The haemochromatosis gene Hfe and Kupffer cells control LDL cholesterol homeostasis and impact on atherosclerosis development Egon Demetz 1 , Piotr Tymoszuk 1 , Richard Hilbe 1 , Chiara Volani 1 , David Haschka 1 , Christiane Heim 1 , Kristina Auer 1 , Daniela Lener 2 , Lucas B. Zeiger 1 , Christa Pfeifhofer-Obermair 1 , Anna Boehm 1 , Gerald J. Obermair 3,4 , Cornelia Ablinger 3 , Stefan Coassin 5 , Claudia Lamina 5 , Juliane Kager 1 , Verena Petzer 1 , Malte Asshoff 1 , Andrea Schroll 1 , Manfred Nairz 1 , Stefanie Dichtl 1 , Markus Seifert 1,6 , Laura von Raffay 1 , Christine Fischer 1 , Marina Barros-Pinkelnig 1 , Natascha Brigo 1 , Lara Valente de Souza 1,6 , Sieghart Sopper 7 , Jakob Hirsch 8 , Michael Graber 8 , Can Gollmann-Tepeko ¨ylu ¨ 8 , Johannes Holfeld 8 , Julia Halper 1 , Sophie Macheiner 9 , Johanna Gostner 10 , Georg F. Vogel 11 , Raimund Pechlaner 12 , Patrizia Moser 13 , Medea Imboden 14,15 , Pedro Marques-Vidal 16 , Nicole M. Probst-Hensch 14,15 , Heike Meiselbach 17 , Konstantin Strauch 18,19 , Annette Peters 20,21,22 , Bernhard Paulweber 23 , Johann Willeit 12 , Stefan Kiechl 12 , Florian Kronenberg 5 , Igor Theurl 1 , Ivan Tancevski 1 *, and Guenter Weiss 1,6 * 1 Department of Internal Medicine II, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria; 2 Department of Internal Medicine III, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria; 3 Department of Physiology and Medical Physics, Medical University of Innsbruck, Fritz-Pregl-Straße 3, 6020 Innsbruck, Austria; 4 Division of Physiology, Karl Landsteiner University of Health Sciences, Dr.-Karl-Dorrek-Straße 30, 3500 Krems, Austria; 5 Department of Genetics and Pharmacology, Institute of Genetic Epidemiology, Medical University of Innsbruck, Scho ¨ pfstraße 41, 6020 Innsbruck, Austria; 6 Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, Innsbruck, Austria; 7 Department of Internal Medicine V, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria; 8 Department of Cardiac Surgery, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria; 9 Department of Internal Medicine I, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria; 10 Division of Medical Biochemistry, Medical University of Innsbruck, Innrain 80/IV, 6020 Innsbruck, Austria; 11 Department of Pediatrics I, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria; 12 Department of Neurology, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria; 13 Department of Pathology, Innsbruck University Hospital, Anichstraße 35, 6020 Innsbruck, Austria; 14 Swiss Tropical and Public Health Institute, Socinstraße 57, 4051 Basel, Switzerland; 15 Department of Public Health, University of Basel, Bernoullistraße 28, 4056 Basel, Switzerland; 16 Department of Internal Medicine, Lausanne University Hospital, Rue du Bugnon 46, 1011 Lausanne, Switzerland; 17 Department of Nephrology and Hypertension, University Hospital Erlangen, Maximiliansplatz 2, 91054 Erlangen, Germany; 18 Institute of Genetic Epidemiology, Helmholtz Zentrum Mu ¨nchen—German Research Center for Environmental Health, Ingolsta ¨dter Landstraße 1, 85764 Neuherberg, Germany; 19 Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universita ¨t, Marchioninistraße 15, 81377 Munich, Germany; 20 Institute of Epidemiology II, Helmholtz Zentrum Mu ¨nchen—German Research Center for Environmental Health, Ingolsta ¨dter Landstraße 1, 85764 Neuherberg, Germany; 21 German Center for Diabetes Research, Ingolsta ¨dter Landstraße 1, 85764 Neuherberg, Germany; 22 German Center for Cardiovascular Research, Lazarettstraße 36, 80636 Munich, Germany; and 23 First Department of Medicine, Paracelsus Medical University Salzburg, Strubergasse 21, 5020 Salzburg, Austria Received 21 July 2019; revised 16 October 2019; editorial decision 14 February 2020; accepted 18 February 2020; online publish-ahead-of-print 30 March 2020 See page 3960 for the editorial comment on this article (doi: 10.1093/eurheartj/ehaa178) Aims Imbalances of iron metabolism have been linked to the development of atherosclerosis. However, subjects with hereditary haemochromatosis have a lower prevalence of cardiovascular disease. The aim of our study was to understand the underlying mechanisms by combining data from genome-wide association study analyses in humans, CRISPR/Cas9 genome editing, and loss-of-function studies in mice. ................................................................................................................................................................................................... * Corresponding authors. Tel: þ43 512 504 23251, Email: Guenter.Weiss@i-med.ac.at (G.W.); Tel: þ43 512 504 23251, Email: Ivan.Tancevski@i-med.ac.at (I.T.) Published on behalf of the European Society of Cardiology. All rights reserved. V C The Author(s) 2020. For permissions, please email: journals.permissions@oup.com. European Heart Journal (2020) 41, 3949–3959 BASIC SCIENCE doi:10.1093/eurheartj/ehaa140 Dyslipidaemias Downloaded from https://academic.oup.com/eurheartj/article/41/40/3949/5813816 by guest on 27 October 2022