Association of novel genetic Loci with circulating fibrinogen levels: a genome-wide association study in 6 population-based cohorts.
Dehghan A., Yang Q., Peters A., Basu S., Bis JC., Rudnicka AR., Kavousi M., Chen M-H., Baumert J., Lowe GDO., McKnight B., Tang W., de Maat M., Larson MG., Eyhermendy S., McArdle WL., Lumley T., Pankow JS., Hofman A., Massaro JM., Rivadeneira F., Kolz M., Taylor KD., van Duijn CM., Kathiresan S., Illig T., Aulchenko YS., Volcik KA., Johnson AD., Uitterlinden AG., Tofler GH., Gieger C., Wellcome Trust Case Control Consortium None., Psaty BM., Couper DJ., Boerwinkle E., Koenig W., O'Donnell CJ., Witteman JC., Strachan DP., Smith NL., Folsom AR.
BACKGROUND:Fibrinogen is both central to blood coagulation and an acute-phase reactant. We aimed to identify common variants influencing circulation fibrinogen levels. METHODS AND RESULTS:We conducted a genome-wide association analysis on 6 population-based studies, the Rotterdam Study, the Framingham Heart Study, the Cardiovascular Health Study, the Atherosclerosis Risk in Communities Study, the Monitoring of Trends and Determinants in Cardiovascular Disease/KORA Augsburg Study, and the British 1958 Birth Cohort Study, including 22 096 participants of European ancestry. Four loci were marked by 1 or more single-nucleotide polymorphisms that demonstrated genome-wide significance (P<5.0 x 10(-8)). These included a single-nucleotide polymorphism located in the fibrinogen beta chain (FGB) gene and 3 single-nucleotide polymorphisms representing newly identified loci. The high-signal single-nucleotide polymorphisms were rs1800789 in exon 7 of FGB (P=1.8 x 10(-30)), rs2522056 downstream from the interferon regulatory factor 1 (IRF1) gene (P=1.3 x 10(-15)), rs511154 within intron 1 of the propionyl coenzyme A carboxylase (PCCB) gene (P=5.9 x 10(-10)), and rs1539019 on the NLR family pyrin domain containing 3 isoforms (NLRP3) gene (P=1.04 x 10(-8)). CONCLUSIONS:Our findings highlight biological pathways that may be important in regulation of inflammation underlying cardiovascular disease.