KCND3 potassium channel gene variant confers susceptibility to electrocardiographic early repolarization pattern
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KCND3 potassium channel gene variant confers susceptibility to electrocardiographic early repolarization pattern. / Teumer, Alexander; Trenkwalder, Teresa; Kessler, Thorsten; Jamshidi, Yalda; van den Berg, Marten E; Kaess, Bernhard; Nelson, Christopher P; Bastiaenen, Rachel; De Bortoli, Marzia; Rossini, Alessandra; Deisenhofer, Isabel; Stark, Klaus; Assa, Solmaz; Braund, Peter S; Cabrera, Claudia; Dominiczak, Anna F; Gögele, Martin; Hall, Leanne M; Ikram, M Arfan; Kavousi, Maryam; Lackner, Karl J; Müller, Christian; Münzel, Thomas; Nauck, Matthias; Padmanabhan, Sandosh; Pfeiffer, Norbert; Spector, Tim D; Uitterlinden, Andre G; Verweij, Niek; Völker, Uwe; Warren, Helen R; Zafar, Mobeen; Felix, Stephan B; Kors, Jan A; Snieder, Harold; Munroe, Patricia B; Pattaro, Cristian; Fuchsberger, Christian; Schmidt, Georg; Nolte, Ilja M; Schunkert, Heribert; Pramstaller, Peter P; Wild, Philipp S; van der Harst, Pim; Stricker, Bruno H; Schnabel, Renate B; Samani, Nilesh J; Hengstenberg, Christian; Dörr, Marcus; Behr, Elijah R; Reinhard, Wibke; LifeLines Cohort Study.
in: JCI INSIGHT, Jahrgang 4, Nr. 23, 05.12.2019.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - KCND3 potassium channel gene variant confers susceptibility to electrocardiographic early repolarization pattern
AU - Teumer, Alexander
AU - Trenkwalder, Teresa
AU - Kessler, Thorsten
AU - Jamshidi, Yalda
AU - van den Berg, Marten E
AU - Kaess, Bernhard
AU - Nelson, Christopher P
AU - Bastiaenen, Rachel
AU - De Bortoli, Marzia
AU - Rossini, Alessandra
AU - Deisenhofer, Isabel
AU - Stark, Klaus
AU - Assa, Solmaz
AU - Braund, Peter S
AU - Cabrera, Claudia
AU - Dominiczak, Anna F
AU - Gögele, Martin
AU - Hall, Leanne M
AU - Ikram, M Arfan
AU - Kavousi, Maryam
AU - Lackner, Karl J
AU - Müller, Christian
AU - Münzel, Thomas
AU - Nauck, Matthias
AU - Padmanabhan, Sandosh
AU - Pfeiffer, Norbert
AU - Spector, Tim D
AU - Uitterlinden, Andre G
AU - Verweij, Niek
AU - Völker, Uwe
AU - Warren, Helen R
AU - Zafar, Mobeen
AU - Felix, Stephan B
AU - Kors, Jan A
AU - Snieder, Harold
AU - Munroe, Patricia B
AU - Pattaro, Cristian
AU - Fuchsberger, Christian
AU - Schmidt, Georg
AU - Nolte, Ilja M
AU - Schunkert, Heribert
AU - Pramstaller, Peter P
AU - Wild, Philipp S
AU - van der Harst, Pim
AU - Stricker, Bruno H
AU - Schnabel, Renate B
AU - Samani, Nilesh J
AU - Hengstenberg, Christian
AU - Dörr, Marcus
AU - Behr, Elijah R
AU - Reinhard, Wibke
AU - LifeLines Cohort Study
PY - 2019/12/5
Y1 - 2019/12/5
N2 - 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.
AB - 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.
KW - Alleles
KW - Death, Sudden, Cardiac
KW - Electrocardiography/methods
KW - European Continental Ancestry Group/genetics
KW - Female
KW - Genetic Loci
KW - Genetic Predisposition to Disease/genetics
KW - Genome-Wide Association Study/methods
KW - Genotype
KW - Heart Ventricles
KW - Humans
KW - Male
KW - Polymorphism, Single Nucleotide
KW - Shal Potassium Channels/genetics
KW - Transcriptome
KW - Ventricular Fibrillation/genetics
U2 - 10.1172/jci.insight.131156
DO - 10.1172/jci.insight.131156
M3 - SCORING: Journal article
C2 - 31600170
VL - 4
JO - JCI INSIGHT
JF - JCI INSIGHT
SN - 2379-3708
IS - 23
ER -