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

Author

Listed:
  • David Stacey

    (University of Cambridge)

  • Lingyan Chen

    (University of Cambridge)

  • Paulina J. Stanczyk

    (University of Leicester
    University of Leicester)

  • Joanna M. M. Howson

    (University of Cambridge
    Novo Nordisk Research Centre Oxford, Innovation Building)

  • Amy M. Mason

    (University of Cambridge)

  • Stephen Burgess

    (University of Cambridge
    University of Cambridge)

  • Stephen MacDonald

    (Cambridge University Hospitals NHS Foundation Trust)

  • Jonathan Langdown

    (Cambridge University Hospitals NHS Foundation Trust)

  • Harriett McKinney

    (University of Cambridge
    National Health Service Blood and Transplant)

  • Kate Downes

    (University of Cambridge
    National Health Service Blood and Transplant
    University of Cambridge)

  • Neda Farahi

    (University of Cambridge)

  • James E. Peters

    (University of Cambridge
    Imperial College London
    Health Data Research UK London)

  • 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
    Karolinska University Hospital)

  • Paul S. Vries

    (The University of Texas Health Science Center at Houston)

  • Nicholas L. Smith

    (University of Washington
    Department of Veterans Affairs Office of Research and Development
    Kaiser Permanente Washington Health Research Institute)

  • Amy D. Gelinas

    (SomaLogic Inc)

  • Daniel J. Schneider

    (SomaLogic Inc)

  • Nebojsa Janjic

    (SomaLogic Inc)

  • Nilesh J. Samani

    (University of Leicester
    University of Leicester)

  • Shu Ye

    (University of Leicester
    University of Leicester)

  • Charlotte Summers

    (University of Cambridge)

  • Edwin R. Chilvers

    (Imperial College London)

  • John Danesh

    (University of Cambridge
    University of Cambridge
    University of Cambridge
    Wellcome Genome Campus and University of Cambridge)

  • Dirk S. Paul

    (University of Cambridge
    University of Cambridge
    Wellcome Sanger Institute)

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.

Suggested Citation

  • 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, 2022. "Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28729-3
    DOI: 10.1038/s41467-022-28729-3
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    References listed on IDEAS

    as
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