A genetic association study of circulating coagulation factor VIII and von Willebrand factor levels
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.
Authors
- Winfried März (ORCID: https://orcid.org/0000-0001-6083-8946)
- Traci M. Bartz (ORCID: https://orcid.org/0000-0003-3403-8763)
- Laura Almasy (ORCID: https://orcid.org/0000-0002-9184-8124)
- Carla G. Wilson (ORCID: https://orcid.org/0000-0002-1076-5205)
- Christoph Lange (ORCID: https://orcid.org/0000-0003-2620-1030)
- Bruce M. Psaty (ORCID: https://orcid.org/0000-0002-7278-2190)
- Marios Arvanitis (ORCID: https://orcid.org/0000-0001-8046-6123)
- T Program
- Charles Kooperberg (ORCID: https://orcid.org/0000-0002-7986-8560)
- John Blangero (ORCID: https://orcid.org/0000-0001-6250-5723)
- Lynette Ekunwe
- Frank J.A. van Rooij (ORCID: https://orcid.org/0000-0002-8600-9852)
- J. Wouter Jukema (ORCID: https://orcid.org/0000-0002-3246-8359)
- Lucija Klarić (ORCID: https://orcid.org/0000-0003-3105-8929)
- Joshua P. Lewis (ORCID: https://orcid.org/0000-0002-4107-6066)
- Pierre Suchon (ORCID: https://orcid.org/0000-0001-8845-9163)
- Jennifer E. Huffman (ORCID: https://orcid.org/0000-0002-9672-2491)
- Ayse Bilge Ozel (ORCID: https://orcid.org/0000-0002-1112-4258)
- Kathleen A. Ryan (ORCID: https://orcid.org/0000-0003-1158-8455)
- Raymond Noordam (ORCID: https://orcid.org/0000-0001-7801-809X)
- Pim van der Harst (ORCID: https://orcid.org/0000-0002-2713-686X)
- Karl C. Desch (ORCID: https://orcid.org/0000-0003-0392-4033)
- Ming‐Huei Chen (ORCID: https://orcid.org/0000-0003-3551-8726)
- Gail Davies (ORCID: https://orcid.org/0000-0003-1120-7026)
- Ivana Kolčić (ORCID: https://orcid.org/0000-0001-7918-6052)
- Kent D. Taylor (ORCID: https://orcid.org/0000-0002-2756-4370)
- Marsha M. Wheeler
- Charles J. Lowenstein (ORCID: https://orcid.org/0000-0003-0485-7514)
- Braxton D. Mitchell (ORCID: https://orcid.org/0000-0003-4920-4744)
- Juan Carlos Souto (ORCID: https://orcid.org/0000-0003-2092-5142)
- Nathan Pankratz (ORCID: https://orcid.org/0000-0001-5958-693X)
- David J. Stott
- Frits R. Rosendaal (ORCID: https://orcid.org/0000-0003-2558-7496)
- Dennis O. Mook‐Kanamori (ORCID: https://orcid.org/0000-0002-0182-5122)
- Allison Bebo (ORCID: https://orcid.org/0000-0001-5734-091X)
- Florian Thibord (ORCID: https://orcid.org/0000-0003-2229-8322)
- Deepti Jain (ORCID: https://orcid.org/0000-0001-5629-2522)
- M. Arfan Ikram (ORCID: https://orcid.org/0000-0003-0372-8585)
- Igor Rudan (ORCID: https://orcid.org/0000-0001-6993-6884)
- Jerome I. Rotter (ORCID: https://orcid.org/0000-0001-7191-1723)
- Laura M. Raffield (ORCID: https://orcid.org/0000-0002-7892-193X)
- José Manuel Soria (ORCID: https://orcid.org/0000-0002-6226-4293)
- Jeffrey R. O’Connell (ORCID: https://orcid.org/0000-0002-7046-6688)
- Eric Boerwinkle (ORCID: https://orcid.org/0000-0001-8813-0544)
- Caroline Hayward (ORCID: https://orcid.org/0000-0002-9405-9550)
- Yoav Ben‐Shlomo (ORCID: https://orcid.org/0000-0001-6648-3007)
- Jean‐François Deleuze (ORCID: https://orcid.org/0000-0002-5358-4463)
- Margaret F. Doyle (ORCID: https://orcid.org/0000-0001-6769-5386)
- Moniek P.M. de Maat (ORCID: https://orcid.org/0000-0001-7749-334X)
- Nauder Faraday (ORCID: https://orcid.org/0000-0002-7397-9980)
- William O. Osburn (ORCID: https://orcid.org/0000-0002-7472-3805)
- Ozren Polašek (ORCID: https://orcid.org/0000-0002-5765-1862)
- Allan Linneberg (ORCID: https://orcid.org/0000-0002-0994-0184)
- Lewis C. Becker (ORCID: https://orcid.org/0000-0003-4805-3403)
- Paul S. de Vries (ORCID: https://orcid.org/0000-0003-0964-0111)
- Tom E. Howard (ORCID: https://orcid.org/0000-0002-4550-278X)
- Andrew D Beswick (ORCID: https://orcid.org/0000-0002-7032-7514)
- Astrid van Hylckama Vlieg (ORCID: https://orcid.org/0000-0001-7386-1168)
- Tuomas O. Kilpeläinen (ORCID: https://orcid.org/0000-0002-8349-3028)
- Adam S. Heath (ORCID: https://orcid.org/0000-0002-5909-9055)
- Paul Livermore Auer (ORCID: https://orcid.org/0000-0003-1735-8044)
- Marcus E. Kleber (ORCID: https://orcid.org/0000-0003-0663-7275)
- Maria Sabater‐Lleal (ORCID: https://orcid.org/0000-0002-0128-379X)
- Ángel Martínez-Pérez (ORCID: https://orcid.org/0000-0002-5934-1454)
- Rasika A. Mathias (ORCID: https://orcid.org/0000-0002-2282-9042)
- Lisa R. Yanek (ORCID: https://orcid.org/0000-0001-7117-1075)
- Mohsen Ghanbari (ORCID: https://orcid.org/0000-0002-9476-7143)
- Gerard Temprano‐Sagrera (ORCID: https://orcid.org/0000-0001-6136-8915)
- Blanca Rodríguez (ORCID: https://orcid.org/0000-0001-6361-3339)
- Jennifer A. Brody (ORCID: https://orcid.org/0000-0001-8509-148X)
- Ruifang Li‐Gao (ORCID: https://orcid.org/0000-0003-0650-1351)
- Germán D. Carrasquilla (ORCID: https://orcid.org/0000-0002-7147-9421)
- Harry J. Campbell (ORCID: https://orcid.org/0000-0002-6169-6262)
- Stephen S. Rich (ORCID: https://orcid.org/0000-0003-3872-7793)
- David‐Alexandre Trégouët (ORCID: https://orcid.org/0000-0001-9084-7800)
- Simon R. Cox (ORCID: https://orcid.org/0000-0003-4036-3642)
- Michael R. Brown (ORCID: https://orcid.org/0000-0002-5235-9037)
- Paula Reventún (ORCID: https://orcid.org/0000-0002-6221-8780)
- Pierre‐Emmanuel Morange (ORCID: https://orcid.org/0000-0002-9065-722X)
- Alex P. Reiner (ORCID: https://orcid.org/0000-0002-1427-4470)
- Alanna C. Morrison (ORCID: https://orcid.org/0000-0001-6381-4296)
- Ngoc‐Quynh Le (ORCID: https://orcid.org/0000-0002-7797-4925)
- Peter K. Joshi (ORCID: https://orcid.org/0000-0002-6361-5059)
- Xiuqing Guo (ORCID: https://orcid.org/0000-0002-5264-5068)
- Lawrence C. Brody (ORCID: https://orcid.org/0000-0001-9435-3592)
- Joanne E. Curran (ORCID: https://orcid.org/0000-0002-6898-155X)
- Angela P. Moissl (ORCID: https://orcid.org/0000-0003-0302-2136)
- Stella Trompet (ORCID: https://orcid.org/0000-0001-5006-0528)
- Jie Yao (ORCID: https://orcid.org/0000-0002-8822-0651)
- Myriam Fornage (ORCID: https://orcid.org/0000-0003-0677-8158)
- Torben Hansen (ORCID: https://orcid.org/0000-0001-8748-3831)
- Albert V. Smith (ORCID: https://orcid.org/0000-0003-1942-5845)
- Andrew D. Johnson (ORCID: https://orcid.org/0000-0002-5183-2072)
- Sarah E. Harris
- Graciela E. Delgado
- Riccardo E. Marioni
- INVENT consortium
Institutions
- University of North Carolina at Chapel Hill (US)
Publication Details
- Journal
- UNC Libraries
- Published
- 2025-05-03
- DOI
- https://doi.org/10.17615/262t-gt07
- Primary Topic
- Hemophilia Treatment and Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- American Heart Association
- National Heart, Lung, and Blood Institute