2. Academic Validation
  3. Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease

Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease

  • Science. 2016 Mar 11;351(6278):1166-71. doi: 10.1126/science.aad3517.
Paolo Zanoni 1,  Sumeet A Khetarpal 1,  Daniel B Larach 1,  William F Hancock-Cerutti 2,  John S Millar 1,  Marina Cuchel 1,  Stephanie DerOhannessian 1,  Anatol Kontush 3,  Praveen Surendran 4,  Danish Saleheen 5,  Stella Trompet 6,  J Wouter Jukema 7,  Anton De Craen 8,  Panos Deloukas 9,  Naveed Sattar 10,  Ian Ford 11,  Chris Packard 12,  Abdullah al Shafi Majumder 13,  Dewan S Alam 14,  Emanuele Di Angelantonio 4,  Goncalo Abecasis 15,  Rajiv Chowdhury 4,  Jeanette Erdmann 16,  Børge G Nordestgaard 17,  Sune F Nielsen 17,  Anne Tybjærg-Hansen 18,  Ruth Frikke Schmidt 19,  Kari Kuulasmaa 20,  Dajiang J Liu 21,  Markus Perola 22,  Stefan Blankenberg 23,  Veikko Salomaa 20,  Satu Männistö 20,  Philippe Amouyel 24,  Dominique Arveiler 25,  Jean Ferrieres 26,  Martina Müller-Nurasyid 27,  Marco Ferrario 28,  Frank Kee 29,  Cristen J Willer 30,  Nilesh Samani 31,  Heribert Schunkert 32,  Adam S Butterworth 4,  Joanna M M Howson 4,  Gina M Peloso 33,  Nathan O Stitziel 34,  John Danesh 35,  Sekar Kathiresan 33,  Daniel J Rader 36,  CHD Exome+ Consortium,  CARDIoGRAM Exome Consortium,  Global Lipids Genetics Consortium
Affiliations

Affiliations

  • 1 Departments of Genetics and Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 2 Departments of Genetics and Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. INSERM UMR 1166 ICAN, Université Pierre et Marie Curie Paris 6, Hôpital de la Pitié, Paris, France.
  • 3 INSERM UMR 1166 ICAN, Université Pierre et Marie Curie Paris 6, Hôpital de la Pitié, Paris, France.
  • 4 Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • 5 Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Centre for Non-Communicable Diseases, Karachi, Pakistan.
  • 6 Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, Netherlands. Department of Cardiology, Leiden University Medical Center, Leiden, Netherlands.
  • 7 Department of Cardiology, Leiden University Medical Center, Leiden, Netherlands. The Interuniversity Cardiology Institute of the Netherlands, Utrecht, Netherlands.
  • 8 Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, Netherlands.
  • 9 Wellcome Trust Sanger Institute, Genome Campus, Hinxton, UK.
  • 10 Institute of Cardiovascular and Medical Sciences, British Heart Foundation, Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
  • 11 Robertson Center for Biostatistics, University of Glasgow, Glasgow, UK.
  • 12 Glasgow Clinical Research Facility, Western Infirmary, Glasgow, UK.
  • 13 National Institute of Cardiovascular Diseases, Sher-e-Bangla Nagar, Dhaka, Bangladesh.
  • 14 International Centre for Diarrhoeal Disease Research, Mohakhali, Dhaka, Bangladesh.
  • 15 Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA.
  • 16 Institute for Integrative and Experimental Genomics, University of Lübeck, Lübeck 23562, Germany.
  • 17 Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
  • 18 Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark.
  • 19 Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospitals, Copenhagen, Denmark.
  • 20 Department of Health, National Institute for Health and Welfare, Helsinki, Finland.
  • 21 Department of Public Health Sciences, College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA.
  • 22 Department of Health, National Institute for Health and Welfare, Helsinki, Finland. Institute of Molecular Medicine FIMM, University of Helsinki, Helsinki, Finland.
  • 23 Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany. University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • 24 Department of Epidemiology and Public Health, Institut Pasteur de Lille, Lille, France.
  • 25 Department of Epidemiology and Public Health, University of Strasbourg, Strasbourg, France.
  • 26 Department of Epidemiology, Toulouse University-CHU Toulouse, Toulouse, France.
  • 27 Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. Department of Medicine I, Ludwig-Maximilians-University Munich, Munich, Germany.
  • 28 Research Centre in Epidemiology and Preventive Medicine, Department of Clinical and Experimental Medicine, University of Insubria, Varese, Italy.
  • 29 UKCRC Centre of Excellence for Public Health, Queens University, Belfast, Northern Ireland.
  • 30 Department of Computational Medicine and Bioinformatics, Department of Human Genetics, and Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • 31 Department of Cardiovascular Sciences, University of Leicester, Leicester, UK. National Institute for Health Research (NIHR) Leicester Cardiovascular Biomedical Research Unit, Glenfield Hotel, Leicester, UK.
  • 32 Deutsches Herzzentrum München, Technische Universität München, Munich, Germany.
  • 33 Broad Institute and Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
  • 34 Department of Medicine, Division of Cardiology, Department of Genetics, and the McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 35 Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. Wellcome Trust Sanger Institute, Genome Campus, Hinxton, UK.
  • 36 Departments of Genetics and Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. [email protected].
PMID: 26965621 DOI: 10.1126/science.aad3517
Abstract

Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL) Cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI knockout mice) have markedly elevated HDL-C levels but, paradoxically, increased atherosclerosis. The impact of SR-BI on HDL metabolism and CHD risk in humans remains unclear. Through targeted sequencing of coding regions of lipid-modifying genes in 328 individuals with extremely high plasma HDL-C levels, we identified a homozygote for a loss-of-function variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene encoding SR-BI. The P376L variant impairs posttranslational processing of SR-BI and abrogates selective HDL Cholesterol uptake in transfected cells, in hepatocyte-like cells derived from induced pluripotent stem cells from the homozygous subject, and in mice. Large population-based studies revealed that subjects who are heterozygous carriers of the P376L variant have significantly increased levels of plasma HDL-C. P376L carriers have a profound HDL-related phenotype and an increased risk of CHD (odds ratio = 1.79, which is statistically significant).

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