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A genetic association study of circulating coagulation factor VIII and von Willebrand factor levels: thrombosis and hemostasis

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...

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Main Authors: Vries, Paul S. de (Author) , Reventun, Paula (Author) , Brown, Michael R. (Author) , Heath, Adam S. (Author) , Huffman, Jennifer E. (Author) , Le, Ngoc-Quynh (Author) , Bebo, Allison (Author) , Brody, Jennifer A. (Author) , Temprano-Sagrera, Gerard (Author) , Raffield, Laura M. (Author) , Ozel, Ayse Bilge (Author) , Thibord, Florian (Author) , Jain, Deepti (Author) , Lewis, Joshua P. (Author) , Rodriguez, Benjamin A. T. (Author) , Pankratz, Nathan (Author) , Taylor, Kent D. (Author) , Polasek, Ozren (Author) , Chen, Ming-Huei (Author) , Yanek, Lisa R. (Author) , Carrasquilla, German D. (Author) , Marioni, Riccardo E. (Author) , Kleber, Marcus E. (Author) , Trégouët, David-Alexandre (Author) , Yao, Jie (Author) , Li-Gao, Ruifang (Author) , Joshi, Peter K. (Author) , Trompet, Stella (Author) , Martinez-Perez, Angel (Author) , Ghanbari, Mohsen (Author) , Howard, Tom E. (Author) , Reiner, Alex P. (Author) , Arvanitis, Marios (Author) , Ryan, Kathleen A. (Author) , Bartz, Traci M. (Author) , Rudan, Igor (Author) , Faraday, Nauder (Author) , Linneberg, Allan (Author) , Ekunwe, Lynette (Author) , Davies, Gail (Author) , Delgado Gonzales de Kleber, Graciela (Author) , Suchon, Pierre (Author) , Guo, Xiuqing (Author) , Rosendaal, Frits R. (Author) , Klaric, Lucija (Author) , Noordam, Raymond (Author) , van Rooij, Frank (Author) , Curran, Joanne E. (Author) , Wheeler, Marsha M. (Author) , Osburn, William O. (Author) , O'Connell, Jeffrey R. (Author) , Boerwinkle, Eric (Author) , Beswick, Andrew (Author) , Psaty, Bruce M. (Author) , Kolcic, Ivana (Author) , Souto, Juan Carlos (Author) , Becker, Lewis C. (Author) , Hansen, Torben (Author) , Doyle, Margaret F. (Author) , Harris, Sarah E. (Author) , Moissl-Blanke, Angela P. (Author) , Deleuze, Jean-François (Author) , Rich, Stephen S. (Author) , van Hylckama Vlieg, Astrid (Author) , Campbell, Harry (Author) , Stott, David J. (Author) , Soria, Jose Manuel (Author) , de Maat, Moniek P. M. (Author) , Almasy, Laura (Author) , Brody, Lawrence C. (Author) , Auer, Paul L. (Author) , Mitchell, Braxton D. (Author) , Ben-Shlomo, Yoav (Author) , Fornage, Myriam (Author) , Hayward, Caroline (Author) , Mathias, Rasika A. (Author) , Kilpeläinen, Tuomas O. (Author) , Lange, Leslie A. (Author) , Cox, Simon R. (Author) , März, Winfried (Author) , Morange, Pierre-Emmanuel (Author) , Rotter, Jerome I. (Author) , Mook-Kanamori, Dennis O. (Author) , Wilson, James F. (Author) , van der Harst, Pim (Author) , Jukema, J. Wouter (Author) , Ikram, M. Arfan (Author) , Blangero, John (Author) , Kooperberg, Charles (Author) , Desch, Karl C. (Author) , Johnson, Andrew D. (Author) , Sabater-Lleal, Maria (Author) , Lowenstein, Charles J. (Author) , Smith, Nicholas L. (Author) , Morrison, Alanna C. (Author)
Format: Article (Journal)
Language:English
Published: 2 MAY 2024
In: Blood
Year: 2024, Volume: 143, Issue: 18, Pages: 1845-1855
ISSN:1528-0020
DOI:10.1182/blood.2023021452
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1182/blood.2023021452
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Author Notes: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. Yanek, German D. Carrasquilla, Riccardo E. 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, and Alanna C. Morrison
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Summary: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 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.
Item Description:Gesehen am 15.05.2025
Physical Description:Online Resource
ISSN:1528-0020
DOI:10.1182/blood.2023021452

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