Genome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels.

Sabater-Lleal, MariaMariaSabater-LlealHuffman, Jennifer EJennifer EHuffmande Vries, Paul SPaul Sde VriesMarten, JonathanJonathanMartenMastrangelo, Michael AMichael AMastrangeloSong, CiCiSongPankratz, NathanNathanPankratzWard-Caviness, Cavin KCavin KWard-CavinessYanek, Lisa RLisa RYanekTrompet, StellaStellaTrompetDelgado, Graciela EGraciela EDelgadoGuo, XiuqingXiuqingGuoBartz, Traci MTraci MBartzMartinez-Perez, AngelAngelMartinez-PerezGermain, MarineMarineGermainde Haan, Hugoline GHugoline Gde HaanOzel, Ayse BAyse BOzelPolasek, OzrenOzrenPolasekSmith, Albert VAlbert VSmithEicher, John DJohn DEicherReiner, Alex PAlex PReinerTang, WeihongWeihongTangDavies, Neil MNeil MDaviesStott, David JDavid JStottRotter, Jerome IJerome IRotterTofler, Geoffrey HGeoffrey HToflerBoerwinkle, EricEricBoerwinklede Maat, Moniek P MMoniek P Mde MaatKleber, Marcus EMarcus EKleberWelsh, PaulPaulWelshBrody, Jennifer AJennifer ABrodyChen, Ming-HueiMing-HueiChenVaidya, DhananjayDhananjayVaidyaSoria, José ManuelJosé ManuelSoriaSuchon, PierrePierreSuchonvan Hylckama Vlieg, AstridAstridvan Hylckama VliegDesch, Karl CKarl CDeschKolcic, IvanaIvanaKolcicJoshi, Peter KPeter KJoshiLauner, Lenore JLenore JLaunerHarris, Tamara BTamara BHarrisCampbell, HarryHarryCampbellRudan, IgorIgorRudanBecker, Diane MDiane MBeckerLi, Jun ZJun ZLiRivadeneira, FernandoFernandoRivadeneiraUitterlinden, André GAndré GUitterlindenHofman, AlbertAlbertHofmanFranco Duran, Oscar HoracioOscar HoracioFranco DuranCushman, MaryMaryCushmanPsaty, Bruce MBruce MPsatyMorange, Pierre-EmmanuelPierre-EmmanuelMorangeMcKnight, BarbaraBarbaraMcKnightChong, Michael RMichael RChongFernandez-Cadenas, IsraelIsraelFernandez-CadenasRosand, JonathanJonathanRosandLindgren, ArneArneLindgrenGudnason, VilmundurVilmundurGudnasonWilson, James FJames FWilsonHayward, CarolineCarolineHaywardGinsburg, DavidDavidGinsburgFornage, MyriamMyriamFornageRosendaal, Frits RFrits RRosendaalSouto, Juan CarlosJuan CarlosSoutoBecker, Lewis CLewis CBeckerJenny, Nancy SNancy SJennyMärz, WinfriedWinfriedMärzJukema, J WouterJ WouterJukemaDehghan, AbbasAbbasDehghanTrégouët, David-AlexandreDavid-AlexandreTrégouëtMorrison, Alanna CAlanna CMorrisonJohnson, Andrew DAndrew DJohnsonO'Donnell, Christopher JChristopher JO'DonnellStrachan, David PDavid PStrachanLowenstein, Charles JCharles JLowensteinSmith, Nicholas LNicholas LSmith2024-10-082024-10-082019-01-29https://boris-portal.unibe.ch/handle/20.500.12422/64817BACKGROUND 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. METHODS We meta-analyzed genome-wide association results from 46 354 individuals of European, African, East Asian, and Hispanic ancestry. All studies performed linear regression analysis using an additive genetic model and associated ≈35 million imputed variants with natural log-transformed 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. RESULTS We identified 13 novel genome-wide significant ( P≤2.5×10) associations, 7 with FVIII levels ( FCHO2/TMEM171/TNPO1, HLA, SOX17/RP1, LINC00583/NFIB, RAB5C-KAT2A, RPL3/TAB1/SYNGR1, and ARSA) and 11 with VWF levels ( PDHB/PXK/KCTD6, SLC39A8, FCHO2/TMEM171/TNPO1, HLA, GIMAP7/GIMAP4, OR13C5/NIPSNAP, DAB2IP, C2CD4B, RAB5C-KAT2A, TAB1/SYNGR1, and ARSA), beyond 10 previously reported associations with these phenotypes. Functional validation provided further evidence of association for all loci on VWF except ARSA and DAB2IP. 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. CONCLUSIONS 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.encardiovascular diseases factor VIII genetics genome-wide association studies risk factors von Willebrand factor600 - Technology::610 - Medicine & health300 - Social sciences, sociology & anthropology::360 - Social problems & social servicesGenome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels.article10.7892/boris.1273743058673710.1161/CIRCULATIONAHA.118.034532