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

Circulation. 2019 Jan 29;139(5):620-635. doi: 10.1161/CIRCULATIONAHA.118.034532.

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.

Keywords: cardiovascular diseases; factor VIII; genetics; genome-wide association studies; risk factors; von Willebrand factor.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arterial Occlusive Diseases / blood
  • Arterial Occlusive Diseases / ethnology
  • Arterial Occlusive Diseases / genetics*
  • Biomarkers / blood
  • Blood Coagulation / genetics*
  • Blood Coagulation Disorders, Inherited / blood
  • Blood Coagulation Disorders, Inherited / ethnology
  • Blood Coagulation Disorders, Inherited / genetics*
  • Factor VIII / analysis*
  • Genetic Loci*
  • Genetic Markers
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Mendelian Randomization Analysis
  • Phenotype
  • Risk Factors
  • Venous Thrombosis / blood
  • Venous Thrombosis / ethnology
  • Venous Thrombosis / genetics*
  • von Willebrand Factor / analysis*

Substances

  • Biomarkers
  • Genetic Markers
  • von Willebrand Factor
  • F8 protein, human
  • Factor VIII