Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease

Maria Sabater-Lleal, Jie Huang, Daniel Chasman, Silvia Naitza, Abbas Dehghan, Andrew D. Johnson, Alexander Teumer, Alex P. Reiner, Lasse Folkersen, Saonli Basu, Alicja R. Rudnicka, Stella Trompet, Anders Mälarstig, Jens Baumert, Joshua C. Bis, Xiuqing Guo, Jouke J. Hottenga, So Youn Shin, Lorna M. Lopez, Jari LahtiToshiko Tanaka, Lisa R. Yanek, Tiphaine Oudot-Mellakh, James F. Wilson, Pau Navarro, Jennifer E. Huffman, Tatijana Zemunik, Susan Redline, Reena Mehra, Drazen Pulanic, Igor Rudan, Alan F. Wright, Ivana Kolcic, Ozren Polasek, Sarah H. Wild, Harry Campbell, J. David Curb, Robert Wallace, Simin Liu, Charles B. Eaton, Diane M. Becker, Lewis C. Becker, Stefania Bandinelli, Katri Räikkönen, Elisabeth Widen, Aarno Palotie, Myriam Fornage, David Green, Myron Gross, Gail Davies, Sarah E. Harris, David C. Liewald, John M. Starr, Frances M K Williams, Peter J. Grant, Timothy D. Spector, Rona J. Strawbridge, Angela Silveira, Bengt Sennblad, Fernando Rivadeneira, Andre G. Uitterlinden, Oscar H. Franco, Albert Hofman, Jenny Van Dongen, Gonneke Willemsen, Dorret I. Boomsma, Jie Yao, Nancy Swords Jenny, Talin Haritunians, Barbara McKnight, Thomas Lumley, Kent D. Taylor, Jerome I. Rotter, Bruce M. Psaty, Annette Peters, Christian Gieger, Thomas Illig, Anne Grotevendt, Georg Homuth, Henry Völzke, Thomas Kocher, Anuj Goel, Maria Grazia Franzosi, Udo Seedorf, Robert Clarke, Maristella Steri, Kirill V. Tarasov, Serena Sanna, David Schlessinger, David J. Stott, Naveed Sattar, Brendan M. Buckley, Ann Rumley, Gordon D. Lowe, Wendy L. McArdle, Ming Huei Chen, Geoffrey H. Tofler, Jaejoon Song, Eric Boerwinkle, Aaron R. Folsom, Lynda M. Rose, Anders Franco-Cereceda, Martina Teichert, M. Arfan Ikram, Thomas H. Mosley, Steve Bevan, Martin Dichgans, Peter M. Rothwell, Cathie L M Sudlow, Jemma C. Hopewell, John C. Chambers, Danish Saleheen, Jaspal S. Kooner, John Danesh, Christopher P. Nelson, Jeanette Erdmann, Muredach P. Reilly, Sekar Kathiresan, Heribert Schunkert, Pierre Emmanuel Morange, Luigi Ferrucci, Johan G. Eriksson, David Jacobs, Ian J. Deary, Nicole Soranzo, Jacqueline C M Witteman, Eco J C De Geus, Russell P. Tracy, Caroline Hayward, Wolfgang Koenig, Francesco Cucca, J. Wouter Jukema, Per Eriksson, Sudha Seshadri, Hugh S. Markus, Hugh Watkins, Nilesh J. Samani, Henri Wallaschofski, Nicholas L. Smith, David Tregouet, Paul M. Ridker, Weihong Tang, David P. Strachan, Anders Hamsten, Christopher J. O'Donnell

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Abstract

BACKGROUND-: Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-wide association studies explain only a small proportion (<2%) of its variation. METHODS AND RESULTS-: We conducted a meta-analysis of 28 genome-wide association studies including >90 000 subjects of European ancestry, the first genome-wide association meta-analysis of fibrinogen levels in 7 studies in blacks totaling 8289 samples, and a genome-wide association study in Hispanics totaling 1366 samples. Evaluation for association of single-nucleotide polymorphisms with clinical outcomes included a total of 40 695 cases and 85 582 controls for coronary artery disease, 4752 cases and 24 030 controls for stroke, and 3208 cases and 46 167 controls for venous thromboembolism. Overall, we identified 24 genome-wide significant (P<5×10) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the 3 structural fibrinogen genes and pathways related to inflammation, adipocytokines, and thyrotrophin-releasing hormone signaling. Whereas lead single-nucleotide polymorphisms in a few loci were significantly associated with coronary artery disease, the combined effect of all 24 fibrinogen-associated lead single-nucleotide polymorphisms was not significant for coronary artery disease, stroke, or venous thromboembolism. CONCLUSIONS-: We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism.

Original languageEnglish (US)
Pages (from-to)1310-1324
Number of pages15
JournalCirculation
Volume128
Issue number12
DOIs
StatePublished - Sep 17 2013

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    Sabater-Lleal, M., Huang, J., Chasman, D., Naitza, S., Dehghan, A., Johnson, A. D., Teumer, A., Reiner, A. P., Folkersen, L., Basu, S., Rudnicka, A. R., Trompet, S., Mälarstig, A., Baumert, J., Bis, J. C., Guo, X., Hottenga, J. J., Shin, S. Y., Lopez, L. M., ... O'Donnell, C. J. (2013). Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease. Circulation, 128(12), 1310-1324. https://doi.org/10.1161/CIRCULATIONAHA.113.002251