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

David Stacey, Lingyan Chen, Paulina J. Stanczyk, Joanna M. M. Howson, Amy M. Mason, Stephen Burgess, Stephen MacDonald, Jonathan Langdown, Harriett McKinney, Kate Downes, Neda Farahi, James E. Peters, Saonli Basu, James S. Pankow, Weihong Tang, Nathan Pankratz, Maria Sabater-Lleal, Paul S. Vries, Nicholas L. Smith, Amy D. Gelinas, Daniel J. Schneider, Nebojsa Janjic, Nilesh J. Samani, Shu Ye, Charlotte Summers, Edwin R. Chilvers, John Danesh and Dirk S. Paul ()
Additional contact information
David Stacey: University of Cambridge
Lingyan Chen: University of Cambridge
Paulina J. Stanczyk: University of Leicester
Joanna M. M. Howson: University of Cambridge
Amy M. Mason: University of Cambridge
Stephen Burgess: University of Cambridge
Stephen MacDonald: Cambridge University Hospitals NHS Foundation Trust
Jonathan Langdown: Cambridge University Hospitals NHS Foundation Trust
Harriett McKinney: University of Cambridge
Kate Downes: University of Cambridge
Neda Farahi: University of Cambridge
James E. Peters: University of Cambridge
Saonli Basu: University of Minnesota
James S. Pankow: University of Minnesota
Weihong Tang: University of Minnesota
Nathan Pankratz: University of Minnesota
Maria Sabater-Lleal: Sant Pau Biomedical Research Institute, IIB-Sant Pau
Paul S. Vries: The University of Texas Health Science Center at Houston
Nicholas L. Smith: University of Washington
Amy D. Gelinas: SomaLogic Inc
Daniel J. Schneider: SomaLogic Inc
Nebojsa Janjic: SomaLogic Inc
Nilesh J. Samani: University of Leicester
Shu Ye: University of Leicester
Charlotte Summers: University of Cambridge
Edwin R. Chilvers: Imperial College London
John Danesh: University of Cambridge
Dirk S. Paul: University of Cambridge

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28729-3

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