TY - JOUR
T1 - A genetic association study of circulating coagulation factor VIII and von Willebrand factor levels
AU - Trans-Omics for Precision Medicine (TOPMed) program
AU - The INVENT Consortium
AU - de Vries, Paul S.
AU - Reventun, Paula
AU - Brown, Michael R.
AU - Heath, Adam S.
AU - Huffman, Jennifer E.
AU - Le, Ngoc Quynh
AU - Bebo, Allison
AU - Brody, Jennifer A.
AU - Temprano-Sagrera, Gerard
AU - Raffield, Laura M.
AU - Ozel, Ayse Bilge
AU - Thibord, Florian
AU - Jain, Deepti
AU - Lewis, Joshua P.
AU - Rodriguez, Benjamin A.T.
AU - Pankratz, Nathan
AU - Taylor, Kent D.
AU - Polasek, Ozren
AU - Chen, Ming Huei
AU - Yanek, Lisa R.
AU - Carrasquilla, German D.
AU - Marioni, Riccardo E.
AU - Kleber, Marcus E.
AU - Trégouët, David Alexandre
AU - Yao, Jie
AU - Li-Gao, Ruifang
AU - Joshi, Peter K.
AU - Trompet, Stella
AU - Martinez-Perez, Angel
AU - Ghanbari, Mohsen
AU - Howard, Tom E.
AU - Reiner, Alex P.
AU - Arvanitis, Marios
AU - Ryan, Kathleen A.
AU - Bartz, Traci M.
AU - Rudan, Igor
AU - Faraday, Nauder
AU - Linneberg, Allan
AU - Ekunwe, Lynette
AU - Davies, Gail
AU - Delgado, Graciela E.
AU - Suchon, Pierre
AU - Guo, Xiuqing
AU - Rosendaal, Frits R.
AU - Klaric, Lucija
AU - Noordam, Raymond
AU - van Rooij, Frank
AU - Curran, Joanne E.
AU - Wheeler, Marsha M.
AU - Ochs-Balcom, Heather
N1 - Publisher Copyright:
© 2024
PY - 2024/5/2
Y1 - 2024/5/2
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85186210770
U2 - 10.1182/blood.2023021452
DO - 10.1182/blood.2023021452
M3 - Article
C2 - 38320121
AN - SCOPUS:85186210770
SN - 0006-4971
VL - 143
SP - 1845
EP - 1855
JO - Blood
JF - Blood
IS - 18
ER -