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Author Notes:

Address correspondence to: Ryan L. Boudreau or Barry London, 2269-B CBRB (R.L. Boudreau) or E315 A-1 GH (B. London), University of Iowa, Department of Internal Medicine, Iowa City, IA 52245, USA. Phone: 319.353.5510; Email: ryan-boudreau@uiowa.edu (R.L. Boudreau). Phone: 319.356.2750; Email: barry-london@uiowa.edu (B. London)

RLB and BL designed and conceived the project, supervised the research, and interpreted the data.

XZ, JYY, JMM, and KAM carried out experimental work, analyzed data, and participated in data interpretation.

RLB, MM, and PB carried out computational and statistical analyses.

RG, HLB, SCD, PTE, AAS, RW, MS, HM, and BL played key roles in overseeing GRADE patient data acquisition, organization, and interpretation.

ALT, CWY, AMF, and DMM played key roles in overseeing GRAHF patient data acquisition, organization, and interpretation.

KBM, WHWT, and CSM provided critical human cardiac tissue samples and accompanying clinical and genotyping data.

KI and DRS guided experimental design and helped with data interpretation.

RLB, BL, and XZ wrote the manuscript.

We also acknowledge members of the Boudreau and London labs for scientific discussion and manuscript feedback.

The authors have declared that no conflict of interest exists.

Subjects:

Research Funding:

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:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Medicine, Research & Experimental
  • Research & Experimental Medicine
  • CARDIAC SODIUM-CHANNEL
  • ATRIAL-FIBRILLATION
  • BRUGADA-SYNDROME
  • SCN5A MUTATION
  • MOLECULAR-MECHANISM
  • GENE SCN5A
  • LONG-QT
  • EXPRESSION
  • CONDUCTION
  • MICRORNAS

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

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Journal Title:

Journal of Clinical Investigation

Volume:

Volume 128, Number 3

Publisher:

, Pages 1154-1163

Type of Work:

Article | Final Publisher PDF

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.

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