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 (PCC vs PCT/TT=0.012, Pallelic=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 (Pallelic=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.
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Acknowledgements
We are grateful to Young Joo Kim (PhD, Korea Research Institute of Bioscience and Biotechnology) for his comments on bioinformatics used in this manuscript. This study was supported by a grant from the Korea Health 21 R&D Project, Ministry of Health, Welfare & Family Affairs, Republic of Korea (A080307) and by a grant (CRI-10005-1) of Chonnam National University Hospital Research Institute of Clinical Medicine.
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Kim, DU., Kim, MK., Cho, YW. et al. Association of a synonymous GAT3 polymorphism with antiepileptic drug pharmacoresistance. J Hum Genet 56, 640–646 (2011). https://doi.org/10.1038/jhg.2011.73
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DOI: https://doi.org/10.1038/jhg.2011.73
