KCND3 potassium channel gene variant confers susceptibility to electrocardiographic early repolarization pattern Alexander Teumer, … , Elijah R. Behr, Wibke Reinhard JCI Insight. 2019. https://doi.org/10.1172/jci.insight.131156. Clinical Medicine In-Press Preview Cardiology Genetics Graphical abstract Find the latest version: https://jci.me/131156/pdf 1 KCND3 potassium channel gene variant confers susceptibility to 2 electrocardiographic early repolarization pattern 3 Alexander Teumer1,2*, Teresa Trenkwalder3*, Thorsten Kessler3, Yalda Jamshidi4, Marten E. van den 4 Berg5, Bernhard Kaess6, Christopher P. Nelson7,8, Rachel Bastiaenen9, Marzia De Bortoli10, 5 Alessandra Rossini10, Isabel Deisenhofer3, Klaus Stark11, Solmaz Assa12, Peter S. Braund7,8, Claudia 6 Cabrera13,14,15, Anna F. Dominiczak16, Martin Gögele10, Leanne M. Hall7,8, M. Arfan Ikram5, Maryam 7 Kavousi5, Karl J. Lackner17,18, Lifelines Cohort Study19, Christian Müller20, Thomas Münzel18,21, 8 Matthias Nauck2,22, Sandosh Padmanabhan16, Norbert Pfeiffer23, Tim D. Spector24, Andre G. 9 Uitterlinden5, Niek Verweij12, Uwe Völker2,25, Helen R. Warren13,14, Mobeen Zafar12, Stephan B. 10 Felix2,26, Jan A. Kors27, Harold Snieder28, Patricia B. Munroe13,14, Cristian Pattaro10, Christian 11 Fuchsberger10, Georg Schmidt29,30, Ilja M. Nolte28, Heribert Schunkert3,30, Peter Pramstaller10, Philipp 12 S. Wild31, Pim van der Harst12, Bruno H. Stricker5, Renate B. Schnabel20, Nilesh J. Samani7,8, 13 Christian Hengstenberg32, Marcus Dörr2,26, Elijah R. Behr33, Wibke Reinhard3 14 15 16 1 Institute for Community Medicine, University Medicine Greifswald, Germany 17 2 DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany 18 3 Klinik für Herz- und Kreislauferkrankungen, Deutsches Herzzentrum München, School of Medicine, 19 Technical University of Munich, Munich, Germany 20 4 Genetics Research Centre, Institute of Molecular and Clinical Sciences, St George's University of 21 London, United Kingdom 22 5 Department of Epidemiology, Erasmus MC - University Medical Center Rotterdam, The Netherlands 23 6 Medizinische Klinik I, St. Josefs-Hospital, Wiesbaden, Germany 24 7 Department of Cardiovascular Sciences, Cardiovascular Research Centre, Leicester, Leicester, 25 United Kingdom 26 8 NIHR Leicester Biomedical Research Centre University of Leicester, Leicester, United Kingdom 27 9 Cardiology Clinial Academic Group, Institute of Molecular and Clinical Sciences, St George's, 28 University of London, United Kingdom 29 10 Institute for Biomedicine, Eurac Research, affiliated with the University of Lübeck, Bolzano, Italy 30 11 Department of Genetic Epidemiology, University Regensburg, Germany 31 12 Department of Cardiology, University of Groningen, University Medical Center Groningen, The 32 Netherlands 33 13 Clinical Pharmacology, William Harvey Research Institute, Barts and The London, Queen Mary 34 University of London, London, UK 35 14 NIHR Barts Cardiovascular Biomedical Research Centre, Barts and The London School of 36 Medicine and Dentistry, Queen Mary University of London, London, UK 37 15 Centre for Translational Bioinformatics, William Harvey Research Institute, Barts and the London 38 School of Medicine and Dentistry, Charterhouse Square, London, UK 39 16 Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, 40 University of Glasgow, Glasgow, Scotland, UK 41 17 Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of the Johannes 42 Gutenberg-University Mainz, Mainz, Germany 43 18 German Center for Cardiovascular Research (DZHK), partner site RhineMain, Mainz, Germany 44 19 The list of the Lifelines Cohort Study group authors is provided in the study acknowledgments 45 20 Department of General and Interventional Cardiology, University Heart Center Hamburg- 46 Eppendorf, Germany, DZHK (German Center for Cardiovascular Research), partner site 47 Hamburg/Kiel/Lübeck, Germany 48 21 Center for Cardiology - Cardiology I, University Medical Center of the Johannes Gutenberg- 49 University Mainz, Mainz, Germany 50 22 Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, 51 Greifswald, Germany 52 23 Department of Ophthalmology, University Medical Center of the Johannes Gutenberg-University 53 Mainz, Mainz, Germany 54 24 Department of Twin Research and Genetic Epidemiology, King’s College London, London, UK 55 25 Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, 56 Greifswald, Germany 57 26 Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany 58 27 Department of Medical Informatics, Erasmus MC - University Medical Center Rotterdam, The 59 Netherlands 1 60 28 Department of Epidemiology, University of Groningen, University Medical Center Groningen, 61 Groningen, The Netherlands 62 29 Innere Medizin I, Klinikum rechts der Isar, Technical University Munich, Munich, Germany 63 30 Deutsches Zentrum für Herz- und Kreislauf-Forschung (DZHK) e.V. (German Center for 64 Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany 65 31 Preventive Cardiology and Preventive Medicine, Center for Cardiology, University Medical Center 66 of the Johannes Gutenberg-University Mainz, Mainz, Germany; Center for Thrombosis and 67 Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, 68 Germany; DZHK (German Center for Cardiovascular Research), partner site Rhine-Main, Mainz, 69 Germany 70 32 Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, 71 Austria 72 33 Cardiology Clinical Academic Group, Institute of Molecular and Clinical Sciences, St George's, 73 University of London, United Kingdom AND St George's University Hospitals NHS Foundation Trust, 74 London, United Kingdom 75 76 * These authors contributed equally to this work. 77 78 Corresponding Author: 79 PD Dr. med. Wibke Reinhard 80 Klinik für Herz- und Kreislauferkrankungen 81 Deutsches Herzzentrum München, Technische Universität München 82 Lazarettstrasse 36 83 80636 München 84 Germany 85 tel: +49 89 1218 4025 86 email: [email protected] 87 88 89 2 90 Abstract 91 Background. The presence of an early repolarization pattern (ERP) on the surface electrocardiogram 92 (ECG) is associated with risk of ventricular fibrillation and sudden cardiac death. Family studies have 93 shown that ERP is a highly heritable trait but molecular genetic determinants are unknown. 94 Methods. To identify genetic susceptibility loci for ERP, we performed a GWAS and meta-analysis in 95 2,181 cases and 23,641 controls of European ancestry. 96 Results. We identified a genome-wide significant (p<5E-8) locus in the KCND3 (potassium voltage 97 gated channel subfamily D member 3) gene that was successfully replicated in additional 1,124 cases 98 and 12,510 controls. A subsequent joint meta-analysis of the discovery and replication cohorts 99 identified rs1545300 as the lead SNP at the KCND3 locus (OR 0.82 per minor T allele, p=7.7E-12), 100 but did not reveal additional loci. Co-localization analyses indicate causal effects of KCND3 gene 101 expression levels on ERP in both cardiac left ventricle and tibial artery. 102 Conclusions. In this study we identified for the first time a genome-wide significant association of a 103 genetic variant with ERP. Our findings of a locus in the KCND3 gene not only provide insights into the 104 genetic determinants but also into the pathophysiological mechanism of ERP, discovering a promising 105 candidate for functional studies. 106 Funding. For detailed information per study, see Acknowledgments. 3 107 Introduction 108 The early repolarization pattern (ERP) is a common ECG finding characterized by an elevation at the 109 QRS-ST junction (J-point) of at least 0.1 mV in two adjacent ECG leads. The prevalence of ERP in the 110 general population ranges from 2 to 13% being more common in young athletic men(1–5). The 111 classical notion of ERP being a benign ECG phenotype was challenged in 2008 by the landmark study 112 of Haissaguerre and colleagues showing an association of ERP with increased risk of ventricular 113 fibrillation and sudden cardiac death(6): the Early Repolarization Syndrome (ERS)(7). Since then 114 several studies demonstrated an elevated risk of cardiovascular and all-cause mortality in individuals 115 with ERP underscoring its arrhythmogenic potential(2, 8, 9). Although the mechanistic basis for 116 malignant arrhythmias in ERS is unclear, it has been suggested that they occur as a result of an 117 augmented transmural electrical dispersion of repolarization(10). Ex vivo studies point towards a 118 central role of the cardiac transient outward potassium current (Ito) in the development of both, ERP 119 and ERS(11). Furthermore, candidate genetic association studies have highlighted a role for several 120 genes encoding cardiac ion channels in the development of ERP and ERS(12–15). These genes 121 include gain-of-function variants in IK-ATP channels (KCNJ8, ABCC9) and loss-of-function variants in 122 cardiac L-type calcium channels (CACNA1C, CACNB2b, CACNA2D1) and sodium channels (SCN5A, 123 SCN10A)(16). Interestingly, co-existence of two genetic variants in different ion channel genes with 124 opposing effects can be observed leading to phenotypic incomplete penetrance of ERP(15). However, 125 data from functional studies confirming causality are scarce(17). 126 Studies among relatives of sudden arrhythmic