PLoS Genetics: Identification of a Sudden Cardiac Death Susceptibility Locus at 2q24.2 through Genome-Wide Association in European Ancestry Individuals

full-text ►PLoS Genetics: Identification of a Sudden Cardiac Death Susceptibility Locus at 2q24.2 through Genome-Wide Association in European Ancestry Individuals: "Identification of a Sudden Cardiac Death Susceptibility Locus at 2q24.2 through Genome-Wide Association in European Ancestry Individuals

Family studies have clearly demonstrated a role for genes in modifying risk for sudden cardiac death (SCD), however genetic studies have been limited by available samples. Here we have assembled over 4,400 SCD cases with >30,000 controls, all of European ancestry, and utilize a two-stage study design. In the first stage, we conducted an unbiased genome-wide scan in 1,283 SCD cases and >20,000 controls, and then performed follow-up genotyping in the remainder of the samples. We demonstrate strong association to a region of the genome not previously implicated in SCD, the BAZ2B locus, which contains 3 genes not previously known to play a role in cardiac biology. In addition, we used the genome-wide scan data to test a focused hypothesis that genetic variants that modulate ECG traits associated with SCD (QT, QRS, and RR intervals) also modify risk for SCD, and we demonstrate that QT- and QRS-prolonging alleles are, as a group, associated with increased risk of SCD. Taken together, these findings begin to elucidate the genetic contribution to SCD susceptibility and provide important targets for functional studies to investigate the etiology and pathogenesis of SCD.

Dan E. Arking1#*, M. Juhani Junttila2,3#, Philippe Goyette4#, Adriana Huertas-Vazquez5#, Mark Eijgelsheim6#, Marieke T. Blom7#, Christopher Newton-Cheh8,9,10#, Kyndaron Reinier5, Carmen Teodorescu5, Audrey Uy-Evanado5, Naima Carter-Monroe11, Kari S. Kaikkonen2, Marja-Leena Kortelainen2, Gabrielle Boucher4, Caroline Lagacé4, Anna Moes1, XiaoQing Zhao11, Frank Kolodgie11, Fernando Rivadeneira6,12,13, Albert Hofman6,13, Jacqueline C. M. Witteman6,13, André G. Uitterlinden6,12,13, Roos F. Marsman7, Raha Pazoki7, Abdennasser Bardai7, Rudolph W. Koster7, Abbas Dehghan6, Shih-Jen Hwang10, Pallav Bhatnagar1, Wendy Post14, Gina Hilton1, Ronald J. Prineas15, Man Li16, Anna Köttgen16, Georg Ehret1,17, Eric Boerwinkle18, Josef Coresh16,19, W. H. Linda Kao16, Bruce M. Psaty20,21, Gordon F. Tomaselli14, Nona Sotoodehnia22, David S. Siscovick20, Greg L. Burke15, Eduardo Marbán5, Peter M. Spooner14, L. Adrienne Cupples10,23, Jonathan Jui24, Karen Gunson25, Y. Antero Kesäniemi2,26, Arthur A. M. Wilde7, Jean-Claude Tardif4, Christopher J. O'Donnell10,27, Connie R. Bezzina7, Renu Virmani11, Bruno H. C. h. Stricker6,12,13,28,29¶, Hanno L. Tan7¶, Christine M. Albert30¶, Aravinda Chakravarti1¶, John D. Rioux4¶, Heikki V. Huikuri2¶, Sumeet S. Chugh5*

1 McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America, 2 Institute of Clinical Medicine, Department of Internal Medicine, University of Oulu, Oulu, Finland, 3 Division of Cardiology, Miller School of Medicine, University of Miami, Miami, Florida, United States of America, 4 Montreal Heart Institute and the Université de Montréal, Montreal, Canada, 5 The Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America, 6 Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands, 7 Heart Failure Research Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, 8 Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America, 9 Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, United States of America, 10 Framingham Heart Study, National Heart, Lung, and Blood Institute, National Institutes of Health, Framingham, Massachusetts, United States of America, 11 CVPath Institute, Gaithersburg, Maryland, United States of America, 12 Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands, 13 Netherlands Consortium for Healthy Aging (NCHA), Netherlands Genomic Initiative (NGI), Rotterdam, The Netherlands, 14 Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America, 15 Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America, 16 Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland, United States of America, 17 Cardiology, Department of Medicine, Geneva University Hospital, Geneva, Switzerland, 18 University of Texas Health Science Center at Houston, Houston, Texas, United States of America, 19 Departments of Medicine and Biostatistics, Johns Hopkins University, Baltimore, Maryland, United States of America, 20 Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology, University of Washington, Seattle, Washington, United States of America, 21 Group Health Research Institute, Group Health Cooperative, Seattle, Washington, United States of America, 22 Cardiovascular Health Research Unit, Division of Cardiology, Department of Medicine, University of Washington, Seattle, Washington, United States of America, 23 Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America, 24 Department of Emergency Medicine, Oregon Health and Science University, Portland, Oregon, United States of America, 25 Department of Pathology, Oregon Health and Science University, Portland, Oregon, United States of America, 26 Biocenter Oulu, University of Oulu, Oulu, Finland, 27 National Heart, Lung, and Blood Institute, Bethesda, Maryland, United States of America, 28 Department of Medical Informatics, Erasmus MC, Rotterdam, The Netherlands, 29 Inspectorate of Health Care, The Hague, The Netherlands, 30 Center for Arrhythmia Prevention, Division of Preventive Medicine, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America


Abstract

Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000–300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10−10). The risk allele, while ancestral, has a frequency of ~1.4%, suggesting strong negative selection and increases risk for SCD by 1.92–fold per allele (95% CI 1.57–2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006).

Author Summary Top

Family studies have clearly demonstrated a role for genes in modifying risk for sudden cardiac death (SCD), however genetic studies have been limited by available samples. Here we have assembled over 4,400 SCD cases with >30,000 controls, all of European ancestry, and utilize a two-stage study design. In the first stage, we conducted an unbiased genome-wide scan in 1,283 SCD cases and >20,000 controls, and then performed follow-up genotyping in the remainder of the samples. We demonstrate strong association to a region of the genome not previously implicated in SCD, the BAZ2B locus, which contains 3 genes not previously known to play a role in cardiac biology. In addition, we used the genome-wide scan data to test a focused hypothesis that genetic variants that modulate ECG traits associated with SCD (QT, QRS, and RR intervals) also modify risk for SCD, and we demonstrate that QT- and QRS-prolonging alleles are, as a group, associated with increased risk of SCD. Taken together, these findings begin to elucidate the genetic contribution to SCD susceptibility and provide important targets for functional studies to investigate the etiology and pathogenesis of SCD.

Citation: Arking DE, Junttila MJ, Goyette P, Huertas-Vazquez A, Eijgelsheim M, et al. (2011) Identification of a Sudden Cardiac Death Susceptibility Locus at 2q24.2 through Genome-Wide Association in European Ancestry Individuals. PLoS Genet 7(6): e1002158. doi:10.1371/journal.pgen.1002158

Editor: Mark I. McCarthy, University of Oxford, United Kingdom

Received: January 29, 2011; Accepted: May 11, 2011; Published: June 30, 2011

Copyright: © 2011 Arking et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: AGNES is supported by the Netherlands Heart Foundation (2001D019, 2003T302, 2007B202), the Leducq Foundation (05-CVD), and the Interuniversity Cardiology Institute of the Netherlands (project 27). ARIC is supported by NHLBI contracts N01-HC-55015, N01-HC-55016, N01-HC-55018 through N01-HC-55022, R01HL087641, R01HL59367, and R01HL086694; NHGRI contract U01HG004402; and NIH contract HHSN268200625226C. Infrastructure was partly supported by UL1RR025005. ARREST is supported by the Netherlands Organization for Scientific Research (Mozaiek 017.003.084, ZonMW Vici 918.86.616) and the Dutch Medicines Evaluation Board MEB/CBG. CHS is supported by N01-HC-80007, N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, U01 HL080295 from the NHLBI, with additional contribution from the NINDS. FHS is supported by the NHLBI and Boston University School of Medicine (N01-HC-25195), its contract with Affymetrix for genotyping services (N02-HL-6-4278), based on analyses by FHS investigators participating in the SHARe project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment at Boston University School of Medicine and Boston Medical Center. FinGesture is supported the Finnish academy of Science, Helsinki, Finland; Sigrid Juselius Foundation, Helsinki, Finland; and Foundation Leducq, Paris, France. The genetic work was supported by the Montreal Heart Institute Foundation (www.fondationicm.org). The Harvard Cohorts are supported by HL068070, HL-26490, HL-34595, HL-34594, HL-35464, HL-46959, HL-080467 (from the NHLBI); by CA-34944, CA 40360, CA55075, CA-87969, CA 97193 (from the NCI); and by a Career Award for Medical Scientists from the Burroughs Wellcome Fund. Oregon-SUDS is funded by the NHLIB (R01 HL105170-01, R01 HL088416, R01 HL088416-03S1 NIH NHLBI). The RS is funded by Erasmus Medical Center and Erasmus University, Rotterdam; Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); the Ministry of Education, Culture, and Science; the Ministry for Health, Welfare, and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. The GWA study was funded by the Netherlands Organization of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012), the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), and the Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) project nr. 050-060-810. This publication was made possible by Grant Number 1UL1RR025005 from the National Center for Research Resources (NCRR). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: AC is a paid member of the Scientific Advisory Board of Affymetrix, a role that is managed by the Committee on Conflict of Interest of the Johns Hopkins University School of Medicine.

* E-mail: arking@jhmi.edu (DEA); Sumeet.Chugh@cshs.org (SSC)

# These authors contributed equally to this work.

¶ These authors also contributed equally to this work.

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