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


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.


CONCLUSIONS
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.
Bezzina
Connie R
CR
Experimental 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
Verkerk
Arie O
AO
Busjahn
Andreas
A
Jeron
Andreas
A
Erdmann
Jeanette
J
Koopmann
Tamara T
TT
Bhuiyan
Zahurul A
ZA
Wilders
Ronald
R
Mannens
Marcel M A M
MM
Tan
Hanno L
HL
Luft
Friedrich C
FC
Schunkert
Heribert
H
Wilde
Arthur A M
AA
D000200:Action Potentials / Q000502:physiology*; D000328:Adult; D000368:Aged; D001483:Base Sequence; D027682:Cation Transport Proteins; D003198:Computer Simulation; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels; D005260:Female; D005819:Genetic Markers; D005838:Genotype; D006321:Heart / Q000502:physiology* / Q000503:physiopathology; D006720:Homozygote; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011110:Polymorphism, Genetic; D015221:Potassium Channels / Q000235:genetics* / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D017422:Sequence Analysis, DNA; D012737:Sex Factors; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D044465:White People
D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D005819:Genetic Markers; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG