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A Mendelian randomization of γ′ and total fibrinogen levels in relation to venous thromboembolism and ischemic stroke
File | Description | Size | Format | |
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Blood fibrinogen paper.pdf | Accepted version | 705.57 kB | Adobe PDF | View/Open |
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 |