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

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. We conducted a meta-analysis o...

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Vydané v:	Circulation (New York, N.Y.) Ročník 128; číslo 12; s. 1310
Hlavní autori:	Sabater-Lleal, Maria, Huang, Jie, Chasman, Daniel, Naitza, Silvia, Dehghan, Abbas, Johnson, Andrew D, Teumer, Alexander, Reiner, Alex P, Folkersen, Lasse, Basu, Saonli, Rudnicka, Alicja R, Trompet, Stella, Mälarstig, Anders, Baumert, Jens, Bis, Joshua C, Guo, Xiuqing, Hottenga, Jouke J, Shin, So-Youn, Lopez, Lorna M, Lahti, Jari, Tanaka, Toshiko, Yanek, Lisa R, Oudot-Mellakh, Tiphaine, Wilson, James F, Navarro, Pau, Huffman, Jennifer E, Zemunik, Tatijana, Redline, Susan, Mehra, Reena, Pulanic, Drazen, Rudan, Igor, Wright, Alan F, Kolcic, Ivana, Polasek, Ozren, Wild, Sarah H, Campbell, Harry, Curb, J David, Wallace, Robert, Liu, Simin, Eaton, Charles B, Becker, Diane M, Becker, Lewis C, Bandinelli, Stefania, Räikkönen, Katri, Widen, Elisabeth, Palotie, Aarno, Fornage, Myriam, Green, David, Gross, Myron, Davies, Gail, Harris, Sarah E, Liewald, David C, Starr, John M, Williams, Frances M K, Grant, Peter J, Spector, Timothy D, Strawbridge, Rona J, Silveira, Angela, Sennblad, Bengt, Rivadeneira, Fernando, Uitterlinden, Andre G, Franco, Oscar H, Hofman, Albert, van Dongen, Jenny, Willemsen, Gonneke, Boomsma, Dorret I, Yao, Jie, Swords Jenny, Nancy, Haritunians, Talin, McKnight, Barbara, Lumley, Thomas, Taylor, Kent D, Rotter, Jerome I, Psaty, Bruce M, Peters, Annette, Gieger, Christian, Illig, Thomas, Grotevendt, Anne, Homuth, Georg, Völzke, Henry, Kocher, Thomas, Goel, Anuj, Franzosi, Maria Grazia, Seedorf, Udo, Clarke, Robert, Steri, Maristella, Tarasov, Kirill V, Sanna, Serena, Schlessinger, David, Stott, David J, Sattar, Naveed, Buckley, Brendan M, Rumley, Ann, Lowe, Gordon D, McArdle, Wendy L, Chen, Ming-Huei, Tofler, Geoffrey H, Song, Jaejoon, Boerwinkle, Eric, Folsom, Aaron R
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States 17.09.2013
Predmet:	Adolescent Adult Aged Aged, 80 and over Black People - genetics Black People - statistics & numerical data Cardiovascular Diseases - ethnology Cardiovascular Diseases - genetics Cardiovascular Diseases - metabolism Coronary Artery Disease - ethnology Coronary Artery Disease - genetics Coronary Artery Disease - metabolism Female Fibrinogen - genetics Fibrinogen - metabolism Genetic Loci - genetics Genetic Predisposition to Disease - ethnology Genome-Wide Association Study Hispanic or Latino - genetics Hispanic or Latino - statistics & numerical data Humans Male Middle Aged Myocardial Infarction - ethnology Myocardial Infarction - genetics Myocardial Infarction - metabolism Polymorphism, Single Nucleotide - genetics Risk Factors Stroke - ethnology Stroke - genetics Stroke - metabolism Venous Thromboembolism - ethnology Venous Thromboembolism - genetics Venous Thromboembolism - metabolism White People - genetics White People - statistics & numerical data Young Adult cardiovascular diseases fibrinogen gene expression genome-wide association study
ISSN:	1524-4539, 1524-4539
On-line prístup:	Zistit podrobnosti o prístupe
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Abstract	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. 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. 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.
AbstractList	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. 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. 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. 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.BACKGROUNDEstimates 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.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.METHODS AND RESULTSWe 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.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.CONCLUSIONSWe 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.
Author	Boomsma, Dorret I Seedorf, Udo Spector, Timothy D Hottenga, Jouke J Franco, Oscar H Räikkönen, Katri Liu, Simin van Dongen, Jenny Silveira, Angela Rotter, Jerome I Chen, Ming-Huei McKnight, Barbara Sanna, Serena Chasman, Daniel Fornage, Myriam Zemunik, Tatijana Basu, Saonli Reiner, Alex P Becker, Diane M Yanek, Lisa R Rudan, Igor Swords Jenny, Nancy Peters, Annette Bis, Joshua C Williams, Frances M K Navarro, Pau Wilson, James F Harris, Sarah E Stott, David J Campbell, Harry Eaton, Charles B Strawbridge, Rona J Redline, Susan Lowe, Gordon D Folsom, Aaron R Naitza, Silvia Davies, Gail Boerwinkle, Eric Dehghan, Abbas Oudot-Mellakh, Tiphaine Song, Jaejoon Gieger, Christian Psaty, Bruce M Yao, Jie Curb, J David Pulanic, Drazen Sattar, Naveed Shin, So-Youn Palotie, Aarno McArdle, Wendy L Haritunians, Talin Kocher, Thomas Goel, Anuj Wright, Alan F Folkersen, Lasse Polasek, Ozren Franzosi, Maria Grazia Gross, Myron Starr, John M Sennblad, Bengt Becker, Lewis C Trompet, Stella Rivadeneira, Fernando Homuth, Georg Lahti, Jari Tanaka, Toshiko Wild, Sarah H Kolci
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BackLink	https://www.ncbi.nlm.nih.gov/pubmed/23969696$$D View this record in MEDLINE/PubMed
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ContentType	Journal Article
Contributor	Rautanen, Anna Bramon, Elvira Cupples, L Adrienne Plomin, Robert Thorleifsson, Gudmar Jankowski, Janusz Wells, George A Pirinen, Matti Ziegler, Andreas Trembath, Richard C Chen, Li McCann, Owen T Hellenthal, Garrett Pearson, Richard Band, Gavin Thompson, John R Markus, Hugh S Hunt, Sarah E Erdmann, Jeanette Palmer, Colin N A Hengstenberg, Christian McPherson, Ruth Reilly, Muredach P Deloukas, Panos Blackburn, Hannah Donnelly, Peter Samani, Nilesh J Ravindrarajah, Radhi Schunkert, Heribert Mathew, Christopher G Sawcer, Stephen J Giannoulatou, Eleni Edkins, Sarah Waller, Matthew Barroso, Ines Gillman, Matthew Kathiresan, Sekar Liddle, Jennifer König, Inke R Whittaker, Pamela Absher, Devin Hammond, Naomi Hall, Alistair Wood, Nicholas W Widaa, Sara Viswanathan, Ananth C Strange, Amy Preuss, Michael Su, Zhan Potter, Simon C Laaksonen, Reijo Thorsteinsdottir, Unnur Vukcevic, Damjan Boerwinkle, Eric Langford, Cordelia Schillert, Arne Voight, Benjamin F Freeman, Colin Musunuru, Kiran Blackwell, Jenefer M Gwilliam, Rhian Holm, Hilma Assimes, Themistocles
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References	23969697 - Circulation. 2013 Sep 17;128(12):1276-80. doi: 10.1161/CIRCULATIONAHA.113.005125.
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Snippet	Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants...
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SubjectTerms	Adolescent Adult Aged Aged, 80 and over Black People - genetics Black People - statistics & numerical data Cardiovascular Diseases - ethnology Cardiovascular Diseases - genetics Cardiovascular Diseases - metabolism Coronary Artery Disease - ethnology Coronary Artery Disease - genetics Coronary Artery Disease - metabolism Female Fibrinogen - genetics Fibrinogen - metabolism Genetic Loci - genetics Genetic Predisposition to Disease - ethnology Genome-Wide Association Study Hispanic or Latino - genetics Hispanic or Latino - statistics & numerical data Humans Male Middle Aged Myocardial Infarction - ethnology Myocardial Infarction - genetics Myocardial Infarction - metabolism Polymorphism, Single Nucleotide - genetics Risk Factors Stroke - ethnology Stroke - genetics Stroke - metabolism Venous Thromboembolism - ethnology Venous Thromboembolism - genetics Venous Thromboembolism - metabolism White People - genetics White People - statistics & numerical data Young Adult
Title	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
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