A common polymorphism in KCNH2 (HERG) hastens cardiac repolarization
Why the study?
Does the K897T polymorphism in KCNH2 (HERG) affect the rate-corrected QT interval in Caucasian subjects?
Population
1,382 Caucasian subjects and in vitro whole-cell voltage clamp models of K897- and T897-HERG channels
Comparison
K897T (2690A>C) polymorphism in KCNH2 (HERG) vs Wild-type or other genotypes
Design
Cross-sectional
Authors
Discussion
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Implication
K897T CC genotype may shorten QTc in females; leaves open utility for arrhythmia risk stratification pending prospective studies.
Key Points
- To determine whether the common K897T polymorphism in KCNH2 (HERG) alters rate-corrected QT interval and affects the biophysical properties of the cardiac potassium channel.
- Analyzed the association between the KCNH2 K897T (2690A>C) polymorphism and rate-corrected QT interval (QTc) in a primary Caucasian cohort (n=1030) and an independent replication cohort (n=352).
- Characterized biophysical channel kinetics of K897- and T897-HERG variants using whole-cell voltage clamp and cardiac action potential modeling.
- Homozygous CC carriers had a significantly shorter mean QTc (388.5 ± 2.9 ms) than AA homozygotes (398.5 ± 0.9 ms) and AC heterozygotes (397.2 ± 1.2 ms; P=0.0025).
- Sex stratification revealed the association was driven by females (P=0.0021), an effect replicated in the second cohort (P=0.044).
- T897-HERG channels displayed a -7 mV shift in activation voltage dependence alongside faster activation and deactivation rates, increasing repolarizing current I(Kr).
Structured PICO
Does the K897T polymorphism in KCNH2 (HERG) affect the rate-corrected QT interval in Caucasian subjects?
P
Population
1,382 Caucasian subjects (initial cohort n=1030, replication cohort n=352) and in vitro whole-cell voltage clamp models of K897- and T897-HERG channels
I
Intervention
K897T (2690A>C) polymorphism in KCNH2 (HERG)
C
Comparator
Wild-type or other genotypes (AA homozygotes and AC heterozygotes)
O
Outcome
Rate-corrected QT interval (QTc)surrogate
The common K897T polymorphism in the HERG channel is associated with a shorter QTc interval, particularly in females, due to altered channel biophysics that hasten cardiac repolarization.
Cite This Study
Connie R. Bezzina (2003) studied this question.