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

Lifelines Cohort Study; 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 Gogele; Leanne M. Hall; M. Arfan Ikram; Maryam Kavousi; Karl J. Lackner; Christian Mueller; Thomas Muenzel; Matthias Nauck; Sandosh Padmanabhan; Norbert Pfeiffer; Tim D. Spector; Andre G. Uitterlinden; Niek Verweij; Uwe Voelker; 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 Doerr; Elijah R. Behr

doi:10.1172/jci.insight.131156

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

Lifelines Cohort Study, 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 Gogele, Leanne M. Hall, M. Arfan IkramMaryam Kavousi, Karl J. Lackner, Christian Mueller, Thomas Muenzel, Matthias Nauck, Sandosh Padmanabhan, Norbert Pfeiffer, Tim D. Spector, Andre G. Uitterlinden, Niek Verweij, Uwe Voelker, 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 Doerr, Elijah R. Behr

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Abstract

BACKGROUND. The 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.

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 <5 x 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 x 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.

CONCLUSIONS. In 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.

Original language	English
Article number	131156
Number of pages	14
Journal	JCI Insight
Volume	4
Issue number	23
Early online date	2019
DOIs	https://doi.org/10.1172/jci.insight.131156
Publication status	Published - 5-Dec-2019

Keywords

GENOME-WIDE ASSOCIATION
CORONARY-ARTERY-DISEASE
J-POINT ELEVATION
VENTRICULAR-FIBRILLATION
METAANALYSIS
MUTATION
S422L
GWAS

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Lifelines Cohort Study, 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., Gogele, M., Hall, L. M., ... Behr, E. R. (2019). KCND3 potassium channel gene variant confers susceptibility to electrocardiographic early repolarization pattern. JCI Insight, 4(23), Article 131156. https://doi.org/10.1172/jci.insight.131156

@article{f381dbd6a8844b57ad58b6fa7d504694,

title = "KCND3 potassium channel gene variant confers susceptibility to electrocardiographic early repolarization pattern",

abstract = "BACKGROUND. The 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.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 <5 x 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 x 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.CONCLUSIONS. In 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.",

keywords = "GENOME-WIDE ASSOCIATION, CORONARY-ARTERY-DISEASE, J-POINT ELEVATION, VENTRICULAR-FIBRILLATION, METAANALYSIS, MUTATION, S422L, GWAS",

author = "{Lifelines Cohort Study} and 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 Gogele and Hall, {Leanne M.} and Ikram, {M. Arfan} and Maryam Kavousi and Lackner, {Karl J.} and Christian Mueller and Thomas Muenzel and Matthias Nauck and Sandosh Padmanabhan and Norbert Pfeiffer and Spector, {Tim D.} and Uitterlinden, {Andre G.} and Niek Verweij and Uwe Voelker 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 Doerr and Behr, {Elijah R.}",

year = "2019",

month = dec,

day = "5",

doi = "10.1172/jci.insight.131156",

language = "English",

volume = "4",

journal = "JCI Insight",

issn = "2379-3708",

publisher = "AMER SOC CLINICAL INVESTIGATION INC",

number = "23",

}

Lifelines Cohort Study, 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, Gogele, M, Hall, LM, Ikram, MA, Kavousi, M, Lackner, KJ, Mueller, C, Muenzel, T, Nauck, M, Padmanabhan, S, Pfeiffer, N, Spector, TD, Uitterlinden, AG, Verweij, N, Voelker, 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, Doerr, M & Behr, ER 2019, 'KCND3 potassium channel gene variant confers susceptibility to electrocardiographic early repolarization pattern', JCI Insight, vol. 4, no. 23, 131156. https://doi.org/10.1172/jci.insight.131156

TY - JOUR

T1 - KCND3 potassium channel gene variant confers susceptibility to electrocardiographic early repolarization pattern

AU - Lifelines Cohort Study

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 - Gogele, Martin

AU - Hall, Leanne M.

AU - Ikram, M. Arfan

AU - Kavousi, Maryam

AU - Lackner, Karl J.

AU - Mueller, Christian

AU - Muenzel, Thomas

AU - Nauck, Matthias

AU - Padmanabhan, Sandosh

AU - Pfeiffer, Norbert

AU - Spector, Tim D.

AU - Uitterlinden, Andre G.

AU - Verweij, Niek

AU - Voelker, 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 - Doerr, Marcus

AU - Behr, Elijah R.

PY - 2019/12/5

Y1 - 2019/12/5

N2 - BACKGROUND. The 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.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 <5 x 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 x 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.CONCLUSIONS. In 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.

AB - BACKGROUND. The 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.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 <5 x 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 x 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.CONCLUSIONS. In 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.

KW - GENOME-WIDE ASSOCIATION

KW - CORONARY-ARTERY-DISEASE

KW - J-POINT ELEVATION

KW - VENTRICULAR-FIBRILLATION

KW - METAANALYSIS

KW - MUTATION

KW - S422L

KW - GWAS

U2 - 10.1172/jci.insight.131156

DO - 10.1172/jci.insight.131156

M3 - Article

C2 - 31600170

SN - 2379-3708

VL - 4

JO - JCI Insight

JF - JCI Insight

IS - 23

M1 - 131156

ER -

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

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Keywords

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