KCND3 potassium channel gene variant confers susceptibility to electrocardiographic early repolarization pattern

Teumer, A. et al. (2019) KCND3 potassium channel gene variant confers susceptibility to electrocardiographic early repolarization pattern. JCI Insight, (doi: 10.1172/jci.insight.131156) (PMID:31600170) (Early Online Publication)

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Abstract

Background. The presence of an early repolarization pattern (ERP) on the surface electrocardiogram (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. Methods. To identify genetic susceptibility loci for ERP, we performed a GWAS and meta-analysis in 2,181 cases and 23,641 controls of European ancestry. Results. We identified a genome-wide significant (p<5E-8) locus in the KCND3 (potassium voltage gated channel subfamily D member 3) 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=7.7E-12), but did not reveal additional loci. Co-localization analyses indicate causal effects of KCND3 gene expression levels on ERP in both cardiac left ventricle and tibial artery. Conclusions. In this study we identified for the first time a genome-wide significant association of a genetic variant with ERP. Our findings of a locus in the KCND3 gene not only provide insights into the genetic determinants but also into the pathophysiological mechanism of ERP, discovering a promising candidate for functional studies.

Item Type:Articles
Status:Early Online Publication
Refereed:Yes
Glasgow Author(s) Enlighten ID:Padmanabhan, Professor Sandosh and Dominiczak, Professor Anna
Authors: Teumer, A., Trenkwalder, T., Kessler, T., Jamshidi, Y., van den Berg, M. E., Kaess, B., Nelson, C. P., Bastiaenen, R., De Bortoli, M., Rossini, A., Deisenhofer, I., Stark, K., Assa, S., Braund, P. S., Cabrera, C., Dominiczak, A. F., Gögele, M., Hall, L. M., Ikram, M. A., Kavousi, M., Lackner, K. J., Müller, C., Münzel, T., Nauck, M., Padmanabhan, S., Pfeiffer, N., Spector, T. D., Uitterlinden, A. G., Verweij, N., Völker, U., Warren, H. R., Zafar, M., Felix, S. B., Kors, J. A., Snieder, H., Munroe, P. B., Pattaro, C., Fuchsberger, C., Schmidt, G., Nolte, I. M., Schunkert, H., Pramstaller, P., Wild, P. S., van der Harst, P., Stricker, B. H., Schnabel, R. B., Samani, N. J., Hengstenberg, C., Dörr, M., Behr, E. R., and Reinhard, W.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:JCI Insight
Publisher:American Society for Clinical Investigation
ISSN:2379-3708
ISSN (Online):2379-3708
Published Online:10 October 2019
Copyright Holders:Copyright © 2019 American Society for Clinical Investigation
First Published:First published in JCI Insight 2019
Publisher Policy:Reproduced with the permission of the publisher

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