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

Pim van der Harst, Kathleen A Ryan, Raymond Noordam, Xiuqing Guo, Tuomas O Kilpeläinen, Alex P Reiner, Bruce M Psaty, Sarah E Harris, Simon R Cox, Mohsen Ghanbari, M Arfan Ikram, Stephen S Rich, Maria Sabater-Lleal, Charles Kooperberg, Alanna C Morrison, Paul S de Vries, Ozren Polasek, Ivana Kolcic, Leslie A Lange, Graciela E Delgado, Marcus E Kleber, Jennifer A Brody, Stella Trompet, Michael R Brown, James F Wilson, Angela P Moissl, William O Osburn, Frank van Rooij, German D Carrasquilla, Benjamin A T Rodriguez, Gerard Temprano-Sagrera, Allison Bebo, Adam S Heath, Paula Reventun, Lynette Ekunwe, Harry Campbell, J Wouter Jukema, Igor Rudan, Jerome I Rotter, Braxton D Mitchell, Winfried März, Allan Linneberg, Peter K Joshi, Caroline Hayward, Myriam Fornage, Eric Boerwinkle, Jie Yao, Kent D Taylor, Juan Carlos Souto, Paul L Auer, Moniek P M de Maat, Lewis C Becker, Rasika A Mathias, Nathan Pankratz, Yoav Ben-Shlomo, Jean-François Deleuze, Joshua P Lewis, Laura M Raffield, Traci M Bartz, Jose Manuel Soria, Marios Arvanitis, Nauder Faraday, Karl C Desch, Margaret F Doyle, Tom E Howard, Andrew Beswick, Laura Almasy, Deepti Jain, Angel Martinez-Perez, Lucija Klaric, Ayse Bilge Ozel, Marsha M Wheeler, Jennifer E Huffman, David J Stott, Lawrence C Brody, John Blangero, Joanne E Curran, Torben Hansen, Gail Davies, Pierre Suchon, Lisa R Yanek, Jeffrey R O'Connell, David-Alexandre Trégouët, Nicholas L Smith, Ngoc-Quynh Le, Dennis O Mook-Kanamori, Astrid van Hylckama Vlieg, Frits R Rosendaal, Ruifang Li-Gao, Andrew D Johnson, Pierre-Emmanuel Morange, Florian Thibord, Ming-Huei Chen, Riccardo E Marioni, Charles J Lowenstein

Journal: Blood 2024;143(18):1845-1855

PMID: 38320121

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.

Address: Department 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.; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.; Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, Boston, MA.; Unit of Genomics of Complex Disease, Institut de Recerca Sant Pau, Barcelona, Spain.; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA.; Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC.; Department of Human Genetics, University of Michigan, Ann Arbor, MI.; Division of Intramural Research, Population Sciences Branch, National Heart, Lung, and Blood Institute, Framingham Heart Study, Framingham, MA.; Department of Biostatistics, Genetic Analysis Center, School of Public Health, University of Washington, Seattle, WA.; Department of Medicine, University of Maryland, Baltimore, MD.; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.; Department of Pediatrics, Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA.; Faculty of Medicine, University of Split, Split, Croatia.; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.; Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.; Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Scotland.; SYNLAB MVZ Humangenetik Mannheim, Mannheim, Germany.; Fifth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.; INSERM UMR 1219, Bordeaux Population Health Research Center, Bordeaux, France.; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.; Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, Scotland.; Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.; Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.; Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX.; Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA.; Departments of Biostatistics and Medicine, Cardiovascular Health Research Unit, University of Washington, Seattle, WA.; Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.; Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark.; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Department of Medicine, University of Mississippi Medical Center, Jackson, MS.; Department of Psychology, Lothian Birth Cohorts, University of Edinburgh, Edinburgh, Scotland.; Fifth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.; C2VN, INSERM, INRAE, Aix Marseille University, Marseille, France.; Laboratory of Haematology, La Timone Hospital, Marseille, France.; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Scotland.; Department of Genome Sciences, University of Washington, Seattle, WA.; Department 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.; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX.; Translational Health Sciences, University of Bristol, Bristol, United Kingdom.; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA.; Departments of Epidemiology and Health Systems and Population Health, Seattle, WA.; Unit of Genomics of Complex Disease, Institut de Recerca Sant Pau, Barcelona, Spain.; Unit of Thrombosis and Hemostasis, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.; Department of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, Colchester, VT.; Institute of Nutritional Sciences, Friedrich-Schiller-University Jena, Jena, Germany.; Competence Cluster for Nutrition and Cardiovascular Health Halle-Jena-Leipzig, Jena, Germany.; Centre National de Recherche en Génomique Humaine, Université Paris-Saclay, CEA, Evry, France.; Centre d'Etude du Polymorphisme Humain, Fondation Jean Dausset, Paris, France.; Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA.; Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland.; Department of Hematology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.; Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA.; National Human Genome Research Institute, National Institutes of Health, Bethesda, MD.; Department of Biostatistics, Medical College of Wisconsin, Milwaukee, WI.; Department of Medicine, University of Maryland, Baltimore, MD.; Geriatric Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD.; Population Health Sciences, University of Bristol, Bristol, United Kingdom.; Department 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.; Brown Foundation Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX.; Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, CO.; Fifth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.; Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim, Germany.; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.; Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands.; Division of Heart and Lungs, Department of Cardiology, Utrecht University, University Medical Center Utrecht, Utrecht, The Netherlands.; Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.; Netherlands Heart Institute, Utrecht, The Netherlands.; Department of Pediatrics, University of Michigan, C.S. Mott Children's Hospital, Ann Arbor, MI.; Unit of Genomics of Complex Disease, Institut de Recerca Sant Pau, Barcelona, Spain.; Department of Medicine, Cardiovascular Medicine Unit, Karolinska Institutet, Center for Molecular Medicine, Stockholm, Sweden.; Department of Epidemiology, University of Washington, Seattle, WA.; Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle, WA.; Department of Veterans Affairs Office of Research and Development, Seattle Epidemiologic and Information Center, Seattle, WA.
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