A common polymorphism in KCNH2 (HERG) hastens cardiac repolarization

Cardiovasc Res. 2003 Jul 1;59(1):27-36. doi: 10.1016/s0008-6363(03)00342-0.

Abstract

Objective: Genetic variants of cardiac ion channels may influence cardiac repolarization. Thereby such variants may modulate the penetrance of primary electrical disorders, contribute to differences in susceptibility to drug-induced QT-prolongation between individuals, or contribute to rhythm disturbances in the context of structural heart disease. Since the current encoded by KCNH2 (HERG; I(Kr)) is a primary determinant of repolarization, we conducted association studies between the respective alleles of the common amino acid-changing polymorphism at codon 897 (2690A>C; K897T) within HERG and rate-corrected QT interval (QTc).

Methods and results: Association analysis in Caucasian subjects (n=1030) revealed a significant association of this polymorphism with QTc (P=0.0025) with CC homozygotes having a significantly shorter QTc (388.5+/-2.9 ms) compared to AA homozygotes (398.5+/-0.9) and heterozygotes (AC, 397.2+/-1.2). The latter two genotypes were associated with comparable mean QTc's, suggesting that the 2690C-allele is recessive. After stratification by sex, the polymorphism was more predictive of QTc in females (P=0.0021), a finding that was replicated in a second population sample (n=352) from the same ethnic background (P=0.044). To assess whether this polymorphism could represent a 'functional' polymorphism, we compared the biophysical properties of K897- and T897-HERG channels by whole-cell voltage clamp. Compared to the K897 channel, the T897 channel displayed a shift of -7 mV in voltage dependence of activation and increased rates of current activation and deactivation.

Conclusion: As confirmed in modeling studies, these changes are expected to shorten action potential duration by an increase in I(Kr). This recapitulates the shorter QTc in females homozygous for the 2690C-allele.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Twin Study

MeSH terms

  • Action Potentials / physiology*
  • Adult
  • Aged
  • Base Sequence
  • Cation Transport Proteins*
  • Computer Simulation
  • DNA-Binding Proteins*
  • ERG1 Potassium Channel
  • Electrocardiography
  • Ether-A-Go-Go Potassium Channels
  • European Continental Ancestry Group
  • Female
  • Genetic Markers
  • Genotype
  • Heart / physiology*
  • Heart / physiopathology
  • Homozygote
  • Humans
  • Long QT Syndrome / genetics
  • Long QT Syndrome / physiopathology
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Polymorphism, Genetic*
  • Potassium Channels / genetics*
  • Potassium Channels / physiology*
  • Potassium Channels, Voltage-Gated*
  • Sequence Analysis, DNA
  • Sex Factors
  • Trans-Activators*
  • Transcriptional Regulator ERG

Substances

  • Cation Transport Proteins
  • DNA-Binding Proteins
  • ERG protein, human
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels
  • Genetic Markers
  • KCNH2 protein, human
  • KCNH6 protein, human
  • Potassium Channels
  • Potassium Channels, Voltage-Gated
  • Trans-Activators
  • Transcriptional Regulator ERG