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

Maria Sabater-Lleal, Jennifer E. Huffman, Paul S. De Vries, Jonathan Marten, Michael A. Mastrangelo, Ci Song, Nathan Pankratz, Cavin K. Ward-Caviness, Lisa R. Yanek, Stella Trompet, Graciela E. Delgado, Xiuqing Guo, Traci M. Bartz, Angel Martinez-Perez, Marine Germain, Hugoline G. De Haan, Ayse B. Ozel, Ozren Polasek, Albert V. Smith, John D. EicherAlex P. Reiner, Weihong Tang, Neil M. Davies, David J. Stott, Jerome I. Rotter, Geoffrey H. Tofler, Eric Boerwinkle, Moniek P.M. De Maat, Marcus E. Kleber, Paul Welsh, Jennifer A. Brody, Ming Huei Chen, Dhananjay Vaidya, José Manuel Soria, Pierre Suchon, Astrid Van Hylckama Vlieg, Karl C. Desch, Ivana Kolcic, Peter K. Joshi, Lenore J. Launer, Tamara B. Harris, Harry Campbell, Igor Rudan, Diane M. Becker, Jun Z. Li, Fernando Rivadeneira, André G. Uitterlinden, Albert Hofman, Oscar H. Franco, Mary Cushman, Bruce M. Psaty, Pierre Emmanuel Morange, Barbara Mcknight, Michael R. Chong, Israel Fernandez-Cadenas, Jonathan Rosand, Arne Lindgren, Vilmundur Gudnason, James F. Wilson, Caroline Hayward, David Ginsburg, Myriam Fornage, Frits R. Rosendaal, Juan Carlos Souto, Lewis C. Becker, Nancy S. Jenny, Winfried März, J. Wouter Jukema, Abbas Dehghan, David Alexandre Trégouët, Alanna C. Morrison, Andrew D. Johnson, Christopher J. O'donnell, David P. Strachan, Charles J. Lowenstein, Nicholas L. Smith

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)620-635
Number of pages16
JournalCirculation
Volume139
Issue number5
DOIs
StatePublished - Jan 29 2019

Keywords

  • Von Willebrand factor
  • cardiovascular diseases
  • factor VIII
  • genetics
  • genome-wide association studies
  • risk factors

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Sabater-Lleal, M., Huffman, J. E., De Vries, P. S., Marten, J., Mastrangelo, M. A., Song, C., Pankratz, N., Ward-Caviness, C. K., Yanek, L. R., Trompet, S., Delgado, G. E., Guo, X., Bartz, T. M., Martinez-Perez, A., Germain, M., De Haan, H. G., Ozel, A. B., Polasek, O., Smith, A. V., ... Smith, N. L. (2019). Genome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and Von Willebrand Factor Plasma Levels. Circulation, 139(5), 620-635. https://doi.org/10.1161/CIRCULATIONAHA.118.034532