Voltage gated sodium channel gene polymorphisms are associated with epilepsy

Abstract

PURPOSE: High frequency action potentials are mediated by voltage-gated sodium channels, composed of one large a subunit and two small β subunits, encoded mainly by SCN1A, SCN2A, SCN3A, SCN1B, and SCN2B genes in the CNS. Since mutations of these can cause certain genetic epilepsy syndromes, we investigated whether polymorphisms in these genes may affect epilepsy risk in general. METHOD: Epilepsy patients and control subjects from Hong Kong and Kuala Lumpur were matched in age, sex and ethnicity. Epilepsy was broadly classified based on ILAE criteria. Blood was withdrawn for DNA extraction. Using Haploview, we tagged the five genes with 43 polymorphisms: 27 in Hong Kong, 28 in Malaysia, and 12 in both locations. Polymorphisms were genotyped by Sequenom Mass Array. RESULTS: The study included 1529 epilepsy patients (mean+/-SD age: 35 +/- 16 years) and 1935 control subjects (34 +/- 16 years) from four ethnic groups or locations: Malay, Indian, and Chinese, all from Malaysia, and Chinese from Hong Kong (the latter comprising 54% of patients and 44% of controls). Of patients, 19% were idiopathic, 42% symptomatic, and 40% cryptogenic. 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 genotypes GG vs. AA (p = 0.003). The association was consistent across ethnicities. Allele G is known to affect splicing and to speed 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 LD with rs2082366 (r2 = 0.67), whose genotypes tended toward association with SCN2A brain expression (p = 0.10). SCN1A rs2298771 was associated with epilepsy in Indians (OR = 0.56, p = 0.005). SCN2B rs602594 was associated with idiopathic epilepsy (OR = 0.62, p = 0.002). CONCLUSION: Common genetic variants in neuronal sodium channel genes are associated with the risk of epilepsy.