A common polymorphism in KCNH2 (HERG) hastens cardiac repolarization

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Item Type:	Article
Title:	A common polymorphism in KCNH2 (HERG) hastens cardiac repolarization
Creators Name:	Bezzina, C.R., Verkerk, A.O., Busjahn, A., Jeron, A., Erdmann, J., Koopmann, T.T., Bhuiyan, Z.A., Wilders, R., Mannens, M.M.A.M., Tan, H.L., Luft, F.C., Schunkert, H. and Wilde, A.A.M.
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; IKr) 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 IKr. This recapitulates the shorter QTc in females homozygous for the 2690C-allele.
Keywords:	K-Channel, Ion Channels, ECG, Epidemiology, Arrhythmias
Source:	Cardiovascular Research
ISSN:	0008-6363
Publisher:	Elsevier
Volume:	59
Number:	1
Page Range:	27-36
Date:	1 July 2003
Official Publication:	https://doi.org/10.1016/S0008-6363(03)00342-0
PubMed:	View item in PubMed

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