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Uva-DARE (Digital Academic Repository) UvA-DARE (Digital Academic Repository) Genetic modifiers in familial cardiac rhythm disorders Kolder, I.C.R.M. Publication date 2012 Document Version Final published version Link to publication Citation for published version (APA): Kolder, I. C. R. M. (2012). Genetic modifiers in familial cardiac rhythm disorders. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) Download date:01 Oct 2021 Genetic modifiers in familial cardiac rhythm disorders -Iris Kolder - © 2012 by Iris Kolder Genetic modifiers in familial cardiac rhythm disorders Iris C.R.M. Kolder / University of Amsterdam, 2012. Thesis Printed by Ipskamp Drukkers B.V. Cover design: Manuel Van Der Graaf ISBN: 978-94-6191-336-4 No part of this thesis may be reproduced, stored in a retrieval system, or transmitted in any form or by any means without permission of the author Genetic modifiers in familial cardiac rhythm disorders ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad van doctor aan de Universiteit van Amsterdam op gezag van de Rector Magnificus prof. dr. D.C. van den Boom ten overstaan van een door het college voor promoties ingestelde commissie, in het openbaar te verdedigen in de Aula der Universiteit. op Vrijdag 29 Juni 2012, te 13:00 uur door Iris Cornelia Roelofje Martine Kolder geboren te Leiden Promotor: Prof. Dr. A.A.M. Wilde en Prof. Dr. A.H. Zwinderman Copromotor: Prof. Dr. C.R. Bezzina en Dr. M.W.T. Tanck Overige leden: Prof. Dr. F. Baas Prof.Dr. R.N.W. Hauer Prof. Dr. J.J.P. Kastelein Prof. Dr. H. Meijers-Heijboer Dr. M.M.A.M. Mannens Dr. J.J. Schott Faculteit der Geneeskunde The research described in this thesis was carried out in the department of Clinical Epidemiology, Biostatistics and Bioinformatics & The Heart Failure Research Center of the Academic Medical Center, Amsterdam. Financial support by the Dutch Heart Foundation for the publication of this thesis is gratefully acknowledged. Additional financial support was generously supplied by Stichting tot Bevordering van de Klinische Epidemiologie Amsterdam; Heart Failure Research Center; Bayer B.V.; Merck Sharpe & Dohme B.V. and the University of Amsterdam Para mis padres Voor mijn ouders Content Chapter 1 General introduction 9 Chapter 2 Common genetic variation modulating cardiac 15 ECG parameters and susceptibility to Sudden cardiac death Chapter 3 The role of renin-angiotensin-aldosterone system 45 polymorphisms in phenotypic expression of MYBPC3-related hypertrophic cardiomyopathy Chapter 4 Genetic Modifiers of disease expression in 61 patients with Long QT Syndrome Type 2 Chapter 5 Identification of RCAN1 as a Genetic Modifier 79 of Atrio-Ventricular Conduction in the Setting of Cardiac Sodium Channel Disease Chapter 6 Family-based genome-wide association analysis 105 for the identification of genetic modifiers of heart rate and electrocardiographic indices of conduction and repolarization in a large Dutch family with a mutation in SCN5A Chapter 7 General discussion and future perspective 131 Summary 139 Samenvatting 145 Dankwoord 151 Chapter 1 General introduction Chapter 1 Introduction Sudden cardiac death (SCD) is one of the most prevalent causes of death in Western societies. It underlies 20% of total mortality, and 50% of cardiovascular mortality 1. In young individuals (below 40 years of age) SCD often occurs in the setting of disorders displaying Mendelian inheritance 2, with the cardiomyopathies 3 and primary electrical disorders 4 being the most prevalent. Here, the inheritance of very rare genetic variants with large effects potentially increases risk for SCD substantially5. The primary electrical disorders have been linked primarily to mutations in genes encoding ion channel subunits or their interacting proteins (Figure 1)4. On the other hand, the cardiomyopathies are caused by mutations affecting genes coding for the contractile apparatus and structural components of the cardiomyocyte such as the sarcomere and desmosomes 6 . Genotype-phenotype studies in these disorders have clearly established that they are not spared from the phenomena of reduced penetrance and variable expression typical of Mendelian diseases 7 . For instance, in the primary arrhythmia syndromes, extensive variability in clinical manifestations is often observed among family members carrying an identical ion channel gene mutation, with some individuals exhibiting overt abnormalities on the electrocardiogram (ECG) and suffering potentially fatal arrhythmias, whereas others do not display any ECG changes and do not develop rhythm disturbances throughout life. Probands and families with these Mendelian disorders, harboring known disease-causing mutations, likely provide a permissive, genetically sensitized setting for the identification of novel genes and pathways modulating cardiac (electrical) function. Focus of this dissertation In this thesis we employ the phenotypic variability evidenced among probands and their relatives with Mendelian cardiac disorders to identify genetic modifiers of disease expression. We focused on two distinct groups of disorders associated with increased risk of SCD, namely the primary electrical disorders (Long QT Syndrome, Brugada Syndrome, Conduction Disease) and hypertrophic cardiomyopathy (HCM). The aim of this thesis was to identify such genetic modifiers using both linkage and (family based) association analyses. Both a candidate SNP / gene approach as well as a genome-wide unbiased approach were used in the study of common genetic variants as possible modifiers of disease severity. In chapter 2, we reviewed the available literature on the genetic and allelic architecture of SCD. In this review we focused on the common genetic variation that has been recently identified through genome-wide association studies to modulate risk of SCD and 10 General introduction 1 FIGURE 1 | A schematic representation of a cardiomyocyte depicting genes encoding channel subunits and interacting proteins involved in the primary electrical disorders or in cardiac electrical function. to modulate heart rate and ECG indices of conduction (PR-interval, QRS-duration) and repolarization (QTc-interval) as intermediate phenotypes of SCD. In chapter 3 we investigated the role of five common candidate SNPs in the renin- angiotensin-aldosterone system in families with HCM who carried one of three functionally-equivalent mutations in the MYBPC3 gene. These SNPs were previously suggested to modify the extent of hypertrophy in HCM. In chapters 4-6, we focused on genetic modifiers of primary electrical disease. In chapter 4 we studied a large set of individuals (probands and, where available, their family- members) carrying a mutation in the KCNH2 gene and presenting clinically with Long QT syndrome type 2. Here we comprehensively investigated the effect of haplotype-tagging SNPs in and around 18 candidate genes on the QTc-interval. In this analysis, for the first time we took the effect ofKCNH2 mutation type and location in our analysis for modifiers of QTc-interval. In the last two chapters we studied a very large Dutch kindred with the SCN5A mutation 1795insD. An extensive genealogical search allowed us to trace this family back to the eighteenth century, enabling the construction of a highly extended pedigree. Individuals 11 Chapter 1 in this kindred present with manifestations of Long QT syndrome, Brugada syndrome and progressive conduction disease occurring either in isolation or in combinations thereof. In chapter 5, we performed linkage and association analysis with heart rate and ECG indices of conduction and repolarization using haplotype-tagging SNPs in and around 18 candidate genes. These genetic studies pointed us to the calcineurin/Nfat pathway as a possible modifier of the PR-interval in the setting of sodium channelopathy. We subsequently provided further insight into the possible role of this pathway by conducting a series of functional studies in mice that are knock-in for the homologousScn5a mutation (Scn5a1798insD/+ mice). Finally, we performed a genome-wide association study (GWAs) in this family (chapter6) uncovering novel interesting candidate genes that can provide insight into novel pathways regulating heart rate and the cardiac conduction and repolarization processes. 12 General introduction Reference List 1. Myerburg,R.J. & Castellanos,A. Cardiac arrest and sudden cardiac death. in Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine (eds. Libby,P., Bonow,R.O., Mann,D.L. & Zipes,D.P.) 933- 1 974 (Elsevier, Oxford, UK, 2007). 2. van der Werf,C., van Langen,I.M., & Wilde,A.A. Sudden death in the young: what do we know about it and how to prevent? Circ. Arrhythm. Electrophysiol. 3, 96-104 (2010). 3. Watkins,H., Ashrafian,H.,
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