Abstract
High-frequency action potentials are mediated by voltage-gated sodium channels, composed of one large α subunit and two small β subunits, encoded mainly by SCN1A, SCN2A, SCN3A, SCN1B, and SCN2B genes in the brain. These play a key role in epilepsy, with the most commonly mutated gene in epilepsy being SCN1A. We examined whether polymorphisms in the above genes affect epilepsy risk in 1,529 epilepsy patients and 1,935 controls from four ethnicities or locations: Malay, Indian, and Chinese, all from Malaysia, and Chinese from Hong Kong. Of patients, 19 % were idiopathic, 42 % symptomatic, and 40 % cryptogenic. We genotyped 43 polymorphisms: 27 in Hong Kong, 28 in Malaysia, and 12 in both locations. The strongest association with epilepsy was rs3812718, or SCN1A IVS5N+5G>A: odds ratio (OR) = 0.85 for allele G (p = 0.0009) and 0.73 for genotype GG versus AA (p = 0.003). The OR was between 0.76 and 0.87 for all ethnicities. Meta-analysis confirmed the association (OR = 0.81 and p = 0.002 for G, and OR = 0.67 and p = 0.007 for GG versus AA), which appeared particularly strong for Indians and for febrile seizures. Allele G affects splicing and speeds recovery from inactivation. Since SCN1A is preferentially expressed in inhibitory neurons, G may decrease epilepsy risk. SCN1A rs10188577 displayed OR = 1.20 for allele C (p = 0.003); SCN2A rs12467383 had OR = 1.16 for allele A (p = 0.01), and displayed linkage disequilibrium with rs2082366 (r 2 = 0.67), whose genotypes tended toward association with SCN2A brain expression (p = 0.10). SCN1A rs2298771 was associated in Indians (OR = 0.56, p = 0.005) and SCN2B rs602594 with idiopathic epilepsy (OR = 0.62, p = 0.002). Therefore, sodium channel polymorphisms are associated with epilepsy.
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References
Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7:248–249. doi:10.1038/nmeth0410-248
Balan S, Vellichirammal NN, Banerjee M, Radhakrishnan K (2012) Failure to find association between febrile seizures and SCN1A rs3812718 polymorphism in south Indian patients with mesial temporal lobe epilepsy and hippocampal sclerosis. Epilepsy Res 101:288–292. doi:10.1016/j.eplepsyres.2012.04.009
Baum L, Zhang C, Wong VCN, Ng PW, Lui CHT, Sin NC, Tomlinson B, Wong KS, Kwan P (2009) Association of epilepsy with voltage gated sodium channel gene polymorphisms in Han Chinese. In:The 63rd annual meeting of the American Epilepsy Society, Boston, 4–8 Dec 2009
Bax L, Yu LM, Ikeda N, Tsuruta H, Moons KG (2006) Development and validation of MIX: comprehensive free software for meta-analysis of causal research data. BMC Med Res Methodol 6:50. doi:10.1186/1471-2288-6-50
Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde BW, 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 51:676–685
Brackenbury WJ, Isom LL (2011) Na channel beta subunits: overachievers of the ion channel family. Front Pharmacol 2:53. doi:10.3389/fphar.2011.00053
Catterall WA, Goldin AL, Waxman SG (2005) International union of pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol Rev 57:397–409
Ferraro TN, Buono RJ (2005) The relationship between the pharmacology of antiepileptic drugs and human gene variation: an overview. Epilepsy Behav 7:18–36
Fletcher EV, Kullmann DM, Schorge S (2011) Alternative splicing modulates inactivation of type 1 voltage-gated sodium channels by toggling an amino acid in the first S3–S4 linker. J Biol Chem 286:36700–36708. doi:10.1074/jbc.M111.250225
Grover S, Gourie-Devi M, Baghel R, Sharma S, Bala K, Gupta M, Narayanasamy K, Varma B, Gupta M, Kaur K, Talwar P, Kaur H, Giddaluru S, Sharma A, Brahmachari SK, Indian Genome Variation C, Kukreti R (2010) Genetic profile of patients with epilepsy on first-line antiepileptic drugs and potential directions for personalized treatment. Pharmacogenomics 11:927–941. doi:10.2217/pgs.10.62
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 14:1153–1166. doi:10.2217/pgs.13.104
Heinzen EL, Yoon W, Tate SK, Sen A, Wood NW, Sisodiya SM, Goldstein DB (2007) Nova2 interacts with a cis-acting polymorphism to influence the proportions of drug-responsive splice variants of SCN1A. Am J Hum Genet 80:876–883. doi:10.1086/516650
Helbig I, Scheffer IE, Mulley JC, Berkovic SF (2008) Navigating the channels and beyond: unravelling the genetics of the epilepsies. Lancet Neurol 7:231–245
Hung CC, Chang WL, Ho JL, Tai JJ, Hsieh TJ, Huang HC, Hsieh YW, Liou HH (2012) Association of polymorphisms in EPHX1, UGT2B7, ABCB1, ABCC2, SCN1A and SCN2A genes with carbamazepine therapy optimization. Pharmacogenomics 13:159–169. doi:10.2217/pgs.11.141
Kumari R, Lakhan R, Kumar S, Garg RK, Misra UK, Kalita J, Mittal B (2013) SCN1AIVS5-91G > A polymorphism is associated with susceptibility to epilepsy but not with drug responsiveness. Biochimie 95:1350–1353. doi:10.1016/j.biochi.2013.02.006
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 18:989–998
Le Gal F, Salzmann A, Crespel A, Malafosse A (2011) Replication of association between a SCN1A splice variant and febrile seizures. Epilepsia 52:e135–e138. doi:10.1111/j.1528-1167.2011.03164.x
Lossin C (2009) A catalog of SCN1A variants. Brain Dev 31:114–130. doi:10.1016/j.braindev.2008.07.011
Makoff A, Lai T, Barratt C, Valentin A, Moran N, Asherson P, Nashef L (2010) High-density SNP screen of sodium channel genes by haplotype tagging and DNA pooling for association with idiopathic generalized epilepsy. Epilepsia 51:694–698. doi:10.1111/j.1528-1167.2009.02473.x
Meisler MH, O’Brien JE, Sharkey LM (2010) Sodium channel gene family: epilepsy mutations, gene interactions and modifier effects. J Physiol 588:1841–1848. doi:10.1113/jphysiol.2010.188482
Myers AJ, Gibbs JR, Webster JA, Rohrer K, Zhao A, Marlowe L, Kaleem M, Leung D, Bryden L, Nath P, Zismann VL, Joshipura K, Huentelman MJ, Hu-Lince D, Coon KD, Craig DW, Pearson JV, Holmans P, Heward CB, Reiman EM, Stephan D, Hardy J (2007) A survey of genetic human cortical gene expression. Nat Genet 39:1494–1499. doi:10.1038/ng.2007.16
Oliva M, Berkovic SF, Petrou S (2012) Sodium channels and the neurobiology of epilepsy. Epilepsia 53:1849–1859. doi:10.1111/j.1528-1167.2012.03631.x
Petrovski S, Scheffer IE, Sisodiya SM, O’Brien TJ, Berkovic SF, EPIGEN Consortium (2009) Lack of replication of association between scn1a SNP and febrile seizures. Neurology 73:1928–1930. doi:10.1212/WNL.0b013e3181c3fd6f
Schlachter K, Gruber-Sedlmayr U, Stogmann E, Lausecker M, Hotzy C, Balzar J, Schuh E, Baumgartner C, Mueller JC, Illig T, Wichmann HE, Lichtner P, Meitinger T, Strom TM, Zimprich A, Zimprich F (2009) A splice site variant in the sodium channel gene SCN1A confers risk of febrile seizures. Neurology 72:974–978
Swartz MK (2011) The PRISMA statement: a guideline for systematic reviews and meta-analyses. J Pediatr Health Care 25:1–2. doi:10.1016/j.pedhc.2010.09.006
Thompson CH, Kahlig KM, George AL Jr (2011) SCN1A splice variants exhibit divergent sensitivity to commonly used antiepileptic drugs. Epilepsia 52:1000–1009. doi:10.1111/j.1528-1167.2011.03040.x
Xia K, Shabalin AA, Huang S, Madar V, Zhou YH, Wang W, Zou F, Sun W, Sullivan PF, Wright FA (2012) seeQTL: a searchable database for human eQTLs. Bioinformatics 28:451–452. doi:10.1093/bioinformatics/btr678
Yu FH, Catterall WA (2003) Overview of the voltage-gated sodium channel family. Genome Biol 4:207
Zhang C, Wong V, Ng PW, Lui CH, Sin NC, Wong KS, Baum L, Kwan P (2010) Failure to detect association between polymorphisms of the sodium channel gene SCN1A and febrile seizures in Chinese patients with epilepsy. Epilepsia 51:1878–1881
Acknowledgments
Support was provided by the Hong Kong Research Grants Council Clinical Research Fellowship Grant (CERG Project CUHK4466/06M), Malaysian Ministry of Higher Education High Impact Research Grant (E000025-20001), and University of Malaya UMRG grant RG520-13HTM. None of the authors has any conflict of interest to disclose. They confirm having read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Larry Baum had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
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The experiments comply with the current laws of Hong Kong and Malaysia.
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L. Baum and B. S. Haerian contributed equally.
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Baum, L., Haerian, B.S., Ng, HK. et al. Case–control association study of polymorphisms in the voltage-gated sodium channel genes SCN1A, SCN2A, SCN3A, SCN1B, and SCN2B and epilepsy. Hum Genet 133, 651–659 (2014). https://doi.org/10.1007/s00439-013-1405-1
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DOI: https://doi.org/10.1007/s00439-013-1405-1