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 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

doi:10.1161/CIRCULATIONAHA.113.002251

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 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

School of Medicine

Research output: Contribution to journal › Article › peer-review

95 Scopus citations

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 language	English (US)
Pages (from-to)	1310-1324
Number of pages	15
Journal	Circulation
Volume	128
Issue number	12
DOIs	https://doi.org/10.1161/CIRCULATIONAHA.113.002251
State	Published - Sep 17 2013

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine
Physiology (medical)

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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

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. / Sabater-Lleal, Maria; Huang, Jie; Chasman, Daniel et al.
In: Circulation, Vol. 128, No. 12, 17.09.2013, p. 1310-1324.

Research output: Contribution to journal › Article › peer-review

Sabater-Lleal, M, Huang, J, Chasman, D, Naitza, S, Dehghan, A, Johnson, AD, Teumer, A, Reiner, AP, Folkersen, L, Basu, S, Rudnicka, AR, Trompet, S, Mälarstig, A, Baumert, J, Bis, JC, Guo, X, Hottenga, JJ, Shin, SY, Lopez, LM, Lahti, J, Tanaka, T, Yanek, LR, Oudot-Mellakh, T, Wilson, JF, Navarro, P, Huffman, JE, Zemunik, T, Redline, S, Mehra, R, Pulanic, D, Rudan, I, Wright, AF, Kolcic, I, Polasek, O, Wild, SH, Campbell, H, Curb, JD, Wallace, R, Liu, S, Eaton, CB, Becker, DM, Becker, L, Bandinelli, S, Räikkönen, K, Widen, E, Palotie, A, Fornage, M, Green, D, Gross, M, Davies, G, Harris, SE, Liewald, DC, Starr, JM, Williams, FMK, Grant, PJ, Spector, TD, Strawbridge, RJ, Silveira, A, Sennblad, B, Rivadeneira, F, Uitterlinden, AG, Franco, OH, Hofman, A, Van Dongen, J, Willemsen, G, Boomsma, DI, Yao, J, Swords Jenny, N, Haritunians, T, McKnight, B, Lumley, T, Taylor, KD, Rotter, JI, Psaty, BM, Peters, A, Gieger, C, Illig, T, Grotevendt, A, Homuth, G, Völzke, H, Kocher, T, Goel, A, Franzosi, MG, Seedorf, U, Clarke, R, Steri, M, Tarasov, KV, Sanna, S, Schlessinger, D, Stott, DJ, Sattar, N, Buckley, BM, Rumley, A, Lowe, GD, McArdle, WL, Chen, MH, Tofler, GH, Song, J, Boerwinkle, E, Folsom, AR, Rose, LM, Franco-Cereceda, A, Teichert, M, Ikram, MA, Mosley, TH, Bevan, S, Dichgans, M, Rothwell, PM, Sudlow, CLM, Hopewell, JC, Chambers, JC, Saleheen, D, Kooner, JS, Danesh, J, Nelson, CP, Erdmann, J, Reilly, MP, Kathiresan, S, Schunkert, H, Morange, PE, Ferrucci, L, Eriksson, JG, Jacobs, D, Deary, IJ, Soranzo, N, Witteman, JCM, De Geus, EJC, Tracy, RP, Hayward, C, Koenig, W, Cucca, F, Jukema, JW, Eriksson, P, Seshadri, S, Markus, HS, Watkins, H, Samani, NJ, Wallaschofski, H, Smith, NL, Tregouet, D, Ridker, PM, Tang, W, Strachan, DP, Hamsten, A & O'Donnell, CJ 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, vol. 128, no. 12, pp. 1310-1324. https://doi.org/10.1161/CIRCULATIONAHA.113.002251

Sabater-Lleal M, Huang J, Chasman D, Naitza S, Dehghan A, Johnson AD et al. 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. 2013 Sep 17;128(12):1310-1324. doi: 10.1161/CIRCULATIONAHA.113.002251

@article{93fe0ba946d449b49e92475fc952d011,

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",

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.",

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

year = "2013",

month = sep,

day = "17",

doi = "10.1161/CIRCULATIONAHA.113.002251",

language = "English (US)",

volume = "128",

pages = "1310--1324",

journal = "Circulation",

issn = "0009-7322",

publisher = "Lippincott Williams and Wilkins",

number = "12",

}

TY - JOUR

T1 - 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

AU - Sabater-Lleal, Maria

AU - Huang, Jie

AU - Chasman, Daniel

AU - Naitza, Silvia

AU - Dehghan, Abbas

AU - Johnson, Andrew D.

AU - Teumer, Alexander

AU - Reiner, Alex P.

AU - Folkersen, Lasse

AU - Basu, Saonli

AU - Rudnicka, Alicja R.

AU - Trompet, Stella

AU - Mälarstig, Anders

AU - Baumert, Jens

AU - Bis, Joshua C.

AU - Guo, Xiuqing

AU - Hottenga, Jouke J.

AU - Shin, So Youn

AU - Lopez, Lorna M.

AU - Lahti, Jari

AU - Tanaka, Toshiko

AU - Yanek, Lisa R.

AU - Oudot-Mellakh, Tiphaine

AU - Wilson, James F.

AU - Navarro, Pau

AU - Huffman, Jennifer E.

AU - Zemunik, Tatijana

AU - Redline, Susan

AU - Mehra, Reena

AU - Pulanic, Drazen

AU - Rudan, Igor

AU - Wright, Alan F.

AU - Kolcic, Ivana

AU - Polasek, Ozren

AU - Wild, Sarah H.

AU - Campbell, Harry

AU - Curb, J. David

AU - Wallace, Robert

AU - Liu, Simin

AU - Eaton, Charles B.

AU - Becker, Diane M

AU - Becker, Lewis

AU - Bandinelli, Stefania

AU - Räikkönen, Katri

AU - Widen, Elisabeth

AU - Palotie, Aarno

AU - Fornage, Myriam

AU - Green, David

AU - Gross, Myron

AU - Davies, Gail

AU - Harris, Sarah E.

AU - Liewald, David C.

AU - Starr, John M.

AU - Williams, Frances M.K.

AU - Grant, Peter J.

AU - Spector, Timothy D.

AU - Strawbridge, Rona J.

AU - Silveira, Angela

AU - Sennblad, Bengt

AU - Rivadeneira, Fernando

AU - Uitterlinden, Andre G.

AU - Franco, Oscar H.

AU - Hofman, Albert

AU - Van Dongen, Jenny

AU - Willemsen, Gonneke

AU - Boomsma, Dorret I.

AU - Yao, Jie

AU - Swords Jenny, Nancy

AU - Haritunians, Talin

AU - McKnight, Barbara

AU - Lumley, Thomas

AU - Taylor, Kent D.

AU - Rotter, Jerome I.

AU - Psaty, Bruce M.

AU - Peters, Annette

AU - Gieger, Christian

AU - Illig, Thomas

AU - Grotevendt, Anne

AU - Homuth, Georg

AU - Völzke, Henry

AU - Kocher, Thomas

AU - Goel, Anuj

AU - Franzosi, Maria Grazia

AU - Seedorf, Udo

AU - Clarke, Robert

AU - Steri, Maristella

AU - Tarasov, Kirill V.

AU - Sanna, Serena

AU - Schlessinger, David

AU - Stott, David J.

AU - Sattar, Naveed

AU - Buckley, Brendan M.

AU - Rumley, Ann

AU - Lowe, Gordon D.

AU - McArdle, Wendy L.

AU - Chen, Ming Huei

AU - Tofler, Geoffrey H.

AU - Song, Jaejoon

AU - Boerwinkle, Eric

AU - Folsom, Aaron R.

AU - Rose, Lynda M.

AU - Franco-Cereceda, Anders

AU - Teichert, Martina

AU - Ikram, M. Arfan

AU - Mosley, Thomas H.

AU - Bevan, Steve

AU - Dichgans, Martin

AU - Rothwell, Peter M.

AU - Sudlow, Cathie L.M.

AU - Hopewell, Jemma C.

AU - Chambers, John C.

AU - Saleheen, Danish

AU - Kooner, Jaspal S.

AU - Danesh, John

AU - Nelson, Christopher P.

AU - Erdmann, Jeanette

AU - Reilly, Muredach P.

AU - Kathiresan, Sekar

AU - Schunkert, Heribert

AU - Morange, Pierre Emmanuel

AU - Ferrucci, Luigi

AU - Eriksson, Johan G.

AU - Jacobs, David

AU - Deary, Ian J.

AU - Soranzo, Nicole

AU - Witteman, Jacqueline C.M.

AU - De Geus, Eco J.C.

AU - Tracy, Russell P.

AU - Hayward, Caroline

AU - Koenig, Wolfgang

AU - Cucca, Francesco

AU - Jukema, J. Wouter

AU - Eriksson, Per

AU - Seshadri, Sudha

AU - Markus, Hugh S.

AU - Watkins, Hugh

AU - Samani, Nilesh J.

AU - Wallaschofski, Henri

AU - Smith, Nicholas L.

AU - Tregouet, David

AU - Ridker, Paul M.

AU - Tang, Weihong

AU - Strachan, David P.

AU - Hamsten, Anders

AU - O'Donnell, Christopher J.

PY - 2013/9/17

Y1 - 2013/9/17

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84884250513&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84884250513&partnerID=8YFLogxK

U2 - 10.1161/CIRCULATIONAHA.113.002251

DO - 10.1161/CIRCULATIONAHA.113.002251

M3 - Article

C2 - 23969696

AN - SCOPUS:84884250513

SN - 0009-7322

VL - 128

SP - 1310

EP - 1324

JO - Circulation

JF - Circulation

IS - 12

ER -

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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