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Meta-Analysis
. 2013 Sep 17;128(12):1310-24.
doi: 10.1161/CIRCULATIONAHA.113.002251. Epub 2013 Aug 22.

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 Lahti, Toshiko 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; VTE Consortium; STROKE Consortium; Wellcome Trust Case Control Consortium 2 (WTCCC2); C4D Consortium; CARDIoGRAM Consortium; Henri Wallaschofski, Nicholas L Smith, David Tregouet, Paul M Ridker, Weihong Tang, David P Strachan, Anders Hamsten, Christopher J O'Donnell
Collaborators
Meta-Analysis

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 et al. Circulation. .

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.

Keywords: cardiovascular diseases; fibrinogen; gene expression; genome-wide association study.

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Conflict of interest statement

Conflict of Interest Disclosures: None of the authors for this manuscript has disclosed a conflict of interest directly related to the manuscript. Martin Dichgans has declared receiving honoraria payments from Bayer Vital, Boehringer Ingelheim Pharma, Biologische Heitmittel heel, Bristol-Myers Squibb Lundbeck, Sanofi-Aventis Deustchland, Shire Deustchland, and the Deutsches Zentrum for Neurodegenerative Erkrankungen, and consults for Bayer Vital, Boehringer Ingelheim Pharma, Biologische Heitmittel heel, Bristol-Myers and Trommsdorff advisory boards. Eco de Geus has declared receiving honoraria payments for grant reviews and associate editorial functions. Bruce M. Psaty is a member of the DSMB for a clinical trial of a device funded by the manufacturer (Zoll LifeCor), and a member of the Steering Committee for the Yale Open Data Access Project funded by Medtronic. Numerous authors have noted their research is supported by government or non-profit agencies or foundations. Paul M. Ridker is a recipient of a research grant from Amgen. Henry Völzke is a recipient of a research grant from Siemens AG.

Figures

Figure 1
Figure 1
Manhattan plot of the association P-values for plasma fibrinogen concentration in the meta-analysis performed on European-ancestry samples. Analyzed SNPs are plotted on the X-axis ordered by chromosomal position. Y-axis plots the logarithm of the P-values. Gene loci labeled in green were previously known; gene loci labeled in black are novel discoveries in this meta-analysis. The dotted line indicates the threshold for genome-wide significance (P=5×10−8).
Figure 2
Figure 2
Mean values for plasma fibrinogen concentration in g/l (right Y-axis) plotted by categories of fibrinogen-associated single nucleotide polymorphism (SNP) score (X-axis), represented by the black dots. Number of individuals in each category is represented by the grey bars (left Y-axis).
See this image and copyright information in PMC

Comment in

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