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 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., 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 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 M-H., 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 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., Jukema JW., Eriksson P., Seshadri S., Markus HS., Watkins H., Samani NJ., VTE Consortium None., STROKE Consortium None., Wellcome Trust Case Control Consortium 2 (WTCCC2) None., C4D Consortium None., CARDIoGRAM Consortium None., Wallaschofski H., Smith NL., Tregouet D., Ridker PM., Tang W., Strachan DP., Hamsten A., O'Donnell CJ.
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.