Multiethnic meta-analysis of genome-wide association studies in &gt;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, 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.; Lahti, J.; Tanaka, T.; Yanek, L.R.; Oudot-Mellakh, T.; Wilson, J.F.; Navarro, P.; Huffman, J.E.; Zemunik, T.; Redline, S.; Mehra, R.; Pulanic, D.; Rudan, I.; Wright, A.F.; Kolcic, I.; Polasek, O.; Wild, S.H.; Campbell, H.; Curb, J.D.; Wallace, R.; Liu, S.; Eaton, C.B.; Becker, D.M.; Becker, L.C.; Bandinelli, S.; Räikkönen, K.; Widen, E.; Palotie, A.; Fornage, M.; Green, D.; Gross, M.; Davies, G.; Harris, S.E.; Liewald, D.C.; Starr, J.M.; Williams, F.M.; Grant, P.J.; Spector, T.D.; Strawbridge, R.J.; Silveira, A.; Sennblad, B.; Rivadeneira, F.; Uitterlinden, A.G.; Franco, O.H.; Hofman, A.; van Dongen, J.; Willemsen, G.; Boomsma, D.I.; Yao, J.; Swords Jenny, N.; Haritunians, T.; McKnight, B.; Lumley, T.; Taylor, K.D.; Rotter, J.I.; Psaty, B.M.; Peters, A.; Gieger, C.; Illig, T.; Grotevendt, A.; Homuth, G.; Völzke, H.; Kocher, T.; Goel, A.; Franzosi, M.G.; Seedorf, U.; Clarke, R.; Steri, M.; Tarasov, K.V.; Sanna, S.; Schlessinger, D.; Stott, D.J.; Sattar, N.; Buckley, B.M.; Rumley, A.; Lowe, G.D.; McArdle, W.L.; Chen, M.H.; Tofler, G.H.; Song, J.; Boerwinkle, E.; Folsom, A.R.; Rose, L.M.; Franco-Cereceda, A.; Teichert, M.; Ikram, M.A.; Mosley, T.H.; Bevan, S.; Dichgans, M.; Rothwell, P.M.; Sudlow, C.L.; Hopewell, J.C.; Chambers, J.C.; Saleheen, D.; Kooner, J.S.; Danesh, J.; Nelson, C.P.; Erdmann, J.; Reilly, M.P.; Kathiresan, S.; Schunkert, H.; Morange, P.E.; Ferrucci, L.; Eriksson, J.G.; Jacobs, D.; Deary, I.J.; Soranzo, N.; Witteman, J.C.; de Geus, E.J.; Tracy, R.P.; Hayward, C.; Koenig, W.; Cucca, F.; Jukema, J.W.; Eriksson, P.; Seshadri, S.; Markus, H.S.; Watkins, H.; Samani, N.J.; Wallaschofski, H.; Wallaschofski, H.; Smith, N.L.; Tregouet, D.; Ridker, P.M.; Tang, W.; Strachan, D.P.; Hamsten, A.; O'Donnell, C.J.

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.

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serval:BIB_EB0BB11CCEF2

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Article: article from journal or magazin.

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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.

Journal

Circulation

Author(s)

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., Lahti J., Tanaka T., Yanek L.R., Oudot-Mellakh T., Wilson J.F., Navarro P., Huffman J.E., Zemunik T., Redline S., Mehra R., Pulanic D., Rudan I., Wright A.F., Kolcic I., Polasek O., Wild S.H., Campbell H., Curb J.D., Wallace R., Liu S., Eaton C.B., Becker D.M., Becker L.C., Bandinelli S., Räikkönen K., Widen E., Palotie A., Fornage M., Green D., Gross M., Davies G., Harris S.E., Liewald D.C., Starr J.M., Williams F.M., Grant P.J., Spector T.D., Strawbridge R.J., Silveira A., Sennblad B., Rivadeneira F., Uitterlinden A.G., Franco O.H., Hofman A., van Dongen J., Willemsen G., Boomsma D.I., Yao J., Swords Jenny N., Haritunians T., McKnight B., Lumley T., Taylor K.D., Rotter J.I., Psaty B.M., Peters A., Gieger C., Illig T., Grotevendt A., Homuth G., Völzke H., Kocher T., Goel A., Franzosi M.G., Seedorf U., Clarke R., Steri M., Tarasov K.V., Sanna S., Schlessinger D., Stott D.J., Sattar N., Buckley B.M., Rumley A., Lowe G.D., McArdle W.L., Chen M.H., Tofler G.H., Song J., Boerwinkle E., Folsom A.R., Rose L.M., Franco-Cereceda A., Teichert M., Ikram M.A., Mosley T.H., Bevan S., Dichgans M., Rothwell P.M., Sudlow C.L., Hopewell J.C., Chambers J.C., Saleheen D., Kooner J.S., Danesh J., Nelson C.P., Erdmann J., Reilly M.P., Kathiresan S., Schunkert H., Morange P.E., Ferrucci L., Eriksson J.G., Jacobs D., Deary I.J., Soranzo N., Witteman J.C., de Geus E.J., Tracy R.P., Hayward C., Koenig W., Cucca F., Jukema J.W., Eriksson P., Seshadri S., Markus H.S., Watkins H., Samani N.J., Wallaschofski H., Wallaschofski H., Smith N.L., Tregouet D., Ridker P.M., Tang W., Strachan D.P., Hamsten A., O'Donnell C.J.

Working group(s)

VTE Consortium, STROKE Consortium, Wellcome Trust Case Control Consortium 2 (WTCCC2), C4D Consortium, CARDIoGRAM Consortium

Contributor(s)

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.

ISSN

1524-4539 (Electronic)

ISSN-L

0009-7322

Publication state

Published

Issued date

2013

Volume

128

Number

Pages

1310-1324

Language

english

Notes

Publication types: Journal Article ; Meta-Analysis ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish

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

Adolescent, Adult, African Continental Ancestry Group/genetics, African Continental Ancestry Group/statistics & numerical data, Aged, Aged, 80 and over, Cardiovascular Diseases/ethnology, Cardiovascular Diseases/genetics, Coronary Artery Disease/ethnology, Coronary Artery Disease/genetics, European Continental Ancestry Group/genetics, European Continental Ancestry Group/statistics & numerical data, Female, Fibrinogen/genetics, Fibrinogen/metabolism, Genetic Loci/genetics, Genetic Predisposition to Disease/ethnology, Genome-Wide Association Study, Hispanic Americans/genetics, Hispanic Americans/statistics & numerical data, Humans, Male, Middle Aged, Myocardial Infarction/ethnology, Myocardial Infarction/genetics, Polymorphism, Single Nucleotide/genetics, Risk Factors, Stroke/ethnology, Stroke/genetics, Venous Thromboembolism/ethnology, Venous Thromboembolism/genetics, Young Adult

DOI

10.1161/CIRCULATIONAHA.113.002251

Pubmed

23969696

Open Access

Yes

Create date

10/10/2014 11:44

Last modification date

20/08/2019 17:13

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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.

Details