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

Clin Exp Pharmacol Physiol. 2018 Mar;45(3):226-233. doi: 10.1111/1440-1681.12877. Epub 2017 Nov 28.


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.

Keywords: HCN1; HCN2; Polymorphisms; drug resistance; genetic generalized epilepsies; susceptibility.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anticonvulsants / therapeutic use*
  • Case-Control Studies
  • Drug Resistance / genetics
  • Epilepsy, Generalized / drug therapy
  • Epilepsy, Generalized / genetics*
  • Female
  • Genetic Predisposition to Disease*
  • Genotype
  • Humans
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / genetics
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / metabolism*
  • Male
  • Polymorphism, Single Nucleotide*
  • Potassium Channels / genetics
  • Potassium Channels / metabolism*


  • Anticonvulsants
  • HCN1 protein, human
  • HCN2 protein, human
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Potassium Channels