{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T12:51:42Z","timestamp":1791550302646,"version":"4.3.4"},"reference-count":40,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2019,1,29]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>Factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are associated with risk of arterial and venous thrombosis and with hemorrhagic disorders. We aimed to identify and functionally test novel genetic associations regulating plasma FVIII and VWF.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>We meta-analyzed genome-wide association results from 46\u2009354 individuals of European, African, East Asian, and Hispanic ancestry. All studies performed linear regression analysis using an additive genetic model and associated \u224835 million imputed variants with natural log\u2013transformed phenotype levels. In vitro gene silencing in cultured endothelial cells was performed for candidate genes to provide additional evidence on association and function. Two-sample Mendelian randomization analyses were applied to test the causal role of FVIII and VWF plasma levels on the risk of arterial and venous thrombotic events.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              We identified 13 novel genome-wide significant (\n              <jats:italic>P<\/jats:italic>\n              \u22642.5\u00d710\n              <jats:sup>\u22128<\/jats:sup>\n              ) associations, 7 with FVIII levels (\n              <jats:italic>FCHO2\/TMEM171\/TNPO1<\/jats:italic>\n              ,\n              <jats:italic>HLA<\/jats:italic>\n              ,\n              <jats:italic>SOX17\/RP1<\/jats:italic>\n              ,\n              <jats:italic>LINC00583\/NFIB<\/jats:italic>\n              ,\n              <jats:italic>RAB5C-KAT2A<\/jats:italic>\n              ,\n              <jats:italic>RPL3\/TAB1\/SYNGR1<\/jats:italic>\n              , and\n              <jats:italic>ARSA<\/jats:italic>\n              ) and 11 with VWF levels (\n              <jats:italic>PDHB\/PXK\/KCTD6<\/jats:italic>\n              ,\n              <jats:italic>SLC39A8<\/jats:italic>\n              ,\n              <jats:italic>FCHO2\/TMEM171\/TNPO1<\/jats:italic>\n              ,\n              <jats:italic>HLA<\/jats:italic>\n              ,\n              <jats:italic>GIMAP7\/GIMAP4<\/jats:italic>\n              ,\n              <jats:italic>OR13C5\/NIPSNAP<\/jats:italic>\n              ,\n              <jats:italic>DAB2IP<\/jats:italic>\n              ,\n              <jats:italic>C2CD4B<\/jats:italic>\n              ,\n              <jats:italic>RAB5C-KAT2A<\/jats:italic>\n              ,\n              <jats:italic>TAB1\/SYNGR1<\/jats:italic>\n              , and\n              <jats:italic>ARSA<\/jats:italic>\n              ), beyond 10 previously reported associations with these phenotypes. Functional validation provided further evidence of association for all loci on VWF except\n              <jats:italic>ARSA<\/jats:italic>\n              and\n              <jats:italic>DAB2IP<\/jats:italic>\n              . Mendelian randomization suggested causal effects of plasma FVIII activity levels on venous thrombosis and coronary artery disease risk and plasma VWF levels on ischemic stroke risk.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>The meta-analysis identified 13 novel genetic loci regulating FVIII and VWF plasma levels, 10 of which we validated functionally. We provide some evidence for a causal role of these proteins in thrombotic events.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.118.034532","type":"journal-article","created":{"date-parts":[[2019,1,17]],"date-time":"2019-01-17T13:44:06Z","timestamp":1547732646000},"page":"620-635","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":156,"title":["Genome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels"],"prefix":"10.1161","volume":"139","author":[{"given":"Maria","family":"Sabater-Lleal","sequence":"first","affiliation":[{"name":"Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden (M.S.-L.)."},{"name":"Unit of Genomics of Complex Diseases, Institut d\u2019Investigaci\u00f3 Biom\u00e8dica Sant Pau, IIB-Sant Pau, Barcelona, Spain (M.S.-L., A.M.-P., J.M.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer E.","family":"Huffman","sequence":"additional","affiliation":[{"name":"Population Sciences Branch, National Heart, Lung, and Blood Institute, Framingham, MA (J.E.H., C.S., J.D.E., M.-H.C., A.D.J., C.J.O.)."},{"name":"Framingham Heart Study, MA (J.E.H., C.S., J.D.E., M.-H.C., A.D.J., C.J.O.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul S.","family":"de Vries","sequence":"additional","affiliation":[{"name":"Human Genetics Center, Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health (P.S.d.V., E.B., M.F., A.C.M.), University of Texas Health Science Center at Houston."},{"name":"Department of Epidemiology (P.S.d.V., A.H., O.H.F., A.D.), Erasmus University Medical Center, Rotterdam, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Marten","sequence":"additional","affiliation":[{"name":"Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine (J.M., J.F.W., C.H.), University of Edinburgh, Scotland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Mastrangelo","sequence":"additional","affiliation":[{"name":"Aab Cardiovascular Research Institute, University of Rochester Medical Center, NY (M.A.M., C.J.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ci","family":"Song","sequence":"additional","affiliation":[{"name":"Population Sciences Branch, National Heart, Lung, and Blood Institute, Framingham, MA (J.E.H., C.S., J.D.E., M.-H.C., A.D.J., C.J.O.)."},{"name":"Framingham Heart Study, MA (J.E.H., C.S., J.D.E., M.-H.C., A.D.J., C.J.O.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan","family":"Pankratz","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, University of Minnesota School of Medicine, Minneapolis (N.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cavin K.","family":"Ward-Caviness","sequence":"additional","affiliation":[{"name":"Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Chapel Hill, NC (C.K.W.-C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa R.","family":"Yanek","sequence":"additional","affiliation":[{"name":"GeneSTAR Research Program, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (L.R.Y., D.V., D.M.B., L.C.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stella","family":"Trompet","sequence":"additional","affiliation":[{"name":"Department of Geriatrics and Gerontology (S.T.), Leiden University Medical Center, the Netherlands."},{"name":"Department of Cardiology (S.T., J.W.J.), Leiden University Medical Center, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graciela E.","family":"Delgado","sequence":"additional","affiliation":[{"name":"Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (G.E.D., M.E.K., W.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuqing","family":"Guo","sequence":"additional","affiliation":[{"name":"Institute for Translational Genomics and Population Sciences, Department of Pediatrics and Medicine, LABioMed at Harbor\u2013UCLA Medical Center, Torrance, CA (X.G., J.I.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Traci M.","family":"Bartz","sequence":"additional","affiliation":[{"name":"Department of Biostatistics (T.M.B., B.M.), University of Washington, Seattle."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angel","family":"Martinez-Perez","sequence":"additional","affiliation":[{"name":"Unit of Genomics of Complex Diseases, Institut d\u2019Investigaci\u00f3 Biom\u00e8dica Sant Pau, IIB-Sant Pau, Barcelona, Spain (M.S.-L., A.M.-P., J.M.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marine","family":"Germain","sequence":"additional","affiliation":[{"name":"Institut national de la sant\u00e9 et de la recherche m\u00e9dicale (INSERM), UMR_S 1166, Team Genomics and Pathophysiology of Cardiovascular Diseases, Sorbonne Universit\u00e9s, Universit\u00e9 Pierre-et-Marie-Curie, Paris, France (M.G., D.-A.T.)."},{"name":"ICAN Institute for Cardiometabolism and Nutrition, Paris, France (M.G., D.-A.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hugoline G.","family":"de Haan","sequence":"additional","affiliation":[{"name":"Department of Clinical Epidemiology (H.G.d.H., A.v.H.V., F.R.R.), Leiden University Medical Center, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayse B.","family":"Ozel","sequence":"additional","affiliation":[{"name":"Department of Human Genetics (A.B.O., J.Z.L., D.G.), University of Michigan, Ann Arbor."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ozren","family":"Polasek","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Split, Croatia (O.P., I.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert V.","family":"Smith","sequence":"additional","affiliation":[{"name":"School of Public Health, Department of Biostatistics (A.V.S.), University of Michigan, Ann Arbor."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D.","family":"Eicher","sequence":"additional","affiliation":[{"name":"Framingham Heart Study, MA (J.E.H., C.S., J.D.E., M.-H.C., A.D.J., C.J.O.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex P.","family":"Reiner","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, (A.P.R., B.M.P., N.L.S.), University of Washington, Seattle."},{"name":"Fred Hutchinson Cancer Research Center, Seattle, WA (A.P.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weihong","family":"Tang","sequence":"additional","affiliation":[{"name":"Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis (W.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil M.","family":"Davies","sequence":"additional","affiliation":[{"name":"Medical Research Council Integrative Epidemiology Unit and Bristol Medical School (N.M.D.), University of Bristol, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Stott","sequence":"additional","affiliation":[{"name":"Academic Section of Geriatrics, Faculty of Medicine (J.D.S.), University of Glasgow, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerome I.","family":"Rotter","sequence":"additional","affiliation":[{"name":"Institute for Translational Genomics and Population Sciences, Department of Pediatrics and Medicine, LABioMed at Harbor\u2013UCLA Medical Center, Torrance, CA (X.G., J.I.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geoffrey H.","family":"Tofler","sequence":"additional","affiliation":[{"name":"Royal North Shore Hospital, University of Sydney, Australia (G.H.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Boerwinkle","sequence":"additional","affiliation":[{"name":"Human Genetics Center, Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health (P.S.d.V., E.B., M.F., A.C.M.), University of Texas Health Science Center at Houston."},{"name":"Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX (E.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moniek P.M.","family":"de Maat","sequence":"additional","affiliation":[{"name":"Department of Hematology (M.P.M.d.M.), Erasmus University Medical Center, Rotterdam, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus E.","family":"Kleber","sequence":"additional","affiliation":[{"name":"Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (G.E.D., M.E.K., W.M.)."},{"name":"Institute of Nutrition, Friedrich-Schiller-University Jena, Mannheim, Germany (M.E.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Welsh","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular and Medical Sciences (P.W.), University of Glasgow, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer A.","family":"Brody","sequence":"additional","affiliation":[{"name":"Department of Medicine (J.A.B., B.M.P.), University of Washington, Seattle."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Huei","family":"Chen","sequence":"additional","affiliation":[{"name":"Population Sciences Branch, National Heart, Lung, and Blood Institute, Framingham, MA (J.E.H., C.S., J.D.E., M.-H.C., A.D.J., C.J.O.)."},{"name":"Framingham Heart Study, MA (J.E.H., C.S., J.D.E., M.-H.C., A.D.J., C.J.O.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dhananjay","family":"Vaidya","sequence":"additional","affiliation":[{"name":"GeneSTAR Research Program, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (L.R.Y., D.V., D.M.B., L.C.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Manuel","family":"Soria","sequence":"additional","affiliation":[{"name":"Unit of Genomics of Complex Diseases, Institut d\u2019Investigaci\u00f3 Biom\u00e8dica Sant Pau, IIB-Sant Pau, Barcelona, Spain (M.S.-L., A.M.-P., J.M.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Suchon","sequence":"additional","affiliation":[{"name":"Laboratory of Haematology, La Timone Hospital, Marseille, France (P.S., P.-E.M.)."},{"name":"Institut national de la sant\u00e9 et de la recherche m\u00e9dicale (INSERM), UMR_S 1062, Nutrition Obesity and Risk of Thrombosis, Marseille, France (P.S., P.-E.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astrid","family":"van Hylckama Vlieg","sequence":"additional","affiliation":[{"name":"Department of Clinical Epidemiology (H.G.d.H., A.v.H.V., F.R.R.), Leiden University Medical Center, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl C.","family":"Desch","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Communicable Disease (K.D.C.), University of Michigan, Ann Arbor."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivana","family":"Kolcic","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Split, Croatia (O.P., I.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter K.","family":"Joshi","sequence":"additional","affiliation":[{"name":"Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics (P.K.J., H.C., I.R., J.F.W.), University of Edinburgh, Scotland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lenore J.","family":"Launer","sequence":"additional","affiliation":[{"name":"Laboratory of Epidemiology and Population Sciences National Institute on Aging, Bethesda, MD (L.J.L., T.B.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamara B.","family":"Harris","sequence":"additional","affiliation":[{"name":"Laboratory of Epidemiology and Population Sciences National Institute on Aging, Bethesda, MD (L.J.L., T.B.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harry","family":"Campbell","sequence":"additional","affiliation":[{"name":"Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics (P.K.J., H.C., I.R., J.F.W.), University of Edinburgh, Scotland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor","family":"Rudan","sequence":"additional","affiliation":[{"name":"Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics (P.K.J., H.C., I.R., J.F.W.), University of Edinburgh, Scotland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane M.","family":"Becker","sequence":"additional","affiliation":[{"name":"GeneSTAR Research Program, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (L.R.Y., D.V., D.M.B., L.C.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun Z.","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Human Genetics (A.B.O., J.Z.L., D.G.), University of Michigan, Ann Arbor."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Rivadeneira","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (F.R., A.G.U.), Erasmus University Medical Center, Rotterdam, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9 G.","family":"Uitterlinden","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (F.R., A.G.U.), Erasmus University Medical Center, Rotterdam, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Hofman","sequence":"additional","affiliation":[{"name":"Department of Epidemiology (P.S.d.V., A.H., O.H.F., A.D.), Erasmus University Medical Center, Rotterdam, the Netherlands."},{"name":"Department of Epidemiology, Harvard H.T. Chan School of Public Health, Boston, MA (A.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oscar H.","family":"Franco","sequence":"additional","affiliation":[{"name":"Department of Epidemiology (P.S.d.V., A.H., O.H.F., A.D.), Erasmus University Medical Center, Rotterdam, the Netherlands."},{"name":"Institute of Social and Preventive Medicine, University of Bern, Switzerland (O.H.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Cushman","sequence":"additional","affiliation":[{"name":"Larner College of Medicine, University of Vermont, Colchester (M.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce M.","family":"Psaty","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, (A.P.R., B.M.P., N.L.S.), University of Washington, Seattle."},{"name":"Department of Medicine (J.A.B., B.M.P.), University of Washington, Seattle."},{"name":"Department of Health Services (B.M.P.), University of Washington, Seattle."},{"name":"Kaiser Permanente Washington Research Institute, Kaiser Permanente Washington, Seattle (B.M.P., N.L.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre-Emmanuel","family":"Morange","sequence":"additional","affiliation":[{"name":"Laboratory of Haematology, La Timone Hospital, Marseille, France (P.S., P.-E.M.)."},{"name":"Institut national de la sant\u00e9 et de la recherche m\u00e9dicale (INSERM), UMR_S 1062, Nutrition Obesity and Risk of Thrombosis, Marseille, France (P.S., P.-E.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"McKnight","sequence":"additional","affiliation":[{"name":"Department of Biostatistics (T.M.B., B.M.), University of Washington, Seattle."},{"name":"Cardiovascular Health Research Unit (B.M.), University of Washington, Seattle."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R.","family":"Chong","sequence":"additional","affiliation":[{"name":"McMaster University, Population Health Research Institute, Population Health Research Institute, Biochemistry and Biomedical Sciences, Hamilton, Canada (M.R.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Israel","family":"Fernandez-Cadenas","sequence":"additional","affiliation":[{"name":"Stroke Pharmacogenomics and genetics, Department of Neurology, Institut d\u2019Investigaci\u00f3 Biomedica Sant Pau, IIB-Sant Pau, Barcelona, Spain (I.F.-C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Rosand","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital, Broad Institute, Harvard Medical School, Boston (J.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arne","family":"Lindgren","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences Lund, Neurology, Lund University, Sweden (A.L.)."},{"name":"Department of Neurology and Rehabilitation Medicine, Neurology, Sk\u00e5ne University Hospital, Lund, Sweden (A.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"INVENT Consortium; 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