Multiethnic Meta-Analysis of Genome-Wide Association Studies in > 100 000 Subjects Identifies 23 FibrinogenAssociated 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 Malarstig; 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 Raikkonen; 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 Voelzke; 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; VTE Consortium

doi:10.1161/CIRCULATIONAHA.113.002251

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Multiethnic Meta-Analysis of Genome-Wide Association Studies in > 100 000 Subjects Identifies 23 FibrinogenAssociated Loci but No Strong Evidence of a Causal Association Between Circulating Fibrinogen and Cardiovascular Disease

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Multiethnic Meta-Analysis of Genome-Wide Association Studies in > 100 000 Subjects Identifies 23 FibrinogenAssociated 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, …

Circulation (New York, N.Y.), Vol.128(12), pp.1310-1324

09/17/2013

DOI: 10.1161/CIRCULATIONAHA.113.002251

PMCID: PMC3842025

PMID: 23969696

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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<5x10(-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.

Cardiac & Cardiovascular Systems

Cardiovascular System & Cardiology

Life Sciences & Biomedicine

Peripheral Vascular Disease

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Title: Subtitle: Multiethnic Meta-Analysis of Genome-Wide Association Studies in > 100 000 Subjects Identifies 23 FibrinogenAssociated Loci but No Strong Evidence of a Causal Association Between Circulating Fibrinogen and Cardiovascular Disease
Creators: Maria Sabater-Lleal - Karolinska University Hospital
Jie Huang - Framingham Heart Study
Daniel Chasman - Brigham and Women's Hospital
Silvia Naitza - CNR, Ist Ric Genet & Biomed, Cagliari, Italy
Abbas Dehghan - Erasmus University Rotterdam
Andrew D. Johnson - Framingham Heart Study
Alexander Teumer - Universitätsmedizin Greifswald
Alex P. Reiner
Lasse Folkersen - Karolinska University Hospital
Saonli Basu - University of Minnesota
Alicja R. Rudnicka - St George's, University of London
Stella Trompet - Leiden University Medical Center
Anders Malarstig - Karolinska University Hospital
Jens Baumert - Helmholtz Zentrum München
Joshua C. Bis - University of Washington
Xiuqing Guo - Cedars-Sinai Medical Center
Jouke J. Hottenga - Vrije Universiteit Amsterdam
So-Youn Shin - Wellcome Sanger Institute
Lorna M. Lopez - University of Edinburgh
Jari Lahti - University of Helsinki
Toshiko Tanaka - National Institutes of Health
Lisa R. Yanek - Johns Hopkins Medicine
Tiphaine Oudot-Mellakh - Inserm
James F. Wilson - University of Edinburgh
Pau Navarro - University of Edinburgh
Jennifer E. Huffman - Western General Hospital
Tatijana Zemunik - University of Split
Susan Redline - Beth Israel Deaconess Medical Center
Reena Mehra - Case Western Reserve University
Drazen Pulanic - University of Osijek
Igor Rudan - University of Edinburgh
Alan F. Wright - Western General Hospital
Ivana Kolcic - University of Split
Ozren Polasek - University of Split
Sarah H. Wild - University of Edinburgh
Harry Campbell - University of Edinburgh
J. David Curb - University of Hawaii System
Robert Wallace - University of Iowa
Simin Liu - University of California, Los Angeles
Charles B. Eaton - Brown University
Diane M. Becker - Johns Hopkins Medicine
Lewis C. Becker - Johns Hopkins Medicine
Stefania Bandinelli
Katri Raikkonen - University of Helsinki
Elisabeth Widen - University of Helsinki
Aarno Palotie - University of Helsinki
Myriam Fornage - The University of Texas Health Science Center at Houston
David Green - Northwestern University
Myron Gross - University of Minnesota
Gail Davies - University of Edinburgh
Sarah E. Harris - Western General Hospital
David C. Liewald - University of Edinburgh
John M. Starr - Western General Hospital
Frances M. K. Williams - King's College London
Peter J. Grant - University of Leeds
Timothy D. Spector - Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England
Rona J. Strawbridge - Karolinska University Hospital
Angela Silveira - Karolinska University Hospital
Bengt Sennblad - Karolinska University Hospital
Fernando Rivadeneira - Erasmus University Rotterdam
Andre G. Uitterlinden - Erasmus University Rotterdam
Oscar H. Franco - Erasmus University Rotterdam
Albert Hofman - Erasmus University Rotterdam
Jenny van Dongen - Vrije Universiteit Amsterdam
Gonneke Willemsen - Vrije Universiteit Amsterdam
Dorret I. Boomsma - Vrije Universiteit Amsterdam
Jie Yao - Cedars-Sinai Medical Center
Nancy Swords Jenny - University of Vermont
Talin Haritunians - Cedars-Sinai Medical Center
Barbara McKnight - University of Washington
Thomas Lumley - University of Washington
Kent D. Taylor - Cedars-Sinai Medical Center
Jerome I. Rotter - Cedars-Sinai Medical Center
Bruce M. Psaty - University of Washington
Annette Peters - Helmholtz Zentrum München
Christian Gieger - Helmholtz Zentrum München
Thomas Illig - Medizinische Hochschule Hannover
Anne Grotevendt - Universitätsmedizin Greifswald
Georg Homuth - Universität Greifswald
Henry Voelzke - Universität Greifswald
Thomas Kocher - Universität Greifswald
Anuj Goel - Centre for Human Genetics
Maria Grazia Franzosi - Mario Negri Institute for Pharmacological Research
Udo Seedorf - University of Münster
Robert Clarke - University of Oxford
Maristella Steri - CNR, Ist Ric Genet & Biomed, Cagliari, Italy
Kirill V. Tarasov - National Institutes of Health
Serena Sanna
David Schlessinger - National Institutes of Health
David J. Stott - University of Glasgow
Naveed Sattar
Brendan M. Buckley - University College Cork
Ann Rumley - University of Glasgow
Gordon D. Lowe - University of Glasgow
Wendy L. McArdle - University of Bristol
Ming-Huei Chen - Boston University
Geoffrey H. Tofler - The University of Sydney
Jaejoon Song - University of Minnesota
Eric Boerwinkle - The University of Texas Health Science Center at Houston
Aaron R. Folsom - University of Minnesota
Lynda M. Rose - Brigham and Women's Hospital
Anders Franco-Cereceda - Karolinska Institutet
Martina Teichert - Erasmus University Rotterdam
M. Arfan Ikram - Erasmus University Rotterdam
Thomas H. Mosley - University of Mississippi Medical Center
Steve Bevan - St George's, University of London
Martin Dichgans - Ludwig-Maximilians-Universität München
Peter M. Rothwell - University of Oxford
Cathie L. M. Sudlow - University of Edinburgh
Jemma C. Hopewell - University of Oxford
John C. Chambers - Imperial College London
Danish Saleheen - University of Pennsylvania
Jaspal S. Kooner - National Institutes of Health
John Danesh - University of Cambridge
Christopher P. Nelson - University of Leicester
Jeanette Erdmann - University of Lübeck
Muredach P. Reilly - National Institutes of Health
Sekar Kathiresan - Harvard University
Heribert Schunkert - University of Lübeck
Pierre-Emmanuel Morange - Aix-Marseille Université
Luigi Ferrucci - National Institutes of Health
Johan G. Eriksson - Helsinki University Hospital
David Jacobs - University of Minnesota
Ian J. Deary - University of Edinburgh
Nicole Soranzo - Wellcome Trust
Jacqueline C. M. Witteman - Erasmus University Rotterdam
Eco J. C. de Geus - Vrije Universiteit Amsterdam
Russell P. Tracy - University of Vermont
Caroline Hayward - Western General Hospital
Wolfgang Koenig - Universität Ulm
Francesco Cucca - CNR, Ist Ric Genet & Biomed, Cagliari, Italy
J. Wouter Jukema - Leiden University Medical Center
Per Eriksson - Karolinska University Hospital
Sudha Seshadri - Boston University
Hugh S. Markus - St George's, University of London
Hugh Watkins - Centre for Human Genetics
Nilesh J. Samani - University of Leicester
Henri Wallaschofski - Universitätsmedizin Greifswald
Nicholas L. Smith - University of Washington
David Tregouet - Sorbonne Université
Paul M. Ridker - Brigham and Women's Hospital
Weihong Tang - University of Minnesota
David P. Strachan - St George's, University of London
Anders Hamsten - Karolinska Institutet
Christopher J. O'Donnell - National Institutes of Health
VTE Consortium
Resource Type: Journal article
Publication Details: Circulation (New York, N.Y.), Vol.128(12), pp.1310-1324
DOI: 10.1161/CIRCULATIONAHA.113.002251
PMID: 23969696
PMCID: PMC3842025
NLM abbreviation: Circulation
ISSN: 0009-7322
eISSN: 1524-4539
Publisher: Lippincott Williams & Wilkins
Number of pages: 15
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Language: English
Date published: 09/17/2013
Academic Unit: Epidemiology; Injury Prevention Research Center; Internal Medicine
Record Identifier: 9984363584402771

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