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

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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References

  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.) 933–974 (Elsevier, Oxford, UK, 2007).

  2. Huikuri, H.V., Castellanos, A. & Myerburg, R.J. Sudden death due to cardiac arrhythmias. N. Engl. J. Med. 345, 1473–1482 (2001).

    Article  CAS  Google Scholar 

  3. Arking, D.E., Chugh, S.S., Chakravarti, A. & Spooner, P.M. Genomics in sudden cardiac death. Circ. Res. 94, 712–723 (2004).

    Article  CAS  Google Scholar 

  4. Wilde, A.A. & Bezzina, C.R. Genetics of cardiac arrhythmias. Heart 91, 1352–1358 (2005).

    Article  CAS  Google Scholar 

  5. Watkins, H., Ashrafian, H. & McKenna, W.J. The genetics of hypertrophic cardiomyopathy: teare redux. Heart 94, 1264–1268 (2008).

    Article  CAS  Google Scholar 

  6. Zipes, D.P. & Wellens, H.J. Sudden cardiac death. Circulation 98, 2334–2351 (1998).

    Article  CAS  Google Scholar 

  7. Zipes, D.P. et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (writing committee to develop guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 114, e385–e484 (2006).

    Article  Google Scholar 

  8. Myerburg, R.J. Sudden cardiac death: exploring the limits of our knowledge. J. Cardiovasc. Electrophysiol. 12, 369–381 (2001).

    Article  CAS  Google Scholar 

  9. Noseworthy, P.A. & Newton-Cheh, C. Genetic determinants of sudden cardiac death. Circulation 118, 1854–1863 (2008).

    Article  Google Scholar 

  10. Myerburg, R.J. & Castellanos, A. Emerging paradigms of the epidemiology and demographics of sudden cardiac arrest. Heart Rhythm 3, 235–239 (2006).

    Article  Google Scholar 

  11. Friedlander, Y. et al. Family history as a risk factor for primary cardiac arrest. Circulation 97, 155–160 (1998).

    Article  CAS  Google Scholar 

  12. Jouven, X., Desnos, M., Guerot, C. & Ducimetiere, P. Predicting sudden death in the population: the Paris Prospective Study I. Circulation 99, 1978–1983 (1999).

    Article  CAS  Google Scholar 

  13. Dekker, L.R. et al. Familial sudden death is an important risk factor for primary ventricular fibrillation: a case-control study in acute myocardial infarction patients. Circulation 114, 1140–1145 (2006).

    Article  Google Scholar 

  14. Agema, W.R. et al. Current PTCA practice and clinical outcomes in The Netherlands: the real world in the pre-drug-eluting stent era. Eur. Heart J. 25, 1163–1170 (2004).

    Article  Google Scholar 

  15. Kleinjan, D.A. & van Heyningen, V. Long-range control of gene expression: emerging mechanisms and disruption in disease. Am. J. Hum. Genet. 76, 8–32 (2005).

    Article  CAS  Google Scholar 

  16. Bergelson, J.M. et al. Isolation of a common receptor for coxsackie B viruses and adenoviruses 2 and 5. Science 275, 1320–1323 (1997).

    Article  CAS  Google Scholar 

  17. Tomko, R.P., Xu, R. & Philipson, L. HCAR and MCAR: the human and mouse cellular receptors for subgroup C adenoviruses and group B coxsackieviruses. Proc. Natl. Acad. Sci. USA 94, 3352–3356 (1997).

    Article  CAS  Google Scholar 

  18. Bowles, N.E., Richardson, P.J., Olsen, E.G. & Archard, L.C. Detection of coxsackie-B-virus-specific RNA sequences in myocardial biopsy samples from patients with myocarditis and dilated cardiomyopathy. Lancet 1, 1120–1123 (1986).

    Article  CAS  Google Scholar 

  19. Pauschinger, M. et al. Detection of adenoviral genome in the myocardium of adult patients with idiopathic left ventricular dysfunction. Circulation 99, 1348–1354 (1999).

    Article  CAS  Google Scholar 

  20. Andréoletti, L. et al. Active coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction. J. Am. Coll. Cardiol. 50, 2207–2214 (2007).

    Article  Google Scholar 

  21. Lisewski, U. et al. The tight junction protein CAR regulates cardiac conduction and cell-cell communication. J. Exp. Med. 205, 2369–2379 (2008).

    Article  CAS  Google Scholar 

  22. Lim, B.K. et al. Coxsackievirus and adenovirus receptor (CAR) mediates atrioventricular-node function and connexin 45 localization in the murine heart. J. Clin. Invest. 118, 2758–2770 (2008).

    Article  CAS  Google Scholar 

  23. Yoshida, Y. et al. ANA, a novel member of Tob/BTG1 family, is expressed in the ventricular zone of the developing central nervous system. Oncogene 16, 2687–2693 (1998).

    Article  CAS  Google Scholar 

  24. Strausberg, R.L. et al. Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proc. Natl. Acad. Sci. USA 99, 16899–16903 (2002).

    Article  Google Scholar 

  25. Godbout, R., Andison, R., Katyal, S. & Bisgrove, D.A. Isolation of a novel cDNA enriched in the undifferentiated chick retina and lens. Dev. Dyn. 227, 409–415 (2003).

    Article  CAS  Google Scholar 

  26. Arking, D.E. et al. A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization. Nat. Genet. 38, 644–651 (2006).

    Article  CAS  Google Scholar 

  27. Newton-Cheh, C. et al. Common variants at ten loci influence QT interval duration in the QTGEN Study. Nat. Genet. 41, 399–406 (2009).

    Article  CAS  Google Scholar 

  28. Pfeufer, A. et al. Common variants at ten loci modulate the QT interval duration in the QTSCD Study. Nat. Genet. 41, 407–414 (2009).

    Article  CAS  Google Scholar 

  29. Kao, W.H. et al. Genetic variations in nitric oxide synthase 1 adaptor protein are associated with sudden cardiac death in US white community-based populations. Circulation 119, 940–951 (2009).

    Article  CAS  Google Scholar 

  30. Eijgelsheim, M. et al. Genetic variation in NOS1AP is associated with sudden cardiac death: evidence from the Rotterdam Study. Hum. Mol. Genet. 18, 4213–4218 (2009).

    Article  CAS  Google Scholar 

  31. Johnson, A.D. et al. SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap. Bioinformatics 24, 2938–2939 (2008).

    Article  CAS  Google Scholar 

  32. Sampietro, M.L. et al. A genome wide association analysis in the GENDER study. Neth. Heart J. 17, 262–264 (2009).

    Article  CAS  Google Scholar 

  33. Agyemang, C. et al. Prevalence, awareness, treatment, and control of hypertension among Black Surinamese, South Asian Surinamese and White Dutch in Amsterdam, The Netherlands: the SUNSET study. J. Hypertens. 23, 1971–1977 (2005).

    Article  CAS  Google Scholar 

  34. Li, Y. & Mach Abecasis, G.R. 1.0: Rapid haplotype reconstruction and missing genotype inference. Am. J. Hum. Genet. S79, 2290 (2006).

    Google Scholar 

  35. Aulchenko, Y.S., Ripke, S., Isaacs, A. & van Duijn, C.M. GenABEL: an R library for genome-wide association analysis. Bioinformatics 23, 1294–1296 (2007).

    Article  CAS  Google Scholar 

  36. Hoggart, C.J., Clark, T.G., De, I.M., Whittaker, J.C. & Balding, D.J. Genome-wide significance for dense SNP and resequencing data. Genet. Epidemiol. 32, 179–185 (2008).

    Article  Google Scholar 

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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.

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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.

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Correspondence to Connie R Bezzina.

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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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