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Large-scale association analysis identifies new risk loci for coronary artery disease

2012; Nature Portfolio; Volume: 45; Issue: 1 Linguagem: Inglês

10.1038/ng.2480

1546-1718

Panos Deloukas, Stavroula Kanoni, Christina Willenborg, Martin Farrall, Themistocles L. Assimes, John R. Thompson, Erik Ingelsson, Danish Saleheen, Jeanette Erdmann, Benjamin A. Goldstein, Kathleen Stirrups, Inke R. König, Jean‐Baptiste Cazier, Åsa Johansson, Alistair S. Hall, Jong‐Young Lee, Cristen J. Willer, John C. Chambers, Tõnu Esko, Lasse Folkersen, Anuj Goel, Elin Grundberg, Aki S. Havulinna, Weang-Kee Ho, Jemma C. Hopewell, Niclas Eriksson, Marcus E. Kleber, Kati Kristiansson, Per Lundmark, Leo‐Pekka Lyytikäinen, Suzanne Rafelt, Dmitry Shungin, Rona J. Strawbridge, Guðmar Þorleifsson, Emmi Tikkanen, Natalie Van Zuydam, Benjamin F. Voight, Lindsay L. Waite, Weihua Zhang, Andreas Ziegler, Devin Absher, David Altshuler, Anthony J. Balmforth, Inês Barroso, Peter S. Braund, Christof Burgdorf, Xueling Sim, David Cox, Maria Dimitriou, Ron Do, Alex S. F. Doney, NourEddine El Mokhtari, Per Eriksson, Krista Fischer, Pierre Fontanillas, Anders Franco‐Cereceda, Bruna Gigante, Per‐Henrik Groop, Stefan Gustafsson, Jörg Hager, Göran Hallmans, Bok-Ghee Han, Sarah Hunt, Hyun Min Kang, Thomas Illig, Thorsten Kessler, Joshua Knowles, Genovefa Kolovou, Johanna Kuusisto, Claudia Langenberg, Cordelia Langford, Karin Leander, Marja‐Liisa Lokki, Anders Lundmark, Mark I. McCarthy, Christa Meisinger, Olle Melander, Evelin Mihailov, Seraya Maouche, Andrew D. Morris, Martina Müller‐Nurasyid, Kjell Nikus, John F. Peden, Nigel W. Rayner, Asif Rasheed, Silke Rosinger, Deborah C. Rubin, Moritz Rumpf, Arne Schäfer, Mohan U. Sivananthan, Ci Song, Alexandre F.R. Stewart, Sian-Tsung Tan, Guðmundur Þorgeirsson, C. Ellen van der Schoot, Peter J. Wagner, George A. Wells, Philipp S. Wild, Tsun-Po Yang, Philippe Amouyel, Dominique Arveiler, Hanneke Basart, Michael Boehnke, Eric Boerwinkle, Paolo Brambilla, François Cambien, L. Adrienne Cupples, Ulf dé Fairé, Abbas Dehghan, Patrick Diemert, Stephen E. Epstein, Alun Evans, Maurizio Ferrario, Jean Ferrières, Dominique Gauguier, Alan S. Go, Alison H. Goodall, Vilmundur Guðnason, Stanley L. Hazen, Hilma Hólm, Carlos Iribarren, Yangsoo Jang, Mika Kähönen, Frank Kee, Hyo‐Soo Kim, Norman Klopp, Wolfgang Köenig, Wolfgang Kratzer, Kari Kuulasmaa, Markku Laakso, Reijo Laaksonen, Ji‐Young Lee, Lars Lind, Willem H. Ouwehand, Sarah Parish, Jeong E. Park, Nancy L. Pedersen, Annette Peters, Thomas Quertermous, Daniel J. Rader, Veikko Salomaa, Eric E. Schadt, Svati H. Shah, Juha Sinisalo, Klaus Stark, Kāri Stefánsson, David‐Alexandre Trégouët, Jarmo Virtamo, Lars Wallentin, Nicholas J. Wareham, Martina E. Zimmermann, Markku S. Nieminen, Christian Hengstenberg, Manjinder S. Sandhu, Tomi Pastinen, Ann-Christine Syvänen, G. Kees Hovingh, George Dedoussis, Paul W. Franks, Terho Lehtimäki, Andres Metspalu, Pierre Zalloua, Agneta Siegbahn, Stefan Schreiber, Samuli Ripatti, Stefan S Blankenberg, Markus Perola, Robert Clarke, Bernhard O. Boehm, Christopher J. O’Donnell, Muredach P. Reilly, Winfried März, Rory Collins, Sekar Kathiresan, Anders Hamsten, Jaspal S. Kooner, Unnur Þorsteinsdóttir, John Danesh, Colin N. A. Palmer, Robert Roberts, Hugh Watkins, Heribert Schunkert, Nilesh J. Samani,

Kruppel-like factors research

Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r(2) < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways.