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Get Free AccessCoagulation 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 3 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. 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 7 new loci for FVIII (ST3GAL4, CLEC4M, B3GNT2, ASGR1, F12, KNG1, and TREM1/NCR2) and 1 for VWF (B3GNT2). VWF, ABO, and STAB2 were associated with FVIII and VWF in gene-based analyses. Multiphenotype analysis of FVIII and VWF identified another 3 new loci, including PDIA3. Silencing of B3GNT2 and the previously reported CD36 gene decreased release of FVIII by HLECs, whereas 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 1 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.
Paul S. de Vries, Paula Reventún, 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, Blanca Rodríguez, Nathan Pankratz, Kent D. Taylor, Ozren Polašek, Ming‐Huei Chen, Lisa R. Yanek, Germán D. Carrasquilla, Riccardo E. Marioni, Marcus E. Kleber, David‐Alexandre Trégouët, Jie Yao, Ruifang Li‐Gao, Peter K. Joshi, Stella Trompet, Ángel Martínez-Pérez, 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 Klarić, Raymond Noordam, Frank J.A. van Rooij, Joanne E. Curran, Marsha M. Wheeler, William O. Osburn, Jeffrey R. O’Connell, Eric Boerwinkle, Andrew D Beswick, Bruce M. Psaty, Ivana Kolčić, 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, José 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 (2024). A genetic association study of circulating coagulation factor VIII and von Willebrand factor levels. Blood, 143(18), pp. 1845-1855, DOI: 10.1182/blood.2023021452.
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Type
Article
Year
2024
Authors
95
Datasets
0
Total Files
0
Language
English
Journal
Blood
DOI
10.1182/blood.2023021452
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