학술논문

A genetic association study of circulating coagulation factor VIII and von Willebrand factor levels.
Document Type
Academic Journal
Author
de Vries PS; 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.; Reventun P; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.; Brown MR; 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.; Heath AS; 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.; Huffman JE; Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, Boston, MA.; Le NQ; Unit of Genomics of Complex Disease, Institut de Recerca Sant Pau, Barcelona, Spain.; Bebo A; 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.; Brody JA; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA.; Temprano-Sagrera G; Unit of Genomics of Complex Disease, Institut de Recerca Sant Pau, Barcelona, Spain.; Raffield LM; Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC.; Ozel AB; Department of Human Genetics, University of Michigan, Ann Arbor, MI.; Thibord F; Division of Intramural Research, Population Sciences Branch, National Heart, Lung, and Blood Institute, Framingham Heart Study, Framingham, MA.; Jain D; Department of Biostatistics, Genetic Analysis Center, School of Public Health, University of Washington, Seattle, WA.; Lewis JP; Department of Medicine, University of Maryland, Baltimore, MD.; Rodriguez BAT; Division of Intramural Research, Population Sciences Branch, National Heart, Lung, and Blood Institute, Framingham Heart Study, Framingham, MA.; Pankratz N; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.; Taylor KD; Department of Pediatrics, Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA.; Polasek O; Faculty of Medicine, University of Split, Split, Croatia.; Chen MH; Division of Intramural Research, Population Sciences Branch, National Heart, Lung, and Blood Institute, Framingham Heart Study, Framingham, MA.; Yanek LR; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.; Carrasquilla GD; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.; Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.; Marioni RE; Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Scotland.; Kleber ME; SYNLAB MVZ Humangenetik Mannheim, Mannheim, Germany.; Fifth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.; Trégouët DA; INSERM UMR 1219, Bordeaux Population Health Research Center, Bordeaux, France.; Yao J; Department of Pediatrics, Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA.; Li-Gao R; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.; Joshi PK; Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, Scotland.; Trompet S; Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.; Martinez-Perez A; Unit of Genomics of Complex Disease, Institut de Recerca Sant Pau, Barcelona, Spain.; Ghanbari M; Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.; Howard TE; Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX.; Reiner AP; Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA.; Arvanitis M; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.; Ryan KA; Department of Medicine, University of Maryland, Baltimore, MD.; Bartz TM; Departments of Biostatistics and Medicine, Cardiovascular Health Research Unit, University of Washington, Seattle, WA.; Rudan I; Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, Scotland.; Faraday N; Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.; Linneberg A; 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.; Ekunwe L; Department of Medicine, University of Mississippi Medical Center, Jackson, MS.; Davies G; Department of Psychology, Lothian Birth Cohorts, University of Edinburgh, Edinburgh, Scotland.; Delgado GE; Fifth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.; Suchon P; C2VN, INSERM, INRAE, Aix Marseille University, Marseille, France.; Laboratory of Haematology, La Timone Hospital, Marseille, France.; Guo X; Department of Pediatrics, Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA.; Rosendaal FR; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.; Klaric L; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Scotland.; Noordam R; Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.; van Rooij F; Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.; Curran JE; Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX.; Wheeler MM; Department of Genome Sciences, University of Washington, Seattle, WA.; Osburn WO; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.; O'Connell JR; Department of Medicine, University of Maryland, Baltimore, MD.; Boerwinkle E; 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.; Beswick A; Translational Health Sciences, University of Bristol, Bristol, United Kingdom.; Psaty BM; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA.; Departments of Epidemiology and Health Systems and Population Health, Seattle, WA.; Kolcic I; Faculty of Medicine, University of Split, Split, Croatia.; Souto JC; 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.; Becker LC; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.; Hansen T; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.; Doyle MF; Department of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, Colchester, VT.; Harris SE; Department of Psychology, Lothian Birth Cohorts, University of Edinburgh, Edinburgh, Scotland.; Moissl AP; Institute of Nutritional Sciences, Friedrich-Schiller-University Jena, Jena, Germany.; Competence Cluster for Nutrition and Cardiovascular Health Halle-Jena-Leipzig, Jena, Germany.; Deleuze JF; Centre National de Recherche en Génomique Humaine, Université Paris-Saclay, CEA, Evry, France.; Centre d'Etude du Polymorphisme Humain, Fondation Jean Dausset, Paris, France.; Rich SS; Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA.; van Hylckama Vlieg A; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.; Campbell H; Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, Scotland.; Stott DJ; Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland.; Soria JM; Unit of Genomics of Complex Disease, Institut de Recerca Sant Pau, Barcelona, Spain.; de Maat MPM; Department of Hematology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.; Almasy L; 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.; Brody LC; National Human Genome Research Institute, National Institutes of Health, Bethesda, MD.; Auer PL; Department of Biostatistics, Medical College of Wisconsin, Milwaukee, WI.; Mitchell BD; Department of Medicine, University of Maryland, Baltimore, MD.; Geriatric Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD.; Ben-Shlomo Y; Population Health Sciences, University of Bristol, Bristol, United Kingdom.; Fornage M; 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.; Hayward C; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Scotland.; Mathias RA; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.; Kilpeläinen TO; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.; Lange LA; Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, CO.; Cox SR; Department of Psychology, Lothian Birth Cohorts, University of Edinburgh, Edinburgh, Scotland.; März W; Fifth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.; Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim, Germany.; Morange PE; C2VN, INSERM, INRAE, Aix Marseille University, Marseille, France.; Laboratory of Haematology, La Timone Hospital, Marseille, France.; Rotter JI; Department of Pediatrics, Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA.; Mook-Kanamori DO; 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.; Wilson JF; Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, Scotland.; van der Harst P; Division of Heart and Lungs, Department of Cardiology, Utrecht University, University Medical Center Utrecht, Utrecht, The Netherlands.; Jukema JW; Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.; Netherlands Heart Institute, Utrecht, The Netherlands.; Ikram MA; Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.; Blangero J; Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX.; Kooperberg C; Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA.; Desch KC; Department of Pediatrics, University of Michigan, C.S. Mott Children's Hospital, Ann Arbor, MI.; Johnson AD; Division of Intramural Research, Population Sciences Branch, National Heart, Lung, and Blood Institute, Framingham Heart Study, Framingham, MA.; Sabater-Lleal M; 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.; Lowenstein CJ; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.; Smith NL; 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.; Morrison AC; 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.
Source
Publisher: Elsevier Country of Publication: United States NLM ID: 7603509 Publication Model: Print Cited Medium: Internet ISSN: 1528-0020 (Electronic) Linking ISSN: 00064971 NLM ISO Abbreviation: Blood Subsets: MEDLINE
Subject
Language
English
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.