Circulation. 2007;116:1128-1136
Published online before print August 20, 2007, doi: 10.1161/CIRCULATIONAHA.107.710780
Published online before print August 20, 2007, doi: 10.1161/CIRCULATIONAHA.107.710780
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(Circulation. 2007;116:1128-1136.)
© 2007 American Heart Association, Inc.
Genetics |
CLINICAL PERSPECTIVE
Disordered myocardial repolarization as manifest in electrocardiographic QT interval prolongation is a consistent risk factor for sudden cardiac death. As a consequence of noncardiac medications, QT prolongation and arrhythmias, in part a result of binding to the HERG channel, are also a major impediment to bringing common drugs to market safely. We tested common genetic variants in the KCNH2 gene encoding the
subunit of the HERG channel and observed association of a novel intronic single nucleotide polymorphism and a previously reported missense single nucleotide polymorphism with continuous QT interval duration in the Framingham Heart Study. The variants contribute to modest changes in QT interval, 3.9- and 3.1-ms increases; thus, their relevance to clinical disease is currently unclear. In trials of drugs that prolong the QT interval on resting ECG, increases of 5 to 10 ms in the group mean have been associated with increased risk of arrhythmia. These group means on resting ECGs reflect some patients with little QT change and some with substantial increases who likely bear a large fraction of risk. Future tests of common variants of modest effect such as those in KCNH2 or the recently identified NOS1AP myocardial repolarization gene (
7-ms increase) in individuals at high risk for arrhythmias (eg, heart failure, status post myocardial infarction) and those exposed to QT-prolonging drugs are needed to determine whether these small changes in group means hide substantially increased risk for certain individuals when combined with other repolarization perturbations.
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Footnotes |
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Guest Editor for this article was Michael E. Cain, MD.
The online Data Supplement, consisting of tables and a figure, can be found with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.107.710780/DC1.
*Dr Hirschhorn and Dr O’Donnell contributed equally. 
Presented in part at the 45th Annual Conference on Cardiovascular Disease Epidemiology and Prevention of the American Heart Association, Washington, DC, May 2005.
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