A genetic association study of circulating coagulation Factor VIII and von Willebrand Factor levels
Journal
Blood
Date Issued
2024-02-06
Author(s)
de Vries, Paul S
Reventun, Paula
Brown, Michael R
Heath, Adam S
Huffman, Jennifer E
Le, Ngoc-Quynh
Bebo, Allison
Brody, Jennifer A
Temprano-Sagrera, Gerard
Raffield, Laura M
Ozel, Ayse Bilge
Thibord, Florian
Jain, Deepti
Lewis, Joshua P
Rodriguez, Benjamin A T
Pankratz, Nathan
Taylor, Kent D
Polasek, Ozren
Chen, Ming-Huei
Yanek, Lisa R
Carrasquilla, German D
Marioni, Riccardo
Kleber, Marcus E
Trégouët, David-Alexandre
Yao, Jie
Li-Gao, Ruifang
Joshi, Peter K
Trompet, Stella
Martinez-Perez, Angel
Ghanbari, Mohsen
Howard, Tom E
Reiner, Alex P
Arvanitis, Marios
Ryan, Kathleen A
Bartz, Traci M
Rudan, Igor
Faraday, Nauder
Linneberg, Allan
Ekunwe, Lynette
Davies, Gail
Delgado, Graciela E
Suchon, Pierre
Guo, Xiuqing
Rosendaal, Frits R
Klaric, Lucija
Noordam, Raymond
van Rooij, Frank
Curran, Joanne E
Wheeler, Marsha M
Osburn, William O
O'Connell, Jeffrey R
Boerwinkle, Eric
Beswick, Andrew
Psaty, Bruce M
Kolcic, Ivana
Souto, Juan Carlos
Becker, Lewis C
Hansen, Torben
Doyle, Margaret F
Harris, Sarah E
Moissl, Angela P
Deleuze, Jean-François
Rich, Stephen S
van Hylckama Vlieg, Astrid
Campbell, Harry
Stott, David J
Soria, Jose Manuel
de Maat, Moniek P M
Almasy, Laura
Brody, Lawrence C
Auer, Paul L
Mitchell, Braxton D
Ben-Shlomo, Yoav
Fornage, Myriam
Hayward, Caroline
Mathias, Rasika A
Kilpeläinen, Tuomas O
Lange, Leslie A
Cox, Simon R
März, Winfried
Morange, Pierre-Emmanuel
Rotter, Jerome I
Mook-Kanamori, Dennis O
Wilson, James F
van der Harst, Pim
Jukema, J Wouter
Ikram, M Arfan
Blangero, John
Kooperberg, Charles
Desch, Karl C
Johnson, Andrew D
Sabater-Lleal, Maria
Lowenstein, Charles J
Smith, Nicholas L
Morrison, Alanna C
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.
Type
journal article