title: Dysfunctional nitric oxide signalling increases risk of myocardial infarction.
abstract: Myocardial infarction, a leading cause of death in the Western world, usually occurs when the fibrous cap overlying an atherosclerotic plaque in a coronary artery ruptures. The resulting exposure of blood to the atherosclerotic material then triggers thrombus formation, which occludes the artery. The importance of genetic predisposition to coronary artery disease and myocardial infarction is best documented by the predictive value of a positive family history. Next-generation sequencing in families with several affected individuals has revolutionized mutation identification. Here we report the segregation of two private, heterozygous mutations in two functionally related genes, GUCY1A3 (p.Leu163Phefs*24) and CCT7 (p.Ser525Leu), in an extended myocardial infarction family. GUCY1A3 encodes the α1 subunit of soluble guanylyl cyclase (α1-sGC), and CCT7 encodes CCTη, a member of the tailless complex polypeptide 1 ring complex, which, among other functions, stabilizes soluble guanylyl cyclase. After stimulation with nitric oxide, soluble guanylyl cyclase generates cGMP, which induces vasodilation and inhibits platelet activation. We demonstrate in vitro that mutations in both GUCY1A3 and CCT7 severely reduce α1-sGC as well as β1-sGC protein content, and impair soluble guanylyl cyclase activity. Moreover, platelets from digenic mutation carriers contained less soluble guanylyl cyclase protein and consequently displayed reduced nitric-oxide-induced cGMP formation. Mice deficient in α1-sGC protein displayed accelerated thrombus formation in the microcirculation after local trauma. Starting with a severely affected family, we have identified a link between impaired soluble-guanylyl-cyclase-dependent nitric oxide signalling and myocardial infarction risk, possibly through accelerated thrombus formation. Reversing this defect may provide a new therapeutic target for reducing the risk of myocardial infarction.
authors.affiliation: 1] Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, 23562 Lübeck, Germany [2] German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Lübeck/Kiel, 23562 Lübeck, Germany [3].
authors.forename: Jeanette
authors.initials: J
authors.lastname: Erdmann
authors.affiliation: 1] Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum Regensburg, 93053 Regensburg, Germany [2] Department of Genetic Epidemiology, University of Regensburg, 93053 Regensburg, Germany [3].
authors.forename: Klaus
authors.initials: K
authors.lastname: Stark
authors.affiliation: 1] Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum Regensburg, 93053 Regensburg, Germany [2] Institut National de la Santé et de la Recherche Médicale (INSERM), UMR-S937 Paris, France [3].
authors.forename: Ulrike B
authors.initials: UB
authors.lastname: Esslinger
authors.affiliation: 1] Deutsches Herzzentrum München and 1. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, 80636 München, Germany [2] German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, 80636 Munich, Germany [3].
authors.forename: Philipp Moritz
authors.initials: PM
authors.lastname: Rumpf
authors.affiliation: Department of Pharmacology and Toxicology, Ruhr-University Bochum, 44801 Bochum, Germany.
authors.forename: Doris
authors.initials: D
authors.lastname: Koesling
authors.affiliation: 1] German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Lübeck/Kiel, 23562 Lübeck, Germany [2] Institut für Physiologie, Universität zu Lübeck, 23562 Lübeck, Germany.
authors.forename: Cor
authors.initials: C
authors.lastname: de Wit
authors.affiliation: 1] German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Lübeck/Kiel, 23562 Lübeck, Germany [2] Institut für Humangenetik, Universität zu Lübeck, 23562 Lübeck, Germany.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Kaiser
authors.affiliation: Institut für Humangenetik, Universität zu Lübeck, 23562 Lübeck, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Braunholz
authors.affiliation: Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, 23562 Lübeck, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Medack
authors.affiliation: Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum Regensburg, 93053 Regensburg, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Fischer
authors.affiliation: Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum Regensburg, 93053 Regensburg, Germany.
authors.forename: Martina E
authors.initials: ME
authors.lastname: Zimmermann
authors.affiliation: Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, 23562 Lübeck, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Tennstedt
authors.affiliation: 1] Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany [2] Institute of Human Genetics, Technische Universität München, 81675 München, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Graf
authors.affiliation: 1] Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany [2] Institute of Human Genetics, Technische Universität München, 81675 München, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Eck
authors.affiliation: 1] Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, 23562 Lübeck, Germany [2] German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Lübeck/Kiel, 23562 Lübeck, Germany.
authors.forename: Zouhair
authors.initials: Z
authors.lastname: Aherrahrou
authors.affiliation: Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, 23562 Lübeck, Germany.
authors.forename: Janja
authors.initials: J
authors.lastname: Nahrstaedt
authors.affiliation: 1] Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, 23562 Lübeck, Germany [2] German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Lübeck/Kiel, 23562 Lübeck, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Willenborg
authors.affiliation: Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, 23562 Lübeck, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Bruse
authors.affiliation: Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, 23562 Lübeck, Germany.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Brænne
authors.affiliation: 1] Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany [2] Department of Genomics, Research Center Life & Brain, University of Bonn, 53127 Bonn, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: 1] Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany [2] Division of Medical Genetics, University Hospital Basel and Department of Biomedicine, University of Basel, 4003 Basel, Switzerland.
authors.forename: Per
authors.initials: P
authors.lastname: Hofmann
authors.affiliation: 1] Department of Cardiovascular Sciences, University of Leicester, Leicester LE1 7RH, UK [2] Leicester National Institute for Health Research Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester LE1 7RH, UK.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Braund
authors.affiliation: Department of Pharmacology and Toxicology, Ruhr-University Bochum, 44801 Bochum, Germany.
authors.forename: Evanthia
authors.initials: E
authors.lastname: Mergia
authors.affiliation: 1] Deutsches Herzzentrum München and 1. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, 80636 München, Germany [2] German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, 80636 Munich, Germany.
authors.forename: Wibke
authors.initials: W
authors.lastname: Reinhard
authors.affiliation: Deutsches Herzzentrum München and 1. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, 80636 München, Germany.
authors.forename: Christof
authors.initials: C
authors.lastname: Burgdorf
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrecht-Universität, 24105 Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.affiliation: Division of Cardiovascular and Diabetes Research, Multidisciplinary Cardiovascular Research Centre, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Balmforth
authors.affiliation: Division of Cardiovascular and Neuronal Remodelling, Multidisciplinary Cardiovascular Research Centre, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Alistair S
authors.initials: AS
authors.lastname: Hall
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Bertram
authors.affiliation: Charité Research Group on Geriatrics, Charité-Universitätsmedizin, 10117 Berlin, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Steinhagen-Thiessen
authors.affiliation: 1] Center for Lifespan Psychology, Max Planck Institute for Human Development, 14195 Berlin, Germany [2] Department of Psychology, TU Dresden, 01062 Dresden, Germany.
authors.forename: Shu-Chen
authors.initials: SC
authors.lastname: Li
authors.affiliation: 1] Synlab Academy and Business Development, synlab Services GmbH, 68165 Mannheim, Germany [2] Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, 8036 Graz, Austria [3] Medical Clinic V, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany.
authors.forename: Winfried
authors.initials: W
authors.lastname: März
authors.affiliation: The Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Muredach
authors.initials: M
authors.lastname: Reilly
authors.affiliation: 1] Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts 02215, USA [2] Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02215, USA [3] Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02215, USA.
authors.forename: Sekar
authors.initials: S
authors.lastname: Kathiresan
authors.affiliation: University of Ottawa, Heart Institute, Ottawa, Ontario K1Y 4W7, Canada.
authors.forename: Ruth
authors.initials: R
authors.lastname: McPherson
authors.affiliation: 1] Centrum für Thrombose und Hämostase (CTH), Universitätsmedizin Mainz, 55131 Mainz, Germany [2] German Centre for Cardiovascular Research (DZHK), partner site RheinMain, 55131 Mainz, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Walter
authors.affiliation: 1] Institute of Psychology, Chinese Academy of Sciences, Beijing 100864, China [2] Laboratory of Statistical Genetics, Rockefeller University, New York 10065, USA.
authors.forename: Jurg
authors.initials: J
authors.lastname: Ott
authors.affiliation: 1] Department of Cardiovascular Sciences, University of Leicester, Leicester LE1 7RH, UK [2] Leicester National Institute for Health Research Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester LE1 7RH, UK.
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.affiliation: 1] Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany [2] Institute of Human Genetics, Technische Universität München, 81675 München, Germany.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.affiliation: 1] Deutsches Herzzentrum München and 1. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, 80636 München, Germany [2] Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany [3] Institute of Human Genetics, Technische Universität München, 81675 München, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.affiliation: 1] Deutsches Herzzentrum München and 1. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, 80636 München, Germany [2] German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, 80636 Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Hengstenberg
authors.affiliation: 1] Deutsches Herzzentrum München and 1. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, 80636 München, Germany [2] German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, 80636 Munich, Germany.
authors.forename: Heribert
authors.initials: H
authors.lastname: Schunkert
mesh_terms: D000818:Animals; D056404:Chaperonin Containing TCP-1 / Q000235:genetics / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004198:Disease Susceptibility / Q000378:metabolism*; D059472:Exome / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006162:Guanylate Cyclase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism*; D010375:Pedigree; D015539:Platelet Activation; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction; D012995:Solubility; D000071756:Soluble Guanylyl Cyclase; D013927:Thrombosis / Q000378:metabolism; D014664:Vasodilation
chemical_list: C533333:CCT7 protein, human; C000605660:GUCY1A2 protein, human; C000605668:Gucy1a3 protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D056404:Chaperonin Containing TCP-1; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP