Abstracts

Rationale: Voltage-gated sodium channels in the brain enable neurons to fire action potentials at high-frequency, which is required for epileptic activity. They are composed of a large alpha subunit and two small beta subunits, encoded in the brain primarily by SCN1A, 2A, 3A, 8A, and SCN1B, 2B, respectively. Mutations in voltage gated sodium channel genes have been associated with certain rare idiopathic epilepsy syndromes. Previous studies in Caucasians did not identify significant association between common variants of the sodium channel genes and several common epilepsy phenotypes. Because the patterns of linkage disequilibrium may differ among ethnic groups, we sought to examine whether polymorphisms in these genes might influence the risk for the broad types of epilepsy in Chinese. Methods: All subjects were of Han Chinese ethnicity. Children and adults with epilepsy were recruited from neurology clinics at four major regional hospitals in Hong Kong. Epilepsy syndromes were classified according to international guidelines. Patients were matched in age and sex with control subjects without epilepsy. Blood was withdrawn for DNA extraction. Using the Tagger function of Haploview software (www.broad.mit.edu/mpg/haploview) and single nucleotide polymorphism (SNP) genotype data from the HapMap database (HapMap.org), we selected 28 SNPs tagging SCN1A, SCN2A, SCN3A, SCN1B, and SCN2B. SNPs were genotyped using a Sequenom Mass Array system. Allele and haplotype frequencies were compared between patients and controls. This work was partly supported by the Research Grants Council of the Hong Kong Special Administration Region (CUHK4466/06M). Results: 829 epilepsy patients and 849 controls matched for sex (both 50% male) and age (control mean=37±17 years; patient mean=38±15 years) were recruited. Among patients, the epilepsy was classified as idiopathic in 109, symptomatic in 374, cryptogenic in 330, and was unclassifiable in 16. Alleles of SNPs in SCN1A and SCN2A, but not in SCN3A, SCN1B, or SCN2B, were associated with epilepsy at p<0.05. The A allele of rs12467383 (in SCN2A), the A allele of rs3812718 (in SCN1A), and the C allele of rs10188577 (in SCN1A) were increased in epilepsy: odds ratio (OR) = 1.2, p=0.0074; OR=1.2, p=0.013; and OR=1.3, p=0.010; respectively. Excluding idiopathic patients from analysis yielded slightly smaller p-values: p=0.0065, 0.012, and 0.0079, respectively. None of the associations remained significant after Bonferroni correction for multiple comparisons. Haplotype analysis of all subjects and all SNPs in SCN2A or SCN1A revealed that the one common haplotype of SCN2A containing the A allele of rs12467383 was not significantly associated with epilepsy (p=0.07), while two of the seven common haplotypes of SCN1A were associated with epilepsy at p=0.007 and p=0.003. Conclusions: Individual SNPs and haplotypes in voltage gated sodium channel genes may be associated with broad epilepsy syndromes in the Chinese population.