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

Xiaoming Zhang; Jin-Young Yoon; Michael Morley; Jared M McLendon; Kranti A Mapuskar; Rebecca Gutmann; Haider Mehdi; Heather L Bloom; Samuel C Dudley; Patrick T Ellinor; Alaa A Shalaby; Raul Weiss; W.H. Wilson Tang; Christine S Moravec; Madhurmeet Singh; Anne L Taylor; Clyde W Yancy; Arthur M Feldman; Dennis M McNamara; Kaikobad Irani; Douglas R Spitz; Patrick Breheny; Kenneth B Margulies; Barry London; Ryan L Boudreau

doi:10.1172/JCI95710

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

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

Xiaoming Zhang, Jin-Young Yoon, Michael Morley, Jared M McLendon, Kranti A Mapuskar, Rebecca Gutmann, Haider Mehdi, Heather L Bloom, Samuel C Dudley, Patrick T Ellinor, …

The Journal of clinical investigation, Vol.128(3), pp.1154-1163

02/19/2018

DOI: 10.1172/JCI95710

PMCID: PMC5824852

PMID: 29457789

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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

Cardiology

Genetics

Ion Channels

Genetic variation

Noncoding RNAs

Details

Title: Subtitle: A common variant alters SCN5A–miR-24 interaction and associates with heart failure mortality
Creators: Xiaoming Zhang - Department of Biostatistics, University of Iowa College of Public Heath, Iowa City, Iowa, USA
Jin-Young Yoon - Department of Biostatistics, University of Iowa College of Public Heath, Iowa City, Iowa, USA
Michael Morley - Department of Biostatistics, University of Iowa College of Public Heath, Iowa City, Iowa, USA
Jared M McLendon - Department of Biostatistics, University of Iowa College of Public Heath, Iowa City, Iowa, USA
Kranti A Mapuskar - Department of Biostatistics, University of Iowa College of Public Heath, Iowa City, Iowa, USA
Rebecca Gutmann - Department of Biostatistics, University of Iowa College of Public Heath, Iowa City, Iowa, USA
Haider Mehdi - Department of Biostatistics, University of Iowa College of Public Heath, Iowa City, Iowa, USA
Heather L Bloom - Department of Biostatistics, University of Iowa College of Public Heath, Iowa City, Iowa, USA
Samuel C Dudley - Department of Biostatistics, University of Iowa College of Public Heath, Iowa City, Iowa, USA
Patrick T Ellinor - Department of Biostatistics, University of Iowa College of Public Heath, Iowa City, Iowa, USA
Alaa A Shalaby - Department of Biostatistics, University of Iowa College of Public Heath, Iowa City, Iowa, USA
Raul Weiss - Department of Biostatistics, University of Iowa College of Public Heath, Iowa City, Iowa, USA
W.H. Wilson Tang - Department of Biostatistics, University of Iowa College of Public Heath, Iowa City, Iowa, USA
Christine S Moravec - Department of Biostatistics, University of Iowa College of Public Heath, Iowa City, Iowa, USA
Madhurmeet Singh - Department of Biostatistics, University of Iowa College of Public Heath, Iowa City, Iowa, USA
Anne L Taylor - Columbia University
Clyde W Yancy - Department of Biostatistics, University of Iowa College of Public Heath, Iowa City, Iowa, USA
Arthur M Feldman - Department of Biostatistics, University of Iowa College of Public Heath, Iowa City, Iowa, USA
Dennis M McNamara - Department of Biostatistics, University of Iowa College of Public Heath, Iowa City, Iowa, USA
Kaikobad Irani - Department of Biostatistics, University of Iowa College of Public Heath, Iowa City, Iowa, USA
Douglas R Spitz - Department of Biostatistics, University of Iowa College of Public Heath, Iowa City, Iowa, USA
Patrick Breheny - Department of Biostatistics, University of Iowa College of Public Heath, Iowa City, Iowa, USA
Kenneth B Margulies - Department of Biostatistics, University of Iowa College of Public Heath, Iowa City, Iowa, USA
Barry London - Department of Biostatistics, University of Iowa College of Public Heath, Iowa City, Iowa, USA
Ryan L Boudreau - Department of Biostatistics, University of Iowa College of Public Heath, Iowa City, Iowa, USA
Resource Type: Journal article
Publication Details: The Journal of clinical investigation, Vol.128(3), pp.1154-1163
DOI: 10.1172/JCI95710
PMID: 29457789
PMCID: PMC5824852
NLM abbreviation: J Clin Invest
ISSN: 0021-9738
eISSN: 1558-8238
Publisher: American Society for Clinical Investigation
Grant note: HL105993 / NIH 14SDG18590008 / American Heart Association HL115955 / NIH HL77398 / NIH CA182804 / NIH HL007121 / NIH
Language: English
Date published: 02/19/2018
Academic Unit: Molecular Physiology and Biophysics; Pathology; Iowa Neuroscience Institute; Biostatistics; Radiation Oncology; Internal Medicine
Record Identifier: 9983997308802771

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