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A Mendelian randomization of γ′ and total fibrinogen levels in relation to venous thromboembolism and ischemic stroke

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Title: A Mendelian randomization of γ′ and total fibrinogen levels in relation to venous thromboembolism and ischemic stroke
Authors: Maners, J
Gill, D
Pankratz, N
Laffan, MA
Wolberg, AS
De Maat, MPM
Ligthart, S
Tang, W
Ward-Caviness, CK
Fomage, M
Debette, S
Dichgans, M
McKnight, B
Boerwinkle, E
Smith, NL
Morrison, AC
Dehghan, A
De Vries, PS
Item Type: Journal Article
Abstract: 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.
Issue Date: 24-Dec-2020
Date of Acceptance: 12-Jul-2020
URI: http://hdl.handle.net/10044/1/88304
DOI: 10.1182/blood.2019004781
ISSN: 0006-4971
Publisher: American Society of Hematology
Start Page: 3062
End Page: 3069
Journal / Book Title: Blood
Volume: 136
Issue: 26
Copyright Statement: ©2020 by American Society of Hematology
Keywords: Science & Technology
Life Sciences & Biomedicine
Hematology
GENETIC-VARIATION
ATHEROSCLEROSIS RISK
GENOTYPE IMPUTATION
SPLICE VARIANT
CHAIN
ASSOCIATION
LOCI
INFLAMMATION
METAANALYSIS
COAGULATION
Female
Fibrinogen
Genetic Variation
Genome-Wide Association Study
Humans
Ischemic Stroke
Male
Mendelian Randomization Analysis
Risk Factors
Venous Thromboembolism
CHARGE Inflammation Working Group
INVENT Consortium
MEGASTROKE consortium of the International Stroke Genetics Consortium (ISGC)
Humans
Fibrinogen
Risk Factors
Female
Male
Venous Thromboembolism
Genetic Variation
Genome-Wide Association Study
Mendelian Randomization Analysis
Ischemic Stroke
Science & Technology
Life Sciences & Biomedicine
Hematology
GENETIC-VARIATION
ATHEROSCLEROSIS RISK
GENOTYPE IMPUTATION
SPLICE VARIANT
CHAIN
ASSOCIATION
LOCI
INFLAMMATION
METAANALYSIS
COAGULATION
Immunology
1102 Cardiorespiratory Medicine and Haematology
1103 Clinical Sciences
1114 Paediatrics and Reproductive Medicine
Publication Status: Published
Online Publication Date: 2020-07-28
Appears in Collections:Department of Immunology and Inflammation
Faculty of Medicine
School of Public Health