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

TitleA Mendelian randomization of γ' and total fibrinogen levels in relation to venous thromboembolism and ischemic stroke.
Publication TypeJournal Article
Year of Publication2020
AuthorsManers, J, Gill, D, Pankratz, N, Laffan, MA, Wolberg, AS, de Maat, MPM, Ligthart, S, Tang, W, Ward-Caviness, CK, Fornage, M, Debette, S, Dichgans, M, McKnight, B, Boerwinkle, E, Smith, NL, Morrison, AC, Dehghan, A, de Vries, PS
Corporate AuthorsCHARGE Inflammation Working Group, INVENT Consortium, MEGASTROKE consortium of the International Stroke Genetics Consortium (ISGC)
JournalBlood
Volume136
Issue26
Pagination3062-3069
Date Published2020 12 24
ISSN1528-0020
KeywordsFemale, Fibrinogen, Genetic Variation, Genome-Wide Association Study, Humans, Ischemic Stroke, Male, Mendelian Randomization Analysis, Risk Factors, Venous Thromboembolism
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.

DOI10.1182/blood.2019004781
Alternate JournalBlood
PubMed ID33367543
PubMed Central IDPMC7770565
Grant ListR01 HL086694 / HL / NHLBI NIH HHS / United States
HHSN268201700001I / HL / NHLBI NIH HHS / United States
R01 HL141291 / HL / NHLBI NIH HHS / United States
HHSN268201700004I / HL / NHLBI NIH HHS / United States
R01 HL059367 / HL / NHLBI NIH HHS / United States
HHSN268201700002I / HL / NHLBI NIH HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
HHSN268201700005I / HL / NHLBI NIH HHS / United States
203928/Z/16/Z / WT_ / Wellcome Trust / United Kingdom
R01 HL139553 / HL / NHLBI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
R01 HL134894 / HL / NHLBI NIH HHS / United States
HHSN268201700003I / HL / NHLBI NIH HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States
RE/18/4/34215 / BHF_ / British Heart Foundation / United Kingdom