uk
authors.initials: DU
authors.lastname: Kim
authors.forename: Myeong-Kyu
authors.initials: MK
authors.lastname: Kim
authors.forename: Yong-Won
authors.initials: YW
authors.lastname: Cho
authors.forename: Yo-Sik
authors.initials: YS
authors.lastname: Kim
authors.forename: Won-Joo
authors.initials: WJ
authors.lastname: Kim
authors.forename: Min Goo
authors.initials: MG
authors.lastname: Lee
authors.forename: Sung Eun
authors.initials: SE
authors.lastname: Kim
authors.forename: Tai-Seung
authors.initials: TS
authors.lastname: Nam
authors.forename: Ki-Hyun
authors.initials: KH
authors.lastname: Cho
authors.forename: Young-Ok
authors.initials: YO
authors.lastname: Kim
authors.forename: Min-Cheol
authors.initials: MC
authors.lastname: Lee
mesh_terms: D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D004351:Drug Resistance / Q000235:genetics*; D004827:Epilepsy / Q000188:drug therapy / Q000209:etiology / Q000235:genetics*; D005260:Female; D050485:GABA Plasma Membrane Transport Proteins / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007223:Infant; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D056910:Republic of Korea; D055815:Young Adult; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000927:Anticonvulsants; D050485:GABA Plasma Membrane Transport Proteins; C493416:SLC6A11 protein, human; D005680:gamma-Aminobutyric Acid