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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.

Wednesday,2013-11-20 15:58 America/Los_Angeles — poolea2
TitleMultiethnic 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.
Publication TypeJournal Article
Year of Publication2013
AuthorsSabater-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, S-Y, 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, J Curb, D, 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, 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, Jenny, NSwords, 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, M-H, Tofler, GH, Song, J, Boerwinkle, E, Folsom, AR, Rose, LM, Franco-Cereceda, A, Teichert, M, Ikram, AM, 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, P-E, Ferrucci, L, Eriksson, JG, Jacobs, D, Deary, IJ, Soranzo, N, Witteman, JCM, de Geus, EJC, Tracy, RP, Hayward, C, Koenig, W, Cucca, F, J Jukema, W, 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
Corporate/Institutional AuthorsVTE Consortium, STROKE Consortium, Wellcome Trust Case Control Consortium 2 (WTCCC2),, C4D Consortium, CARDIoGRAM consortium
JournalCirculation
Volume128
Issue12
Pagination1310-24
Date Published2013 Sep 17
ISSN1524-4539
KeywordsAdolescent, Adult, African Continental Ancestry Group, Aged, Aged, 80 and over, Cardiovascular Diseases, Coronary Artery Disease, European Continental Ancestry Group, Female, Fibrinogen, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Hispanic Americans, Humans, Male, Middle Aged, Myocardial Infarction, Polymorphism, Single Nucleotide, Risk Factors, Stroke, Venous Thromboembolism, Young Adult
Abstract<p><b>BACKGROUND: </b>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.</p><p><b>METHODS AND RESULTS: </b>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.</p><p><b>CONCLUSIONS: </b>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.</p>
DOI10.1161/CIRCULATIONAHA.113.002251
Alternate JournalCirculation
PubMed ID23969696
PubMed Central IDPMC3842025
Grant ListETM/55 / / Chief Scientist Office / United Kingdom
N01HC55020 / HL / NHLBI NIH HHS / United States
HHSN268201100012C / HL / NHLBI NIH HHS / United States
RC2 MH089951 / MH / NIMH NIH HHS / United States
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UL1RR025005 / RR / NCRR NIH HHS / United States
R01 HL071025 / HL / NHLBI NIH HHS / United States
N01-HC-25195 / HC / NHLBI NIH HHS / United States
CZB/4/710 / / Chief Scientist Office / United Kingdom
HHSN268201100009I / HL / NHLBI NIH HHS / United States
N01-HC-45205 / HC / NHLBI NIH HHS / United States
PG/09/022/26739 / / British Heart Foundation / United Kingdom
R01 HL089650 / HL / NHLBI NIH HHS / United States
UL1TR000124 / TR / NCATS NIH HHS / United States
/ / British Heart Foundation / United Kingdom
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095626 / / Wellcome Trust / United Kingdom
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