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Mutations in Conserved Amino Acids in the KCNQ1 Channel and Risk of Cardiac Events in Type-1 Long-QT Syndrome |
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| Authors: | CHRISTIAN JONS,M.D.,&dagger ,ARTHUR J. MOSS,M.D.,COELI M. LOPES, Ph.D,SCOTT MCNITT,M.S.,WOJCIECH ZAREBA,M.D.,Ph.D.,ILAN GOLDENBERG,M.D.,MING QI, Ph.D.,&Dagger ,ARTHUR A. M. WILDE,M.D.,Ph.D.,¶ ,WATARU SHIMIZU,M.D.,§ ,JORGEN K. KANTERS,M.D.,&dagger ,,JEFFREY A. TOWBIN,M.D.,&dagger &dagger ,MICHAEL J. ACKERMAN,M.D.,Ph.D.,&Dagger &Dagger , JENNIFER L. ROBINSON,M.S. |
| Affiliation: | From the Cardiology Division, Department of Medicine, University of Rochester Medical Center, Rochester, New York, USA;;University Hospital of Gentofte, Copenhagen, Denmark;;Department of Pathology, University of Rochester Medical Center, Rochester, New York, USA;;Division of Cardiology, Department of Internal Medicine, National Cardiovascular Center, Suita, Japan;;Department of Cardiology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands;;Danish National Research Foundation Center of Arrhythmias, University of Copenhagen, Denmark;;Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas, USA;;and Department of Medicine, Pediatrics, and Molecular Pharmacology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA |
| Abstract: | Background: Type-1 long-QT syndrome (LQT1) is caused by mutations in the KCNQ1 gene. The purpose of this study was to investigate whether KCNQ1 mutations in highly conserved amino acid residues within the voltage-gated potassium channel family are associated with an increased risk of cardiac events. Methods and Results: The study population involved 492 LQT1 patients with 54 missense mutations in the transmembrane region of the KCNQ1 channel. The amino acid sequences of the transmembrane region of 38 human voltage-gated potassium channels were aligned. An adjusted Shannon entropy score for each amino acid residue was calculated ranging from 0 (no conservation) to 1.0 (full conservation). Cox analysis was used to identify independent factors associated with the first cardiac event (syncope, aborted cardiac arrest, or death). Patients were subcategorized into tertiles by their adjusted Shannon entropy scores. The lowest tertile (score 0–0.469; n = 146) was used as a reference group; patients with intermediate tertile scores (0.470–0.665; n = 150) had no increased risk of cardiac events (HR = 1.19, P = 0.42) or aborted cardiac arrest/sudden cardiac death (HR = 1.58, P = 0.26), and those with the highest tertile scores (>0.665; n = 196) showed significantly increased risk of cardiac events (HR = 3.32, P <0.001) and aborted cardiac arrest/sudden cardiac death (HR = 2.62, P = 0.04). The increased risk in patients with the highest conservation scores was independent of QTc, gender, age, and beta-blocker therapy. Conclusions: Mutations in highly conserved amino acid residues in the KCNQ1 gene are associated with a significant risk of cardiac events independent of QTc, gender, and beta-blocker therapy. |
| Keywords: | long-QT syndrome sudden cardiac death KCNQ1 Shannon entropy conservation |