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

  • Alexander Teumer
  • Teresa Trenkwalder
  • Thorsten Kessler
  • Yalda Jamshidi
  • Marten E van den Berg
  • Bernhard Kaess
  • Christopher P Nelson
  • Rachel Bastiaenen
  • Marzia De Bortoli
  • Alessandra Rossini
  • Isabel Deisenhofer
  • Klaus Stark
  • Solmaz Assa
  • Peter S Braund
  • Claudia Cabrera
  • Anna F Dominiczak
  • Martin Gögele
  • Leanne M Hall
  • M Arfan Ikram
  • Maryam Kavousi
  • Karl J Lackner
  • Christian Müller
  • Thomas Münzel
  • Matthias Nauck
  • Sandosh Padmanabhan
  • Norbert Pfeiffer
  • Tim D Spector
  • Andre G Uitterlinden
  • Niek Verweij
  • Uwe Völker
  • Helen R Warren
  • Mobeen Zafar
  • Stephan B Felix
  • Jan A Kors
  • Harold Snieder
  • Patricia B Munroe
  • Cristian Pattaro
  • Christian Fuchsberger
  • Georg Schmidt
  • Ilja M Nolte
  • Heribert Schunkert
  • Peter P Pramstaller
  • Philipp S Wild
  • Pim van der Harst
  • Bruno H Stricker
  • Renate B Schnabel
  • Nilesh J Samani
  • Christian Hengstenberg
  • Marcus Dörr
  • Elijah R Behr
  • Wibke Reinhard
  • LifeLines Cohort Study

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.

Bibliografische Daten

OriginalspracheEnglisch
ISSN2379-3708
DOIs
StatusVeröffentlicht - 05.12.2019
PubMed 31600170