Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus.
Authors
Stacey, David
Stanczyk, Paulina J
MacDonald, Stephen
Langdown, Jonathan
McKinney, Harriett
Downes, Kate
Farahi, Neda
Basu, Saonli
Tang, Weihong
de Vries, Paul S
Smith, Nicholas L
CHARGE Hemostasis Working Group
Gelinas, Amy D
Janjic, Nebojsa
Publication Date
2022-03-09Journal Title
Nat Commun
ISSN
2041-1723
Publisher
Nature Research
Volume
13
Issue
1
Language
en
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Stacey, D., Chen, L., Stanczyk, P. J., Howson, J. M., Mason, A., Burgess, S., MacDonald, S., et al. (2022). Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus.. Nat Commun, 13 (1) https://doi.org/10.1038/s41467-022-28729-3
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.
Keywords
Article, /631/208/212/2301, /692/4019/592/2727, /45/43, /45/88, /13/31, /13/106, /13/1, article
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 (NIHRDH-IS-BRC-1215-20014)
Identifiers
s41467-022-28729-3, 28729
External DOI: https://doi.org/10.1038/s41467-022-28729-3
This record's URL: https://www.repository.cam.ac.uk/handle/1810/335878
Rights
Licence:
http://creativecommons.org/licenses/by/4.0/
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