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

Abstract

Objective

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

Methods

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.

Results

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.

Conclusion

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.

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Abbreviations

VPA:

Valproic acid

ABCB1:

ATP binding cassette subfamily B member 1

ABCC2:

ATP binding cassette subfamily C member 2

GABA:

Gamma-aminobutyric acid

ABAT:

4-Aminobutyrate aminotransferase

GABR:

GABA receptor

GABRG2:

GABA type A receptor gamma 2 subunit

SCN:

Sodium voltage-gated channel

NMDA:

N-methyl-D-aspartate

GRIN:

Glutamate ionotropic receptor NMDA type

MAF:

Minor allele frequency

HWE:

Hardy–Weinberg equilibrium

OR:

Odds ratio

95% CI:

95% confidence interval

GABRA6:

Gamma-aminobutyric acid type A receptor alpha 6 subunit

CYP2C9:

Cytochrome P450 family 2 subfamily C member 9.

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Acknowledgments

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.

Funding

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

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Authors

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.

Corresponding authors

Correspondence to Zhigang Zhao or Fang Fang.

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Weixing Feng, Shenghui Mei, and Jiaqi Han are equal first authors

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Feng, W., Mei, S., Han, J. et al. Lack of association between valproic acid response and polymorphisms of its metabolism, transport, and receptor genes in children with focal seizures. Neurol Sci 40, 523–528 (2019). https://doi.org/10.1007/s10072-018-3681-y

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Keywords

  • Children
  • Valproic acid
  • Genetic polymorphisms
  • Drug-resistant epilepsy
  • Focal seizures