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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
  • 17 Downloads

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.

Keywords

Children Valproic acid Genetic polymorphisms Drug-resistant epilepsy Focal seizures 

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.

Notes

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.

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.

Funding

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)

References

  1. 1.
    Tomson T, Battino D, Perucca E (2016) Valproic acid after five decades of use in epilepsy: time to reconsider the indications of a time-honoured drug. Lancet Neurol 15(2):210–218PubMedCrossRefGoogle Scholar
  2. 2.
    Dedei Daryan M, Guveli BT, Baslo SA, Mulhan K, Sari H, Balcik ZE, Atakli D (2018) Prevalence and clinical characteristics of headache in juvenile myoclonic epilepsy: experience from a tertiary epilepsy center. Neurol Sci 39(3):519–525PubMedCrossRefGoogle Scholar
  3. 3.
    Steinlein OK (2010) Gene polymorphisms and their role in epilepsy treatment and prognosis. Naunyn Schmiedeberg's Arch Pharmacol 382(2):109–118CrossRefGoogle Scholar
  4. 4.
    Ghodke-Puranik Y, Thorn CF, Lamba JK, Leeder JS, Song W, Birnbaum AK, Altman RB, Klein TE (2013) Valproic acid pathway: pharmacokinetics and pharmacodynamics. Pharmacogenet Genomics 23(4):236–241PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    de Wildt SN, Kearns GL, Leeder JS, van den Anker JN (1999) Glucuronidation in humans. Pharmacogenetic and developmental aspects. Clin Pharmacokinet 36(6):439–452PubMedCrossRefGoogle Scholar
  6. 6.
    Budi T, Toth K, Nagy A, Szever Z, Kiss A, Temesvari M, Hafra E, Garami M, Tapodi A, Monostory K (2015) Clinical significance of CYP2C9-status guided valproic acid therapy in children. Epilepsia 56(6):849–855PubMedCrossRefGoogle Scholar
  7. 7.
    Hung CC, Ho JL, Chang WL, Tai JJ, Hsieh TJ, Hsieh YW, Liou HH (2011) Association of genetic variants in six candidate genes with valproic acid therapy optimization. Pharmacogenomics 12(8):1107–1117PubMedCrossRefGoogle Scholar
  8. 8.
    Guo Y, Hu C, He X, Qiu F, Zhao L (2012) Effects of UGT1A6, UGT2B7, and CYP2C9 genotypes on plasma concentrations of valproic acid in Chinese children with epilepsy. Drug Metab Pharmacokinet 27(5):536–542PubMedCrossRefGoogle Scholar
  9. 9.
    Mei S, Feng W, Zhu L, Li X, Yu Y, Yang W, Gao B, Wu X, Fang F, Zhao Z (2018) Effect of CYP2C19, UGT1A8, and UGT2B7 on valproic acid clearance in children with epilepsy: a population pharmacokinetic model. Eur J Clin Pharmacol 74(8):1029–1036PubMedCrossRefGoogle Scholar
  10. 10.
    Mei S, Feng W, Zhu L, Yu Y, Yang W, Gao B, Wu X, Zhao Z, Fang F (2017) Genetic polymorphisms and valproic acid plasma concentration in children with epilepsy on valproic acid monotherapy. Seizure 51:22–26PubMedCrossRefGoogle Scholar
  11. 11.
    Feng W, Mei S, Zhu L, Yu Y, Yang W, Gao B, Wu X, Zhao Z, Fang F (2016) Effects of UGT1A6 and GABRA1 on standardized valproic acid plasma concentrations and treatment effect in children with epilepsy in China. Ther Drug Monit 38(6):738–743PubMedCrossRefGoogle Scholar
  12. 12.
    Qu J, Zhou BT, Yin JY, Xu XJ, Zhao YC, Lei GH, Tang Q, Zhou HH, Liu ZQ (2012) ABCC2 polymorphisms and haplotype are associated with drug resistance in Chinese epileptic patients. CNS Neurosci Ther 18(8):647–651PubMedCrossRefGoogle Scholar
  13. 13.
    Siddiqui A, Kerb R, Weale ME, Brinkmann U, Smith A, Goldstein DB, Wood NW, Sisodiya SM (2003) Association of multidrug resistance in epilepsy with a polymorphism in the drug-transporter gene ABCB1. N Engl J Med 348(15):1442–1448PubMedCrossRefGoogle Scholar
  14. 14.
    Chouchi M, Kaabachi W, Klaa H, Tizaoui K, Turki IB, Hila L (2017) Relationship between ABCB1 3435TT genotype and antiepileptic drugs resistance in epilepsy: updated systematic review and meta-analysis. BMC Neurol 17(1):32PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Qian L, Fang S, Yan YL, Zeng SS, Xu ZJ, Gong ZC (2017) The ABCC2 c.-24C>T polymorphism increases the risk of resistance to antiepileptic drugs: a meta-analysis. J Clin Neurosci 37:6–14PubMedCrossRefGoogle Scholar
  16. 16.
    Haerian BS, Lim KS, Mohamed EH, Tan HJ, Tan CT, Raymond AA, Wong CP, Wong SW, Mohamed Z (2011) Lack of association of ABCB1 haplotypes on five loci with response to treatment in epilepsy. Seizure 20(7):546–553PubMedCrossRefGoogle Scholar
  17. 17.
    Zhou L, Cao Y, Long H, Long L, Xu L, Liu Z, Zhang Y, Xiao B (2015) ABCB1, ABCC2, SCN1A, SCN2A, GABRA1 gene polymorphisms and drug resistant epilepsy in the Chinese Han population. Pharmazie 70(6):416–420PubMedGoogle Scholar
  18. 18.
    Rogawski MA, Loscher W (2004) The neurobiology of antiepileptic drugs. Nat Rev Neurosci 5(7):553–564PubMedCrossRefGoogle Scholar
  19. 19.
    Kumari R, Lakhan R, Kalita J, Misra UK, Mittal B (2010) Association of alpha subunit of GABAA receptor subtype gene polymorphisms with epilepsy susceptibility and drug resistance in north Indian population. Seizure 19(4):237–241PubMedCrossRefGoogle Scholar
  20. 20.
    Haerian BS, Baum L, Kwan P, Cherny SS, Shin JG, Kim SE, Han BG, Tan HJ, Raymond AA, Tan CT, Mohamed Z (2016) Contribution of GABRG2 polymorphisms to risk of epilepsy and febrile seizure: a multicenter cohort study and meta-analysis. Mol Neurobiol 53(8):5457–5467PubMedCrossRefGoogle Scholar
  21. 21.
    Balan S, Sathyan S, Radha SK, Joseph V, Radhakrishnan K, Banerjee M (2013) GABRG2, rs211037 is associated with epilepsy susceptibility, but not with antiepileptic drug resistance and febrile seizures. Pharmacogenet Genomics 23(11):605–610PubMedCrossRefGoogle Scholar
  22. 22.
    Loscher W (2002) Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy. CNS Drugs 16(10):669–694PubMedCrossRefGoogle Scholar
  23. 23.
    Tang L, Lu X, Tao Y, Zheng J, Zhao P, Li K, Li L (2014) SCN1A rs3812718 polymorphism and susceptibility to epilepsy with febrile seizures: a meta-analysis. Gene 533(1):26–31PubMedCrossRefGoogle Scholar
  24. 24.
    Li X, Zhang J, Wu X, Yan H, Zhang Y, He RH, Tang YJ, He YJ, Tan D, Mao XY, Yin JY, Liu ZQ, Zhou HH, Liu J (2016) Polymorphisms of ABAT, SCN2A and ALDH5A1 may affect valproic acid responses in the treatment of epilepsy in Chinese. Pharmacogenomics 17(18):2007–2014PubMedCrossRefGoogle Scholar
  25. 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
  26. 26.
    Haerian BS, Baum L, Kwan P, Tan HJ, Raymond AA, Mohamed Z (2013) SCN1A, SCN2A and SCN3A gene polymorphisms and responsiveness to antiepileptic drugs: a multicenter cohort study and meta-analysis. Pharmacogenomics 14(10):1153–1166PubMedCrossRefGoogle Scholar
  27. 27.
    DeVane CL (2003) Pharmacokinetics, drug interactions, and tolerability of valproate. Psychopharmacol Bull 37(Suppl 2):25–42PubMedGoogle Scholar
  28. 28.
    Marahatta A, Bhandary B, Jeong SK, Kim HR, Chae HJ (2014) Soybean greatly reduces valproic acid plasma concentrations: a food-drug interaction study. Sci Rep 4:4362PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Golmohammadi R, Pejhan A, Azhdari-Zarmehri H, Mohammad-Zadeh M (2013) The role of ethanol on the anticonvulsant effect of valproic acid and cortical microvascular changes after epileptogenesis in mice. Neurol Sci 34(7):1125–1131PubMedCrossRefGoogle Scholar
  30. 30.
    Feng W, Mei S, Zhu L, Yu Y, Yang W, Gao B, Wu X, Zhao Z, Fang F (2018) Effects of UGT2B7, SCN1A and CYP3A4 on the therapeutic response of sodium valproate treatment in children with generalized seizures. Seizure 58:96–100PubMedCrossRefGoogle Scholar
  31. 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. 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
  33. 33.
    Meng H, Guo G, Ren J, Zhou H, Ge Y, Guo Y (2011) Effects of ABCB1 polymorphisms on plasma carbamazepine concentrations and pharmacoresistance in Chinese patients with epilepsy. Epilepsy Behav 21(1):27–30PubMedCrossRefGoogle Scholar
  34. 34.
    Ellis JA, Ong B (2017) The MassARRAY(R) system for targeted SNP genotyping. Methods Mol Biol 1492:77–94PubMedCrossRefGoogle Scholar
  35. 35.
    Clarke GM, Anderson CA, Pettersson FH, Cardon LR, Morris AP, Zondervan KT (2011) Basic statistical analysis in genetic case-control studies. Nat Protoc 6(2):121–133PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Pedley TA, Hirano M (2003) Is refractory epilepsy due to genetically determined resistance to antiepileptic drugs? N Engl J Med 348(15):1480–1482PubMedCrossRefGoogle Scholar
  37. 37.
    Dombrowski SM, Desai SY, Marroni M, Cucullo L, Goodrich K, Bingaman W, Mayberg MR, Bengez L, Janigro D (2001) Overexpression of multiple drug resistance genes in endothelial cells from patients with refractory epilepsy. Epilepsia 42(12):1501–1506PubMedCrossRefGoogle Scholar
  38. 38.
    Kwan P, Sills GJ, Butler E, Gant TW, Meldrum BS, Brodie MJ (2002) Regional expression of multidrug resistance genes in genetically epilepsy-prone rat brain after a single audiogenic seizure. Epilepsia 43(11):1318–1323PubMedCrossRefGoogle Scholar
  39. 39.
    Gitai LL, de Almeida DH, Born JP, Gameleira FT, de Andrade TG, Machado LC, Gitai DL (2012) Lack of association between rs211037 of the GABRG2 gene and juvenile myoclonic epilepsy in Brazilian population. Neurol India 60(6):585–588PubMedCrossRefGoogle Scholar
  40. 40.
    Dixit AB, Banerjee J, Ansari A, Tripathi M, Chandra SP (2016) Mutations in GABRG2 receptor gene are not a major factor in the pathogenesis of mesial temporal lobe epilepsy in Indian population. Ann Indian Acad Neurol 19(2):236–241PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Rai V, Kumar P (2018) Methylenetetrahydrofolate reductase C677T polymorphism and susceptibility to epilepsy. Neurol Sci 39:2033–2041PubMedCrossRefGoogle Scholar

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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