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

著者: Paolo Zanoni, Sumeet A. Khetarpal, Daniel B. Larach, William Hancock‐Cerutti, John S. Millar, Marina Cuchel, Stephanie DerOhannessian, Anatol Kontush, Praveen Surendran, Danish Saleheen, Stella Trompet, J. Wouter Jukema, Anton de Craen, Panos Deloukas, Naveed Sattar, Ian Ford, Chris J. Packard, Abdullah Al Shafi Majumder, Dewan S Alam, Emanuele Di Angelantonio, Gonçalo R. Abecasis, Rajiv Chowdhury, Jeanette Erdmann, Børge G. Nordestgaard, Sune F. Nielsen, Anne Tybjærg‐Hansen, Ruth Frikke‐Schmidt, Kari Kuulasmaa, Dajiang J. Liu, Markus Perola, Stefan Blankenberg, Veikko Salomaa, Satu Männistö, Philippe Amouyel, Dominique Arveiler, Jean Ferrières, Martina Müller‐Nurasyid, Maurizio Ferrario, Frank Kee, Cristen J. Willer, Nilesh J. Samani, Heribert Schunkert, Adam S. Butterworth, Joanna M. M. Howson, Gina M. Peloso, Nathan O. Stitziel, John Danesh, Sekar Kathiresan, Daniel J. Rader, Sarah Watson, Ellen M. Schmidt, Sebanti Sengupta, Stefan Gustafsson, Stavroula Kanoni, Andrea Ganna, Jin Chen, Martin L. Buchkovich, Samia Mora, J. Beckmann, Jennifer L. Bragg‐Gresham, Hsing‐Yi Chang, Ayşe Demirkan, Heleen M. den Hertog, Ron Do, Louise A. Donnelly, Georg Ehret, Tõnu Esko, Mary F. Feitosa, Teresa Ferreira, Krista Fischer, Pierre Fontanillas, Ross M. Fraser, Daniel F. Freitag, Deepti Gurdasani, Kauko Heikkilä, Elina Hyppönen, Aaron Isaacs, Anne Jackson, Åsa Johansson, Toby Johnson, Marika Kaakinen, Johannes Kettunen, Marcus E. Kleber, Xiaohui Li, Jian’an Luan, Leo‐Pekka Lyytikäinen, Patrik K. E. Magnusson, Massimo Mangino, Evelin Mihailov, May E. Montasser, Ilja M. Nolte, Jeffrey R. O’Connell, Cameron D. Palmer, Ann-Kristin Petersen, Serena Sanna, Richa Saxena, Susan K. Service, Sonia Shah, Dmitry Shungin, Carlo Sidore, Ci Song, Rona J. Strawbridge, Ida Surakka, Toshiko Tanaka, Tanya M. Teslovich, Guðmar Þorleifsson, Evita G. van den Herik, Benjamin F. Voight, Kelly A. Volcik, Lindsay L. Waite, Andrew Wong, Ying Wu, Weihua Zhang, Devin Absher, Gershim Asiki, Inês Barroso, Latonya Been, Jennifer L. Bolton, Lori L. Bonnycastle, Paolo Brambilla, Mary Susan Burnett, Giancarlo Cesana, Maria Dimitriou, Alex S. F. Doney, Angela Döring, Paul Elliott, Stephen E. Epstein, Guðmundur I. Eyjólfsson, Bruna Gigante, Mark O. Goodarzi, Harald Grallert, Martha L. Gravito, Christopher J. Groves, Göran Hallmans, Anna‐Liisa Hartikainen, Caroline Hayward, Dena Hernandez, Andrew A. Hicks, Hilma Hólm, Yi‐Jen Hung, Thomas Illig, Michelle R. Jones, Pontiano Kaleebu, John J.P. Kastelein, Kay‐Tee Khaw, Eric H. Kim, Norman Klopp, Pirjo Komulainen, Meena Kumari, Claudia Langenberg, Terho Lehtimäki, Shih-Yi Lin, Jaana Lindström, Ruth J. F. Loos, François Mach, Wendy L. McArdle, Christa Meisinger, Braxton D. Mitchell, Gabrielle Müller, Ramaiah Nagaraja, Narisu Narisu, Tuomo Nieminen, Rebecca N. Nsubuga, Ísleifur Ólafsson, Ken K. Ong, Aarno Palotie, Theodore Papamarkou, Cristina Pomilla, Anneli Pouta, Muredach P. Reilly, Paul M. Ridker, Fernando Rivadeneira, Igor Rudan, A Ruokonen, Hubert Scharnagl, Janet Seeley, Kaisa Silander, Alena Stančáková, Kathleen Stirrups, Amy J. Swift, Laurence Tiret, André G. Uitterlinden, L. J. van Pelt, Sailaja Vedantam, Nicholas W.J. Wainwright, Cisca Wijmenga, Sarah H. Wild, Gonneke Willemsen, Tom Wilsgaard, James F. Wilson, Elizabeth Young, Wei Zhao, Linda S. Adair, Dominique Arveiler, Themistocles L. Assimes, Stefania Bandinelli, Franklyn I. Bennett, Murielle Bochud, Bernhard O. Boehm, Dorret I. Boomsma, Ingrid B. Borecki, Stefan R. Bornstein, Pascal Bovet, Michel Burnier, Harry Campbell, Aravinda Chakravarti, John C. Chambers, Yii‐Der Ida Chen, Francis S. Collins, Richard S. Cooper, George Dedoussis, Ulf dé Fairé, Alan B. Feranil, Luigi Ferrucci, Nelson B. Freimer, Christian Gieger, Leif Groop, Vilmundur Guðnason, Ulf Gyllensten, Anders Hamsten, Tamara B. Harris, Aroon D. Hingorani, Joel N. Hirschhorn, Albert Hofman, G. Kees Hovingh, Chao A. Hsiung, Steve E. Humphries, Steven C. Hunt, Kristian Hveem, Carlos Iribarren, Marjo‐Riitta Järvelin, Antti Jula, Mika Kähönen, Jaakko Kaprio, Antero Kesäniemi, Mika Kivimäki, Jaspal S. Kooner, Peter J. Koudstaal, Ronald M. Krauss, Diana Kuh, Johanna Kuusisto, Kirsten Ohm Kyvik, Markku Laakso, Timo A. Lakka, Lars Lind, Cecilia M. Lindgren, Nicholas G. Martin, Winfried März, Mark I. McCarthy, Colin A. McKenzie, Pierre Meneton, Andres Metspalu, Leena Moilanen, Andrew D. Morris, Patricia B. Munroe, Inger Njølstad, Nancy L. Pedersen, Chris Power, Peter P. Pramstaller, Jackie F. Price, Bruce M. Psaty, Thomas Quertermous, Rainer Rauramaa, Veikko Salomaa, Dharambir K. Sanghera, Jouko Saramies, Peter E. H. Schwarz, Wayne H.-H. Sheu, Alan R. Shuldiner, Agneta Siegbahn, Tim D. Spector, Kāri Stefánsson, David P. Strachan, Bamidele O. Tayo, Elena Tremoli, Jaakko Tuomilehto, Matti Uusitupa, Cornelia M. van Duijn, Péter Vollenweider, Lars Wallentin, Nicholas J. Wareham, John B. Whitfield, Bruce H. R. Wolffenbuttel, José M. Ordovás, Eric Boerwinkle, Colin N. A. Palmer, Unnur Þorsteinsdóttir, Daniel I. Chasman, Jerome I. Rotter, Paul W. Franks, Samuli Riatti, L. Adrienne Cupples, Manjinder S. Sandhu, Stephen S. Rich, Michael Boehnke, Panos Deloukas, Karen L. Mohlke, Erik Ingelsson, Dongfeng Gu, Robert Roberts, Hugh Watkins, Stefan Blankenberg, Robert Clarke, Rory Collins, Bong-Jo Kim, Ruth McPherson, Markku S. Nieminen, Christopher J. O’Donnell, Stefan Schreiber, Agneta Siegbahn, Pierre Zalloua - Science 2016 被引用: 551

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).