Fibrinogen is a key component of the coagulation cascade, and variation in its circulating levels may contribute to thrombotic diseases, such as venous thromboembolism (VTE) and ischemic stroke. Gamma prime (γ') fibrinogen is an isoform of fibrinogen that has anticoagulant properties. We applied 2-sample Mendelian randomization (MR) to estimate the causal effect of total circulating fibrinogen and its isoform, γ' fibrinogen, on risk of VTE and ischemic stroke subtypes using summary statistics from genome-wide association studies. Genetic instruments for γ' fibrinogen and total fibrinogen were selected, and the inverse-variance weighted MR approach was used to estimate causal effects in the main analysis, complemented by sensitivity analyses that are more robust to the inclusion of pleiotropic variants, including MR-Egger, weighted median MR, and weighted mode MR. The main inverse-variance weighted MR estimates based on a combination of 16 genetic instruments for γ' fibrinogen and 75 genetic instruments for total fibrinogen indicated a protective effect of higher γ' fibrinogen and higher total fibrinogen on VTE risk. There was also a protective effect of higher γ' fibrinogen levels on cardioembolic and large artery stroke risk. Effect estimates were consistent across sensitivity analyses. Our results provide evidence to support effects of genetically determined γ' fibrinogen on VTE and ischemic stroke risk. Further research is needed to explore mechanisms underlying these effects and their clinical applications.
Bibliographical noteFunding Information:
A.S.W., M.F., N.L.S., A.C.M., and P.S.d.V. were supported by National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI) grant R01HL141291. N.L.S., A.C.M., B.M., and P.S.d.V. were supported by NIH/NHLBI grant R01HL139553. P.S.d.V. was additionally supported by American Heart Association (AHA) grant 18CDA34110116. N.P. and W.T. were supported by NIH/NHLBI grant R01HL59367. D.G. was supported by the Wellcome Trust 4i Programme (203928/Z/16/Z) and British Heart Foundation Centre of Research Excellence (RE/18/4/34215) at Imperial College London. The CHARGE Consortium Hemostasis Working Group is partially supported by NIH/NHLBI grant R01HL134894, and infrastructure for the CHARGE Consortium is supported, in part, by NIH/NHLBI grant R01HL105756. The Atherosclerosis Risk in Communities (ARIC) study has been funded in whole, or in part, with federal funds from the NIH/NHLBI, Department of Health and Human Services (contracts HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I, and HHSN268201700005I); Grants R01HL087641, R01HL059367, and R01HL086694; NIH/National Human Genome Research Institute (NHGRI) contract U01HG004402; and NIH contract HHSN268200625226C. Infrastructure was partly supported by grant UL1RR025005, a component of the NIH and NIH Roadmap for Medical Research. Measurement of g9 fibrinogen in the ARIC study was supported by NIH/NHLBI grant R01HL59367.