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Genetic Variants Modulating Ventricular Fibrillation in the Setting of Myocardial Infarction

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Genetic Variants Modulating Ventricular Fibrillation in the Setting of Myocardial Infarction UvA-DARE (Digital Academic Repository) Subtle killers and sudden death: Genetic variants modulating ventricular fibrillation in the setting of myocardial infarction Pazoki, R. Publication date 2015 Document Version Final published version Link to publication Citation for published version (APA): Pazoki, R. (2015). Subtle killers and sudden death: Genetic variants modulating ventricular fibrillation in the setting of myocardial infarction. 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:28 Sep 2021 C hapter 5 Multiple genomic approaches for identifi cation of genetic modifi ers of ventricular fi brillation risk in the setting of acute myocardial infarction in the AGNES study Manuscript in preparation for submission Raha Pazoki, Lia Crotti, Reza Jabbari, Jonas S.S.G. de Jong, Nienke Bruinsma, Michiel E. Adriaens, Leander Beekman, Lukas R.C. Dekker, Anna M. Di Blasio, Jacob Tfelt-Hansen, Peter J. Schwartz, Gaetano M. De Ferrari, Arthur A.M. Wilde, Michael W.T. Tanck, Connie R. Bezzina 74 Chapter 5 Abstract Background: Sudden cardiac death (SCD) from ventricular fibrillation (VF) during acute myocardial infarction (MI) is a leading cause of total and cardiovascular mortality. Genetic factors underlying risk for VF in the setting of acute MI remain largely unknown. We previously started exploring the role of common genetic variants in modulation of VF risk in acute MI by a genome-wide association study (GWAS) in the AGNES popula- tion, consisting of Dutch individuals with a first acute MI, where cases suffered VF and controls not. The aim of the current study was to carry out GWAS in an extended set of AGNES patients to identify additional susceptibility loci and to overlay this GWAS data with other genomic data in an effort to identify loci modulating risk of VF in this setting. Methods: In total, 1433 AGNES patients with a first acute MI (672 cases, 761 controls) were analyzed by GWAS. We sought to replicate SNPs displaying association P-values < 1 × 10−5 in two additional independent but similar case-control sets, namely PREDES- TINATION and GEVAMI, recruited in Italy and Denmark, respectively. We additionally reviewed literature to find SNPs previously implicated in SCD and investigated their association with VF in the AGNES study. In an effort to identify candidate causal genes at associating loci, the most strongly associating SNPs from the AGNES GWAS were searched in our human heart eQTL (expression quantitative trait locus) database and in publicly available heart and blood eQTL databases in order to investigate whether any of these SNPs could be related to the expression of genes located in cis. In a reverse approach, we selected previously-identified eQTLs from the human heart eQTL da- tabases (representing putatively functional SNPs) and investigated their association with VF in the AGNES sample. We additionally performed pathway analysis on the SNPs identified in the AGNES GWAS in an effort to identify biological mechanisms that may be involved in the occurrence of VF in the setting of MI. Results: rs2824292 remained as most-strongly and only genome-wide significant SNP associated with VF in the AGNES study (OR = 0.65; 95% CI: 0.56, 0.76; P = 2.75 × 10−8). Out of the 10 top independent AGNES SNPs, only rs1750041 (OR = 1.64; 95% CI: 1.09, 2.46; P = 0.02) was nominally significant in the PREDESTINATION study. This SNP was however not associated with VF in the GEVAMI case-control set. Our candidate SNP analysis in AGNES uncovered a nominal association with VF for rs6795970 in the SCN10A gene (OR = 0.85; 95% C.I: 0.73, 0.99; P = 0.02). Among the 10 most-strongly associated SNPs in the AGNES GWAS, rs1750041 and rs10096381 displayed eQTL ef- fects with genes in cis. in peripheral blood. In the reverse approach, we uncovered that rs6982308 (an eQTL SNP that controls the expression of XPR6 in human heart) increased the risk of VF by 1.58 fold (95% CI: 1.28, 1.94; P = 1.8 × 10−5). Pathway analysis showed that VF-associated genes from the current study are enriched in pathways mainly involved in signal transmission. Multiple genomic approaches to identify genetic susceptibility to VF in MI 75 Conclusion: Using several integrated approaches, we highlighted several SNPs (i.e. rs2824292, rs1750041, rs10096381, rs6982308, and rs6795970) that merit further analy- sis in future studies. We also highlighted several pathways that connected together to possibly form a larger relevant biological mechanisms for risk of VF in the setting of MI. Chapter 5 76 Chapter 5 Introduction Sudden cardiac death (SCD) accounts for 20% of total mortality and up to 50% of cardiovascular mortality among adults in Western Societies 1,2. Ventricular fibrillation (VF) is the most common cardiac arrhythmia underlying SCD 3. SCD in the general population occurs in individuals with an average age of 65 years 4 who have complex disease stemming from multiple common acquired disorders, especially coronary artery disease (CAD) or associated conditions such as myocardial ischemia, infarction (MI), post-MI myocardial scarring, and ischemic cardiomyopa- thy 3. While multiple studies have provided evidence for a heritable component in the determination of SCD risk in these settings 5-8, the identification of genetic risk factors has only recently started to be explored and progress has been slow 9-11. Difficulties in gene identification are hindered by a number of factors, amongst which are the paucity of patients that are available for genetic studies and the likely complex under- lying genetic architecture of SCD. While as for other complex phenotypes, the genetic architecture of SCD susceptibility is unknown, SCD in the individual patient is likely governed by the cumulative effect of a broad spectrum of inherited genetic variants that occur at different frequencies in the general population and that carry different effect sizes on risk for SCD 1. Molecular mechanism underlying SCD may differ between different cardiac pathologies and gene identification efforts are therefore likely to benefit from a deep characterization of the cardiac condition in which SCD occurs as this allows the identification of different disease sub-groups for genetic studies. In the last years, our group has been focused on the identification of genetic factors modulating risk of VF in the setting of a first acute MI 5,9,12. To this aim we established the Arrhythmia Genetics in the NEtherlandS (AGNES) study, consisting of patients with a first acute ST-segment elevation MI presenting with VF (ECG-documented; cases) and without VF (controls) 5. In this case-control set we established that family history of sudden death is a risk factor for VF 5, providing a strong rationale for the exploration of genetic factors modulating risk of VF. Subsequently, through a genome-wide association study (GWAS) for common genetic variants in this case-control set, we identified the first susceptibility locus at chromosome (chr.) 21q21 9. The aim of the current study was to identify additional VF susceptibility loci by (1) conducting GWAS in an extended set of AGNES, (2) testing the role of expression quantitative trait loci (eQTL), and (3) implementing a pathway-based analysis. Multiple genomic approaches to identify genetic susceptibility to VF in MI 77 Methods Patient samples The AGNES sample: The AGNES case-control set has been described in detail previ- ously 5,9. In brief, it consists of cases that survived to hospital admission and had ECG- registered VF that occurred within 24 hours after the onset of symptoms and before reperfusion therapy in the setting of an acute and first ST-segment elevation MI. The majority (89%) of the VF events occurred within the first 2 hours after the onset of the symptoms and 99% occurred in the first 12 hours. Controls were patients with a first acute ST-segment elevation MI without VF. Cases and controls (age > 18 and < 80 years 5) were recruited at seven heart centers in the Netherlands between 2001 and 2011. We excluded individuals with an actual non-ST-segment elevation MI, prior MI, congenital heart defects, known structural heart disease, severe co-morbidity, electrolyte disturbances, trauma at presentation, recent surgery, previous coronary artery bypass graft or use of class I and III antiarrhythmic drugs. Individuals who developed VF during or after percutaneous coronary intervention were not eligible. Furthermore, because early reperfusion limits the odds of developing VF, potential control subjects undergoing percutaneous coronary intervention within 2 hours after onset of myocardial ischemia symptoms were not included. This time interval was based on the observation that a majority (> 90%) of cases develop VF within 2 hours after the onset of symptoms. Chapter 5 The study protocol was approved by the Institutional Review Board of the Aca- demic Medical Centre, University of Amsterdam, and was conducted according to the principles of the Declaration of Helsinki. The medical ethics committees of the hospi- tals participating in the study approved the study protocols, and all participants gave written informed consent.
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