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


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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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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Authors and Affiliations



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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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).

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