A genetic association study of circulating coagulation factor VIII and von Willebrand factor levels-Reference-Cited by-同舟云学术

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

Published:2024-05-02 Issue:18 Volume:143 Page:1845-1855
ISSN:0006-4971
Container-title:Blood
language:en
Short-container-title:

Author:

de Vries Paul S.¹,Reventun Paula²,Brown Michael R.¹,Heath Adam S.¹^ORCID,Huffman Jennifer E.³^ORCID,Le Ngoc-Quynh⁴,Bebo Allison¹,Brody Jennifer A.⁵^ORCID,Temprano-Sagrera Gerard⁴^ORCID,Raffield Laura M.⁶^ORCID,Ozel Ayse Bilge⁷^ORCID,Thibord Florian⁸^ORCID,Jain Deepti⁹,Lewis Joshua P.¹⁰,Rodriguez Benjamin A. T.⁸,Pankratz Nathan¹¹,Taylor Kent D.¹²^ORCID,Polasek Ozren¹³,Chen Ming-Huei⁸,Yanek Lisa R.²^ORCID,Carrasquilla German D.¹⁴¹⁵^ORCID,Marioni Riccardo E.¹⁶,Kleber Marcus E.¹⁷¹⁸,Trégouët David-Alexandre¹⁹,Yao Jie¹²,Li-Gao Ruifang²⁰^ORCID,Joshi Peter K.²¹^ORCID,Trompet Stella²²,Martinez-Perez Angel⁴^ORCID,Ghanbari Mohsen²³^ORCID,Howard Tom E.²⁴,Reiner Alex P.²⁵,Arvanitis Marios²,Ryan Kathleen A.¹⁰^ORCID,Bartz Traci M.²⁶,Rudan Igor²¹,Faraday Nauder²⁷,Linneberg Allan²⁸²⁹^ORCID,Ekunwe Lynette³⁰,Davies Gail³¹^ORCID,Delgado Graciela E.¹⁸,Suchon Pierre³²³³,Guo Xiuqing¹²^ORCID,Rosendaal Frits R.²⁰^ORCID,Klaric Lucija³⁴^ORCID,Noordam Raymond²²,van Rooij Frank²³^ORCID,Curran Joanne E.²⁴,Wheeler Marsha M.³⁵,Osburn William O.²,O'Connell Jeffrey R.¹⁰,Boerwinkle Eric¹³⁶,Beswick Andrew³⁷^ORCID,Psaty Bruce M.⁵³⁸,Kolcic Ivana¹³^ORCID,Souto Juan Carlos⁴³⁹^ORCID,Becker Lewis C.²,Hansen Torben¹⁴^ORCID,Doyle Margaret F.⁴⁰,Harris Sarah E.³¹^ORCID,Moissl Angela P.⁴¹⁴²^ORCID,Deleuze Jean-François⁴³⁴⁴,Rich Stephen S.⁴⁵,van Hylckama Vlieg Astrid²⁰,Campbell Harry²¹^ORCID,Stott David J.⁴⁶^ORCID,Soria Jose Manuel⁴,de Maat Moniek P. M.⁴⁷^ORCID,Almasy Laura⁴⁸⁴⁹,Brody Lawrence C.⁵⁰,Auer Paul L.⁵¹^ORCID,Mitchell Braxton D.¹⁰⁵²^ORCID,Ben-Shlomo Yoav⁵³,Fornage Myriam¹⁵⁴^ORCID,Hayward Caroline³⁴^ORCID,Mathias Rasika A.²,Kilpeläinen Tuomas O.¹⁴,Lange Leslie A.⁵⁵,Cox Simon R.³¹^ORCID,März Winfried¹⁸⁵⁶^ORCID,Morange Pierre-Emmanuel³²³³,Rotter Jerome I.¹²,Mook-Kanamori Dennis O.²⁰⁵⁷,Wilson James F.²¹^ORCID,van der Harst Pim⁵⁸^ORCID,Jukema J. Wouter⁵⁹⁶⁰^ORCID,Ikram M. Arfan²³,Blangero John²⁴,Kooperberg Charles²⁵,Desch Karl C.⁶¹^ORCID,Johnson Andrew D.⁸^ORCID,Sabater-Lleal Maria⁴⁶²^ORCID,Lowenstein Charles J.²,Smith Nicholas L.⁶³⁶⁴⁶⁵,Morrison Alanna C.¹

Affiliation:

1. 1Department of Epidemiology, Human Genetics, and Environmental Sciences, Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX

2. 2Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD

3. 3Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, Boston, MA

4. 4Unit of Genomics of Complex Disease, Institut de Recerca Sant Pau, Barcelona, Spain

5. 5Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA

6. 6Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC

7. 7Department of Human Genetics, University of Michigan, Ann Arbor, MI

8. 8Division of Intramural Research, Population Sciences Branch, National Heart, Lung, and Blood Institute, Framingham Heart Study, Framingham, MA

9. 9Department of Biostatistics, Genetic Analysis Center, School of Public Health, University of Washington, Seattle, WA

10. 10Department of Medicine, University of Maryland, Baltimore, MD

11. 11Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA

12. 12Department of Pediatrics, Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA

13. 13Faculty of Medicine, University of Split, Split, Croatia

14. 14Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark

15. 15Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden

16. 16Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Scotland

17. 17SYNLAB MVZ Humangenetik Mannheim, Mannheim, Germany

18. 18Fifth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

19. 19INSERM UMR 1219, Bordeaux Population Health Research Center, Bordeaux, France

20. 20Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands

21. 21Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, Scotland

22. 22Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands

23. 23Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands

24. 24Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX

25. 25Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA

26. 26Departments of Biostatistics and Medicine, Cardiovascular Health Research Unit, University of Washington, Seattle, WA

27. 27Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD

28. 28Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark

29. 29Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

30. 30Department of Medicine, University of Mississippi Medical Center, Jackson, MS

31. 31Department of Psychology, Lothian Birth Cohorts, University of Edinburgh, Edinburgh, Scotland

32. 32C2VN, INSERM, INRAE, Aix Marseille University, Marseille, France

33. 33Laboratory of Haematology, La Timone Hospital, Marseille, France

34. 34MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Scotland

35. 35Department of Genome Sciences, University of Washington, Seattle, WA

36. 36Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX

37. 37Translational Health Sciences, University of Bristol, Bristol, United Kingdom

38. 38Departments of Epidemiology and Health Systems and Population Health, Seattle, WA

39. 39Unit of Thrombosis and Hemostasis, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

40. 40Department of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, Colchester, VT

41. 41Institute of Nutritional Sciences, Friedrich-Schiller-University Jena, Jena, Germany

42. 42Competence Cluster for Nutrition and Cardiovascular Health Halle-Jena-Leipzig, Jena, Germany

43. 43Centre National de Recherche en Génomique Humaine, Université Paris-Saclay, CEA, Evry, France

44. 44Centre d'Etude du Polymorphisme Humain, Fondation Jean Dausset, Paris, France

45. 45Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA

46. 46Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland

47. 47Department of Hematology, Erasmus MC University Medical Center, Rotterdam, The Netherlands

48. 48Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA

49. 49Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA

50. 50National Human Genome Research Institute, National Institutes of Health, Bethesda, MD

51. 51Department of Biostatistics, Medical College of Wisconsin, Milwaukee, WI

52. 52Geriatric Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD

53. 53Population Health Sciences, University of Bristol, Bristol, United Kingdom

54. 54Brown Foundation Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX

55. 55Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, CO

56. 56Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim, Germany

57. 57Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands

58. 58Division of Heart and Lungs, Department of Cardiology, Utrecht University, University Medical Center Utrecht, Utrecht, The Netherlands

59. 59Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands

60. 60Netherlands Heart Institute, Utrecht, The Netherlands

61. 61Department of Pediatrics, University of Michigan, C.S. Mott Children's Hospital, Ann Arbor, MI

62. 62Department of Medicine, Cardiovascular Medicine Unit, Karolinska Institutet, Center for Molecular Medicine, Stockholm, Sweden

63. 63Department of Epidemiology, University of Washington, Seattle, WA

64. 64Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle, WA

65. 65Department of Veterans Affairs Office of Research and Development, Seattle Epidemiologic and Information Center, Seattle, WA

Abstract

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.

Publisher

American Society of Hematology

Link

https://ashpublications.org/blood/article-pdf/doi/10.1182/blood.2023021452/2223731/blood_bld-2023-021452-main.pdf

Reference53 articles.

1. A concise review and update for the practicing physician;Swami;Clin Appl Thromb Hemost,2017

2. Factor VIII: structure and function in blood clotting;Chavin;Am J Hematol,1984

3. Factor VIII and von Willebrand factor interaction: biological, clinical and therapeutic importance;Terraube;Haemophilia,2010

4. Correlation between von Willebrand factor antigen, von Willebrand factor ristocetin cofactor activity and factor VIII activity in plasma;Lippi;J Thromb Thrombolysis,2008

5. Multi-phenotype analyses of hemostatic traits with cardiovascular events reveal novel genetic associations;Temprano-Sagrera;J Thromb Haemost,2022

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