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 af dette arbejde

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

2 Citationer (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.

Originalsprog	Engelsk
Tidsskrift	Blood
Vol/bind	143
Udgave nummer	18
Sider (fra-til)	1845-1855
ISSN	0006-4971
DOI	https://doi.org/10.1182/blood.2023021452
Status	Udgivet - 2024

Bibliografisk note

Funding Information:
This work and the CHARGE-TOPMed (Cohorts for Heart and Aging Research in Genomic Epidemiology-Trans-Omics for Precision Medicine) Hemostasis Working Group was funded in part by the National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI) grant numbers R01 HL134894 and R01 HL139553 . Infrastructure for the CHARGE consortium was supported by NIH/NHLBI grant number R01HL105756. The Analysis Commons was funded by NIH/NHBLI grant number R01 HL131136. PR was supported by the American Heart Association and the DC Women's Board (23POST1021300). C.J.L. was supported by NIH/NHLBI grant number R33 HL141791 and the Michel Mirowski M.D. Professorship in Cardiology. C.H. and J.F.W. were supported by the UK Medical Research Council grant U. MC_UU_00007/10. G.T.-S. is supported by the Pla Estratègic de Recerca i Innovació en Salut grant from the Catalan Department of Health ( SLT017/20/000100 ). M.S.-L is supported by a Miguel Servet contract from the Instituto de Salud Carlos III Spanish Health Institute (CPII22/00007) and cofinanced by the European Social Fund. L.M.R. was supported by the National Center for Advancing Translational Sciences, National Institutes of Health , through grant KL2TR002490 . Molecular data for the TOPMed program was supported by the NIH/ NHLBI . Core support including centralized genomic read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I). Core support including phenotype harmonization, data management, sample-identity QC, and general program coordination were provided by the TOPMed Data Coordinating Center (R01HL-120393; U01HL-120393; contract HHSN268201800001I). The study-specific omics support information is provided in the TOPMed Omics Support Table ( supplemental Table 15 ). Further study-specific funding and acknowledgments are detailed in the supplemental Methods .

Funding Information:
The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the NHLBI, the National Institutes of Health, or the US Department of Health and Human Services.The authors thank the CARDIoGRAMplusC4D and MEGASTROKE consortium investigators for making their summary statistics publicly available, as well as the MVP study investigators for making their summary statistics available through dbGaP (database of Genotypes and Phenotypes). The authors also acknowledge the participants and staff of the contributing studies. This work and the CHARGE-TOPMed (Cohorts for Heart and Aging Research in Genomic Epidemiology-Trans-Omics for Precision Medicine) Hemostasis Working Group was funded in part by the National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI) grant numbers R01 HL134894 and R01 HL139553. Infrastructure for the CHARGE consortium was supported by NIH/NHLBI grant number R01HL105756. The Analysis Commons was funded by NIH/NHBLI grant number R01 HL131136. PR was supported by the American Heart Association and the DC Women's Board (23POST1021300). C.J.L. was supported by NIH/NHLBI grant number R33 HL141791 and the Michel Mirowski M.D. Professorship in Cardiology. C.H. and J.F.W. were supported by the UK Medical Research Council grant U. MC_UU_00007/10. G.T.-S. is supported by the Pla Estratègic de Recerca i Innovació en Salut grant from the Catalan Department of Health (SLT017/20/000100). M.S.-L is supported by a Miguel Servet contract from the Instituto de Salud Carlos III Spanish Health Institute (CPII22/00007) and cofinanced by the European Social Fund. L.M.R. was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through grant KL2TR002490. Molecular data for the TOPMed program was supported by the NIH/NHLBI. Core support including centralized genomic read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I). Core support including phenotype harmonization, data management, sample-identity QC, and general program coordination were provided by the TOPMed Data Coordinating Center (R01HL-120393; U01HL-120393; contract HHSN268201800001I). The study-specific omics support information is provided in the TOPMed Omics Support Table (supplemental Table 15). Further study-specific funding and acknowledgments are detailed in the supplemental Methods. 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. P.S.d.V. drafted the initial manuscript; and all coauthors participated in critical review of the manuscript.

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Citationsformater

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.

I: Blood, Bind 143, Nr. 18, 2024, s. 1845-1855.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › 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, bind 143, nr. 18, s. 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. I: Blood. 2024 ; Bind 143, Nr. 18. s. 1845-1855.

@article{6e5afab3e02f4419818b6de86d963b9e,

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 -