A genetic association study of circulating coagulation Factor VIII and von Willebrand Factor levels

Paul S. de Vries*, Paula Reventun, Michael R. Brown, Adam S Heath, Andrew D Beswick, Ben M Brumpton, Yoav Ben-Shlomo, Alanna C Morrison*, et al

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

1 Citation (Scopus)
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Abstract

Coagulation Factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are critical to coagulation and platelet aggregation. We leveraged whole genome sequence data from the Trans-Omics for Precision Medicine (TOPMed) program along with TOPMed-based imputation of genotypes in additional samples to identify genetic associations with circulating FVIII and VWF levels in a single variant meta-analysis including up to 45,289 participants. Gene-based aggregate tests were implemented in TOPMed. We identified three candidate causal genes and tested their functional effect on FVIII release from human liver endothelial cells (HLECs) and VWF release from human umbilical vein endothelial cells (HUVECs). Mendelian randomization was also performed to provide evidence for causal associations of FVIII and VWF with thrombotic outcomes. We identified associations (P<5×10-9 ) at seven new loci for FVIII (ST3GAL4, CLEC4M, B3GNT2, ASGR1, F12, KNG1, and TREM1/NCR2) and one for VWF (B3GNT2). VWF, ABO, and STAB2 were associated with FVIII and VWF in gene-based analyses. Multi-phenotype analysis of FVIII and VWF identified another three new loci, including PDIA3. Silencing of B3GNT2 and the previously reported CD36 gene decreased release of FVIII by HLECs, while silencing of B3GNT2, CD36, and PDIA3 decreased release of VWF by HVECs. Mendelian randomization supports causal association of higher FVIII and VWF with increased risk of thrombotic outcomes. Seven new loci were identified for FVIII and one for VWF, with evidence supporting causal associations of FVIII and VWF with thrombotic outcomes. B3GNT2, CD36, and PDIA3 modulate the release of FVIII and/or VWF in vitro.
Original languageEnglish
Pages (from-to)1845-1855
Number of pages11
JournalBlood
Volume143
Issue number18
Early online date6 Feb 2024
DOIs
Publication statusE-pub ahead of print - 6 Feb 2024

Bibliographical note

Funding Information: This work and the CHARGE-TOPMed Hemostasis Working Group was funded in part by National Heart, Lung and Blood Institute (NHLBI) grant numbers R01 HL134894 and R01 HL139553. Infrastructure for the CHARGE consortium was supported by R01HL105756. The Analysis Commons was funded by R01 HL131136. Charles Lowenstein was supported by R33 HL141791 and the Michel Mirowski M.D. Professorship in Cardiology. Caroline Hayward and James Wilson were supported by the UK Medical Research Council grant U. MC_UU_00007/10. Gerard Temprano-Sagrera is supported by the "Pla Estratègic de Recerca i Innovació en Salut (PERIS)" grant from the Catalan Department of Health (SLT017/20/000100). Maria Sabater-Lleal is supported by a Miguel Servet contract from the ISCIII Spanish Health Institute (CPII22/00007) and co-financed by the European Social Fund. Laura Raffield was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant KL2TR002490.

Molecular data for the TOPMed program was supported by the NHLBI. Core support including centralized genomic read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I). Core support including phenotype harmonization, data management, sampleidentity QC, and general program coordination were provided by the TOPMed Data Coordinating Center (R01HL-120393; U01HL-120393; contract HHSN268201800001I). See the TOPMed Omics Support Table (Supplementary Table 15) for study specific omics support information. Further study-specific funding and acknowledgements are detailed in the Supplementary Methods. We gratefully acknowledge the participants and staff of the contributing studies.

Publisher copyright: © 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

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