Novel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: The CHARGE Consortium
ARIC: Divisions of Biostatistics (SB, XK), Epidemiology and Community Health (JSP, ARF, WT), University of Minnesota, Minneapolis, Minnesota, USA; DNA Laboratory (NA), Human Genetics Center and Institute of Molecular Medicine (EB), University of Texas Health Science Center at Houston, Houston, Texas, USA; B58C: Division of Community Health Sciences, St George’s, University of London, UK (DPS); Division of Cardiovascular and Medical Sciences, University of Glasgow, Royal Infirmary, Glasgow, UK (AR); ALSPAC Laboratory, University of Bristol, UK (WLM); CHS: Departments of Epidemiology (NLS, BMP), Medicine (JCB, KLW, BMP), Biostatistics (TL, BM), Health Services (BMP), University of Washington; and Group Health Research Institute (BMP), Group Health Cooperative, Seattle, Washington, USA; Departments of Pathology (MC, EGB), Medicine (MC), University of Vermont, Burlington, Vermont USA; Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA (JIR); FHS: National Heart, Lung and Blood Institute’s Framingham Heart Study, Framingham, MA, USA (MHC, QY, ADJ, SK, MGL, CJO); Departments of Biostatistics (QY), Neurology (MHC), and Mathematics (MGL), Boston University, Boston, MA, USA; Division of Intramural Research, National Heart, Lung and Blood Institute, Bethesda MD, USA (ADJ, CJO); General Medicine Division, Massachusetts General Hospital, Harvard Medical School, Boston MA, USA (JBM); Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston MA, USA (SK, CJO); Royal North Shore Hospital, Sydney, Australia (GHT); RS: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands (AD, CVD, AH, AU, JCM), Department of Hematology, Erasmus Medical Center, Rotterdam, The Netherlands (MdM, FL), Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands (AU), Member of the Netherlands Consortium on Healthy Aging (AD, JCM); Twins UK: Wellcome Trust Sanger Institute, Hinxton, (NS), Department of Twin Research & Genetic Epidemiology, King’s College London, London UK (NS, FMKW, TDS); VIS: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Edinburgh, Scotland, UK (CH, VV, AFW), Croatian Centre for Global Health, University of Split Medical School, Soltanska, Croatia (IR), Centre for Population Health Sciences, University of Edinburgh Medical School, Teviot Place, Edinburgh, Scotland, UK (IR, HC, JFW); ORCADES: Centre for Population Health Sciences, University of Edinburgh Medical School, Teviot Place, Edinburgh, Scotland, UK (IR, HC, JFW).MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Edinburgh, Scotland, UK (CH, VV, AFW), Croatian Centre for Global Health, University of Split Medical School, Soltanska, Croatia (IR); PROCARDIS: Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden (MSL, AM, AS, AH), Department of Cardiovascular Medicine, University of Oxford, Oxford, UK (JFP); KORA: Institute of Epidemiology, Helmholtz Zentrum München – German Research Center for Environment and Health, Neuherberg (AP); Internal Medicine II – Cardiology, University of Ulm, Ulm, Germany (WK)
A complex cascade of coagulation factors underlies hemostasis and prevents life-threatening blood loss from damaged blood vessels. The hemostatic factors VII and VIII, both produced in the liver, play central roles in the initiation and propagation, respectively, of fibrin formation. In the tissue-factor pathway, blood coagulation factor VII (FVII), once activated, serves as a catalyst for factor X (FX) activation, which converts prothrombin to thrombin. During propagation, activated factor VIII (FVIII) activates FX in the presence of activated factor IX. Von Willebrand factor (vWF), produced by endothelial cells and megakaryocytes, has multiple roles in hemostasis. Its primary role is to serve as an adhesion molecule that anchors platelets to exposed collagen after endothelial cell damage. The factor also acts as a carrier protein of FVIII, thereby prolonging the half-life of FVIII.
Elevated circulating levels of FVIII and vWF are risk factors for venous thrombosis but the data supporting an association of FVII levels with arterial thrombosis are less consistent.1-5
Hemorrhagic complications are associated with deficiency in FVII and vWF (von Willebrand disease), as well as X-linked deficiency in FVIII (Hemophilia A).6-9
Plasma levels of these proteins are affected by environmental factors but they also are genetically influenced.10-13
Heritability estimates range from 0.53-0.63 for FVII, 0.40-0.61 for FVIII, and 0.31-0.75 for vWF.12, 13
To date, our understanding of genetic variation influencing plasma levels has been focused primarily on cis
-acting variation in the genes encoding each protein product (F7, F8
, and VWF
, respectively). A large-scale genome-wide investigation of the genomic correlates of plasma levels has not been previously published. Using data from 23,608 adults, we investigated genome-wide associations between common genetic variation and plasma levels of FVII, FVIII, and vWF.