PMID- 26965621 OWN - NLM STAT- MEDLINE DCOM- 20160331 LR - 20230621 IS - 1095-9203 (Electronic) IS - 0036-8075 (Print) IS - 0036-8075 (Linking) VI - 351 IP - 6278 DP - 2016 Mar 11 TI - Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease. PG - 1166-71 LID - 10.1126/science.aad3517 [doi] AB - 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). CI - Copyright (c) 2016, American Association for the Advancement of Science. FAU - Zanoni, Paolo AU - Zanoni P AD - Departments of Genetics and Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. FAU - Khetarpal, Sumeet A AU - Khetarpal SA AD - Departments of Genetics and Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. FAU - Larach, Daniel B AU - Larach DB AD - Departments of Genetics and Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. FAU - Hancock-Cerutti, William F AU - Hancock-Cerutti WF AD - 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, Universite Pierre et Marie Curie Paris 6, Hopital de la Pitie, Paris, France. FAU - Millar, John S AU - Millar JS AD - Departments of Genetics and Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. FAU - Cuchel, Marina AU - Cuchel M AD - Departments of Genetics and Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. FAU - DerOhannessian, Stephanie AU - DerOhannessian S AD - Departments of Genetics and Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. FAU - Kontush, Anatol AU - Kontush A AD - INSERM UMR 1166 ICAN, Universite Pierre et Marie Curie Paris 6, Hopital de la Pitie, Paris, France. FAU - Surendran, Praveen AU - Surendran P AD - Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. FAU - Saleheen, Danish AU - Saleheen D AD - 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. FAU - Trompet, Stella AU - Trompet S AD - Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, Netherlands. Department of Cardiology, Leiden University Medical Center, Leiden, Netherlands. FAU - Jukema, J Wouter AU - Jukema JW AD - Department of Cardiology, Leiden University Medical Center, Leiden, Netherlands. The Interuniversity Cardiology Institute of the Netherlands, Utrecht, Netherlands. FAU - De Craen, Anton AU - De Craen A AD - Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, Netherlands. FAU - Deloukas, Panos AU - Deloukas P AD - Wellcome Trust Sanger Institute, Genome Campus, Hinxton, UK. FAU - Sattar, Naveed AU - Sattar N AD - Institute of Cardiovascular and Medical Sciences, British Heart Foundation, Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK. FAU - Ford, Ian AU - Ford I AD - Robertson Center for Biostatistics, University of Glasgow, Glasgow, UK. FAU - Packard, Chris AU - Packard C AD - Glasgow Clinical Research Facility, Western Infirmary, Glasgow, UK. FAU - Majumder, Abdullah al Shafi AU - Majumder Aa AD - National Institute of Cardiovascular Diseases, Sher-e-Bangla Nagar, Dhaka, Bangladesh. FAU - Alam, Dewan S AU - Alam DS AD - International Centre for Diarrhoeal Disease Research, Mohakhali, Dhaka, Bangladesh. FAU - Di Angelantonio, Emanuele AU - Di Angelantonio E AD - Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. FAU - Abecasis, Goncalo AU - Abecasis G AD - Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA. FAU - Chowdhury, Rajiv AU - Chowdhury R AD - Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. FAU - Erdmann, Jeanette AU - Erdmann J AD - Institute for Integrative and Experimental Genomics, University of Lubeck, Lubeck 23562, Germany. FAU - Nordestgaard, Borge G AU - Nordestgaard BG AD - Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark. FAU - Nielsen, Sune F AU - Nielsen SF AD - Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark. FAU - Tybjaerg-Hansen, Anne AU - Tybjaerg-Hansen A AD - Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark. FAU - Schmidt, Ruth Frikke AU - Schmidt RF AD - Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospitals, Copenhagen, Denmark. FAU - Kuulasmaa, Kari AU - Kuulasmaa K AD - Department of Health, National Institute for Health and Welfare, Helsinki, Finland. FAU - Liu, Dajiang J AU - Liu DJ AD - Department of Public Health Sciences, College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA. FAU - Perola, Markus AU - Perola M AD - Department of Health, National Institute for Health and Welfare, Helsinki, Finland. Institute of Molecular Medicine FIMM, University of Helsinki, Helsinki, Finland. FAU - Blankenberg, Stefan AU - Blankenberg S AD - Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany. University Medical Center Hamburg-Eppendorf, Hamburg, Germany. FAU - Salomaa, Veikko AU - Salomaa V AD - Department of Health, National Institute for Health and Welfare, Helsinki, Finland. FAU - Mannisto, Satu AU - Mannisto S AD - Department of Health, National Institute for Health and Welfare, Helsinki, Finland. FAU - Amouyel, Philippe AU - Amouyel P AD - Department of Epidemiology and Public Health, Institut Pasteur de Lille, Lille, France. FAU - Arveiler, Dominique AU - Arveiler D AD - Department of Epidemiology and Public Health, University of Strasbourg, Strasbourg, France. FAU - Ferrieres, Jean AU - Ferrieres J AD - Department of Epidemiology, Toulouse University-CHU Toulouse, Toulouse, France. FAU - Muller-Nurasyid, Martina AU - Muller-Nurasyid M AD - Institute of Genetic Epidemiology, Helmholtz Zentrum Munchen-German Research Center for Environmental Health, Neuherberg, Germany. Department of Medicine I, Ludwig-Maximilians-University Munich, Munich, Germany. FAU - Ferrario, Marco AU - Ferrario M AD - Research Centre in Epidemiology and Preventive Medicine, Department of Clinical and Experimental Medicine, University of Insubria, Varese, Italy. FAU - Kee, Frank AU - Kee F AD - UKCRC Centre of Excellence for Public Health, Queens University, Belfast, Northern Ireland. FAU - Willer, Cristen J AU - Willer CJ AD - Department of Computational Medicine and Bioinformatics, Department of Human Genetics, and Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA. FAU - Samani, Nilesh AU - Samani N AD - Department of Cardiovascular Sciences, University of Leicester, Leicester, UK. National Institute for Health Research (NIHR) Leicester Cardiovascular Biomedical Research Unit, Glenfield Hotel, Leicester, UK. FAU - Schunkert, Heribert AU - Schunkert H AD - Deutsches Herzzentrum Munchen, Technische Universitat Munchen, Munich, Germany. FAU - Butterworth, Adam S AU - Butterworth AS AD - Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. FAU - Howson, Joanna M M AU - Howson JM AD - Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. FAU - Peloso, Gina M AU - Peloso GM AD - Broad Institute and Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA. FAU - Stitziel, Nathan O AU - Stitziel NO AD - Department of Medicine, Division of Cardiology, Department of Genetics, and the McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63110, USA. FAU - Danesh, John AU - Danesh J AD - Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. Wellcome Trust Sanger Institute, Genome Campus, Hinxton, UK. FAU - Kathiresan, Sekar AU - Kathiresan S AD - Broad Institute and Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA. FAU - Rader, Daniel J AU - Rader DJ AD - Departments of Genetics and Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. rader@mail.med.upenn.edu. CN - CHD Exome+ Consortium CN - CARDIoGRAM Exome Consortium CN - Global Lipids Genetics Consortium LA - eng SI - GEO/GSE76065 SI - SRA/SRX1458096 GR - MR/K013351/1/MRC_/Medical Research Council/United Kingdom GR - MR/N003284/1/MRC_/Medical Research Council/United Kingdom GR - G0801566/MRC_/Medical Research Council/United Kingdom GR - G0401527/MRC_/Medical Research Council/United Kingdom GR - TL1 RR024133/RR/NCRR NIH HHS/United States GR - R01 DK089256/DK/NIDDK NIH HHS/United States GR - R01 HL117078/HL/NHLBI NIH HHS/United States GR - U01 HG006398/HG/NHGRI NIH HHS/United States GR - PG/08/094/26019/BHF_/British Heart Foundation/United Kingdom GR - TL1RR024133/RR/NCRR NIH HHS/United States GR - R01 HL111398/HL/NHLBI NIH HHS/United States GR - MR/L003120/1/MRC_/Medical Research Council/United Kingdom GR - RG/13/13/30194/BHF_/British Heart Foundation/United Kingdom GR - R01 HL089309/HL/NHLBI NIH HHS/United States GR - G0800270/MRC_/Medical Research Council/United Kingdom GR - R21 DA040177/DA/NIDA NIH HHS/United States GR - K08 HL114642/HL/NHLBI NIH HHS/United States GR - R01 HG008983/HG/NHGRI NIH HHS/United States GR - R01 DK082766/DK/NIDDK NIH HHS/United States GR - RG/08/014/24067/BHF_/British Heart Foundation/United Kingdom GR - RG/14/5/30893/BHF_/British Heart Foundation/United Kingdom PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Science JT - Science (New York, N.Y.) JID - 0404511 RN - 0 (Cholesterol, HDL) RN - 0 (SCARB1 protein, human) RN - 0 (Scavenger Receptors, Class B) RN - 9DLQ4CIU6V (Proline) RN - GMW67QNF9C (Leucine) SB - IM CIN - Science. 2016 Mar 11;351(6278):1126. PMID: 26965598 CIN - Nat Rev Cardiol. 2016 May;13(5):249-50. PMID: 27053456 MH - Aged MH - Amino Acid Substitution MH - Animals MH - Cholesterol, HDL/*blood MH - Coronary Disease/*blood/*genetics MH - DNA Mutational Analysis MH - Female MH - Genetic Variation MH - Heterozygote MH - Homozygote MH - Humans MH - Leucine/genetics MH - Male MH - Mice MH - Middle Aged MH - Proline/genetics MH - Protein Processing, Post-Translational MH - Risk MH - Scavenger Receptors, Class B/*genetics/metabolism PMC - PMC4889017 MID - NIHMS785494 FIR - Watson, Sarah IR - Watson S FIR - Schmidt, Ellen M IR - Schmidt EM FIR - Sengupta, Sebanti IR - Sengupta S FIR - Gustafsson, Stefan IR - Gustafsson S FIR - Kanoni, Stavroula IR - Kanoni S FIR - Ganna, Andrea IR - Ganna A FIR - Chen, Jin IR - Chen J FIR - Buchkovich, Martin L IR - Buchkovich ML FIR - Mora, Samia IR - Mora S FIR - Beckmann, Jacques S IR - Beckmann JS FIR - Bragg-Gresham, Jennifer L IR - Bragg-Gresham JL FIR - Chang, Hsing-Yi IR - Chang HY FIR - Demirkan, Ayse IR - Demirkan A FIR - Den Hertog, Heleen M IR - Den Hertog HM FIR - Do, Ron IR - Do R FIR - Donnelly, Louise A IR - Donnelly LA FIR - Ehret, Georg B IR - Ehret GB FIR - Esko, Tonu IR - Esko T FIR - Feitosa, Mary F IR - Feitosa MF FIR - Ferreira, Teresa IR - Ferreira T FIR - Fischer, Krista IR - Fischer K FIR - Fontanillas, Pierre IR - Fontanillas P FIR - Fraser, Ross M IR - Fraser RM FIR - Freitag, Daniel F IR - Freitag DF FIR - Gurdasani, Deepti IR - Gurdasani D FIR - Heikkila, Kauko IR - Heikkila K FIR - Hypponen, Elina IR - Hypponen E FIR - Isaacs, Aaron IR - Isaacs A FIR - Jackson, Anne U IR - Jackson AU FIR - Johansson, Asa IR - Johansson A FIR - Johnson, Toby IR - Johnson T FIR - Kaakinen, Marika IR - Kaakinen M FIR - Kettunen, Johannes IR - Kettunen J FIR - Kleber, Marcus E IR - Kleber ME FIR - Li, Xiaohui IR - Li X FIR - Luan, Jian'an IR - Luan J FIR - Lyytikainen, Leo-Pekka IR - Lyytikainen LP FIR - Magnusson, Patrik K E IR - Magnusson PK FIR - Mangino, Massimo IR - Mangino M FIR - Mihailov, Evelin IR - Mihailov E FIR - Montasser, May E IR - Montasser ME FIR - Nolte, Ilja M IR - Nolte IM FIR - O'Connell, Jeffrey R IR - O'Connell JR FIR - Palmer, Cameron D IR - Palmer CD FIR - Petersen, Ann-Kristin IR - Petersen AK FIR - Sanna, Serena IR - Sanna S FIR - Saxena, Richa IR - Saxena R FIR - Service, Susan K IR - Service SK FIR - Shah, Sonia IR - Shah S FIR - Shungin, Dmitry IR - Shungin D FIR - Sidore, Carlo IR - Sidore C FIR - Song, Ci IR - Song C FIR - Strawbridge, Rona J IR - Strawbridge RJ FIR - Surakka, Ida IR - Surakka I FIR - Tanaka, Toshiko IR - Tanaka T FIR - Teslovich, Tanya M IR - Teslovich TM FIR - Thorleifsson, Gudmar IR - Thorleifsson G FIR - Van den Herik, Evita G IR - Van den Herik EG FIR - Voight, Benjamin F IR - Voight BF FIR - Volcik, Kelly A IR - Volcik KA FIR - Waite, Lindsay L IR - Waite LL FIR - Wong, Andrew IR - Wong A FIR - Wu, Ying IR - Wu Y FIR - Zhang, Weihua IR - Zhang W FIR - Absher, Devin IR - Absher D FIR - Asiki, Gershim IR - Asiki G FIR - Barroso, Ines IR - Barroso I FIR - Been, Latonya F IR - 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Reilly MP FIR - Ridker, Paul M IR - Ridker PM FIR - Rivadeneira, Fernando IR - Rivadeneira F FIR - Rudan, Igor IR - Rudan I FIR - Ruokonen, Aimo IR - Ruokonen A FIR - Scharnagl, Hubert IR - Scharnagl H FIR - Seeley, Janet IR - Seeley J FIR - Silander, Kaisa IR - Silander K FIR - Stancakova, Alena IR - Stancakova A FIR - Stirrups, Kathleen IR - Stirrups K FIR - Swift, Amy J IR - Swift AJ FIR - Tiret, Laurence IR - Tiret L FIR - Uitterlinden, Andre G IR - Uitterlinden AG FIR - van Pelt, L J IR - van Pelt LJ FIR - Vedantam, Sailaja IR - Vedantam S FIR - Wainwright, Nicholas IR - Wainwright N FIR - Wijmenga, Cisca IR - Wijmenga C FIR - Wild, Sarah H IR - Wild SH FIR - Willemsen, Gonneke IR - Willemsen G FIR - Wilsgaard, Tom IR - Wilsgaard T FIR - Wilson, James F IR - Wilson JF FIR - Young, Elizabeth H IR - Young EH FIR - Zhao, Jing Hua IR - Zhao JH FIR - Adair, Linda S IR - Adair LS FIR - Arveiler, Dominique IR - Arveiler D FIR - Assimes, Themistocles L IR - Assimes TL FIR - Bandinelli, Stefania IR - 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Roberts R FIR - Watkins, Hugh IR - Watkins H FIR - Blankenberg, Stefan IR - Blankenberg S FIR - Clarke, Robert IR - Clarke R FIR - Collins, Rory IR - Collins R FIR - Kim, Bong-Jo IR - Kim BJ FIR - McPherson, Ruth IR - McPherson R FIR - Nieminen, Markku S IR - Nieminen MS FIR - O'Donnell, Christopher IR - O'Donnell C FIR - Schreiber, Stefan IR - Schreiber S FIR - Siegbahn, Agneta IR - Siegbahn A FIR - Zalloua, Pierre A IR - Zalloua PA EDAT- 2016/03/12 06:00 MHDA- 2016/04/01 06:00 PMCR- 2016/09/11 CRDT- 2016/03/12 06:00 PHST- 2016/03/12 06:00 [entrez] PHST- 2016/03/12 06:00 [pubmed] PHST- 2016/04/01 06:00 [medline] PHST- 2016/09/11 00:00 [pmc-release] AID - 351/6278/1166 [pii] AID - 10.1126/science.aad3517 [doi] PST - ppublish SO - Science. 2016 Mar 11;351(6278):1166-71. doi: 10.1126/science.aad3517.