Abstract
Abstract 395: A Synonymous Coding SNP Alters SCN5A Regulation by miR-24 and Associates With Non-Arrhythmic Death in Heart Failure
Circulation research, Vol.121(suppl_1)
07/21/2017
DOI: 10.1161/res.121.suppl_1.395
Abstract
Mutations disrupting
SCN5A
coding sequence cause inherited arrhythmias and cardiomyopathy, and 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. Recently, we generated a transcriptome-wide map of microRNA (miR) binding sites in human heart and evaluated their interface with polymorphisms. Among >500 common SNPs residing within miR target regions, we identified a synonymous SNP (rs1805126) adjacent to a miR-24 site within
SCN5A
coding sequence. This SNP is known to reproducibly associate with heart rhythm measurements, but is not considered to be “causal”. Here, we show that miR-24 potently suppresses
SCN5A
and that rs1805126 modulates this regulation. In further exploring the clinical significance of this, we found that rs1805126 minor allele homozygosity associates with decreased cardiac
SCN5A
expression and increased mortality in heart failure patients. Unexpectedly, this risk was not linked with arrhythmic sudden cardiac death, but rather, with clinical signs of worsening heart failure (e.g. reduced ejection fraction) and myocardial gene expression changes related to bioenergetics, inflammation and extracellular remodeling. Together, these data attribute a molecular mechanism to this firmly-established GWAS SNP and highlight a novel and surprising link between common variations in
SCN5A
expression and non-arrhythmic death in heart failure.
Details
- Title: Subtitle
- Abstract 395: A Synonymous Coding SNP Alters SCN5A Regulation by miR-24 and Associates With Non-Arrhythmic Death in Heart Failure
- Creators
- Xiaoming Zhang - University of IowaJin-Young Yoon - University of IowaMichael Morley - University of PennsylvaniaPatrick Breheny - University of IowaHeather Bloom - Emory Univ, Atlanta, GASamuel Dudley - Brown UniversityPatrick Ellinor - Massachusetts General Hosp, Boston, MAKenneth Margulies - Univ of Pennsylvania, Philadelphia, PABarry London - University of IowaRyan L Boudreau - University of Iowa
- Resource Type
- Abstract
- Publication Details
- Circulation research, Vol.121(suppl_1)
- DOI
- 10.1161/res.121.suppl_1.395
- ISSN
- 0009-7330
- eISSN
- 1524-4571
- Language
- English
- Date published
- 07/21/2017
- Academic Unit
- Iowa Neuroscience Institute; Biostatistics; Molecular Physiology and Biophysics; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
- Record Identifier
- 9984302998702771
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