Sabater-Lleal, Maria and Huang, Jie and Chasman, Daniel and Naitza, Silvia and Dehghan, Abbas and Johnson, Andrew D. and Teumer, Alexander and Reiner, Alex P. and Folkersen, Lasse and Basu, Saonli and Rudnicka, Alicja R. and Trompet, Stella and Mälarstig, Anders and Baumert, Jens and Bis, Joshua C. and Guo, Xiuqing and Hottenga, Jouke J. and Shin, So-Youn and Lopez, Lorna M. and Lahti, Jari and Tanaka, Toshiko and Yanek, Lisa R. and Oudot-Mellakh, Tiphaine and Wilson, James F. and Navarro, Pau and Huffman, Jennifer E. and Zemunik, Tatijana and Redline, Susan and Mehra, Reena and Pulanic, Drazen and Rudan, Igor and Wright, Alan F. and Kolcic, Ivana and Polasek, Ozren and Wild, Sarah H. and Campbell, Harry and Curb, J. David and Wallace, Robert and Liu, Simin and Eaton, Charles B. and Becker, Diane M. and Becker, Lewis C. and Bandinelli, Stefania and Räikkönen, Katri and Widen, Elisabeth and Palotie, Aarno and Fornage, Myriam and Green, David and Gross, Myron and Davies, Gail and Harris, Sarah E. and Liewald, David C. and Starr, John M. and Williams, Frances M.K. and Grant, Peter J. and Spector, Timothy D. and Strawbridge, Rona J. and Silveira, Angela and Sennblad, Bengt and Rivadeneira, Fernando and Uitterlinden, Andre G. and Franco, Oscar H. and Hofman, Albert and van Dongen, Jenny and Willemsen, Gonneke and Boomsma, Dorret I. and Yao, Jie and Swords Jenny, Nancy and Haritunians, Talin and McKnight, Barbara and Lumley, Thomas and Taylor, Kent D. and Rotter, Jerome I. and Psaty, Bruce M. and Peters, Annette and Gieger, Christian and Illig, Thomas and Grotevendt, Anne and Homuth, Georg and Völzke, Henry and Kocher, Thomas and Goel, Anuj and Franzosi, Maria Grazia and Seedorf, Udo and Clarke, Robert and Steri, Maristella and Tarasov, Kirill V. and Sanna, Serena and Schlessinger, David and Stott, David J. and Sattar, Naveed and Buckley, Brendan M. and Rumley, Ann and Lowe, Gordon D. and McArdle, Wendy L. and Chen, Ming-Huei and Tofler, Geoffrey H. and Song, Jaejoon and Boerwinkle, Eric and Folsom, Aaron R. and Rose, Lynda M. and Franco-Cereceda, Anders and Teichert, Martina and Ikram, M. Arfan and Mosley, Thomas H. and Bevan, Steve and Dichgans, Martin and Rothwell, Peter M. and Sudlow, Cathie L.M. and Hopewell, Jemma C. and Chambers, John C. and Saleheen, Danish and Kooner, Jaspal S. and Danesh, John and Nelson, Christopher P. and Erdmann, Jeanette and Reilly, Muredach P. and Kathiresan, Sekar and Schunkert, Heribert and Morange, Pierre-Emmanuel and Ferrucci, Luigi and Eriksson, Johan G. and Jacobs, David and Deary, Ian J. and Soranzo, Nicole and Witteman, Jacqueline C.M. and de Geus, Eco J.C. and Tracy, Russell P. and Hayward, Caroline and Koenig, Wolfgang and Cucca, Francesco and Jukema, J. Wouter and Eriksson, Per and Seshadri, Sudha and Markus, Hugh S. and Watkins, Hugh and Samani, Nilesh J. and Wallaschofski, Henri and Smith, Nicholas L. and Tregouet, David and Ridker, Paul M and Tang, Weihong and Strachan, David P. and Hamsten, Anders and O’Donnell, Christopher 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). pp. 1310-1324. ISSN 0009-7322

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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(-8)) 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.

Item Type:	Article
Keywords:	cardiovascular diseases; fibrinogen; gene expression; genome-wide association study;
Academic Unit:	Faculty of Science and Engineering > Biology Faculty of Science and Engineering > Research Institutes > Human Health Institute
Item ID:	17250
Identification Number:	https://doi.org/10.1161/CIRCULATIONAHA.113.002251
Depositing User:	Lorna Lopez
Date Deposited:	29 May 2023 15:17
Journal or Publication Title:	Circulation
Publisher:	Lippincott, Williams & Wilkins
Refereed:	Yes
URI:	Publisher
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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