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Stacey, D.* ; Chen, L.* ; Stanczyk, P.J.* ; Howson, J.M.M.* ; Mason, A.M.* ; Burgess, S.* ; MacDonald, S.* ; Langdown, J.* ; McKinney, H.* ; Downes, K.* ; Farahi, N.* ; Peters, J.E.* ; Basu, S.* ; Pankow, J.S.* ; Tang, W.* ; Pankratz, N.* ; Sabater-Lleal, M.* ; de Vries, P.S.* ; Smith, N.L.* ; CHARGE Hemostasis Working Group (Peters, A.) ; Gelinas, A.D.* ; Schneider, D.J.* ; Janjic, N.* ; Samani, N.J.* ; Ye, S.* ; Summers, C.* ; Chilvers, E.R.* ; Paul, D.S.*

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

Nat. Commun. 13:1222 (2022)
Publ. Version/Full Text Research data DOI
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Quellenangaben Volume: 13, Issue: 1, Pages: , Article Number: 1222 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed
Grants NHGRI NIH HHS
Wellcome Trust
Chief Scientist Office
Department of Health
British Heart Foundation
Medical Research Council
NHLBI NIH HHS
NCRR NIH HHS