Research Article

Polymorphisms of ABAT, SCN2A and ALDH5A1 may affect valproic acid responses in the treatment of epilepsy in Chinese

Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, People’s Republic of China

Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, Hunan, People’s Republic of China

^‡Authors contributed equally

Search for more papers by this author

Jun Zhang^‡

Department of nephrology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, P. R. China;

^‡Authors contributed equally

Search for more papers by this author

Xi Wu

Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, People’s Republic of China

Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, Hunan, People’s Republic of China

Search for more papers by this author

Han Yan

Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, People’s Republic of China

Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, Hunan, People’s Republic of China

Search for more papers by this author

Yin Zhang

Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, People’s Republic of China

Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, Hunan, People’s Republic of China

Search for more papers by this author

Ruo-Hui He

Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, People’s Republic of China

Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, Hunan, People’s Republic of China

Search for more papers by this author

Yong-Jun Tang

Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, People’s Republic of China

Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, Hunan, People’s Republic of China

Search for more papers by this author

Yi-Jing He

Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, People’s Republic of China

Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, Hunan, People’s Republic of China

Search for more papers by this author

Dan Tan

Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, People’s Republic of China

Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, Hunan, People’s Republic of China

Search for more papers by this author

Xiao-Yuan Mao

Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, People’s Republic of China

Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, Hunan, People’s Republic of China

Search for more papers by this author

Ji-Ye Yin

Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, People’s Republic of China

Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, Hunan, People’s Republic of China

Search for more papers by this author

Zhao-Qian Liu

Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, People’s Republic of China

Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, Hunan, People’s Republic of China

Search for more papers by this author

Hong-Hao Zhou

Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, People’s Republic of China

Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, Hunan, People’s Republic of China

Search for more papers by this author

Jie Liu

*Author for correspondence:

E-mail Address: liujiezhj@126.com

Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, People’s Republic of China

Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, Hunan, People’s Republic of China

Search for more papers by this author

Published Online:5 Dec 2016https://doi.org/10.2217/pgs-2016-0093

View article

Abstract

Aim: The clinical efficacy of valproic acid (VPA) varies greatly among epileptic patients. To find the potential genetic factors related to VPA responses, the pharmacogenetics study was conducted. Methods: Two hundred and one Chinese Han epileptic patients who were treated by VPA for at least 1 year were recruited. Up to 24 SNPs in 11 candidate genes that correlate with the metabolism, transport or target of VPA were genotyped. Results: Three SNPs, rs1731017 (ABAT), rs2304016 (SCN2A) and rs1054899 (ALDH5A1) were found associated with VPA responses with the p-values of 0.003, 0.007 and 0.048, respectively. Further interaction analysis showed that the interaction between rs17183814 (ABAT) and rs1641022 (SCN2A) was also correlated with the response of VPA (p = 0.006). Conclusion: This study found three SNPs and one interaction among ABAT, SCN2A and ALDH5A1 were significantly associated with VPA response, which indicated that these genes may play important roles in the pharmacological mechanism of VPA.

Keywords:

References

1 Chang BS, Lowenstein DH. Epilepsy. N. Engl. J. Med. 349(13), 1257–1266 (2003).
MedlineGoogle Scholar
2 Fisher RS, Acevedo C, Arzimanoglou A et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia 55(4), 475–482 (2014).
MedlineGoogle Scholar
3 Thurman DJ, Beghi E, Begley CE et al. Standards for epidemiologic studies and surveillance of epilepsy. Epilepsia 52(Suppl. 7), 2–26 (2011).
Medline CASGoogle Scholar
4 Hitiris N, Mohanraj R, Norrie J, Brodie MJ. Mortality in epilepsy. Epilepsy Behav. 10(3), 363–376 (2007).
MedlineGoogle Scholar
5 Naghavi M, Wang H, Lozano R et al. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 385(9963), 117–171 (2015).
MedlineGoogle Scholar
6 Wilden JA, Cohen-Gadol AA. Evaluation of first nonfebrile seizures. Am. Fam. Physician. 86(4), 334–340 (2012).
MedlineGoogle Scholar
7 Martindale JL, Goldstein JN, Pallin DJ. Emergency department seizure epidemiology. Emerg. Med. Clin. North Am. 29(1), 15–27 (2011).
MedlineGoogle Scholar
8 Laxer KD, Trinka E, Hirsch LJ et al. The consequences of refractory epilepsy and its treatment. Epilepsy Behav. 37, 59–70 (2014).
MedlineGoogle Scholar
9 Ferraro TN, Buono RJ. The relationship between the pharmacology of antiepileptic drugs and human gene variation: an overview. Epilepsy Behav. 7(1), 18–36 (2005).
MedlineGoogle Scholar
10 Chadwick DW. Concentration-effect relationships of valproic acid. Clin. Pharmacokinet. 10(2), 155–163 (1985).
Medline CASGoogle Scholar
11 Guo Y, Hu C, He X, Qiu F, Zhao L. Effects of UGT1A6, UGT2B7, and CYP2C9 genotypes on plasma concentrations of valproic acid in Chinese children with epilepsy. Drug Metab. Pharmacokinet. 27(5), 536–542 (2012).
Medline CASGoogle Scholar
12 Hung CC, Ho JL, Chang WL et al. Association of genetic variants in six candidate genes with valproic acid therapy optimization. Pharmacogenomics 12(8), 1107–1117 (2011).
CASGoogle Scholar
13 Voso MT, Santini V, Finelli C et al. Valproic acid at therapeutic plasma levels may increase 5-azacytidine efficacy in higher risk myelodysplastic syndromes. Clin. Cancer Res. 15(15), 5002–5007 (2009).
Medline CASGoogle Scholar
14 Kwan P, Wong V, Ng PW et al. Gene-wide tagging study of association between ABCB1 polymorphisms and multidrug resistance in epilepsy in Han Chinese. Pharmacogenomics 10(5), 723–732 (2009).
CASGoogle Scholar
15 Qu J, Zhang Y, Yang ZQ et al. Gene-wide tagging study of the association between KCNT1 polymorphisms and the susceptibility and efficacy of genetic generalized epilepsy in Chinese population. CNS Neurosci. Ther. 20(2), 140–146 (2014).
Medline CASGoogle Scholar
16 Proposal for revised classification of epilepsies and epileptic syndromes. Commission on classification and terminology of the International League Against Epilepsy. Epilepsi. 30(4), 389–399 (1989).
MedlineGoogle Scholar
17 Kwan P, Arzimanoglou A, Berg AT et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 51(6), 1069–1077 (2010).
Medline CASGoogle Scholar
18 Piana C, Antunes NJ, Della Pasqua O. Implications of pharmacogenetics for the therapeutic use of antiepileptic drugs. Expert Opin. Drug Metab.Toxicol. 10(3), 341–358 (2014).
Medline CASGoogle Scholar
19 Zhou BT, Zhou QH, Yin JY et al. Effects of SCN1A and GABA receptor genetic polymorphisms on carbamazepine tolerability and efficacy in Chinese patients with partial seizures: 2-year longitudinal clinical follow-up. CNS Neurosci. Ther. 18(7), 566–572 (2012).
Medline CASGoogle Scholar
20 Haerian BS, Baum L, Kwan P et al. SCN1A, SCN2A and SCN3A gene polymorphisms and responsiveness to antiepileptic drugs: a multicenter cohort study and meta-analysis. Pharmacogenomics. 14(10), 1153–1166 (2013).
CASGoogle Scholar
21 Ghodke-Puranik Y, Thorn CF, Lamba JK et al. Valproic acid pathway: pharmacokinetics and pharmacodynamics. Pharmacogenet. Genomics 23(4), 236–241 (2013).
Medline CASGoogle Scholar
22 Massachusetts General Hospital. http://pngu.mgh.harvard.edu/˜purcell/plink/
Google Scholar
23 Baldino F, Geller HM. Effect of sodium valproate on hypothalamic neurons in vivo and in vitro. Brain Res. 219(1), 231–237 (1981).
Medline CASGoogle Scholar
24 Chapman AG, Riley K, Evans MC, Meldrum BS. Acute effects of sodium valproate and gamma-vinyl GABA on regional amino acid metabolism in the rat brain: incorporation of 2-[¹⁴C]glucose into amino acids. Neurochem. Res. 7(9), 1089–1105 (1982).
Medline CASGoogle Scholar
25 Hariton C, Ciesielski L, Simler S et al. Distribution of sodium valproate and GABA metabolism in CNS of the rat. Biopharm. Drug Dispos. 5(4), 9–14 (1984).
Google Scholar
26 Loscher W. Valproate enhances GABA turnover in the substantia nigra. Brain Res. 501(1), 198–203 (1989).
Medline CASGoogle Scholar
27 Bruni J, Wilder BJ. Valproic acid. Review of a new antiepileptic drug. Arch. Neurol. 36(7), 393–398 (1979).
Medline CASGoogle Scholar
28 Osei YD, Churchich JE. Screening and sequence determination of a cDNA encoding the human brain 4-aminobutyrate aminotransferase. Gene 155(2), 185–187 (1995).
Medline CASGoogle Scholar
29 Chambliss KL, Slaughter CA, Schreiner R, Hoffmann GF, Gibson KM. Molecular cloning of the mature NAD(⁺)-dependent succinic semialdehyde dehydrogenase from rat and human. cDNA isolation, evolutionary homology, and tissue expression. J. Biol. Chem. 270(1), 461–467 (1995).
MedlineGoogle Scholar
30 Farber NB, Jiang XP, Heinkel C, Nemmers B. Antiepileptic drugs and agents that inhibit voltage-gated sodium channels prevent NMDA antagonist neurotoxicity. Mol. Psychiatry 7(7), 726–733 (2002).
Medline CASGoogle Scholar
31 Kwan P, Poon WS, Ng HK et al. 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), 989–998 (2008).
Medline CASGoogle Scholar
32 Fernando-Dongas MC, Radtke RA, VanLandingham KE, Husain AM. Characteristics of valproic acid resistant juvenile myoclonic epilepsy. Seizure 9(6), 385–388 (2000).
Medline CASGoogle Scholar

Vol. 17, No. 18

Supplemental Materials

Metrics

Downloaded 287 times

History

Published online 5 December 2016

Published in print December 2016

Information

Keywords

Acknowledgements

The authors thank the medical staff from the Xiangya Hospitals of Hunan Province, China, for their help and collaboration, as well as their patients and volunteers.

Financial & competing interest disclosure

The authors extend their sincere thanks to the National High Technology Research and Development Program (863 Program; no. 2012AA02A517), National Natural Science Foundation of China (no 81070902), Young Scientists Fund of the National Natural Science Foundation of China (no. 30600774 and 81403017), Postdoctoral Science Foundation (no. 201104515, 2012M510138 and 2013M531818) and Project supported by the Program for New Century Excellent Talents in University of Ministry of Education of China (grant no. NCET-08-0567) for funding this research. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

PDF download