Brief Communication | Published:

New susceptibility locus for coronary artery disease on chromosome 3q22.3

Nature Genetics volume 41, pages 280282 (2009) | Download Citation

Abstract

We present a three-stage analysis of genome-wide SNP data in 1,222 German individuals with myocardial infarction and 1,298 controls, in silico replication in three additional genome-wide datasets of coronary artery disease (CAD) and subsequent replication in 25,000 subjects. We identified one new CAD risk locus on 3q22.3 in MRAS (P = 7.44 × 10−13; OR = 1.15, 95% CI = 1.11–1.19), and suggestive association with a locus on 12q24.31 near HNF1A-C12orf43 (P = 4.81 × 10−7; OR = 1.08, 95% CI = 1.05–1.11).

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Acknowledgements

We thank J. Stegmann, A. Medack, S. Wrobel and A. Thiemig for assistance. We thank M. Scholz and J. Neudert (Trium Analysis Online GmbH, Munich, Germany) for database management. The German Study was supported by the Deutsche Forschungsgemeinschaft and the German Federal Ministry of Education and Research (BMBF) in the context of the German National Genome Research Network (NGFN-2 and NGFN-plus). The WTCCC Study was funded by the Wellcome Trust. Recruitment of cases for the WTCCC Study was carried out by the British Heart Foundation (BHF) Family Heart Study Research Group and supported by the BHF and the UK Medical Research Council. We also acknowledge support of the Wellcome Trust Functional Genomics Initiative in Cardiovascular Genetics. The KORA research platform (KORA, Cooperative Research in the Region of Augsburg) was initiated and financed by the GSF-National Research centre for Environment and Health, which is funded by the German Federal Ministry of Education and Research and of the State of Bavaria. N.J.S. and S.G.B. are supported by Chairs funded by the BHF. Recruitment for the Italian Atherosclerosis, Thrombosis and Vascular Biology Working Group was supported by the “Associazione per lo Studio della Trombosi in Cardiologia.” The MIGen/IATVB genotyping was supported by a grant to D. Altshuler (R01HL087676) from the STAMPEED program of the National Heart, Lung, and Blood Institute, US National Institutes of Health. In addition, the MIGen study was supported by grants from the Fannie Rippel Foundation (to S.K.) and the Doris Duke Charitable Foundation (to S.K.). The Broad Institute Center for Genotyping and Analysis subsidized genotyping in the MIGen study with support from the National Center for Research Resources (U54RR020278). The main sponsor of the current analysis is the EU-funded integrated project Cardiogenics (LSHM-CT-2006-037593).

Author information

Affiliations

  1. Medizinische Klinik II, Universität zu Lübeck, 23538 Lübeck, Germany.

    • Jeanette Erdmann
    • , Anika Großhennig
    • , Patrick Linsel-Nitschke
    • , Petra Bruse
    • , Zouhair Aherrahrou
    • , Arnika K Wagner
    •  & Heribert Schunkert
  2. Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, 23538 Lübeck, Germany.

    • Anika Großhennig
    • , Inke R König
    • , Arne Schillert
    • , Daniel F Schwarz
    •  & Andreas Ziegler
  3. Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, LE3 9QP, UK.

    • Peter S Braund
    •  & Nilesh J Samani
  4. Klinik und Poliklinik für Innere Medizin II, Universität Regensburg, 93053 Regensburg, Germany.

    • Christian Hengstenberg
    • , Klaus Stark
    •  & Marcus Fischer
  5. LIGHT, University of Leeds, Leeds, LS1 3EX, UK.

    • Alistair S Hall
    • , Stephen G Ball
    •  & Anthony J Balmforth
  6. Cardiovascular Research Center and Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Sekar Kathiresan
  7. Departments of Health Sciences and Genetics, University of Leicester, LE1 7RH Leicester, UK.

    • Ben Wright
    •  & John R Thompson
  8. Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche UMR_S 525, Université Pierre et Marie Curie (UPMC) Univ. Paris 06, Paris, France.

    • David-Alexandre Trégouët
    • , Francois Cambien
    • , Laurence Tiret
    •  & Claire Perret
  9. Cardiovascular Health Research Unit, Departments of Epidemiology and General Medicine, University of Washington, Seattle, Washington 98109, USA.

    • Stephen M Schwartz
    •  & David S Siscovick
  10. Chronic Disease Epidemiology Unit, Department of Health Promotion and Chronic Disease Prevention, National Public Health Institute, FI-00271 Helsinki, Finland.

    • Veikko Salomaa
  11. Cardiovascular Epidemiology and Genetics Group, Institut Municipal d'Investigació Mèdica, Barcelona 08036; Ciber Epidemiología y Salud Pública (CIBERSP), Spain.

    • Roberto Elosua
  12. Department of Clinical Sciences, Hypertension and Cardiovascular Diseases, University Hospital Malmö, Lund University, SE-20502 Malmö, Sweden.

    • Olle Melander
  13. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Benjamin F Voight
  14. National Heart, Lung, and Blood Institute, National Institutes of Health, Framingham, Bethesda, Maryland 20824, USA.

    • Christopher J O'Donnell
  15. The Wellcome Trust Sanger Institute, The Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.

    • Leena Peltonen
    •  & Panos Deloukas
  16. Department of Molecular Biology and Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • David Altshuler
  17. Division of Cardiology, Azienda Ospedaliera Niguarda Ca' Granda, 20162 Milan, Italy.

    • Piera Angelica Merlini
  18. Department of Internal Medicine and Medical Specialities, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Maggiore, Mangiagalli e Regina Elena, University of Milan, 20162 Milan, Italy.

    • Flora Peyvandi
  19. Department of Applied Health Sciences, University of Pavia, 27100 Italy.

    • Luisa Bernardinelli
  20. Biostatistics Unit, Medical Research Council, CB2 0SR Cambridge, UK.

    • Luisa Bernardinelli
  21. Division of Cardiology, Azienda Ospedaliero-Universitaria di Parma, 43100 Parma, Italy.

    • Diego Ardissino
  22. Department of Medicine II, Johannes Gutenberg-University 55099 Mainz, Germany.

    • Stefan Blankenberg
    • , Tanja Zeller
    •  & Philipp Wild
  23. Institut für Klinische Molekularbiologie, Christian-Albrechts Universität, 24118 Kiel, Germany.

    • Stefan Schreiber
    • , Nour Eddine El Mokhtari
    •  & Arne Schäfer
  24. Synlab Centre of Laboratory Diagnostics Heidelberg, 69037 Heidelberg, Germany.

    • Winfried März
  25. Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, 8036 Graz, Austria.

    • Winfried März
    •  & Wilfried Renner
  26. Department of Public Health, Social and Preventive Medicine, University of Heidelberg 69117 Heidelberg, Medical Faculty of Mannheim, 68131 Mannheim, Germany.

    • Winfried März
  27. Institute of Transfusion Medicine and Immunology, University of Heidelberg 69117 Heidelberg, Medical Faculty of Mannheim, 68131 Mannheim, Germany.

    • Peter Bugert
    •  & Harald Klüter
  28. Bundesforschungsanstalt für Ernährung und Lebensmittel, Institut für Physiologie und Biochemie der Ernährung, 24118 Kiel, Germany.

    • Jürgen Schrezenmeir
    •  & Diana Rubin
  29. Institute of Epidemiology, Helmholtz Zentrum München – German Research Center for Environmental Health, 85764 Neuherberg, Germany.

    • H-Erich Wichmann
    • , Christa Meisinger
    • , Jens Baumert
    •  & Annette Peters
  30. Institute of Medical Information Science, Biometry and Epidemiology, LMU 80539 Munich, Germany.

    • H-Erich Wichmann
  31. Institut für Humangenetik, Helmholtz Zentrum München, Deutsches Forschungszentrum für Umwelt und Gesundheit, 85764 Neuherberg, Germany.

    • Thomas Meitinger
  32. Institut für Humangenetik, Technische Universität München, 80333 München, Germany.

    • Thomas Meitinger
  33. Department of Haematology, University of Cambridge, Long Road, Cambridge, CB2 2PT, UK.

    • Willem H Ouwehand

Consortia

  1. Italian Atherosclerosis, Thrombosis, and Vascular Biology Working Group

    A full list of members is provided in the Supplementary Note.

  2. Myocardial Infarction Genetics Consortium

    A full list of members is provided in the Supplementary Note.

  3. Wellcome Trust Case Control Consortium

    A full list of members is provided in the Supplementary Note.

  4. Cardiogenics Consortium

    A full list of members is provided in the Supplementary Note.

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Contributions

The study was designed by H.S., N.J.S., A.Z., I.R.K., J.R.T. and J.E. Subject ascertainment, recruitment and medical record review was organized and carried out by C.H., P.L.-N. and M.F. DNA material collection, handling and genotyping (Affymetrix 500K, 6.0, and TaqMan) was supervised by P.D., T.M., P. Bruse, W.H.O., P.S.B., K.S., C.P. and A. Schäfer Statistical analysis was carried out by A.G., D.F.S., I.R.K., B.W., A. Schillert, D.-A.T., J.R.T. and A.Z. RT-PCRs were carried out by Z.A. and A.K.W., J.E., N.J.S and H.S. drafted the manuscript with substantial contributions from I.R.K, A.G. and A.Z. Principal collaborators for the case cohorts were W.M. and W.R. (LURIC), H.K. and P. Bugert (GerBS), P.L.-N. (Angio-Luebeck), N.E.M., S.S., J.S. and D.R. (PopGen), H.-E.W., T.M., C.M., A.P., and J.B. (KORA), N.J.S., A.S.H., S.G.B., P.S.B. and A.J.B. (UKMI), C.H., M.F., K.S. (GO-KARD), S.K., D. Altshuler, B.F.V., D. Ardissino, O.M., C.J.O´D., R.E., V.S., L.P., D.S.S. and S.M.S. (MIGen), P.A.M., F.P., L.B. and D. Ardissino (IATVB), S.B., T.Z. and P.W. (Atherogene), L.T., C.P. and F.C. (ECTIM). All authors contributed to the final version of the manuscript.

Corresponding author

Correspondence to Jeanette Erdmann.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Methods, Supplementary Figures 1–5, Supplementary Tables 1–4 and Supplementary Note

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DOI

https://doi.org/10.1038/ng.307

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