Ermeg L Akylbekova1, John P Payne2, Christopher Newton-Cheh3, Warren L May4, Ervin R Fox5, James G Wilson6, Daniel F Sarpong1, Herman A Taylor7, Joseph F Maher8. 1. Jackson Heart Study, Jackson State University, Jackson, MS. 2. G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, MS. 3. Cardiolovascular Research Center and Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA. 4. Departments of Biostatistics and Bioinformatics, University of Mississippi Medical Center, Jackson, MS. 5. Medicine, University of Mississippi Medical Center, Jackson, MS. 6. Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS. 7. Jackson Heart Study, Jackson State University, Jackson, MS; Medicine, University of Mississippi Medical Center, Jackson, MS. 8. Medicine, University of Mississippi Medical Center, Jackson, MS; Cancer Institute, University of Mississippi Medical Center, Jackson, MS. Electronic address: jmaher@umc.edu.
Abstract
BACKGROUND: African-American ancestry, hypokalemia, and QT interval prolongation on the electrocardiogram are all risk factors for sudden cardiac death (SCD), but their interactions remain to be characterized. SCN5A-1103Y is a common missense variant, of African ancestry, of the cardiac sodium channel gene. SCN5A-1103Y is known to interact with QT-prolonging factors to promote ventricular arrhythmias in persons at high risk for SCD, but its clinical impact in the general African-American population has not been established. METHODS: We genotyped SCN5A-S1103Y in 4,476 participants of the Jackson Heart Study, a population-based cohort of African Americans. We investigated the effect of SCN5A-1103Y, including interaction with hypokalemia, on QT interval prolongation, a widely-used indicator of prolonged myocardial repolarization and predisposition to SCD. We then evaluated the two sub-components of the QT interval: QRS duration and JT interval. RESULTS: The carrier frequency for SCN5A-1103Y was 15.4%. SCN5A-1103Y was associated with QT interval prolongation (2.7 milliseconds; P < .001) and potentiated the effect of hypokalemia on QT interval prolongation (14.6 milliseconds; P = .02). SCN5A-1103Y had opposing effects on the two sub-components of the QT interval, with shortening of QRS duration (-1.5 milliseconds; P = .001) and prolongation of the JT interval (3.4 milliseconds; P < .001). Hypokalemia was associated with diuretic use (78%; P < .001). CONCLUSIONS: SCN5A-1103Y potentiates the effect of hypokalemia on prolonging myocardial repolarization in the general African-American population. These findings have clinical implications for modification of QT prolonging factors, such as hypokalemia, in the 15% of African Americans who are carriers of SCN5A-1103Y.
BACKGROUND: African-American ancestry, hypokalemia, and QT interval prolongation on the electrocardiogram are all risk factors for sudden cardiac death (SCD), but their interactions remain to be characterized. SCN5A-1103Y is a common missense variant, of African ancestry, of the cardiac sodium channel gene. SCN5A-1103Y is known to interact with QT-prolonging factors to promote ventricular arrhythmias in persons at high risk for SCD, but its clinical impact in the general African-American population has not been established. METHODS: We genotyped SCN5A-S1103Y in 4,476 participants of the Jackson Heart Study, a population-based cohort of African Americans. We investigated the effect of SCN5A-1103Y, including interaction with hypokalemia, on QT interval prolongation, a widely-used indicator of prolonged myocardial repolarization and predisposition to SCD. We then evaluated the two sub-components of the QT interval: QRS duration and JT interval. RESULTS: The carrier frequency for SCN5A-1103Y was 15.4%. SCN5A-1103Y was associated with QT interval prolongation (2.7 milliseconds; P < .001) and potentiated the effect of hypokalemia on QT interval prolongation (14.6 milliseconds; P = .02). SCN5A-1103Y had opposing effects on the two sub-components of the QT interval, with shortening of QRS duration (-1.5 milliseconds; P = .001) and prolongation of the JT interval (3.4 milliseconds; P < .001). Hypokalemia was associated with diuretic use (78%; P < .001). CONCLUSIONS:SCN5A-1103Y potentiates the effect of hypokalemia on prolonging myocardial repolarization in the general African-American population. These findings have clinical implications for modification of QT prolonging factors, such as hypokalemia, in the 15% of African Americans who are carriers of SCN5A-1103Y.
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