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Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Stacey, David 
Stanczyk, Paulina J 

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.

Description

Funder: Wellcome Trust

Keywords

Antigens, CD, Crosses, Genetic, Endothelial Cells, Endothelial Protein C Receptor, Humans, Protein C, Receptors, Cell Surface, Thrombosis, Venous Thromboembolism

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

13

Publisher

Nature Research
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 and Care Research (IS-BRC-1215-20014)
Medical Research Council (MR/P502091/1)
Wellcome Trust (204623/Z/16/Z)
Medical Research Council (MC_UU_00002/7)