title: Gene-environment interaction between SCN5A-1103Y and hypokalemia influences QT interval prolongation in African Americans: the Jackson Heart Study.
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.
authors: Jackson Heart Study, Jackson State University, Jackson, MS.
authors: Ermeg L
authors: EL
authors: Akylbekova
authors: G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, MS.
authors: John P
authors: JP
authors: Payne
authors: Cardiolovascular Research Center and Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA.
authors: Christopher
authors: C
authors: Newton-Cheh
authors: Departments of Biostatistics and Bioinformatics, University of Mississippi Medical Center, Jackson, MS.
authors: Warren L
authors: WL
authors: May
authors: Medicine, University of Mississippi Medical Center, Jackson, MS.
authors: Ervin R
authors: ER
authors: Fox
authors: Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS.
authors: James G
authors: JG
authors: Wilson
authors: Jackson Heart Study, Jackson State University, Jackson, MS.
authors: Daniel F
authors: DF
authors: Sarpong
authors: Jackson Heart Study, Jackson State University, Jackson, MS; Medicine, University of Mississippi Medical Center, Jackson, MS.
authors: Herman A
authors: HA
authors: Taylor
authors: Medicine, University of Mississippi Medical Center, Jackson, MS; Cancer Institute, University of Mississippi Medical Center, Jackson, MS. Electronic address: jmaher@umc.edu.
authors: Joseph F
authors: JF
authors: Maher
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000368:Aged; D000483:Alleles; D016757:Death, Sudden, Cardiac; D004562:Electrocardiography; D005260:Female; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D006329:Heart Conduction System / Q000503:physiopathology*; D006801:Humans; D007008:Hypokalemia / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics*
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human