Dysfunctional nitric oxide signalling increases risk of myocardial infarction (original) (raw)

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Variant data is available in ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/) with accession numbers SCV000083870 for NM_001130683.2:c.488dup and SCV000083871 for NM_001166284.1:c.1313C>T.

References

1. World Health Organization. The top 10 causes of death. Fact sheet no. 310; http://www.who.int/mediacentre/factsheets/fs310/en/index.html (2011)
2. Finn, A. V., Nakano, M., Narula, J., Kolodgie, F. D. & Virmani, R. Concept of vulnerable/unstable plaque. Arterioscler. Thromb. Vasc. Biol. 30, 1282–1292 (2010)
   Article CAS Google Scholar
3. Lloyd-Jones, D. M. et al. Parental cardiovascular disease as a risk factor for cardiovascular disease in middle-aged adults: a prospective study of parents and offspring. J. Am. Med. Assoc. 291, 2204–2211 (2004)
   Article CAS Google Scholar
4. Bamshad, M. J. et al. Exome sequencing as a tool for Mendelian disease gene discovery. Nature Rev. Genet. 12, 745–755 (2011)
   Article CAS Google Scholar
5. Mergia, E., Friebe, A., Dangel, O., Russwurm, M. & Koesling, D. Spare guanylyl cyclase NO receptors ensure high NO sensitivity in the vascular system. J. Clin. Invest. 116, 1731–1737 (2006)
   Article CAS Google Scholar
6. Leitner, A. et al. The molecular architecture of the eukaryotic chaperonin TRiC/CCT. Structure 20, 814–825 (2012)
   Article CAS Google Scholar
7. Zabel, U., Weeger, M., La, M. & Schmidt, H. H. Human soluble guanylate cyclase: functional expression and revised isoenzyme family. Biochem. J. 335, 51–57 (1998)
   Article CAS Google Scholar
8. The 1000 Genomes Project Consortium. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010)
9. Moro, M. A. et al. cGMP mediates the vascular and platelet actions of nitric oxide: confirmation using an inhibitor of the soluble guanylyl cyclase. Proc. Natl Acad. Sci. USA 93, 1480–1485 (1996)
   Article CAS ADS Google Scholar
10. Deloukas, P. et al. Large-scale association analysis identifies new risk loci for coronary artery disease. Nature Genet. 45, 25–33 (2013)
    Article CAS Google Scholar
11. Lu, X. et al. Genome-wide association study in Han Chinese identifies four new susceptibility loci for coronary artery disease. Nature Genet. 44, 890–894 (2012)
    Article CAS Google Scholar
12. Stasch, J. P., Pacher, P. & Evgenov, O. V. Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease. Circulation 123, 2263–2273 (2011)
    Article Google Scholar
13. Broeckel, U. et al. A comprehensive linkage analysis for myocardial infarction and its related risk factors. Nature Genet. 30, 210–214 (2002)
    Article CAS Google Scholar
14. Fischer, M. et al. Distinct heritable patterns of angiographic coronary artery disease in families with myocardial infarction. Circulation 111, 855–862 (2005)
    Article Google Scholar
15. Adzhubei, I. A. et al. A method and server for predicting damaging missense mutations. Nature Methods 7, 248–249 (2010)
    Article CAS Google Scholar
16. Risch, N. Linkage strategies for genetically complex traits. III. The effect of marker polymorphism on analysis of affected relative pairs. Am. J. Hum. Genet. 46, 242–253 (1990)
    CAS PubMed PubMed Central Google Scholar
17. Dekker, C. et al. The crystal structure of yeast CCT reveals intrinsic asymmetry of eukaryotic cytosolic chaperonins. EMBO J. 30, 3078–3090 (2011)
    Article CAS Google Scholar
18. Krieger, E. et al. Improving physical realism, stereochemistry, and side-chain accuracy in homology modeling: Four approaches that performed well in CASP8. Proteins 77, 114–122 (2009)
    Article CAS Google Scholar
19. Krieger, E., Darden, T., Nabuurs, S. B., Finkelstein, A. & Vriend, G. Making optimal use of empirical energy functions: force-field parameterization in crystal space. Proteins 57, 678–683 (2004)
    Article CAS Google Scholar
20. Krieger, E., Nielsen, J. E., Spronk, C. A. & Vriend, G. Fast empirical p_K_ a prediction by Ewald summation. J. Mol. Graph. Model. 25, 481–486 (2006)
    Article CAS Google Scholar
21. Liu, Y., Ruoho, A. E., Rao, V. D. & Hurley, J. H. Catalytic mechanism of the adenylyl and guanylyl cyclases: modeling and mutational analysis. Proc. Natl Acad. Sci. USA 94, 13414–13419 (1997)
    Article CAS ADS Google Scholar
22. Wölfle, S. E., Schmidt, V. J., Hoyer, J., Kohler, R. & de Wit, C. Prominent role of KCa3.1 in endothelium-derived hyperpolarizing factor-type dilations and conducted responses in the microcirculation in vivo . Cardiovasc. Res. 82, 476–483 (2009)
    Article Google Scholar
23. Schunkert, H. et al. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nature Genet. 43, 333–338 (2011)
    Article CAS Google Scholar
24. Preuss, U. W., Koller, G., Zill, P., Bondy, B. & Soyka, M. Alcoholism-related phenotypes and genetic variants of the CB1 receptor. Eur. Arch. Psychiatry Clin. Neurosci. 253, 275–280 (2003)
    Article CAS Google Scholar
25. Ritsch, A. et al. Cholesteryl ester transfer protein and mortality in patients undergoing coronary angiography: the Ludwigshafen Risk and Cardiovascular Health study. Circulation 121, 366–374 (2010)
    Article CAS Google Scholar
26. Haenle, M. M. et al. Overweight, physical activity, tobacco and alcohol consumption in a cross-sectional random sample of German adults. BMC Public Health 6, 233 (2006)
    Article Google Scholar
27. Schunkert, H. et al. Repeated replication and a prospective meta-analysis of the association between chromosome 9p21.3 and coronary artery disease. Circulation 117, 1675–1684 (2008)
    Article Google Scholar
28. Marchini, J., Howie, B., Myers, S., McVean, G. & Donnelly, P. A new multipoint method for genome-wide association studies by imputation of genotypes. Nature Genet. 39, 906–913 (2007)
    Article CAS Google Scholar

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Acknowledgements

We thank all the family members who participated in this research. Without the continuous support of these patients over more than 15 years, the present work would not have been possible. We would like to thank S. Wrobel, S. Stark, A. Liebers, K. Franke, J. Stegmann-Frehse, M. Behrensen, M. Schmid, J. Eckhold, D. Wöllner, U. Krabbe and J. Simon for technical assistance. Furthermore, we would like to thank M. Becker, N. Buchholz, I. Demuth, R. Eckardt, H. Heekeren, U. Lindenberger, M. Lövdén, L. Müller, W. Nietfeld, G. Pawelec, F. Schmiedeck, T. Siedler and G. G. Wagner for their contributions to BASE-II. We also would like to thank S. Herterich and S. Gambaryan for advice, and B. Mayer, U. Hubauer, K.-H. Ameln and A. Großhennig for help with GerMIFS. We thank WTCCC+ and the WTCCC-CAD2 investigators for access to their data. The study is 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 (01GS0417) and NGFN-plus (01GS0832)), the FP6 and FP7 EU-funded integrated projects Cardiogenics (LSHM-CT-2006-037593), ENGAGE (201413), and GEUVADIS (261123), the binational BMBF/ANR funded project CARDomics (01KU0908A), the local focus programs ‘Kardiovaskuläre Genomforschung’ and ‘Medizinische Genetik’ of the Universität zu Lübeck, and the University Hospital of Regensburg, Germany. The German Federal Ministry for Education and Research provided funding for BASE-II (BMBF; grant no. 16SV5538). Support by NSFC grant 30730057 from the Chinese Government (to J.O.) is gratefully acknowledged. N.J.S. holds a Chair funded by the British Heart Foundation, and is supported by the Leicester NIHR Biomedical Research Unit in Cardiovascular Disease. U.W. is supported by the BMBF (01EO1003). M.M.N. is a member of the DFG-funded Excellence Cluster ImmunoSensation.

Author information

Author notes

1. Jeanette Erdmann, Klaus Stark, Ulrike B. Esslinger and Philipp Moritz Rumpf: These authors contributed equally to this work.

Authors and Affiliations

1. Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, 23562 Lübeck, Germany ,
   Jeanette Erdmann, Anja Medack, Stephanie Tennstedt, Zouhair Aherrahrou, Janja Nahrstaedt, Christina Willenborg, Petra Bruse & Ingrid Brænne
2. German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Lübeck/Kiel, 23562 Lübeck, Germany ,
   Jeanette Erdmann, Cor de Wit, Frank J. Kaiser, Zouhair Aherrahrou & Christina Willenborg
3. Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum Regensburg, 93053 Regensburg, Germany ,
   Klaus Stark, Ulrike B. Esslinger, Marcus Fischer & Martina E. Zimmermann
4. Department of Genetic Epidemiology, University of Regensburg, 93053 Regensburg, Germany,
   Klaus Stark
5. Institut National de la Santé et de la Recherche Médicale (INSERM), UMR-S937 Paris, France ,
   Ulrike B. Esslinger
6. Deutsches Herzzentrum München and 1. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, 80636 München, Germany ,
   Philipp Moritz Rumpf, Wibke Reinhard, Christof Burgdorf, Thomas Meitinger, Christian Hengstenberg & Heribert Schunkert
7. German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, 80636 Munich, Germany ,
   Philipp Moritz Rumpf, Wibke Reinhard, Christian Hengstenberg & Heribert Schunkert
8. Department of Pharmacology and Toxicology, Ruhr-University Bochum, 44801 Bochum, Germany,
   Doris Koesling & Evanthia Mergia
9. Institut für Physiologie, Universität zu Lübeck, 23562 Lübeck, Germany ,
   Cor de Wit
10. Institut für Humangenetik, Universität zu Lübeck, 23562 Lübeck, Germany ,
    Frank J. Kaiser & Diana Braunholz
11. Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany ,
    Elisabeth Graf, Sebastian Eck, Tim M. Strom & Thomas Meitinger
12. Institute of Human Genetics, Technische Universität München, 81675 München, Germany ,
    Elisabeth Graf, Sebastian Eck, Tim M. Strom & Thomas Meitinger
13. Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany ,
    Markus M. Nöthen & Per Hofmann
14. Department of Genomics, Research Center Life & Brain, University of Bonn, 53127 Bonn, Germany,
    Markus M. Nöthen
15. Division of Medical Genetics, University Hospital Basel and Department of Biomedicine, University of Basel, 4003 Basel, Switzerland,
    Per Hofmann
16. Department of Cardiovascular Sciences, University of Leicester, Leicester LE1 7RH, UK,
    Peter S. Braund & Nilesh J. Samani
17. Leicester National Institute for Health Research Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester LE1 7RH, UK ,
    Peter S. Braund & Nilesh J. Samani
18. Institute of Clinical Molecular Biology, Christian-Albrecht-Universität, 24105 Kiel, Germany ,
    Stefan Schreiber
19. Division of Cardiovascular and Diabetes Research, Multidisciplinary Cardiovascular Research Centre, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds LS2 9JT, UK,
    Anthony J. Balmforth
20. Division of Cardiovascular and Neuronal Remodelling, Multidisciplinary Cardiovascular Research Centre, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds LS2 9JT, UK,
    Alistair S. Hall
21. Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany,
    Lars Bertram
22. Charité Research Group on Geriatrics, Charité-Universitätsmedizin, 10117 Berlin, Germany ,
    Elisabeth Steinhagen-Thiessen
23. Center for Lifespan Psychology, Max Planck Institute for Human Development, 14195 Berlin, Germany ,
    Shu-Chen Li
24. Department of Psychology, TU Dresden, 01062 Dresden, Germany,
    Shu-Chen Li
25. Synlab Academy and Business Development, synlab Services GmbH, 68165 Mannheim, Germany ,
    Winfried März
26. Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, 8036 Graz, Austria ,
    Winfried März
27. Medical Clinic V, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany ,
    Winfried März
28. The Cardiovascular Institute, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA
    Muredach Reilly
29. Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Boston, 02215, Massachusetts, USA
    Sekar Kathiresan
30. Center for Human Genetic Research, Massachusetts General Hospital, Boston, 02215, Massachusetts, USA
    Sekar Kathiresan
31. Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), Cambridge, 02215, Massachusetts, USA
    Sekar Kathiresan
32. University of Ottawa, Heart Institute, Ottawa, Ontario K1Y 4W7, Canada ,
    Ruth McPherson
33. Centrum für Thrombose und Hämostase (CTH), Universitätsmedizin Mainz, 55131 Mainz, Germany ,
    Ulrich Walter
34. German Centre for Cardiovascular Research (DZHK), partner site RheinMain, 55131 Mainz, Germany ,
    Ulrich Walter
35. Institute of Psychology, Chinese Academy of Sciences, Beijing, 100864, China
    Jurg Ott
36. Laboratory of Statistical Genetics, Rockefeller University, 10065, New York, USA
    Jurg Ott

Authors

1. Jeanette Erdmann
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2. Klaus Stark
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3. Ulrike B. Esslinger
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4. Philipp Moritz Rumpf
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5. Doris Koesling
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6. Cor de Wit
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7. Frank J. Kaiser
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8. Diana Braunholz
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9. Anja Medack
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10. Marcus Fischer
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11. Martina E. Zimmermann
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12. Stephanie Tennstedt
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13. Elisabeth Graf
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14. Sebastian Eck
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15. Zouhair Aherrahrou
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16. Janja Nahrstaedt
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17. Christina Willenborg
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18. Petra Bruse
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19. Ingrid Brænne
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20. Markus M. Nöthen
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21. Per Hofmann
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22. Peter S. Braund
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23. Evanthia Mergia
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24. Wibke Reinhard
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25. Christof Burgdorf
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26. Stefan Schreiber
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27. Anthony J. Balmforth
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28. Alistair S. Hall
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29. Lars Bertram
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30. Elisabeth Steinhagen-Thiessen
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31. Shu-Chen Li
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32. Winfried März
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33. Muredach Reilly
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34. Sekar Kathiresan
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35. Ruth McPherson
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36. Ulrich Walter
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37. Jurg Ott
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38. Nilesh J. Samani
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39. Tim M. Strom
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40. Thomas Meitinger
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41. Christian Hengstenberg
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42. Heribert Schunkert
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Consortia

CARDIoGRAM

Contributions

J.E., C.H., F.J.K., T.M., N.J.S., H.S. and K.S. designed the study. Z.A., D.B., P.B., C.d.W., S.E., U.B.E., E.G., F.J.K., D.K., A.M., E.M., W.R., P.M.R., T.M.S. and M.E.Z. conducted the experiments. I.B., M.F., J.N., J.O., K.S., T.M.S., S.T. and C.W. analysed the data. A.J.B., L.B., P.S.B., C.B., A.S.H., P.H., S.K., S.-C.L., W.M., R.M., T.M., M.M.N., M.R., N.J.S., S.S., E.S.-T. and U.W. provided material, data and analysis tools. J.E., C.d.W., C.H., F.J.K., N.J.S. and H.S. wrote the paper. C.H. and H.S. contributed equally. See Supplementary Information for Members of CARDIoGRAM.

Corresponding authors

Correspondence toJeanette Erdmann or Christian Hengstenberg.

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Competing interests

The authors declare no competing financial interests.

Additional information

A list of authors and their affiliations appears in the Supplementary Information.

Supplementary information

Supplementary Information

This file contains Supplementary Materials and Methods, Supplementary Tables 1-7, Supplementary Figures 1-8 and funding and affiliation details for CARDIoGRAM. (PDF 3117 kb)

Thrombus formation in arterioles in vivo

An arteriole in cremaster-microcirculation with a diameter of about 40 µm. Blood flow is from bottom to top, the animal has received high molecular weight FITC-dextran intravenously which is photoexcited by illuminating the preparation at 450-490nm using mercury lamp at time point 01:07:00. This is visible as a light spot in arteriole, which reflects the excitation of the dye. Thrombus formation starts to be visible downstream of the excitated area in the upper right corner 42 s later. Thereafter, flow decelerates and comes to complete stop 88 s after starting the photoexcitation, which is turned-off at this point. (AVI 7116 kb)

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Erdmann, J., Stark, K., Esslinger, U. et al. Dysfunctional nitric oxide signalling increases risk of myocardial infarction.Nature 504, 432–436 (2013). https://doi.org/10.1038/nature12722

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• Received: 22 March 2012
• Accepted: 27 September 2013
• Published: 10 November 2013
• Issue Date: 19 December 2013
• DOI: https://doi.org/10.1038/nature12722