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.
Bibliographical noteFunding Information:
This study is supported in part by the National Heart, Lung, and Blood Institute grant HL134894. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the US Department of Health and Human Services. Dr Sabater-Lleal was partially supported by a European Hematology Association-International Society of Thrombosis and Hemostasis Research Fellowship award to study genetic determinants of FVIII and VWF and by the Swedish Heart-Lung Foundation (20160290) and is a recipient of a Miguel Servet contract from the Spanish Ministry of Health (ISCIII CP17/00142). Dr de Vries is supported by American Heart Association grant 17POST33350042. Sources of funding for the specific cohorts can be found in the online-only Data Supplement.
Dr Psaty serves on the Data Safety and Monitory Board of a clinical trial funded by Zoll LifeCor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Dr Ginsburg reports equity Ownership in Shire, membership on an entity’s Board of Directors or advisory committees in Portola Pharmaceuticals, and a patent in recombinant VWF and recombinant ADAMTS13. Dr März reports grants and personal fees from Amgen, BASF, Sanofi, Siemens Diagnostics, Aegerion Pharmaceuticals, AstraZeneca, Danone Research, Numares, Pfizer, and Hoffmann LaRoche; personal fees from MSD and Alexion; and grants from Abbott Diagnostics. Dr März is employed by SYN-LAB Holding Deutschland GmbH.
- Von Willebrand factor
- cardiovascular diseases
- factor VIII
- genome-wide association studies
- risk factors