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Genome-wide association study identifies a susceptibility locus at 21q21 for ventricular fibrillation in acute myocardial infarction

Nature Genetics volume 42, pages 688–691 (2010)Cite this article

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Abstract

Sudden cardiac death from ventricular fibrillation during acute myocardial infarction is a leading cause of total and cardiovascular mortality. To our knowledge, we here report the first genome-wide association study for this trait, conducted in a set of 972 individuals with a first acute myocardial infarction, 515 of whom had ventricular fibrillation and 457 of whom did not, from the Arrhythmia Genetics in The Netherlands (AGNES) study. The most significant association to ventricular fibrillation was found at 21q21 (rs2824292, odds ratio = 1.78, 95% CI 1.47–2.13, P = 3.3 × 10−10). The association of rs2824292 with ventricular fibrillation was replicated in an independent case-control set consisting of 146 out-of-hospital cardiac arrest individuals with myocardial infarction complicated by ventricular fibrillation and 391 individuals who survived a myocardial infarction (controls) (odds ratio = 1.49, 95% CI 1.14–1.95, P = 0.004). The closest gene to this SNP is CXADR, which encodes a viral receptor previously implicated in myocarditis and dilated cardiomyopathy and which has recently been identified as a modulator of cardiac conduction. This locus has not previously been implicated in arrhythmia susceptibility.

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Figure 1: Results of genome-wide association analysis in the AGNES case-control set.

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Acknowledgements

This study was supported by research grants from The Netherlands Heart Foundation (grants 2001D019, 2003T302 and 2007B202), the Leducq Foundation (grant 05-CVD), the Center for Translational Molecular Medicine (CTMM COHFAR) and the Interuniversity Cardiology Institute of The Netherlands (project 27). C.R.B. is an Established Investigator of The Netherlands Heart Foundation (grant 2005T024). H.L.T. is supported by The Netherlands Organization for Scientific Research (NWO, grant ZonMW Vici 918.86.616) and the Medicines Evaluation Board Netherlands (CBG). A.B. was supported by The Netherlands Organization for Scientific Research (NWO, grant Mozaiek 017.003.084). A.H. Zwinderman and E.P.A. van Iperen provided the genotype data from the GENDER study. We thank L. Beekman for technical support and N. Bruinsma for assistance in collection of subject data.

Author information

Author notes

  1. Connie R Bezzina, Raha Pazoki, Abdennasser Bardai, Roos F Marsman and Jonas S S G de Jong: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Experimental Cardiology, Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    Connie R Bezzina, Raha Pazoki, Abdennasser Bardai, Roos F Marsman, Marieke T Blom, Brendon P Scicluna, Hanno L Tan & Arthur A M Wilde

  2. Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    Raha Pazoki & Michael W T Tanck

  3. Department of Cardiology, Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    Jonas S S G de Jong, Navin R Bindraban, Lukas R C Dekker, Hanno L Tan & Arthur A M Wilde

  4. Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands

    J Wouter Jukema

  5. Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands

    J Wouter Jukema

  6. Department of Social Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    Navin R Bindraban

  7. Institute of Human Genetics, Klinikum Rechts der Isar Technische Universität München, Munich, Germany

    Peter Lichtner, Arne Pfeufer & Thomas Meitinger

  8. Institute of Human Genetics, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt, Neuherberg, Germany

    Arne Pfeufer & Thomas Meitinger

  9. Division of Cardiology, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA

    Nanette H Bishopric & Robert J Myerburg

  10. Department of Pediatrics, University of Miami Miller School of Medicine, Miami, Florida, USA

    Nanette H Bishopric

  11. Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida, USA

    Nanette H Bishopric

  12. Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA

    Dan M Roden

  13. The Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA

    Sumeet S Chugh

  14. Université Paris Descartes, Assistance Publique-Hopitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France

    Xavier Jouven

  15. Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany

    Stefan Kääb

  16. Department of Cardiology, Catharina Hospital, Eindhoven, The Netherlands

    Lukas R C Dekker

Authors
  1. Connie R Bezzina
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Contributions

C.R.B., A.A.M.W. and L.R.C.D. conceived the study. C.R.B. and A.A.M.W. supervised the study. L.R.C.D., J.S.S.G.d.J. and R.F.M. collected clinical data and DNA from the AGNES samples. A.B., M.T.B. and H.L.T. collected clinical data and DNA from the ARREST-MI samples. J.W.J. collected clinical data and DNA from the GENDER-MI samples. N.R.B. collected DNA from the Dutch European descent population sample. B.P.S., A.P., P.L. and T.M. performed the genome-wide genotyping. R.F.M. performed the genotyping in the replication case-control set and in the sample of the Dutch European descent population. R.P., A.P. and M.W.T.T. performed statistical analysis of the data. R.P. and M.W.T.T. carried out SNP imputation. C.R.B., R.P., S.S.C., S.K., X.J., R.J.M., D.M.R. and A.A.M.W. wrote the manuscript. C.R.B., A.A.M.W., D.M.R., N.H.B. and R.J.M. obtained funding for the study.

Corresponding author

Correspondence to Connie R Bezzina.

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Competing interests

C.R.B and A.A.M.W. have a pending patent application for the findings described in this work.

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Bezzina, C., Pazoki, R., Bardai, A. et al. Genome-wide association study identifies a susceptibility locus at 21q21 for ventricular fibrillation in acute myocardial infarction. Nat Genet 42, 688–691 (2010). https://doi.org/10.1038/ng.623

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