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

• Published in: Circulation (New York, N.Y.) Vol. 128; no. 12; pp. 1310 - 1324
• Main Authors: Sabater-Lleal, Maria, Huang, Jie, Chasman, Daniel, Naitza, Silvia, Dehghan, Abbas, Teumer, Alexander, Folkersen, Lasse, Basu, Saonli, Rudnicka, Alicja R., Trompet, Stella, Mälarstig, Anders, Baumert, Jens, Guo, Xiuqing, Hottenga, Jouke J., Shin, So-Youn, Lopez, Lorna M., Lahti, Jari, Oudot-Mellakh, Tiphaine, Wilson, James F., Navarro, Pau, Huffman, Jennifer E., Zemunik, Tatijana, Mehra, Reena, Rudan, Igor, Wright, Alan F., Campbell, Harry, Wallace, Robert, Liu, Simin, Eaton, Charles B., Becker, Diane M., Becker, Lewis C., Räikkönen, Katri, Widen, Elisabeth, Palotie, Aarno, Fornage, Myriam, Green, David, Gross, Myron, Harris, Sarah E., Starr, John M., Williams, Frances M.K., Spector, Timothy D., Strawbridge, Rona J., Silveira, Angela, Sennblad, Bengt, Uitterlinden, Andre G., Franco, Oscar H., Hofman, Albert, van Dongen, Jenny, Yao, Jie, Swords Jenny, Nancy, Haritunians, Talin, Lumley, Thomas, Taylor, Kent D., Peters, Annette, Illig, Thomas, Kocher, Thomas, Franzosi, Maria Grazia, Seedorf, Udo, Clarke, Robert, Schlessinger, David, Stott, David J., Sattar, Naveed, Buckley, Brendan M., Lowe, Gordon D., Chen, Ming-Huei, Tofler, Geoffrey H., Song, Jaejoon, Boerwinkle, Eric, Rose, Lynda M., Franco-Cereceda, Anders, Teichert, Martina, Mosley, Thomas H., Bevan, Steve, Dichgans, Martin, Sudlow, Cathie L.M., Hopewell, Jemma C., Chambers, John C., Saleheen, Danish, Kooner, Jaspal S., Danesh, John, Nelson, Christopher P., Reilly, Muredach P., Kathiresan, Sekar, Schunkert, Heribert, Morange, Pierre-Emmanuel, Ferrucci, Luigi, Eriksson, Johan G., Jacobs, David, Deary, Ian J., Soranzo, Nicole, Tracy, Russell P., Hayward, Caroline, Koenig, Wolfgang, Cucca, Francesco, Samani, Nilesh J., Smith, Nicholas L., Ridker, Paul M, Tang, Weihong, Hamsten, Anders, O’Donnell, Christopher J.
• Format: Journal Article
• Language: English
• Published: United States by the American College of Cardiology Foundation and the American Heart Association, Inc 17.09.2013
• Subjects: 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: 0009-7322; 1524-4539; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.113.002251

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.