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American Society of Hematology, Blood, 2024

DOI: 10.1182/blood.2023021452

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

Journal article published in 2024 by Paul S. de Vries, Paula Reventun, Michael R. Brown, Adam S. Heath ORCID, Jennifer E. Huffman ORCID, Ngoc-Quynh Le, Allison Bebo, Jennifer A. Brody ORCID, Gerard Temprano-Sagrera ORCID, Laura M. Raffield ORCID, Ayse Bilge Ozel ORCID, Florian Thibord ORCID, Deepti Jain, Joshua P. Lewis, Benjamin A. T. Rodriguez and other authors.
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Distributing this paper is prohibited by the publisher

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Data provided by SHERPA/RoMEO

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.