Your browser doesn't support javascript.
loading
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; Suchon, Pierre; Guo, Xiuqing; Rosendaal, Frits R; Klaric, Lucija; Noordam, Raymond; van Rooij, Frank; Curran, Joanne E; Wheeler, Marsha M; Osburn, William O.
Afiliação
  • 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.
  • Marioni RE; Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
  • Kleber ME; Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Scotland.
  • Trégouët DA; SYNLAB MVZ Humangenetik Mannheim, Mannheim, Germany.
  • Yao J; Fifth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
  • Li-Gao R; INSERM UMR 1219, Bordeaux Population Health Research Center, Bordeaux, France.
  • Joshi PK; Department of Pediatrics, Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA.
  • Trompet S; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
  • Martinez-Perez A; Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, Scotland.
  • Ghanbari M; Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
  • Howard TE; Unit of Genomics of Complex Disease, Institut de Recerca Sant Pau, Barcelona, Spain.
  • Reiner AP; Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
  • Arvanitis M; Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX.
  • Ryan KA; Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA.
  • Bartz TM; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
  • Rudan I; Department of Medicine, University of Maryland, Baltimore, MD.
  • Faraday N; Departments of Biostatistics and Medicine, Cardiovascular Health Research Unit, University of Washington, Seattle, WA.
  • Linneberg A; Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, Scotland.
  • Ekunwe L; Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
  • Davies G; Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark.
  • Delgado GE; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Suchon P; Department of Medicine, University of Mississippi Medical Center, Jackson, MS.
  • Guo X; Department of Psychology, Lothian Birth Cohorts, University of Edinburgh, Edinburgh, Scotland.
  • Rosendaal FR; Fifth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
  • Klaric L; C2VN, INSERM, INRAE, Aix Marseille University, Marseille, France.
  • Noordam R; Laboratory of Haematology, La Timone Hospital, Marseille, France.
  • van Rooij F; Department of Pediatrics, Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA.
  • Curran JE; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
  • Wheeler MM; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Scotland.
  • Osburn WO; Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
Blood ; 143(18): 1845-1855, 2024 May 02.
Article em En | MEDLINE | ID: mdl-38320121
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.
Assuntos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Fator VIII / Fator de von Willebrand / Moléculas de Adesão Celular / Cininogênios / Receptores de Superfície Celular / Lectinas Tipo C Idioma: En Ano de publicação: 2024 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Fator VIII / Fator de von Willebrand / Moléculas de Adesão Celular / Cininogênios / Receptores de Superfície Celular / Lectinas Tipo C Idioma: En Ano de publicação: 2024 Tipo de documento: Article