{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T02:23:00Z","timestamp":1791339780571,"version":"4.3.1"},"reference-count":53,"publisher":"American Society of Hematology","issue":"18","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2024,5,2]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>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\u2009289 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 &amp;lt; 5\u00a0\u00d7 10\u22129) 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\u00a0vitro.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2023021452","type":"journal-article","created":{"date-parts":[[2024,2,6]],"date-time":"2024-02-06T14:54:45Z","timestamp":1707231285000},"page":"1845-1855","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":29,"title":["A genetic association study of circulating coagulation factor VIII and von Willebrand factor levels"],"prefix":"10.1182","volume":"143","author":[{"given":"Paul S.","family":"de Vries","sequence":"first","affiliation":[{"name":"1Department 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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Reventun","sequence":"additional","affiliation":[{"name":"2Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R.","family":"Brown","sequence":"additional","affiliation":[{"name":"1Department 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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5909-9055","authenticated-orcid":false,"given":"Adam S.","family":"Heath","sequence":"additional","affiliation":[{"name":"1Department 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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9672-2491","authenticated-orcid":false,"given":"Jennifer E.","family":"Huffman","sequence":"additional","affiliation":[{"name":"3Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ngoc-Quynh","family":"Le","sequence":"additional","affiliation":[{"name":"4Unit of Genomics of Complex Disease, Institut de Recerca Sant Pau, Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison","family":"Bebo","sequence":"additional","affiliation":[{"name":"1Department 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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8509-148X","authenticated-orcid":false,"given":"Jennifer A.","family":"Brody","sequence":"additional","affiliation":[{"name":"5Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6136-8915","authenticated-orcid":false,"given":"Gerard","family":"Temprano-Sagrera","sequence":"additional","affiliation":[{"name":"4Unit of Genomics of Complex Disease, Institut de Recerca Sant Pau, Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7892-193X","authenticated-orcid":false,"given":"Laura M.","family":"Raffield","sequence":"additional","affiliation":[{"name":"6Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1112-4258","authenticated-orcid":false,"given":"Ayse Bilge","family":"Ozel","sequence":"additional","affiliation":[{"name":"7Department of Human Genetics, University of Michigan, Ann Arbor, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2229-8322","authenticated-orcid":false,"given":"Florian","family":"Thibord","sequence":"additional","affiliation":[{"name":"8Division of Intramural Research, Population Sciences Branch, National Heart, Lung, and Blood Institute, Framingham Heart Study, Framingham, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepti","family":"Jain","sequence":"additional","affiliation":[{"name":"9Department of Biostatistics, Genetic Analysis Center, School of Public Health, University of Washington, Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua P.","family":"Lewis","sequence":"additional","affiliation":[{"name":"10Department of Medicine, University of Maryland, Baltimore, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin A. 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