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; Lifelines Cohort Study; 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

doi:10.1172/jci.insight.131156

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 KavousiKarl J. Lackner, Lifelines Cohort Study, 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

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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 × 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. 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	e131156
Journal	JCI Insight
Volume	4
Issue number	23
DOIs	https://doi.org/10.1172/jci.insight.131156
State	Published - 5 Dec 2019

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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., Arfan Ikram, M., ... Reinhard, W. (2019). KCND3 potassium channel gene variant confers susceptibility to electrocardiographic early repolarization pattern. JCI Insight, 4(23), Article e131156. https://doi.org/10.1172/jci.insight.131156

@article{5b46d31fdcb84383be9de46ee9b94136,

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 × 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. 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.",

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 {Arfan Ikram}, M. and Maryam Kavousi and Lackner, {Karl J.} and Study, {Lifelines Cohort} 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",

note = "Publisher Copyright: Copyright: {\textcopyright} 2019, Teumer et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.",

year = "2019",

month = dec,

day = "5",

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

language = "English",

volume = "4",

journal = "JCI Insight",

issn = "2379-3708",

publisher = "American Society for Clinical Investigation",

number = "23",

}

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, Arfan Ikram, M, Kavousi, M, Lackner, KJ, Study, LC, 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 2019, 'KCND3 potassium channel gene variant confers susceptibility to electrocardiographic early repolarization pattern', JCI Insight, vol. 4, no. 23, e131156. https://doi.org/10.1172/jci.insight.131156

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 - Arfan Ikram, M.

AU - Kavousi, Maryam

AU - Lackner, Karl J.

AU - Study, Lifelines Cohort

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

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 × 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. 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 × 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. 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.

UR - http://www.scopus.com/inward/record.url?scp=85078449379&partnerID=8YFLogxK

U2 - 10.1172/jci.insight.131156

DO - 10.1172/jci.insight.131156

M3 - Article

C2 - 31600170

AN - SCOPUS:85078449379

SN - 2379-3708

VL - 4

JO - JCI Insight

JF - JCI Insight

IS - 23

M1 - e131156

ER -

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

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