title: Case-control association study of polymorphisms in the voltage-gated sodium channel genes SCN1A, SCN2A, SCN3A, SCN1B, and SCN2B and epilepsy.
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.
authors: School of Pharmacy, The Chinese University of Hong Kong, Shatin, Hong Kong, China, lwbaum@cuhk.edu.hk.
authors: Larry
authors: L
authors: Baum
authors: Batoul Sadat
authors: BS
authors: Haerian
authors: Ho-Keung
authors: HK
authors: Ng
authors: Virginia C N
authors: VC
authors: Wong
authors: Ping Wing
authors: PW
authors: Ng
authors: Colin H T
authors: CH
authors: Lui
authors: Ngai Chuen
authors: NC
authors: Sin
authors: Chunbo
authors: C
authors: Zhang
authors: Brian
authors: B
authors: Tomlinson
authors: Gary Wing-Kin
authors: GW
authors: Wong
authors: Hui Jan
authors: HJ
authors: Tan
authors: Azman Ali
authors: AA
authors: Raymond
authors: Zahurin
authors: Z
authors: Mohamed
authors: Patrick
authors: P
authors: Kwan
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D004827:Epilepsy / Q000235:genetics*; D005260:Female; D006801:Humans; D015640:Ion Channel Gating; D008297:Male; D020641:Polymorphism, Single Nucleotide; D015222:Sodium Channels / Q000235:genetics* / Q000502:physiology; D055815:Young Adult
chemical_list: D015222:Sodium Channels