Annalisa Milano1, Marieke T Blom1, Elisabeth M Lodder1, Daniel A van Hoeijen1, Julien Barc1, Tamara T Koopmann1, Abdennasser Bardai1, Leander Beekman1, Peter Lichtner1, Maarten P van den Berg1, Arthur A M Wilde1, Connie R Bezzina2, Hanno L Tan2. 1. From the Department of Clinical & Experimental Cardiology, Heart Center, Amsterdam Medical Center, University of Amsterdam, Amsterdam, the Netherlands (A.M., M.T.B., E.M.L., D.A.v.H., J.B., T.T.K., A.B., L.B., A.A.M.W., C.R.B., H.L.T.); Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany; Institut für Humangenetik, Technische Universität München, Munich, Germany (P.L.); Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands (M.P.v.d.B.); and Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Kingdom of Saudi Arabia (A.A.M.W.). 2. From the Department of Clinical & Experimental Cardiology, Heart Center, Amsterdam Medical Center, University of Amsterdam, Amsterdam, the Netherlands (A.M., M.T.B., E.M.L., D.A.v.H., J.B., T.T.K., A.B., L.B., A.A.M.W., C.R.B., H.L.T.); Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany; Institut für Humangenetik, Technische Universität München, Munich, Germany (P.L.); Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands (M.P.v.d.B.); and Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Kingdom of Saudi Arabia (A.A.M.W.). h.l.tan@amc.nl c.r.bezzina@amc.nl.
Abstract
BACKGROUND: Sudden cardiac arrest (SCA) ranks among the most common causes of death worldwide. Because SCA is most often lethal, yet mostly occurs in individuals without previously known cardiac disease, the identification of patients at risk for SCA could save many lives. In unselected SCA victims from the community, common genetic variants (which are not disease-causing per se, but may increase susceptibility to ventricular fibrillation) are found to be associated with increased SCA risk. However, whether rare genetic variants contribute to SCA risk in the community is largely unexplored. METHODS AND RESULTS: We here investigated the involvement of rare genetic variants in SCA risk at the population level by studying the prevalence of 6 founder genetic variants present in the Dutch population (PLN-p.Arg14del, MYBPC3-p.Trp792fsX17, MYBPC3-p.Arg943X, MYBPC3-p.Pro955fsX95, PKP2-p.Arg79X, and the Chr7q36 idiopathic ventricular fibrillation risk haplotype) in a cohort of 1440 unselected Dutch SCA victims included in the Amsterdam Resuscitation Study (ARREST). The six studied founder mutations were found to be more prevalent (1.1%) in the ARREST SCA cohort compared with an ethnically and geographically matched set of controls (0.4%, n=1379; P<0.05) or a set of Dutch individuals drawn from the Genome of the Netherlands (GoNL) study (0%, n=500; P<0.02). CONCLUSIONS: This finding provides proof-of-concept for the notion that rare genetic variants contribute to some extent to SCA risk in the community.
BACKGROUND:Sudden cardiac arrest (SCA) ranks among the most common causes of death worldwide. Because SCA is most often lethal, yet mostly occurs in individuals without previously known cardiac disease, the identification of patients at risk for SCA could save many lives. In unselected SCA victims from the community, common genetic variants (which are not disease-causing per se, but may increase susceptibility to ventricular fibrillation) are found to be associated with increased SCA risk. However, whether rare genetic variants contribute to SCA risk in the community is largely unexplored. METHODS AND RESULTS: We here investigated the involvement of rare genetic variants in SCA risk at the population level by studying the prevalence of 6 founder genetic variants present in the Dutch population (PLN-p.Arg14del, MYBPC3-p.Trp792fsX17, MYBPC3-p.Arg943X, MYBPC3-p.Pro955fsX95, PKP2-p.Arg79X, and the Chr7q36 idiopathic ventricular fibrillation risk haplotype) in a cohort of 1440 unselected Dutch SCA victims included in the Amsterdam Resuscitation Study (ARREST). The six studied founder mutations were found to be more prevalent (1.1%) in the ARREST SCA cohort compared with an ethnically and geographically matched set of controls (0.4%, n=1379; P<0.05) or a set of Dutch individuals drawn from the Genome of the Netherlands (GoNL) study (0%, n=500; P<0.02). CONCLUSIONS: This finding provides proof-of-concept for the notion that rare genetic variants contribute to some extent to SCA risk in the community.
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