Skip to main content

Research Repository

Advanced Search

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

Authors

Ahmad H. Mufti

Kenichi Ogiwara

Laura L. Swystun

Jeroen C. J. Eikenboom

Ulrich Budde

Wilma M. Hopman

Christer Halldén

Jenny Goudemand

Ian R. Peake

Anne C. Goodeve

David Lillicrap

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., … 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
Electronic ISSN 2473-9537
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

Files

Published article (1.8 Mb)
PDF

Copyright Statement
© 2018 by The American Society of Hematology







You might also like



Downloadable Citations