Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus
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Authors
Stacey, David
Chen, Lingyan
Howson, Joanna
Farahi, Neda
Publication Date
2022-03-09Journal Title
Nature Communications
ISSN
2041-1723
Publisher
Nature Research
Volume
13
Issue
1
Language
eng
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Paul, D., Stacey, D., Chen, L., Howson, J., Mason, A., Burgess, S., Farahi, N., et al. (2022). Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus. Nature Communications, 13 (1) https://doi.org/10.1038/s41467-022-28729-3
Description
Funder: Wellcome Trust
Abstract
Many individual genetic risk loci have been associated with multiple common human diseases. However, the molecular basis of this pleiotropy often remains unclear. We present an integrative approach to reveal the molecular mechanism underlying the PROCR locus, associated with lower coronary artery disease (CAD) risk but higher venous thromboembolism (VTE) risk. We identify PROCR-p.Ser219Gly as the likely causal variant at the locus and protein C as a causal factor. Using genetic analyses, human recall-by-genotype and in vitro experimentation, we demonstrate that PROCR-219Gly increases plasma levels of (activated) protein C through endothelial protein C receptor (EPCR) ectodomain shedding in endothelial cells, attenuating leukocyte–endothelial cell adhesion and vascular inflammation. We also associate PROCR-219Gly with an increased pro-thrombotic state via coagulation factor VII, a ligand of EPCR. Our study, which links PROCR-219Gly to CAD through anti-inflammatory mechanisms and to VTE through pro-thrombotic mechanisms, provides a framework to reveal the mechanisms underlying similar cross-phenotype associations.
Sponsorship
Medical Research Council (MR/L003120/1)
British Heart Foundation (None)
British Heart Foundation (None)
British Heart Foundation (RG/16/4/32218)
British Heart Foundation (RG/18/13/33946)
National Institute for Health Research (IS-BRC-1215-20014)
Medical Research Council (MR/P502091/1)
Identifiers
35264566, PMC8907312
External DOI: https://doi.org/10.1038/s41467-022-28729-3
This record's URL: https://www.repository.cam.ac.uk/handle/1810/335972
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