TY - JOUR
T1 - Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus
AU - CHARGE Hemostasis Working Group
AU - Stacey, David
AU - Chen, Lingyan
AU - Stanczyk, Paulina J.
AU - Howson, Joanna M.M.
AU - Mason, Amy M.
AU - Burgess, Stephen
AU - MacDonald, Stephen
AU - Langdown, Jonathan
AU - McKinney, Harriett
AU - Downes, Kate
AU - Farahi, Neda
AU - Peters, James E.
AU - Basu, Saonli
AU - Pankow, James S.
AU - Tang, Weihong
AU - Pankratz, Nathan
AU - Sabater-Lleal, Maria
AU - de Vries, Paul S.
AU - Smith, Nicholas L.
AU - Dehghan, Abbas
AU - Heath, Adam S.
AU - Morrison, Alanna C.
AU - Reiner, Alex P.
AU - Johnson, Andrew
AU - Richmond, Anne
AU - Peters, Annette
AU - van Hylckama Vlieg, Astrid
AU - McKnight, Barbara
AU - Psaty, Bruce M.
AU - Hayward, Caroline
AU - Ward-Caviness, Cavin
AU - O’Donnell, Christopher
AU - Chasman, Daniel
AU - Strachan, David P.
AU - Tregouet, David A.
AU - Mook-Kanamori, Dennis
AU - Gill, Dipender
AU - Thibord, Florian
AU - Asselbergs, Folkert W.
AU - Leebeek, Frank W.G.
AU - Rosendaal, Frits R.
AU - Davies, Gail
AU - Homuth, Georg
AU - Temprano, Gerard
AU - Campbell, Harry
AU - Taylor, Herman A.
AU - Bressler, Jan
AU - Huffman, Jennifer E.
AU - Rotter, Jerome I.
AU - Wei, Peng
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85126077134&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85126077134&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-28729-3
DO - 10.1038/s41467-022-28729-3
M3 - Article
C2 - 35264566
AN - SCOPUS:85126077134
SN - 2041-1723
VL - 13
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1222
ER -