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Association of a synonymous GAT3 polymorphism with antiepileptic drug pharmacoresistance

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Affiliated Author(s)
조용원
Alternative Author(s)
Cho, Yong Won
Journal Title
Journal of Human Genetics
ISSN
1434-5161
Issued Date
2011
Keyword
antiepileptic drugsassociation analysisGAT3pharmacoresistancepolymorphism
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 (PCC vs PCT/TT¼0.012, Pallelic¼0.01). 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 (Pallelic¼0.037, 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.
Department
Dept. of Neurology (신경과학)
Publisher
School of Medicine
Citation
Dong-Uk Kim et al. (2011). Association of a synonymous GAT3 polymorphism with antiepileptic drug pharmacoresistance. Journal of Human Genetics, 56(9), 640–646. doi: 10.1038/jhg.2011.73
Type
Article
ISSN
1434-5161
DOI
10.1038/jhg.2011.73
URI
https://kumel.medlib.dsmc.or.kr/handle/2015.oak/34049
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Neurology (신경과학)
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