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Human Genetics

, Volume 133, Issue 5, pp 651–659 | Cite as

Case–control association study of polymorphisms in the voltage-gated sodium channel genes SCN1A, SCN2A, SCN3A, SCN1B, and SCN2B and epilepsy

  • Larry BaumEmail author
  • Batoul Sadat HaerianEmail author
  • Ho-Keung Ng
  • Virginia C. N. Wong
  • Ping Wing Ng
  • Colin H. T. Lui
  • Ngai Chuen Sin
  • Chunbo Zhang
  • Brian Tomlinson
  • Gary Wing-Kin Wong
  • Hui Jan Tan
  • Azman Ali Raymond
  • Zahurin Mohamed
  • Patrick Kwan
Original Investigation

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.

Keywords

Linkage Disequilibrium Febrile Seizure Epilepsy Patient Epilepsy Syndrome Idiopathic Epilepsy 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

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.

Ethical standards

The experiments comply with the current laws of Hong Kong and Malaysia.

Conflict of interest

None declared.

Supplementary material

439_2013_1405_MOESM1_ESM.docx (827 kb)
Supplementary material 1 (DOCX 824 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Larry Baum
    • 1
    Email author
  • Batoul Sadat Haerian
    • 2
    Email author
  • Ho-Keung Ng
    • 3
  • Virginia C. N. Wong
    • 4
  • Ping Wing Ng
    • 5
  • Colin H. T. Lui
    • 6
  • Ngai Chuen Sin
    • 7
  • Chunbo Zhang
    • 8
  • Brian Tomlinson
    • 9
  • Gary Wing-Kin Wong
    • 7
  • Hui Jan Tan
    • 10
  • Azman Ali Raymond
    • 10
  • Zahurin Mohamed
    • 2
  • Patrick Kwan
    • 11
    • 12
  1. 1.School of PharmacyThe Chinese University of Hong KongHong KongChina
  2. 2.Pharmacogenomics Laboratory, Department of Pharmacology, Faculty of MedicineUniversity of MalayaKuala LumpurMalaysia
  3. 3.Department of Anatomical and Cellular PathologyThe Chinese University of Hong KongHong KongChina
  4. 4.Department of Paediatrics and Adolescent MedicineThe University of Hong KongHong KongChina
  5. 5.Department of Medicine and GeriatricsUnited Christian HospitalHong KongChina
  6. 6.Department of MedicineTseung Kwan O HospitalHong KongChina
  7. 7.Department of PaediatricsThe Chinese University of Hong KongHong KongChina
  8. 8.Department of Pharmaceutical and Biomedical SciencesUniversity of Georgia College of PharmacyAthensUSA
  9. 9.Division of Clinical Pharmacology, Department of Medicine and TherapeuticsThe Chinese University of Hong KongHong KongChina
  10. 10.Department of Medicine, Faculty of MedicineUniversiti Kebangsaan MalaysiaKuala LumpurMalaysia
  11. 11.Division of Neurology, Department of Medicine and TherapeuticsThe Chinese University of Hong KongHong KongChina
  12. 12.Departments of Medicine and Neurology, Royal Melbourne HospitalThe University of MelbourneMelbourneAustralia

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