Abstract
BACKGROUNDThe presence of an early repolarization pattern (ERP) on the surface ECG is associated with risk of ventricular fibrillation and sudden cardiac death. Family studies have shown that ERP is a highly heritable trait, but molecular genetic determinants are unknown.METHODSTo identify genetic susceptibility loci for ERP, we performed a GWAS and meta-analysis in 2,181 cases and 23,641 controls of European ancestry.RESULTSWe identified a genome-wide significant (P < 5 × 10–8) locus in the potassium voltage-gated channel subfamily D member 3 (KCND3) gene that was successfully replicated in additional 1,124 cases and 12,510 controls. A subsequent joint meta-analysis of the discovery and replication cohorts identified rs1545300 as the lead SNP at the KCND3 locus (OR 0.82 per minor T allele, P = 7.7 × 10–12) but did not reveal additional loci. Colocalization analyses indicate causal effects of KCND3 gene expression levels on ERP in both cardiac left ventricle and tibial artery.CONCLUSIONSIn this study, we identified for the first time to our knowledge a genome-wide significant association of a genetic variant with ERP. Our findings of a locus in the KCND3 gene provide insights not only into the genetic determinants but also into the pathophysiological mechanism of ERP, discovering a promising candidate for functional studies.FUNDINGThis project was funded by the German Center for Cardiovascular Research (DZHK Shared Expertise SE081 – STATS). For detailed funding information per study, see the Supplemental Acknowledgments.
Highlights
The early repolarization pattern (ERP) is a common ECG finding characterized by an elevation at the QRSST junction (J point) of at least 0.1 mV in 2 adjacent ECG leads
We identified for the first time to our knowledge a genome-wide significant association of a genetic variant with ERP
The proportion of ERP based on the definition by Haïssaguerre and Macfarlane [6, 23] ranged from 6% to 14%, which is in line with the previously reported prevalence in the general population [2,3,4]
Summary
The early repolarization pattern (ERP) is a common ECG finding characterized by an elevation at the QRSST junction (J point) of at least 0.1 mV in 2 adjacent ECG leads. Candidate genetic association studies have highlighted a role for several genes encoding cardiac ion channels in the development of ERP and ERS [12,13,14,15]. These genes include gain-of-function variants in IK-ATP channels (KCNJ8, ABCC9) and loss-of-function variants in cardiac L-type calcium channels (CACNA1C, CACNB2b, CACNA2D1) and sodium channels (SCN5A, SCN10A) [16]. The presence of an early repolarization pattern (ERP) on the surface ECG is associated with risk of ventricular fibrillation and sudden cardiac death. Studies have shown that ERP is a highly heritable trait, but molecular genetic determinants are unknown
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