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

NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; INVENT Consortium; Braxton D. Mitchell; Yoav Ben-shlomo; Myriam Fornage; 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

doi:10.1182/blood.2023021452

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

NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, INVENT Consortium, Braxton D. Mitchell, Yoav Ben-shlomo, Myriam Fornage, 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

Research output: Contribution to journal › Article › peer-review

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 three 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 (HUVECs). 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 seven new loci for FVIII (ST3GAL4, CLEC4M, B3GNT2, ASGR1, F12, KNG1, and TREM1/NCR2) and one for VWF (B3GNT2). VWF, ABO, and STAB2 were associated with FVIII and VWF in gene-based analyses. Multi-phenotype analysis of FVIII and VWF identified another three new loci, including PDIA3. Silencing of B3GNT2 and the previously reported CD36 gene decreased release of FVIII by HLECs, while 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 one 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
Pages (from-to)	1845-1855
Number of pages	11
Journal	Blood
Volume	143
Issue number	18
Early online date	9 Feb 2024
DOIs	https://doi.org/10.1182/blood.2023021452
Publication status	Published - May 2024

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10.1182/blood.2023021452

DeVriesEtalB2024AGeneticAssociationStudyAccepted author manuscript, 450 KBLicence: Creative Commons: Attribution (CC-BY)

https://eprints.gla.ac.uk/319793/

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NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, INVENT Consortium, Mitchell, B. D., Ben-shlomo, Y., Fornage, M., Morange, P.-E., Rotter, J. I., Mook-Kanamori, D. O., Wilson, J. F., van der Harst, P., Wouter Jukema, J., Arfan Ikram, M., Blangero, J., Kooperberg, C., Desch, K. C., Johnson, A. D., Sabater-Lleal, M., Lowenstein, C. J., Smith, N. L., & Morrison, A. C. (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

@article{67f5c958f3b44cea9dff89c0957f58b0,

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 three 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 (HUVECs). 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 seven new loci for FVIII (ST3GAL4, CLEC4M, B3GNT2, ASGR1, F12, KNG1, and TREM1/NCR2) and one for VWF (B3GNT2). VWF, ABO, and STAB2 were associated with FVIII and VWF in gene-based analyses. Multi-phenotype analysis of FVIII and VWF identified another three new loci, including PDIA3. Silencing of B3GNT2 and the previously reported CD36 gene decreased release of FVIII by HLECs, while 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 one 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 Cox, {Simon R.} 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 Oze, {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 Ming-Huei Chen and Yanek, {Lisa R.} and Carrasquilla, {German D.} and Riccardo Marioni 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 Pierre Suchon and Xiuqing Guo and Rosendaal, {Frits R.} and Lucija Klaric and Raymond Noordam and {van Rooij}, Frank and Curran, {Joanne E.} and Wheeler, {Marsha M.} and Osburn, {William O.} and O'Connel, {Jeffrey R.} and Eric Boerwinkle and Andrew Beswick and Psaty, {Bruce M.} and Ivana Kolcic and Souto, {Juan Carlos} and Becker, {Lewis C.} and Torben Hansen and Doyle, {Margaret F.} and Harris, {Sarah E.} and Moissl, {Angela P.} and Jean-Fran{\c c}ois Deleuze and Rich, {Stephen S.} and {van Hylckama Vlieg}, Astrid and Harry Campbell and Stott, {David J.} and Soria, {Jose Manuel} and {de Maat}, {Moniek P. M.} and Laura Almasy and Brody, {Lawrence C.} and Auer, {Paul L.} and {NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium} and {INVENT Consortium} and Mitchell, {Braxton D.} and Yoav Ben-shlomo and Myriam Fornage and Pierre-Emmanuel Morange and Rotter, {Jerome I.} and Mook-Kanamori, {Dennis O.} and Wilson, {James F.} and {van der Harst}, Pim and {Wouter Jukema}, J. and {Arfan Ikram}, M. and John Blangero and Charles Kooperberg and Desch, {Karl C.} and Johnson, {Andrew D.} and Maria Sabater-Lleal and Lowenstein, {Charles J.} and Smith, {Nicholas L.} and Morrison, {Alanna C.}",

note = "Contribution: A.C.M., A.P.R., A.L., A. Beswick, A.D.J., A.v.H.V., B.D.M., B.M.P., C.H., D.J.S., D.-A.T., D.O.M.-K., F.R.R., H.C., I.R., J.W.J., J.F.W., J.-F.D., J.I.R., J.E.C., J.B., J.M.S., J.P.L., J.C.S., K.C.D., K.D.T., L.M.R., L.A., L. C. Becker, L.A.L., L. C. Brody, L.E., M.F.D., M.A.I., M.-H.C., M.F., N.F., N.L.S., O.P., P.-E.M., R.A.M., S.R.C., S.S.R., T.E.H., W.M., and Y.B.-S. contributed to the design and/or funding of the included studies from the TOPMed program and/or CHARGE consortium; A.C.M., A.P.R., A.L., A. Beswick, A.D.J., A.M.-P., A.v.H.V., A.B.O., B.A.T.R., B.D.M., B.M.P., C.H., D.J.S., D.-A.T., D.J., D.O.M.-K., F.v.R., F.R.R., G.D., G.D.C., I.R., I.K., J.W.J., J.F.W., J.-F.D., J.R.O., J.E.H., J.E.C., J.B., J.P.L., J.C.S., K.C.D., K.A.R., K.D.T., L.A., L. C. Brody, L.R.Y., M.E.K., M.S.-L., M.R.B., M.-H.C., M.P.M.d.M., M.F., N.P., N.F., N.-Q.L., O.P., P.S.d.V., P.S., P.-E.M., P.v.d.H., R.A.M., R.L.G., S.E.H., S.R.C., S.T., T.H.E., T.H., T.O.K., and Y.B.-S. contributed to the acquisition of genotype and/or phenotype data; A.S.H., A.C.M., A. Bebo, A.D.J., A.M.-P., A.P.M., A.B.O., B.A.T.R., B.D.M., C.H., D.-A.T., D.J., F.T., G.D., G.T.S., G.D.C., G.E.D., J.F.D., J.R.O.C., J.E.H., J.A.B., J.Y., J.P.L., K.C.D., K.A.R., L.M.R., L.R.Y., L.K., M.E.K., M.S.-L., M.R.B., M.-H.C., M.G., N.-Q.L., N.L.S., P.S.d.V., P.K.J., R.A.M., R.N., R.E.M., R.L.G., S.T., T.M.B., and X.G. contributed to the genetic epidemiology analyses and interpretation; C.J.L., M.A., P.R., and W.O.O. contributed to the design of the gene silencing experiments; P.R. performed the gene silencing experiments; P.R. and C.J.L. contributed to data analysis and interpretation of the gene silencing experiments; A.S.H., A.C.M., C.J.L., M.R.B., M.S.-L., N.L.S., P.R., and P.S.d.V. drafted the initial manuscript; and all coauthors participated in critical review of the manuscript.",

year = "2024",

month = may,

doi = "10.1182/blood.2023021452",

language = "English",

volume = "143",

pages = "1845--1855",

journal = "Blood",

issn = "0006-4971",

publisher = "Elsevier",

number = "18",

}

NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, INVENT Consortium, Mitchell, BD, Ben-shlomo, Y, Fornage, M, Morange, P-E, Rotter, JI, Mook-Kanamori, DO, Wilson, JF, van der Harst, P, Wouter Jukema, J, Arfan Ikram, M, Blangero, J, Kooperberg, C, Desch, KC, Johnson, AD, Sabater-Lleal, M, Lowenstein, CJ, Smith, NL & Morrison, AC 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

TY - JOUR

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

AU - de Vries, Paul S.

AU - Cox, Simon R.

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 - Oze, 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

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 - Osburn, William O.

AU - O'Connel, Jeffrey R.

AU - Boerwinkle, Eric

AU - Beswick, Andrew

AU - Psaty, Bruce M.

AU - Kolcic, Ivana

AU - Souto, Juan Carlos

AU - Becker, Lewis C.

AU - Hansen, Torben

AU - Doyle, Margaret F.

AU - Harris, Sarah E.

AU - Moissl, Angela P.

AU - Deleuze, Jean-François

AU - Rich, Stephen S.

AU - van Hylckama Vlieg, Astrid

AU - Campbell, Harry

AU - Stott, David J.

AU - Soria, Jose Manuel

AU - de Maat, Moniek P. M.

AU - Almasy, Laura

AU - Brody, Lawrence C.

AU - Auer, Paul L.

AU - NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium

AU - INVENT Consortium

AU - Mitchell, Braxton D.

AU - Ben-shlomo, Yoav

AU - Fornage, Myriam

AU - Morange, Pierre-Emmanuel

AU - Rotter, Jerome I.

AU - Mook-Kanamori, Dennis O.

AU - Wilson, James F.

AU - van der Harst, Pim

AU - Wouter Jukema, J.

AU - Arfan Ikram, M.

AU - Blangero, John

AU - Kooperberg, Charles

AU - Desch, Karl C.

AU - Johnson, Andrew D.

AU - Sabater-Lleal, Maria

AU - Lowenstein, Charles J.

AU - Smith, Nicholas L.

AU - Morrison, Alanna C.

N1 - Contribution: A.C.M., A.P.R., A.L., A. Beswick, A.D.J., A.v.H.V., B.D.M., B.M.P., C.H., D.J.S., D.-A.T., D.O.M.-K., F.R.R., H.C., I.R., J.W.J., J.F.W., J.-F.D., J.I.R., J.E.C., J.B., J.M.S., J.P.L., J.C.S., K.C.D., K.D.T., L.M.R., L.A., L. C. Becker, L.A.L., L. C. Brody, L.E., M.F.D., M.A.I., M.-H.C., M.F., N.F., N.L.S., O.P., P.-E.M., R.A.M., S.R.C., S.S.R., T.E.H., W.M., and Y.B.-S. contributed to the design and/or funding of the included studies from the TOPMed program and/or CHARGE consortium; A.C.M., A.P.R., A.L., A. Beswick, A.D.J., A.M.-P., A.v.H.V., A.B.O., B.A.T.R., B.D.M., B.M.P., C.H., D.J.S., D.-A.T., D.J., D.O.M.-K., F.v.R., F.R.R., G.D., G.D.C., I.R., I.K., J.W.J., J.F.W., J.-F.D., J.R.O., J.E.H., J.E.C., J.B., J.P.L., J.C.S., K.C.D., K.A.R., K.D.T., L.A., L. C. Brody, L.R.Y., M.E.K., M.S.-L., M.R.B., M.-H.C., M.P.M.d.M., M.F., N.P., N.F., N.-Q.L., O.P., P.S.d.V., P.S., P.-E.M., P.v.d.H., R.A.M., R.L.G., S.E.H., S.R.C., S.T., T.H.E., T.H., T.O.K., and Y.B.-S. contributed to the acquisition of genotype and/or phenotype data; A.S.H., A.C.M., A. Bebo, A.D.J., A.M.-P., A.P.M., A.B.O., B.A.T.R., B.D.M., C.H., D.-A.T., D.J., F.T., G.D., G.T.S., G.D.C., G.E.D., J.F.D., J.R.O.C., J.E.H., J.A.B., J.Y., J.P.L., K.C.D., K.A.R., L.M.R., L.R.Y., L.K., M.E.K., M.S.-L., M.R.B., M.-H.C., M.G., N.-Q.L., N.L.S., P.S.d.V., P.K.J., R.A.M., R.N., R.E.M., R.L.G., S.T., T.M.B., and X.G. contributed to the genetic epidemiology analyses and interpretation; C.J.L., M.A., P.R., and W.O.O. contributed to the design of the gene silencing experiments; P.R. performed the gene silencing experiments; P.R. and C.J.L. contributed to data analysis and interpretation of the gene silencing experiments; A.S.H., A.C.M., C.J.L., M.R.B., M.S.-L., N.L.S., P.R., and P.S.d.V. drafted the initial manuscript; and all coauthors participated in critical review of the manuscript.

PY - 2024/5

Y1 - 2024/5

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 three 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 (HUVECs). 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 seven new loci for FVIII (ST3GAL4, CLEC4M, B3GNT2, ASGR1, F12, KNG1, and TREM1/NCR2) and one for VWF (B3GNT2). VWF, ABO, and STAB2 were associated with FVIII and VWF in gene-based analyses. Multi-phenotype analysis of FVIII and VWF identified another three new loci, including PDIA3. Silencing of B3GNT2 and the previously reported CD36 gene decreased release of FVIII by HLECs, while 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 one 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 three 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 (HUVECs). 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 seven new loci for FVIII (ST3GAL4, CLEC4M, B3GNT2, ASGR1, F12, KNG1, and TREM1/NCR2) and one for VWF (B3GNT2). VWF, ABO, and STAB2 were associated with FVIII and VWF in gene-based analyses. Multi-phenotype analysis of FVIII and VWF identified another three new loci, including PDIA3. Silencing of B3GNT2 and the previously reported CD36 gene decreased release of FVIII by HLECs, while 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 one 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 - Article

SN - 0006-4971

VL - 143

SP - 1845

EP - 1855

JO - Blood

JF - Blood

IS - 18

ER -

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

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