Lack of association between valproic acid response and polymorphisms of its metabolism, transport, and receptor genes in children with focal seizures

  • Weixing Feng
  • Shenghui Mei
  • Jiaqi Han
  • Leting Zhu
  • Yazhen Yu
  • Baoqin Gao
  • Yun Wu
  • Jiuwei Li
  • Zhigang ZhaoEmail author
  • Fang FangEmail author
Original Article



This study aims to describe the associations between genetic polymorphisms and therapeutic effect of valproic acid (VPA) in children with focal seizures.


Eighty-nine children with focal seizures on VPA therapy were enrolled. Patients’ basic information, dosage regimens, and plasma concentrations were recorded. A 1-year follow-up was performed to evaluate the treatment response. Sixty-six single nucleotide polymorphisms involved in the metabolism, transport, and target receptor of VPA were identified, and their associations with VPA response were analyzed using logistic regression adjusted by various influence factors. Selected polymorphisms involved in the metabolism, transport, and target receptor of VPA were not associated with treatment effect in children with focal seizures.


Three variants, rs9313892 (GABRA6, G > A, OR = 2.73, 95% CI 1.00 to 7.48, P = 0.051), rs4921195 (GABRA6, T > C, OR = 2.71, 95% CI 0.99 to 7.42, P = 0.053), and rs424740 (GABRG2, A > T, OR = 0.39, 95% CI 0.15 to 1.01, P = 0.053) had the potential to be associated with the VPA response.


Selected genetic polymorphisms were not significantly associated with VPA response in children with focal seizures. However, three GABR variants showed potential to be associated with the response to VPA. Further and larger studies are warranted to confirm the results.


Children Valproic acid Genetic polymorphisms Drug-resistant epilepsy Focal seizures 



Valproic acid


ATP binding cassette subfamily B member 1


ATP binding cassette subfamily C member 2


Gamma-aminobutyric acid


4-Aminobutyrate aminotransferase


GABA receptor


GABA type A receptor gamma 2 subunit


Sodium voltage-gated channel




Glutamate ionotropic receptor NMDA type


Minor allele frequency


Hardy–Weinberg equilibrium


Odds ratio

95% CI

95% confidence interval


Gamma-aminobutyric acid type A receptor alpha 6 subunit


Cytochrome P450 family 2 subfamily C member 9.



Thanks to our patients and our whole team. Particularly grateful to professor Shiqi Peng, Ming Zhao, Yuji Wang (College of Pharmaceutical Science, Capital Medical University, Beijing, China), Jiawang Liu (Medicinal Chemistry Core, Division of Vice Chancellor for Research, University of Tennessee Health Science Center), and the reviewers for their help in manuscript revision.

Author contributions

Weixing Feng: study design, data analysis, follow-up, and manuscript revising.

Shenghui Mei: study design, data analysis, and manuscript revising.

Jiaqi Han: data analysis, follow-up, and manuscript revising.

Leting Zhu: sample collection and valproic acid plasma concentration analysis.

Yazhen Yu: patient’s information collection and follow-up.

Baoqin Gao: study design and manuscript revising.

Yun Wu: patient’s information collection and follow-up.

Jiuwei Li: patient’s information collection and follow-up.

Zhigang Zhao: study design and manuscript revising.

Fang Fang: study design and manuscript revising.


This study was funded by the National Natural Science Foundation of China (no. 81301118).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

10072_2018_3681_MOESM1_ESM.xlsx (58 kb)
ESM 1 (XLSX 57 kb)


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Copyright information

© Fondazione Società Italiana di Neurologia 2018

Authors and Affiliations

  1. 1.Department of Neurology, Beijing Children’s HospitalCapital Medical UniversityBeijingPeople’s Republic of China
  2. 2.Department of Pediatrics, Beijing Tiantan HospitalCapital Medical UniversityBeijingPeople’s Republic of China
  3. 3.Department of Pharmacy, Beijing Tiantan HospitalCapital Medical UniversityBeijingPeople’s Republic of China
  4. 4.Department of Clinical Pharmacology, College of Pharmaceutical SciencesCapital Medical UniversityBeijingPeople’s Republic of China

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