A common variant alters SCN5A-miR-24 interaction and associates with heart failure mortality

• Type of Material: Article
• Authors: Xiaoming Zhang, University of Iowa; Jin-Young Yoon, University of Iowa; Michael Morley, University of Pennsylvania; Jared M. McLendon, University of Iowa; Kranti A. Mapuskar, University of Iowa; Rebecca Gutmann, University of Iowa; Haider Mehdi, University of Iowa; Heather Bloom, Emory University; Samuel C. Dudley, University of Minnesota; Patrick T. Ellinor, Massachusetts General Hospital; Alaa A. Shalaby, University of Pittsburgh; Raul Weiss, Ohio State University; W.H. Wilson Tang, Cleveland Clinic; Christine S. Moravec, Cleveland Clinic; Madhurmeet Singh, University of Pittsburgh; Anne L. Taylor, Columbia University College Physician & Surgeons; Clyde W. Yancy, Northwestern University; Arthur M. Feldman, Temple University; Dennis M. McNamara, University of Pittsburgh; Kaikobad Irani, University of Iowa; Douglas R. Spitz, University of Iowa; Patrick Breheny Breheny, University of Iowa; Kenneth B. Margulies, University of Pennsylvania; Barry London, University of Iowa; Ryan L. Boudreau, University of Iowa
• Language: English
• Date: 2018-03-01
• Publisher: American Society for Clinical Investigation
• Publication Version: Final Published Version
• Copyright Statement: © 2018 Blackwell Publishing Ltd. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1172/JCI95710
• Title of Journal or Parent Work: Journal of Clinical Investigation
• ISSN: 0021-9738
• Volume: 128
• Issue: 3
• Start Page: 1154
• End Page: 1163
• Grant/Funding Information: This work was supported by the American Heart Association (14SDG18590008 to R.L. Boudreau), Roy J. Carver Trust (University of Iowa to R.L. Boudreau), NIH NCI (CA182804 to D.R. Spitz), NIH NHLBI (HL77398 to B. London, HL115955 to K. Irani and B. London, HL105993 to K.B. Margulies and W.H.W. Tang, and HL007121 to J.M. McLendon).
• Keywords: Research & Experimental Medicine; Science & Technology; GENE SCN5A; CONDUCTION; MOLECULAR-MECHANISM; Life Sciences & Biomedicine; MICRORNAS; ATRIAL-FIBRILLATION; EXPRESSION; SCN5A MUTATION; CARDIAC SODIUM-CHANNEL; LONG-QT; BRUGADA-SYNDROME; Medicine, Research & Experimental
• Research Categories: Health Sciences, Radiology; Health Sciences, General; Health Sciences, Oncology

Abstract

SCN5A encodes the voltage-gated Na+channel NaV1.5 that is responsible for depolarization of the cardiac action potential and rapid intercellular conduction. Mutations disrupting the SCN5A coding sequence cause inherited arrhythmias and cardiomyopathy, and single-nucleotide polymorphisms (SNPs) linked to SCN5A splicing, localization, and function associate with heart failure-related sudden cardiac death. However, the clinical relevance of SNPs that modulate SCN5A expression levels remains understudied. We recently generated a transcriptome-wide map of microRNA (miR) binding sites in human heart, evaluated their overlap with common SNPs, and identified a synonymous SNP (rs1805126) adjacent to a miR-24 site within the SCN5A coding sequence. This SNP was previously shown to reproducibly associate with cardiac electrophysiological parameters, but was not considered to be causal. Here, we show that miR-24 potently suppresses SCN5A expression and that rs1805126 modulates this regulation. We found that the rs1805126 minor allele associates with decreased cardiac SCN5A expression and that heart failure subjects homozygous for the minor allele have decreased ejection fraction and increased mortality, but not increased ventricular tachyarrhythmias. In mice, we identified a potential basis for this in discovering that decreased Scn5a expression leads to accumulation of myocardial reactive oxygen species. Together, these data reiterate the importance of considering the mechanistic significance of synonymous SNPs as they relate to miRs and disease, and highlight a surprising link between SCN5A expression and nonarrhythmic death in heart failure.