de Vries, Paul SPaul Sde VriesReventun, PaulaPaulaReventunBrown, Michael RMichael RBrownHeath, Adam SAdam SHeathHuffman, Jennifer EJennifer EHuffmanLe, Ngoc-QuynhNgoc-QuynhLeBebo, AllisonAllisonBeboBrody, Jennifer AJennifer ABrodyTemprano-Sagrera, GerardGerardTemprano-SagreraRaffield, Laura MLaura MRaffieldOzel, Ayse BilgeAyse BilgeOzelThibord, FlorianFlorianThibordJain, DeeptiDeeptiJainLewis, Joshua PJoshua PLewisRodriguez, Benjamin A TBenjamin A TRodriguezPankratz, NathanNathanPankratzTaylor, Kent DKent DTaylorPolasek, OzrenOzrenPolasekChen, Ming-HueiMing-HueiChenYanek, Lisa RLisa RYanekCarrasquilla, German DGerman DCarrasquillaMarioni, RiccardoRiccardoMarioniKleber, Marcus EMarcus EKleberTrégouët, David-AlexandreDavid-AlexandreTrégouëtYao, JieJieYaoLi-Gao, RuifangRuifangLi-GaoJoshi, Peter KPeter KJoshiTrompet, StellaStellaTrompetMartinez-Perez, AngelAngelMartinez-PerezGhanbari, MohsenMohsenGhanbariHoward, Tom ETom EHowardReiner, Alex PAlex PReinerArvanitis, MariosMariosArvanitisRyan, Kathleen AKathleen ARyanBartz, Traci MTraci MBartzRudan, IgorIgorRudanFaraday, NauderNauderFaradayLinneberg, AllanAllanLinnebergEkunwe, LynetteLynetteEkunweDavies, GailGailDaviesDelgado, Graciela EGraciela EDelgadoSuchon, PierrePierreSuchonGuo, XiuqingXiuqingGuoRosendaal, Frits RFrits RRosendaalKlaric, LucijaLucijaKlaricNoordam, RaymondRaymondNoordamvan Rooij, FrankFrankvan RooijCurran, Joanne EJoanne ECurranWheeler, Marsha MMarsha MWheelerOsburn, William OWilliam OOsburnO'Connell, Jeffrey RJeffrey RO'ConnellBoerwinkle, EricEricBoerwinkleBeswick, AndrewAndrewBeswickPsaty, Bruce MBruce MPsatyKolcic, IvanaIvanaKolcicSouto, Juan CarlosJuan CarlosSoutoBecker, Lewis CLewis CBeckerHansen, TorbenTorbenHansenDoyle, Margaret FMargaret FDoyleHarris, Sarah ESarah EHarrisMoissl, Angela PAngela PMoisslDeleuze, Jean-FrançoisJean-FrançoisDeleuzeRich, Stephen SStephen SRichvan Hylckama Vlieg, AstridAstridvan Hylckama VliegCampbell, HarryHarryCampbellStott, David JDavid JStottSoria, Jose ManuelJose ManuelSoriade Maat, Moniek P MMoniek P Mde MaatAlmasy, LauraLauraAlmasyBrody, Lawrence CLawrence CBrodyAuer, Paul LPaul LAuerMitchell, Braxton DBraxton DMitchellBen-Shlomo, YoavYoavBen-ShlomoFornage, MyriamMyriamFornageHayward, CarolineCarolineHaywardMathias, Rasika ARasika AMathiasKilpeläinen, Tuomas OTuomas OKilpeläinenLange, Leslie ALeslie ALangeCox, Simon RSimon RCoxMärz, WinfriedWinfriedMärzMorange, Pierre-EmmanuelPierre-EmmanuelMorangeRotter, Jerome IJerome IRotterMook-Kanamori, Dennis ODennis OMook-KanamoriWilson, James FJames FWilsonvan der Harst, PimPimvan der HarstJukema, J WouterJ WouterJukemaIkram, M ArfanM ArfanIkramBlangero, JohnJohnBlangeroKooperberg, CharlesCharlesKooperbergDesch, Karl CKarl CDeschJohnson, Andrew DAndrew DJohnsonSabater-Lleal, MariaMariaSabater-LlealLowenstein, Charles JCharles JLowensteinSmith, Nicholas LNicholas LSmithMorrison, Alanna CAlanna CMorrisonLEE-MING CHUANG et al.2024-04-262024-04-262024-02-060006-49711528-0020https://scholars.lib.ntu.edu.tw/handle/123456789/642057Coagulation 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 three 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 (HUVECs). 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 seven new loci for FVIII (ST3GAL4, CLEC4M, B3GNT2, ASGR1, F12, KNG1, and TREM1/NCR2) and one for VWF (B3GNT2). VWF, ABO, and STAB2 were associated with FVIII and VWF in gene-based analyses. Multi-phenotype analysis of FVIII and VWF identified another three new loci, including PDIA3. Silencing of B3GNT2 and the previously reported CD36 gene decreased release of FVIII by HLECs, while 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 one 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.enjournal article10.1182/blood.2023021452383201212-s2.0-85186210770https://api.elsevier.com/content/abstract/scopus_id/85186210770