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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, Vol. 4, No. 23, 05.12.2019.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Teumer, A, Trenkwalder, T, Kessler, T, Jamshidi, Y, van den Berg, ME, Kaess, B, Nelson, CP, Bastiaenen, R, De Bortoli, M, Rossini, A, Deisenhofer, I, Stark, K, Assa, S, Braund, PS, Cabrera, C, Dominiczak, AF, Gögele, M, Hall, LM, Ikram, MA, Kavousi, M, Lackner, KJ, Müller, C, Münzel, T, Nauck, M, Padmanabhan, S, Pfeiffer, N, Spector, TD, Uitterlinden, AG, Verweij, N, Völker, U, Warren, HR, Zafar, M, Felix, SB, Kors, JA, Snieder, H, Munroe, PB, Pattaro, C, Fuchsberger, C, Schmidt, G, Nolte, IM, Schunkert, H, Pramstaller, PP, Wild, PS, van der Harst, P, Stricker, BH, Schnabel, RB, Samani, NJ, Hengstenberg, C, Dörr, M, Behr, ER, Reinhard, W & LifeLines Cohort Study 2019, 'KCND3 potassium channel gene variant confers susceptibility to electrocardiographic early repolarization pattern', JCI INSIGHT, vol. 4, no. 23. https://doi.org/10.1172/jci.insight.131156

APA

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., ... LifeLines Cohort Study (2019). KCND3 potassium channel gene variant confers susceptibility to electrocardiographic early repolarization pattern. JCI INSIGHT, 4(23). https://doi.org/10.1172/jci.insight.131156

Vancouver

Teumer A, Trenkwalder T, Kessler T, Jamshidi Y, van den Berg ME, Kaess B et al. KCND3 potassium channel gene variant confers susceptibility to electrocardiographic early repolarization pattern. JCI INSIGHT. 2019 Dec 5;4(23). https://doi.org/10.1172/jci.insight.131156

Bibtex

@article{fef0bd1f31ce466eb690524b0ae9579d,
title = "KCND3 potassium channel gene variant confers susceptibility to electrocardiographic early repolarization pattern",
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.",
keywords = "Alleles, Death, Sudden, Cardiac, Electrocardiography/methods, European Continental Ancestry Group/genetics, Female, Genetic Loci, Genetic Predisposition to Disease/genetics, Genome-Wide Association Study/methods, Genotype, Heart Ventricles, Humans, Male, Polymorphism, Single Nucleotide, Shal Potassium Channels/genetics, Transcriptome, Ventricular Fibrillation/genetics",
author = "Alexander Teumer and Teresa Trenkwalder and Thorsten Kessler and Yalda Jamshidi and {van den Berg}, {Marten E} and Bernhard Kaess and Nelson, {Christopher P} and Rachel Bastiaenen and {De Bortoli}, Marzia and Alessandra Rossini and Isabel Deisenhofer and Klaus Stark and Solmaz Assa and Braund, {Peter S} and Claudia Cabrera and Dominiczak, {Anna F} and Martin G{\"o}gele and Hall, {Leanne M} and Ikram, {M Arfan} and Maryam Kavousi and Lackner, {Karl J} and Christian M{\"u}ller and Thomas M{\"u}nzel and Matthias Nauck and Sandosh Padmanabhan and Norbert Pfeiffer and Spector, {Tim D} and Uitterlinden, {Andre G} and Niek Verweij and Uwe V{\"o}lker and Warren, {Helen R} and Mobeen Zafar and Felix, {Stephan B} and Kors, {Jan A} and Harold Snieder and Munroe, {Patricia B} and Cristian Pattaro and Christian Fuchsberger and Georg Schmidt and Nolte, {Ilja M} and Heribert Schunkert and Pramstaller, {Peter P} and Wild, {Philipp S} and {van der Harst}, Pim and Stricker, {Bruno H} and Schnabel, {Renate B} and Samani, {Nilesh J} and Christian Hengstenberg and Marcus D{\"o}rr and Behr, {Elijah R} and Wibke Reinhard and {LifeLines Cohort Study}",
year = "2019",
month = dec,
day = "5",
doi = "10.1172/jci.insight.131156",
language = "English",
volume = "4",
journal = "JCI INSIGHT",
issn = "2379-3708",
publisher = "The American Society for Clinical Investigation",
number = "23",

}

RIS

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 -