05032nas a2201033 4500008004100000022001400041245016100055210006900216260001600285520189700301100002502198700002502223700002202248700002102270700002802291700001302319700002102332700002802353700001902381700002002400700002502420700001702445700002002462700002602482700002002508700002502528700001802553700001902571700002102590700002002611700002002631700001802651700002002669700002002689700002202709700002402731700002102755700002502776700002202801700001602823700002302839700002002862700002202882700002502904700001902929700003002948700001902978700001802997700002003015700002203035700002203057700002003079700001603099700002103115700001503136700002603151700002803177700001903205700002103224700001803245700002003263700002903283700002203312700002203334700003003356700002103386700001903407700002403426700002103450700002203471700002003493700002003513700002403533700002403557700002103581700002003602700002003622700001903642700001903661700003203680700002403712700002303736700003003759700002303789700002703812700002303839710010003862856003603962 2018 eng d a1524-453900aGenome-Wide Association Trans-Ethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels.0 aGenomeWide Association TransEthnic MetaAnalyses Identifies Novel c2018 Nov 203 a
BACKGROUND: 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 approximately 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 (MR) 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≤2.5x10) 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. MR 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.
1 aSabater-Lleal, Maria1 aHuffman, Jennifer, E1 ade Vries, Paul, S1 aMarten, Jonathan1 aMastrangelo, Michael, A1 aSong, Ci1 aPankratz, Nathan1 aWard-Caviness, Cavin, K1 aYanek, Lisa, R1 aTrompet, Stella1 aDelgado, Graciela, E1 aGuo, Xiuqing1 aBartz, Traci, M1 aMartinez-Perez, Angel1 aGermain, Marine1 ade Haan, Hugoline, G1 aOzel, Ayse, B1 aPolasek, Ozren1 aSmith, Albert, V1 aEicher, John, D1 aReiner, Alex, P1 aTang, Weihong1 aDavies, Neil, M1 aStott, David, J1 aRotter, Jerome, I1 aTofler, Geoffrey, H1 aBoerwinkle, Eric1 ade Maat, Moniek, P M1 aKleber, Marcus, E1 aWelsh, Paul1 aBrody, Jennifer, A1 aChen, Ming-Huei1 aVaidya, Dhananjay1 aSoria, José, Manuel1 aSuchon, Pierre1 aVlieg, Astrid, van Hylcka1 aDesch, Karl, C1 aKolcic, Ivana1 aJoshi, Peter, K1 aLauner, Lenore, J1 aHarris, Tamara, B1 aCampbell, Harry1 aRudan, Igor1 aBecker, Diane, M1 aLi, Jun, Z1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aHofman, Albert1 aFranco, Oscar, H1 aCushman, Mary1 aPsaty, Bruce, M1 aMorange, Pierre-Emmanuel1 aMcKnight, Barbara1 aChong, Michael, R1 aFernandez-Cadenas, Israel1 aRosand, Jonathan1 aLindgren, Arne1 aGudnason, Vilmundur1 aWilson, James, F1 aHayward, Caroline1 aGinsburg, David1 aFornage, Myriam1 aRosendaal, Frits, R1 aSouto, Juan, Carlos1 aBecker, Lewis, C1 aJenny, Nancy, S1 aMärz, Winfried1 aJukema, Wouter1 aDehghan, Abbas1 aTrégouët, David-Alexandre1 aMorrison, Alanna, C1 aJohnson, Andrew, D1 aO'Donnell, Christopher, J1 aStrachan, David, P1 aLowenstein, Charles, J1 aSmith, Nicholas, L1 aINVENT Consortium; MEGASTROKE consortium of the International Stroke Genetics Consortium (ISGC) uhttps://chs-nhlbi.org/node/7924