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A common polymorphism in KCNH2 (HERG) hastens cardiac repolarization
Connie R Bezzina1, Arie O Verkerk, Andreas Busjahn
1Experimental and Molecular Cardiology Group, Room M0-052, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. c.r.bezzini@amc.uva.nl
Cardiovascular Research
|June 28, 2003
Summary
Genetic variants in the KCNH2 gene (HERG) impact cardiac repolarization. A common KCNH2 polymorphism (K897T) is associated with shorter QT intervals, particularly in females.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Electrophysiology
Background:
- Genetic variants in cardiac ion channels influence heart repolarization and susceptibility to arrhythmias.
- The KCNH2 gene encodes the HERG channel (I(Kr)), a key determinant of cardiac repolarization.
Purpose of the Study:
- To investigate the association between a common KCNH2 gene polymorphism (K897T) and the rate-corrected QT interval (QTc).
- To explore the functional consequences of this polymorphism on HERG channel biophysics and its impact on cardiac repolarization.
Main Methods:
- Association analysis of the KCNH2 2690A>C polymorphism with QTc in Caucasian subjects (n=1030).
- Sex-stratified analysis and replication in a second population sample (n=352).
- Whole-cell voltage clamp experiments to compare biophysical properties of K897- and T897-HERG channels.
Main Results:
- A significant association was found between the KCNH2 polymorphism and QTc (P=0.0025), with CC homozygotes exhibiting shorter QTc.
- The association was more pronounced in females and replicated in an independent cohort.
- T897-HERG channels showed altered voltage dependence of activation and faster current kinetics compared to K897-HERG channels.
Conclusions:
- The K897T polymorphism in KCNH2 influences cardiac repolarization by altering HERG channel function.
- These functional changes are predicted to shorten action potential duration, explaining the shorter QTc observed in individuals with the 2690C-allele, especially females.