TY - JOUR
T1 - A mendelian randomization of γ' and total fibrinogen levels in relation to venous thromboembolism and ischemic stroke
AU - CHARGE Inflammation Working Group, INVENT Consortium, MEGASTROKE consortium of the International Stroke Genetics Consortium (ISGC)
AU - Maners, Jillian
AU - Gill, Dipender
AU - Pankratz, Nathan
AU - Laffan, Michael A.
AU - Wolberg, Alisa S.
AU - de Maat, Moniek P.M.
AU - Ligthart, Symen
AU - Tang, Weihong
AU - Ward-Caviness, Cavin K.
AU - Fornage, Myriam
AU - Debette, Stephanie
AU - Dichgans, Martin
AU - McKnight, Barbara
AU - Boerwinkle, Eric
AU - Smith, Nicholas L.
AU - Morrison, Alanna C.
AU - Dehghan, Abbas
AU - de Vries, Paul S.
N1 - Publisher Copyright:
© 2020 American Society of Hematology. All rights reserved.
PY - 2020/12/24
Y1 - 2020/12/24
N2 - 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.
AB - 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.
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U2 - 10.1182/blood.2019004781
DO - 10.1182/blood.2019004781
M3 - Article
C2 - 33367543
AN - SCOPUS:85098503894
SN - 0006-4971
VL - 136
SP - 3062
EP - 3069
JO - Blood
JF - Blood
IS - 26
ER -