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52 Genetic Loci Influencing Myocardial Mass
Título de la revista
Autores
van der Harst, Pim
van Setten, Jessica
Verweij, Niek
Vogler, Georg
Franke, Lude
Maurano, Matthew T.
Wang, Xinchen
Leach, Irene Mateo
Eijgelsheim, Mark
Sotoodehnia, Nona
Archivos
Fecha
2016
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ISSN de la revista
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Editor
Elsevier USA
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Resumen
Abstract
Background Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death. Objectives This meta-analysis sought to gain insights into the genetic determinants of myocardial mass. Methods We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment. Results We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p and lt; 1 × 10?8. These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus. We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in vitro and in vivo. Conclusions Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets. © 2016 American College of Cardiology Foundation
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Keywords
Sodium channel Nav1.5 , Sodium channel Nav1.8 , Transcription factor , Article , Biological functions , Cardiac muscle , Cardiovascular parameters , Chromatin , Drosophila melanogaster , European , Functional assessment , Gene identification , Gene locus , Genetic association , Genetic parameters , Genetic trait , Genetic variability , Genome-wide association study , Heart , Heart ventricle hypertrophy , Histone modification , Human , Human genome , In vitro study , In vivo study , Major clinical study , Meta analysis (topic) , Mus musculus , Myocardial mass , Phenotype , Priority journal , Protein binding , QRS complex , Reliability , SCN10A gene , SCN5A gene , Validation study , Animal , Cardiomegaly , Genetics , Genome-wide association study , Animals , Cardiomegaly , Genetic Loci , Genome-Wide Association Study , Humans , Electrocardiogram , Genetic association study , Heart failure , Left ventricular hypertrophy , QRS
