期刊
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
卷 68, 期 13, 页码 1435-1448出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jacc.2016.07.729
关键词
electrocardiogram; genetic association study; heart failure; left ventricular hypertrophy; QRS
资金
- GlaxoSmithKline
- Zoll LifeCor
- Johnson Johnson
- Metabiota
- British Heart Foundation [PG/12/38/29615] Funding Source: researchfish
- Lundbeck Foundation [R190-2014-3904] Funding Source: researchfish
- Medical Research Council [MC_PC_U127561128] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0514-10027, NF-SI-0611-10170, NF-SI-0507-10228] Funding Source: researchfish
- NNF Center for Basic Metabolic Research [Pers Group] Funding Source: researchfish
- Novo Nordisk Foundation Center for Protein Research [PI Jesper Velgaard Olsen] Funding Source: researchfish
- MRC [MC_PC_U127561128] Funding Source: UKRI
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 < 1 x 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. (C) 2016 by the American College of Cardiology Foundation.
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