Lack of association between valproic acid response and polymorphisms of its metabolism, transport, and receptor genes in children with focal seizures
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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.
KeywordsChildren Valproic acid Genetic polymorphisms Drug-resistant epilepsy Focal seizures
ATP binding cassette subfamily B member 1
ATP binding cassette subfamily C member 2
GABA type A receptor gamma 2 subunit
Sodium voltage-gated channel
Glutamate ionotropic receptor NMDA type
Minor allele frequency
- 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.
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.
- 25.Kwan P, Poon WS, Ng HK, Kang DE, Wong V, Ng PW, Lui CH, Sin NC, Wong KS, Baum L (2008) Multidrug resistance in epilepsy and polymorphisms in the voltage-gated sodium channel genes SCN1A, SCN2A, and SCN3A: correlation among phenotype, genotype, and mRNA expression. Pharmacogenet Genomics 18(11):989–998PubMedCrossRefGoogle Scholar
- 31.Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, Engel J Jr, Forsgren L, French JA, Glynn M, Hesdorffer DC, Lee BI, Mathern GW, Moshe SL, Perucca E, Scheffer IE, Tomson T, Watanabe M, Wiebe S (2014) ILAE official report: a practical clinical definition of epilepsy. Epilepsia 55(4):475–482PubMedCrossRefGoogle Scholar
- 32.Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, Engel J, French J, Glauser TA, Mathern GW, Moshe SL, Nordli D, Plouin P, Scheffer IE (2010) Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE commission on classification and terminology, 2005-2009. Epilepsia 51(4):676–685PubMedCrossRefGoogle Scholar