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Genome-wide haplotype association study identifies the SLC22A3-LPAL2-LPA gene cluster as a risk locus for coronary artery disease

Nature Genetics volume 41, pages 283–285 (2009)Cite this article

Abstract

We identify the SLC22A3-LPAL2-LPA gene cluster as a strong susceptibility locus for coronary artery disease (CAD) through a genome-wide haplotype association (GWHA) study. This locus was not identified from previous genome-wide association (GWA) studies focused on univariate analyses of SNPs. The proposed approach may have wide utility for analyzing GWA data for other complex traits.

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Figure 1: Haplotypic odds ratios (ORs) for CAD associated with the CCTC and CTTG haplotypes derived from rs2048327, rs3127599, rs7767084 and rs10755578 on chromosome 6q26–q27.

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Acknowledgements

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 German Study was supported by the Deutsche Forschungsgemeinschaft, the German Federal Ministry of Education and Research in the context of the German National Genome Research Network (NGFN-2 and NGFN-plus). 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. This work has also been partially supported by the EGEE-II project funded by the European Union INFSO-RI-031688. N.J.S. is supported by a Chair funded by the BHF. The main sponsor of the current analysis is the EU funded integrated project 'Cardiogenics' (LSHM-CT-2006-037593).

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Authors and Affiliations

  1. Institut National de la Santé Et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR_S) 525, Université Pierre et Marie Curie (UPMC). Paris 06, Paris, 75013, France

    David-Alexandre Trégouët, Alexandru Munteanu, Claire Perret, Maylis DeSuremain, Laurence Tiret & Francois Cambien

  2. Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Lübeck, D-23538, Germany

    Inke R König, Anika Großhennig, Michael Preuss & Andreas Ziegler

  3. Medizinische Klinik II, Universität zu Lübeck, Ratzeburger Allee 160, Lübeck, D-23538, Germany

    Jeanette Erdmann, Anika Großhennig, Patrick Linsel-Nitschke & Heribert Schunkert

  4. Department of Cardiovascular Sciences, University of Leicester, Clinical Sciences Wing, Glenfield Hospital, Groby Road, Leicester, LE3 9QP, UK

    Peter S Braund, Pim van der Harst & Nilesh J Samani

  5. Leeds Institute of Genetics, Health and Therapeutics (LIGHT), University of Leeds, Leeds, LS1 3EX, UK

    Alistair S Hall, Anthony J Balmforth & Stephen G Ball

  6. Institut für Humangenetik, Helmholtz Zentrum München, Deutsches Forschungszentrum für Umwelt und Gesundheit, Neuherberg, D-85764, Germany

    Thomas Meitinger, Christa Meisinger & H-Erich Wichmann

  7. Department of Health Sciences and Genetics, University of Leicester, Leicester, LE1 7RH, UK

    Ben J Wright & John R Thompson

  8. Centre National de la Recherche Scientifique (CNRS), UMR_S 8623, Université Paris-Sud, Laboratoire de Recherche en Informatique, Orsay, 91403, France

    Cécile Germain

  9. Department of Epidemiology and Public Health, Queen's University of Belfast, Belfast, BT7 1NN, UK

    Alun Evans

  10. EA1801-Laboratoire d'Epidémiologie et de Santé Publique, Faculté de Médecine, Multinational MONItoring of Trends and Determinants in CArdiovascular Disease (MONICA), Strasbourg, Strasbourg, 67085, France

    Dominique Arveiler

  11. INSERM U545, Pasteur Institute of Lille, University of Lille 2, Lille, 59019, France

    Gérald Luc

  12. INSERM U518, Faculté de Médecine, MONICA Toulouse, Toulouse, 31073, France

    Jean-Bernard Ruidavets

  13. The MONICA Project, Glasgow Royal Infirmary, Scotland, G4 0SF, UK

    Caroline Morrison

  14. Institut für Klinische Molekularbiologie, Christian-Albrechts Universität, Kiel, D-24105, Germany

    Stefan Schreiber, Arne Schäfer & Nour E El Mokhtari

  15. Klinik und Poliklinik für Innere Medizin II, Universität Regensburg, Regensburg, D-93042, Germany

    Katharina Neureuther, Klaus Stark & Christian Hengstenberg

  16. Molecular Biology Laboratory, Institute of Transfusion Medicine and Immunology, University of Heidelberg, Medical Faculty of Mannheim Mannheim, D-69117, Germany

    Peter Bugert

  17. Bundesforschungsanstalt für Ernährung und Lebensmittel, Institut für Physiologie und Biochemie der Ernährung, Kiel, D-24121, Germany

    Jürgen Schrezenmeir & Diana Rubin

  18. Department of Haematology, University of Cambridge, Long Road, Cambridge, CB2 2PT, UK

    Willem Ouwehand

Authors
  1. David-Alexandre Trégouët
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  2. Inke R König
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  11. Thomas Meitinger
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  22. Caroline Morrison
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  40. Nilesh J Samani
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Consortia

Wellcome Trust Case Control Consortium

Cardiogenics Consortium

Contributions

This work was designed by D.-A.T., L.T., F.C., H.S. and N.J.S. Statistical analyses were carried out by D.-A.T., I.R.K., A.G., M.P., P.H., A.Z. and J.R.T., J.E., P.S.B., C.P., M.D., P.B. and W.O. supervised and/or participated in the genetic laboratory analyses. A.M. developed the computing grid program under the supervision of D.-A.T. and C.G. Case collections were coordinated by P.S.B., A.S.H., B.J.W., A.J.B., S.G.B., W.O., J.R.T., N.J.S. (WTCCC), J.E., T.M., H.-E.W., C. Meisinger, C.H., K.N., K.S., J.S., D.R. (GerMIFS), S.S., A.S., N.E.E.-M. (PopGene), J.E., P.L.-N. (Angio-Luebeck), A.E., D.A., G.L., J.-B.R., and C. Morrison (ECTIM). D.A.T., L.T., F.C., H.S. and N.J.S. drafted the manuscript with substantial contributions from I.R.K., J.E., A.Z.

Corresponding author

Correspondence to David-Alexandre Trégouët.

Additional information

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

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

Supplementary information

Supplementary Text and Figures

Supplementary Methods, Supplementary Tables 1–3, Supplementary Figures 1–3 and Supplementary Note (PDF 746 kb)

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Trégouët, DA., König, I., Erdmann, J. et al. Genome-wide haplotype association study identifies the SLC22A3-LPAL2-LPA gene cluster as a risk locus for coronary artery disease. Nat Genet 41, 283–285 (2009). https://doi.org/10.1038/ng.314

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