Letter | Published:

Common variants in KCNN3 are associated with lone atrial fibrillation

Nature Genetics volume 42, pages 240244 (2010) | Download Citation

Abstract

Atrial fibrillation (AF) is the most common sustained arrhythmia. Previous studies have identified several genetic loci associated with typical AF. We sought to identify common genetic variants underlying lone AF. This condition affects a subset of individuals without overt heart disease and with an increased heritability of AF. We report a meta-analysis of genome-wide association studies conducted using 1,335 individuals with lone AF (cases) and 12,844 unaffected individuals (referents). Cases were obtained from the German AF Network, Heart and Vascular Health Study, the Atherosclerosis Risk in Communities Study, the Cleveland Clinic and Massachusetts General Hospital. We identified an association on chromosome 1q21 to lone AF (rs13376333, adjusted odds ratio = 1.56; P = 6.3 × 10−12), and we replicated this association in two independent cohorts with lone AF (overall combined odds ratio = 1.52, 95% CI 1.40–1.64; P = 1.83 × 10−21). rs13376333 is intronic to KCNN3, which encodes a potassium channel protein involved in atrial repolarization.

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Acknowledgements

Acknowledgements are contained in the Supplementary Note.

Author information

Author notes

    • Georg B Ehret

    Present address: Cardiology Center, Geneva University Hospital, Geneva, Switzerland.

    • Patrick T Ellinor
    • , Kathryn L Lunetta
    • , Nicole L Glazer
    • , Arne Pfeufer
    • , Alvaro Alonso
    • , Mina K Chung
    • , Moritz F Sinner
    • , Jacqueline C M Witteman
    • , John Barnard
    • , Dan E Arking
    • , Emelia J Benjamin
    • , Susan R Heckbert
    •  & Stefan Kääb

    These authors contributed equally to this work.

Affiliations

  1. Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Patrick T Ellinor
    • , Steven A Lubitz
    • , Seiko Makino
    • , David J Milan
    •  & Christopher Newton-Cheh
  2. Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Patrick T Ellinor
    •  & David J Milan
  3. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Patrick T Ellinor
    •  & Christopher Newton-Cheh
  4. Department of Biostatistics, School of Public Health, Boston University, Boston, Massachusetts, USA.

    • Kathryn L Lunetta
    •  & Ke Wang
  5. National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA.

    • Kathryn L Lunetta
    • , Renate B Schnabel
    • , Thomas J Wang
    • , Ramachandran S Vasan
    •  & Emelia J Benjamin
  6. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.

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

    • 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 Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA.

    • Alvaro Alonso
  10. Department of Cardiovascular Medicine, Heart and Vascular Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.

    • Mina K Chung
    • , David R Van Wagoner
    •  & Stanley L Hazen
  11. Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany.

    • Moritz F Sinner
    • , Martina Mueller
    • , Britt-M Beckmann
    • , Gerhard Steinbeck
    •  & Stefan Kääb
  12. Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Paul I W de Bakker
  13. Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Paul I W de Bakker
    •  & Christopher Newton-Cheh
  14. Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

    • Martina Mueller
    •  & H-Erich Wichmann
  15. Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.

    • Martina Mueller
    •  & H-Erich Wichmann
  16. Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Steven A Lubitz
  17. Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA.

    • Ervin Fox
  18. Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

    • Dawood Darbar
  19. Department of Epidemiology, University of Washington, Seattle, Washington, USA.

    • Nicholas L Smith
    •  & Susan R Heckbert
  20. Seattle Epidemiologic Research and Information Center of the Department of Veterans Affairs Office of Research and Development, Seattle, Washington, USA.

    • Nicholas L Smith
  21. Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.

    • Jonathan D Smith
  22. Epidemiological Cardiology Research Center (EPICARE), Department of Epidemiology and Prevention, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.

    • Elsayed Z Soliman
  23. Department of Biostatistics, University of Washington, Seattle, Washington, USA.

    • Kenneth M Rice
  24. Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Charlotte van Noord
    • , Bruno H Ch Stricker
    • , Albert Hofman
    • , André G Uitterlinden
    •  & Jacqueline C M Witteman
  25. Dutch Medicines Evaluation Board, The Hague, The Netherlands.

    • Charlotte van Noord
  26. Netherlands Consortium on Healthy Aging (NCHA), Leiden, The Netherlands.

    • Charlotte van Noord
    • , Bruno H Ch Stricker
    • , Albert Hofman
    • , André G Uitterlinden
    •  & Jacqueline C M Witteman
  27. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Georg B Ehret
    • , Aravinda Chakravarti
    •  & Dan E Arking
  28. Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Jerome I Rotter
  29. Icelandic Heart Association, Kópavogur, Iceland.

    • Albert V Smith
    •  & Vilmundur Gudnason
  30. University of Iceland, Reykjavik, Iceland.

    • Albert V Smith
    •  & Vilmundur Gudnason
  31. Laboratory of Epidemiology, Demography and Biometry, Intramural Research Program, National Institute on Aging, Bethesda, Maryland, USA.

    • Lenore J Launer
    •  & Tamara B Harris
  32. Estonian Biocenter, Genotyping Core Facility, Tartu, Estonia.

    • Mari Nelis
    • , Tõnu Esko
    •  & Andres Metspalu
  33. Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.

    • Mari Nelis
    • , Tõnu Esko
    •  & Andres Metspalu
  34. Institute for Biological and Medical Imaging, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

    • Siegfried Perz
  35. Estonian Genome Center, University of Tartu, Tartu, Estonia.

    • Tõnu Esko
    •  & Andres Metspalu
  36. Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland, USA.

    • Anna Köttgen
    • , Man Li
    •  & W H Linda Kao
  37. Institute of Medical Informatics, Biometry and Epidemiology, University Duisburg-Essen, Essen, Germany.

    • Susanne Moebus
  38. Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Christopher Newton-Cheh
    •  & Thomas J Wang
  39. Department of Cardiology, West German Heart Center Essen, University Duisburg-Essen, Essen, Germany.

    • Stefan Möhlenkamp
  40. Section of Preventive Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.

    • Ramachandran S Vasan
  41. Section of Cardiology, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.

    • Ramachandran S Vasan
  42. Institute of Human Genetics, University of Bonn, Bonn, Germany.

    • Markus M Nöthen
  43. Department of Genomics, Life and Brain Center Bonn, Bonn, Germany.

    • Markus M Nöthen
  44. Cardiovascular Division, Brigham and Woman's Hospital, Boston, Massachusetts, USA.

    • Calum A MacRae
  45. Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Bruno H Ch Stricker
    •  & André G Uitterlinden
  46. Inspectorate for Health Care, The Hague, The Netherlands.

    • Bruno H Ch Stricker
  47. Department of Medical Informatics, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Bruno H Ch Stricker
  48. Center for Population Studies, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.

    • Daniel Levy
  49. Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, USA.

    • Eric Boerwinkle
  50. Institute for Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA.

    • Eric Boerwinkle
  51. Scripps Translational Science Institute, The Scripps Research Institute, Scripps Health, La Jolla, California, USA.

    • Eric J Topol
  52. Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, Washington, USA.

    • Bruce M Psaty
  53. Group Health Research Institute, Group Health, Seattle, Washington, USA.

    • Bruce M Psaty
    •  & Susan R Heckbert
  54. Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

    • Dan M Roden
  55. Klinikum Grosshadern, Munich, Germany.

    • H-Erich Wichmann
  56. Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.

    • John Barnard
  57. Department of Epidemiology, School of Public Health, Boston University, Boston, Massachusetts, USA.

    • Emelia J Benjamin
  58. Cardiology and Preventive Medicine Division, Evans Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts.

    • Emelia J Benjamin

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Contributions

Study concept and design: P.T.E., K.L.L., N.L.G., A.P., M.K.C., A.A., J.C.M.W., D.E.A., E.J.B., S.R.H. and S.K.

Acquisition of data: P.T.E., K.L.L., N.L.G., A.P., A.A., M.K.C., M.F.S., P.I.W.d.B., M.M., S.A.L., E.F., D.D., N.L.S., J.D.S., R.B.S., E.Z.S., K.M.R., D.R.V.W., B.-M.B, C.v.N., K.W., G.B.E., J.I.R., S.L.H., G.S., A.V.S., L.J.L., T.B.H., S.M., M.N., D.J.M., S.P., T.E., S.M., C.N.-C., M.L., S.M., K.W., T.J.W., W.H.L.K., E.B., V.G., B.M.P., J.C.M.W., J.B., D.E.A., E.J.B., S.R.H. and S.K.

Analysis and interpretations of data: K.L.L., N.L.G., A.P., M.M., J.B., D.E.A. and K.W.

Drafting of the manuscript: P.T.E., K.L.L., E.J.B., S.R.H. and S.K.

Critical revision of the manuscript for important intellectual content: K.L.L., N.L.G., A.P., A.A., M.K.C., M.F.S., P.I.W.d.B., M.M., S.A.L., E.F., D.D., N.L.S., J.D.S., R.B.S., E.Z.S., K.M.R., D.R.V.W., B.-M.B., C.v.N., K.W., G.B.E., S.L.H., G.S., A.V.S., L.J.L., T.B.H., S.M., M.M.N., D.J.M., S.P., T.E., A.K., S.M., C.N.-C., M.L., S.M.,T.J.W., W.H.L.K., R.S.V., M.N., C.A.M., B.H.C.S., A.H., A.G.U., D.L., E.B., A.M., E.J.T., A.C., V.G., B.M.P., D.M.R., T.M., H.-E.W., J.C.M.W., J.B., D.E.A., E.J.B. and S.R.H.

Statistical analysis: K.L.L., N.L.G., A.P., M.M., J.B., D.E.A. and K.W.

Obtained funding: P.T.E., A.P., A.A., M.K.C., M.F.S., P.I.W.d.B., M.M., S.A.L., E.F., N.L.S., J.D.S., K.M.R., D.R.V.W., J.I.R., S.L.H., S.M., B.H.Ch.S., A.H., A.G.U., D.L., E.B., A.M., E.J.T., A.C., V.G., B.M.P., D.M.R., T.M., J.C.M.W., J.B., D.E.A., E.J.B., S.R.H. and S.K.

Study supervision: P.T.E., K.L.L., N.L.G., A.P., A.A., M.K.C., M.F.S., J.C.M.W., J.B., D.E.A., E.J.B., S.R.H. and S.K.

P.T.E., K.L.L., N.L.G., A.P., A.A., M.K.C., M.F.S., J.C.M.W., J.B., D.E.A., E.J.B., S.R.H. and S.K. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Competing interests

A.C. 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.

Corresponding authors

Correspondence to Patrick T Ellinor or Stefan Kääb.

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https://doi.org/10.1038/ng.537

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