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Circulation. 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.

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 LC, Bandinelli S, Räikkönen K, Widen E, Palotie A, Fornage M, Green D, Gross M, Davies G, Harris SE, Liewald DC, Starr JM, Williams FM, 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 CL, 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 JC, de Geus EJ, Tracy RP, Hayward C, Koenig W, Cucca F, Jukema JW, Eriksson P, Seshadri S, Markus HS, Watkins H, Samani NJ; VTE Consortium; STROKE Consortium; Wellcome Trust Case Control Consortium 2 (WTCCC2); C4D Consortium; CARDIoGRAM Consortium, Wallaschofski H, Smith NL, Tregouet D, Ridker PM, Tang W, Strachan DP, Hamsten A, O'Donnell CJ.

Collaborators (268)

Donnelly P, Barroso I, Blackwell JM, Bramon E, Brown MA, Casas JP, Corvin A, Deloukas P, Jankowski J, Markus HS, Mathew CG, Palmer CN, Plomin R, Rautanen A, Sawcer SJ, Trembath RC, Viswanathan AC, Wood NW, Spencer CC, Band G, Bellenguez C, Freeman C, Hellenthal G, Giannoulatou E, Pirinen M, Pearson R, Strange A, Su Z, Vukcevic D, Donnelly P, Langford C, Hunt SE, Edkins S, Gwilliam R, Blackburn H, Bumpstead SJ, Dronov S, Gillman M, Gray E, Hammond N, Jayakumar A, McCann OT, Liddle J, Potter SC, Ravindrarajah R, Ricketts M, Waller M, Weston P, Widaa S, Whittaker P, Barroso I, Deloukas P, Mathew CG, Blackwell JM, Brown MA, Corvin A, Spencer CC, Kathiresan S, Reilly MP, Samani NJ, Schunkert H, Erdmann J, Assimes TL, Boerwinkle E, Erdmann J, Hall A, Hengstenberg C, Kathiresan S, König IR, Laaksonen R, McPherson R, Reilly MP, Samani NJ, Schunkert H, Thompson JR, Thorsteinsdottir U, Ziegler A, König IR, Thompson JR, Absher D, Chen L, Cupples L, Halperin E, Li M, Musunuru K, Preuss M, Schillert A, Thorleifsson G, Voight BF, Wells GA, Assimes TL, Deloukas P, Erdmann J, Holm H, Kathiresan S, König IR, McPherson R, Reilly MP, Roberts R, Samani NJ, Schunkert H, Stewart AF, Absher D, Assimes TL, Fortmann S, Go A, Hlatky M, Iribarren C, Knowles J, Myers R, Quertermous T, Sidney S, Risch N, Tang H, Blankenberg S, Zeller T, Schillert A, Wild P, Ziegler A, Schnabel R, Sinning C, Lackner K, Tiret L, Nicaud V, Cambien F, Bickel C, Rupprecht HJ, Perret C, Proust C, Münzel T, Barbalic M, Bis J, Boerwinkle E, Chen IY, Cupples L, Dehghan A, Demissie-Banjaw S, Folsom A, Glazer N, Gudnason V, Harris T, Heckbert S, Levy D, Lumley T, Marciante K, Morrison A, O'Donnell CJ, Psaty BM, Rice K, Rotter JI, Siscovick DS, Smith N, Smith A, Taylor KD, van Duijn C, Volcik K, Whitteman J, Ramachandran V, Hofman A, Uitterlinden A, Gretarsdottir S, Gulcher JR, Holm H, Kong A, Stefansson K, Thorgeirsson G, Andersen K, Thorleifsson G, Thorsteinsdottir U, Erdmann J, Fischer M, Grosshennig A, Hengstenberg C, König IR, Lieb W, Linsel-Nitschke P, Preuss M, Stark K, Schreiber S, Wichmann H-, Ziegler A, Schunkert H, Aherrahrou Z, Bruse P, Doering A, Erdmann J, Hengstenberg C, Illig T, Klopp N, König IR, Diemert P, Loley C, Medack A, Meisinger C, Meitinger T, Nahrstedt J, Peters A, Preuss M, Stark K, Wagner AK, Wichmann H-, Willenborg C, Ziegler A, Schunkert H, Böhm BO, Dobnig H, Grammer TB, Halperin E, Hoffmann MM, Kleber M, Laaksonen R, März W, Meinitzer A, Winkelmann BR, Pilz S, Renner W, Scharnagl H, Stojakovic T, Tomaschitz A, Winkler K, Voight BF, Musunuru K, Guiducci C, Burtt N, Gabriel SB, Siscovick DS, O'Donnell CJ, Elosua R, Peltonen L, Salomaa V, Schwartz SM, Melander O, Altshuler D, Kathiresan S, Stewart AF, Chen L, Dandona S, Wells GA, Jarinova O, McPherson R, Roberts R, Reilly MP, Li M, Qu L, Wilensky R, Matthai W, Hakonarson HH, Devaney J, Burnett MS, Pichard AD, Kent KM, Satler L, Lindsay JM, Waksman R, Knouff CW, Waterworth DM, Walker MC, Mooser V, Epstein SE, Rader DJ, Samani NJ, Thompson JR, Braund PS, Nelson CP, Wright BJ, Balmforth AJ, Ball SG, Hall AS.

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

PMID:
23969696
PMCID:
PMC3842025
DOI:
10.1161/CIRCULATIONAHA.113.002251
[Indexed for MEDLINE]
Free PMC Article

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