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. 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; Torben Hansen; Wei Min Chen; Rebecca Jackson; Yu Liu; Ruth J.F. Loos; D. C. Rao; Lu Wang; Jonas B. Nielsen; Tuomas O. Kilpeläinen; Trans-Omics for Precision Medicine (TOPMed) program; the INVENT consortium

doi:10.1182/blood.2023021452

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 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, Torben Hansen, Wei Min Chen, Rebecca Jackson, Yu Liu, Ruth J.F. Loos, D. C. Rao, Lu Wang, Jonas B. Nielsen, Tuomas O. Kilpeläinen, Trans-Omics for Precision Medicine (TOPMed) program, the INVENT consortium

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › Research › peer-review

1 Citation (Scopus)

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.

Original language	English
Journal	Blood
Volume	143
Issue number	18
Pages (from-to)	1845-1855
ISSN	0006-4971
DOIs	https://doi.org/10.1182/blood.2023021452
Publication status	Published - 2024

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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., ... the INVENT consortium (2024). A genetic association study of circulating coagulation factor VIII and von Willebrand factor levels. Blood, 143(18), 1845-1855. https://doi.org/10.1182/blood.2023021452

A genetic association study of circulating coagulation factor VIII and von Willebrand factor levels. / 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.; Trans-Omics for Precision Medicine (TOPMed) program; the INVENT consortium.

In: Blood, Vol. 143, No. 18, 2024, p. 1845-1855.

Research output: Contribution to journal › Journal article › Research › peer-review

de Vries, PS, Reventun, P, Brown, MR, Heath, AS, Huffman, JE, Le, NQ, Bebo, A, Brody, JA, Temprano-Sagrera, G, Raffield, LM, Ozel, AB, Thibord, F, Jain, D, Lewis, JP, Rodriguez, BAT, Pankratz, N, Taylor, KD, Polasek, O, Chen, MH, Yanek, LR, Carrasquilla, GD, Marioni, RE, Kleber, ME, Trégouët, DA, Yao, J, Li-Gao, R, Joshi, PK, Trompet, S, Martinez-Perez, A, Ghanbari, M, Howard, TE, Reiner, AP, Arvanitis, M, Ryan, KA, Bartz, TM, Rudan, I, Faraday, N, Linneberg, A, Ekunwe, L, Davies, G, Delgado, GE, Hansen, T, Chen, WM, Jackson, R, Liu, Y, Loos, RJF , Rao, DC, Wang, L, Nielsen, JB, Kilpeläinen, TO, 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. https://doi.org/10.1182/blood.2023021452

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. ; Trans-Omics for Precision Medicine (TOPMed) program ; the INVENT consortium. / A genetic association study of circulating coagulation factor VIII and von Willebrand factor levels. In: Blood. 2024 ; Vol. 143, No. 18. pp. 1845-1855.

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title = "A genetic association study of circulating coagulation factor VIII and von Willebrand factor levels",

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.",

author = "{de Vries}, {Paul S.} and Paula Reventun and Brown, {Michael R.} and Heath, {Adam S.} and Huffman, {Jennifer E.} and Le, {Ngoc Quynh} and Allison Bebo and Brody, {Jennifer A.} and Gerard Temprano-Sagrera and Raffield, {Laura M.} and Ozel, {Ayse Bilge} and Florian Thibord and Deepti Jain and Lewis, {Joshua P.} and Rodriguez, {Benjamin A.T.} and Nathan Pankratz and Taylor, {Kent D.} and Ozren Polasek and Chen, {Ming Huei} and Yanek, {Lisa R.} and Carrasquilla, {German D.} and Marioni, {Riccardo E.} and Kleber, {Marcus E.} and Tr{\'e}gou{\"e}t, {David Alexandre} and Jie Yao and Ruifang Li-Gao and Joshi, {Peter K.} and Stella Trompet and Angel Martinez-Perez and Mohsen Ghanbari and Howard, {Tom E.} and Reiner, {Alex P.} and Marios Arvanitis and Ryan, {Kathleen A.} and Bartz, {Traci M.} and Igor Rudan and Nauder Faraday and Allan Linneberg and Lynette Ekunwe and Gail Davies and Delgado, {Graciela E.} and Torben Hansen and Chen, {Wei Min} and Rebecca Jackson and Yu Liu and Loos, {Ruth J.F.} and Rao, {D. C.} and Lu Wang and Nielsen, {Jonas B.} and Kilpel{\"a}inen, {Tuomas O.} and {Trans-Omics for Precision Medicine (TOPMed) program} and {the INVENT consortium}",

note = "Publisher Copyright: {\textcopyright} 2024",

year = "2024",

doi = "10.1182/blood.2023021452",

language = "English",

volume = "143",

pages = "1845--1855",

journal = "Blood",

issn = "0006-4971",

publisher = "American Society of Hematology",

number = "18",

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TY - JOUR

T1 - A genetic association study of circulating coagulation factor VIII and von Willebrand factor levels

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 - Hansen, Torben

AU - Chen, Wei Min

AU - Jackson, Rebecca

AU - Liu, Yu

AU - Loos, Ruth J.F.

AU - Rao, D. C.

AU - Wang, Lu

AU - Nielsen, Jonas B.

AU - Kilpeläinen, Tuomas O.

AU - Trans-Omics for Precision Medicine (TOPMed) program

AU - the INVENT consortium

PY - 2024

Y1 - 2024

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.

U2 - 10.1182/blood.2023021452

DO - 10.1182/blood.2023021452

M3 - Journal article

C2 - 38320121

AN - SCOPUS:85186210770

VL - 143

SP - 1845

EP - 1855

JO - Blood

JF - Blood

SN - 0006-4971

IS - 18

ER -