A common polymorphism in KCNH2 (HERG) hastens cardiac repolarization.

Details

Serval ID
serval:BIB_97BD9F1FF270
Type
Article: article from journal or magazin.
Collection
Publications
Title
A common polymorphism in KCNH2 (HERG) hastens cardiac repolarization.
Journal
Cardiovascular research
Author(s)
Bezzina C.R., Verkerk A.O., Busjahn A., Jeron A., Erdmann J., Koopmann T.T., Bhuiyan Z.A., Wilders R., Mannens M.M., Tan H.L., Luft F.C., Schunkert H., Wilde A.A.
ISSN
0008-6363 (Print)
ISSN-L
0008-6363
Publication state
Published
Issued date
01/07/2003
Peer-reviewed
Oui
Volume
59
Number
1
Pages
27-36
Language
english
Notes
Publication types: Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't ; Twin Study
Publication Status: ppublish
Abstract
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).
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.
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.

Keywords
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
Pubmed
Web of science
Create date
01/03/2018 16:40
Last modification date
20/08/2019 15:59
Usage data