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

Authors :
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 E.
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.
Hansen, Torben
Chen, Wei Min
Jackson, Rebecca
Liu, Yu
Loos, Ruth J.F.
Rao, D. C.
Wang, Lu
Nielsen, Jonas B.
Kilpeläinen, Tuomas O.
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 E.
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.
Hansen, Torben
Chen, Wei Min
Jackson, Rebecca
Liu, Yu
Loos, Ruth J.F.
Rao, D. C.
Wang, Lu
Nielsen, Jonas B.
Kilpeläinen, Tuomas O.
Source :
de Vries , P S , Reventun , P , Brown , M R , Heath , A S , Huffman , J E , Le , N Q , Bebo , A , Brody , J A , Temprano-Sagrera , G , Raffield , L M , Ozel , A B , Thibord , F , Jain , D , Lewis , J P , Rodriguez , B A T , Pankratz , N , Taylor , K D , Polasek , O , Chen , M H , Yanek , L R , Carrasquilla , G D , Marioni , R E , Kleber , M E , Trégouët , D A , Yao , J , Li-Gao , R , Joshi , P K , Trompet , S , Martinez-Perez , A , Ghanbari , M , Howard , T E , Reiner , A P , Arvanitis , M , Ryan , K A , Bartz , T M , Rudan , I , Faraday , N , Linneberg , A , Ekunwe , L , Davies , G , Delgado , G E , Hansen , T , Chen , W M , Jackson , R , Liu , Y , Loos , R J F , Rao , D C , Wang , L , Nielsen , J B , Kilpeläinen , T O , Trans-Omics for Precision Medicine (TOPMed) program & the INVENT consortium 2024 , ' A genetic association study of circulating coagulation factor VIII and von Willebrand factor levels ' , Blood , vol. 143 , no. 18 , pp. 1845-1855 .
Publication Year :
2024

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 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.<br />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.

Details

Database :
OAIster
Journal :
de Vries , P S , Reventun , P , Brown , M R , Heath , A S , Huffman , J E , Le , N Q , Bebo , A , Brody , J A , Temprano-Sagrera , G , Raffield , L M , Ozel , A B , Thibord , F , Jain , D , Lewis , J P , Rodriguez , B A T , Pankratz , N , Taylor , K D , Polasek , O , Chen , M H , Yanek , L R , Carrasquilla , G D , Marioni , R E , Kleber , M E , Trégouët , D A , Yao , J , Li-Gao , R , Joshi , P K , Trompet , S , Martinez-Perez , A , Ghanbari , M , Howard , T E , Reiner , A P , Arvanitis , M , Ryan , K A , Bartz , T M , Rudan , I , Faraday , N , Linneberg , A , Ekunwe , L , Davies , G , Delgado , G E , Hansen , T , Chen , W M , Jackson , R , Liu , Y , Loos , R J F , Rao , D C , Wang , L , Nielsen , J B , Kilpeläinen , T O , Trans-Omics for Precision Medicine (TOPMed) program & the INVENT consortium 2024 , ' A genetic association study of circulating coagulation factor VIII and von Willebrand factor levels ' , Blood , vol. 143 , no. 18 , pp. 1845-1855 .
Notes :
English
Publication Type :
Electronic Resource
Accession number :
edsoai.on1439558399
Document Type :
Electronic Resource