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

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.

OriginalsprogEngelsk
TidsskriftBlood
ISSN0006-4971
DOI
StatusE-pub ahead of print - 6 feb. 2024

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