The common VWF single nucleotide variants c.2365A>G and c.2385T>C modify VWF biosynthesis and clearance

Mufti, Ahmad H.; Ogiwara, Kenichi; Swystun, Laura L.; Eikenboom, Jeroen C. J.; Budde, Ulrich; Hopman, Wilma M.; Halldén, Christer; Goudemand, Jenny; Peake, Ian R.; Goodeve, Anne C.; Lillicrap, David; Hampshire, Daniel J.; on behalf of the European Group on von Willebrand disease (EU-VWD) and Zimmerman Program for the Molecular and Clinical Biology of von Willebrand disease (ZPMCB-VWD) Study Groups

Abstract

Plasma levels of von Willebrand factor (VWF) vary considerably in the general population and this variation has been linked to several genetic and environmental factors. Genetic factors include 2 common single nucleotide variants (SNVs) located in VWF, rs1063856 (c.2365A>G) and rs1063857 (c.2385T>C), although to date the mechanistic basis for their association with VWF level is unknown. Using genotypic/phenotypic information from a European healthy control population, in vitro analyses of recombinant VWF expressing both SNVs, and in vivo murine models, this study determined the precise nature of their association with VWF level and investigated the mechanism(s) involved. Possession of either SNV corresponded with a significant increase in plasma VWF in healthy controls (P < .0001). In vitro expression confirmed this observation and highlighted an independent effect for each SNV (P < .0001 and P < .01, respectively), despite close proximity and strong linkage disequilibrium between them both. The influence of c.2365A>G on VWF levels was also confirmed in vivo. This increase in VWF protein corresponded to an increase in VWF messenger RNA (mRNA) resulting, in part, from prolonged mRNA half-life. In addition, coinheritance of both SNVs was associated with a lower VWF propeptide-to-VWF antigen ratio in healthy controls (P < .05) and a longer VWF half-life in VWF knockout mice (P < .0001). Both SNVs therefore directly increase VWF plasma levels through a combined influence on VWF biosynthesis and clearance, and may have an impact on disease phenotype in both hemostatic and thrombotic disorders.

Citation

Mufti, A. H., Ogiwara, K., Swystun, L. L., Eikenboom, J. C. J., Budde, U., Hopman, W. M., Halldén, C., Goudemand, J., Peake, I. R., Goodeve, A. C., Lillicrap, D., Hampshire, D. J., & on behalf of the European Group on von Willebrand disease (EU-VWD) and Zimmerman Program for the Molecular and Clinical Biology of von Willebrand disease (ZPMCB-VWD) Study Groups. (2018). The common VWF single nucleotide variants c.2365A>G and c.2385T>C modify VWF biosynthesis and clearance. Blood Advances, 2(13), 1585-1594. https://doi.org/10.1182/bloodadvances.2017011643

• Journal Article Type: Article
• Acceptance Date: May 24, 2018
• Online Publication Date: Jul 6, 2018
• Publication Date: Jul 10, 2018
• Deposit Date: Apr 10, 2019
• Publicly Available Date: Apr 10, 2019
• Journal: Blood Advances
• Print ISSN: 2473-9529
• Publisher: American Society of Hematology
• Peer Reviewed: Peer Reviewed
• Volume: 2
• Issue: 13
• Pages: 1585-1594
• DOI: https://doi.org/10.1182/bloodadvances.2017011643
• Keywords: Biosynthesis; Drug clearance; Genotype; Half-life; Mice; Nucleotides; Plasma; Rna; Messenger; Von Willebrand factor; Hemostatics
• Public URL: https://hull-repository.worktribe.com/output/1581284
• Publisher URL: http://www.bloodadvances.org/content/2/13/1585
• Contract Date: Apr 10, 2019