Case-control pharmacogenetic study of HCN1/HCN2 variants and genetic generalized epilepsies

Epilepsy is a common complex neurological disorder, and some forms are resistant to drug treatment. The HCN1/HCN2 genes encode hyperpolarization-activated cyclic nucleotide-gated channels, which play important roles in the electrophysiology of neurons. We investigated the association between HCN1/HCN2 variants and drug resistance or the risk of genetic generalized epilepsies (GGEs). We used matrix-assisted laser desorption/ionization time-of-flight mass spectrometry to assess nine variants of HCN1/HCN2 in 284 healthy participants and 483 GGEs (279 drug-responsive, 204 drug-resistant). Frequencies of HCN2 rs7255568 and rs3752158 G alleles differed in GGEs and in controls (P = .039, P = .027, respectively). The frequency of HCN2 haplotype (CAC) was higher in patients than controls (P = .046). The frequency of the HCN1 rs10462087 CC+CT genotype was lower in patients with childhood absence epilepsy (CAE) than controls (P = .047). Rs7255568 was associated with the risk of CAE (P = .028) and juvenile myoclonic epilepsy (JME) (P = .02). Rs3752158 was associated with the risk of generalized tonic-clonic seizures, JME, and febrile seizures (all P < .05). The frequency of the HCN2 haplotype (CAC) was higher in patients with JME (P = .015) and in those with febrile seizures (P = .024) than in controls. No significant association was found between HCN1/HCN2 alleles, genotypes or haplotypes, and drug resistance in patients. After Bonferroni's multiple comparisons correction, only the HCN2 rs3752158 C allele and GC+CC genotype frequencies in patients with JME were higher than those in controls (19.2% vs 11.6%, odds ratio (OR) = 1.71, 95% CI = 1.18-2.32), P = .004 < 0.05/9; 36% vs 22.2%, OR = 1.62(1.18-2.23), P = .003 < 0.05/9). Our study suggests that HCN2 rs3752158 is involved in the susceptibility to JME.