TY - JOUR
T1 - Genome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and Von Willebrand Factor Plasma Levels
AU - Sabater-Lleal, Maria
AU - Huffman, Jennifer E.
AU - De Vries, Paul S.
AU - Marten, Jonathan
AU - Mastrangelo, Michael A.
AU - Song, Ci
AU - Pankratz, Nathan
AU - Ward-Caviness, Cavin K.
AU - Yanek, Lisa R.
AU - Trompet, Stella
AU - Delgado, Graciela E.
AU - Guo, Xiuqing
AU - Bartz, Traci M.
AU - Martinez-Perez, Angel
AU - Germain, Marine
AU - De Haan, Hugoline G.
AU - Ozel, Ayse B.
AU - Polasek, Ozren
AU - Smith, Albert V.
AU - Eicher, John D.
AU - Reiner, Alex P.
AU - Tang, Weihong
AU - Davies, Neil M.
AU - Stott, David J.
AU - Rotter, Jerome I.
AU - Tofler, Geoffrey H.
AU - Boerwinkle, Eric
AU - De Maat, Moniek P.M.
AU - Kleber, Marcus E.
AU - Welsh, Paul
AU - Brody, Jennifer A.
AU - Chen, Ming Huei
AU - Vaidya, Dhananjay
AU - Soria, José Manuel
AU - Suchon, Pierre
AU - Van Hylckama Vlieg, Astrid
AU - Desch, Karl C.
AU - Kolcic, Ivana
AU - Joshi, Peter K.
AU - Launer, Lenore J.
AU - Harris, Tamara B.
AU - Campbell, Harry
AU - Rudan, Igor
AU - Becker, Diane M.
AU - Li, Jun Z.
AU - Rivadeneira, Fernando
AU - Uitterlinden, André G.
AU - Hofman, Albert
AU - Franco, Oscar H.
AU - Cushman, Mary
AU - Psaty, Bruce M.
AU - Morange, Pierre Emmanuel
AU - Mcknight, Barbara
AU - Chong, Michael R.
AU - Fernandez-Cadenas, Israel
AU - Rosand, Jonathan
AU - Lindgren, Arne
AU - Gudnason, Vilmundur
AU - Wilson, James F.
AU - Hayward, Caroline
AU - Ginsburg, David
AU - Fornage, Myriam
AU - Rosendaal, Frits R.
AU - Souto, Juan Carlos
AU - Becker, Lewis C.
AU - Jenny, Nancy S.
AU - März, Winfried
AU - Jukema, J. Wouter
AU - Dehghan, Abbas
AU - Trégouët, David Alexandre
AU - Morrison, Alanna C.
AU - Johnson, Andrew D.
AU - O'donnell, Christopher J.
AU - Strachan, David P.
AU - Lowenstein, Charles J.
AU - Smith, Nicholas L.
N1 - Publisher Copyright:
© 2019 American Heart Association, Inc.
PY - 2019/1/29
Y1 - 2019/1/29
N2 - 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 ≈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≤2.5×10-8) 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.
AB - 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 ≈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≤2.5×10-8) 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.
KW - Von Willebrand factor
KW - cardiovascular diseases
KW - factor VIII
KW - genetics
KW - genome-wide association studies
KW - risk factors
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U2 - 10.1161/CIRCULATIONAHA.118.034532
DO - 10.1161/CIRCULATIONAHA.118.034532
M3 - Article
C2 - 30586737
AN - SCOPUS:85060618199
SN - 0009-7322
VL - 139
SP - 620
EP - 635
JO - Circulation
JF - Circulation
IS - 5
ER -