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dc.contributor.authorStacey, David
dc.contributor.authorChen, Lingyan
dc.contributor.authorStanczyk, Paulina J
dc.contributor.authorHowson, Joanna MM
dc.contributor.authorMason, Amy
dc.contributor.authorBurgess, Stephen
dc.contributor.authorMacDonald, Stephen
dc.contributor.authorLangdown, Jonathan
dc.contributor.authorMcKinney, Harriett
dc.contributor.authorDownes, Kate
dc.contributor.authorFarahi, Neda
dc.contributor.authorPeters, James E
dc.contributor.authorBasu, Saonli
dc.contributor.authorPankow, James S
dc.contributor.authorTang, Weihong
dc.contributor.authorPankratz, Nathan
dc.contributor.authorSabater-Lleal, Maria
dc.contributor.authorde Vries, Paul S
dc.contributor.authorSmith, Nicholas L
dc.contributor.authorCHARGE Hemostasis Working Group
dc.contributor.authorGelinas, Amy D
dc.contributor.authorSchneider, Daniel J
dc.contributor.authorJanjic, Nebojsa
dc.contributor.authorSamani, Nilesh J
dc.contributor.authorYe, Shu
dc.contributor.authorSummers, Charlotte
dc.contributor.authorChilvers, Edwin R
dc.contributor.authorDanesh, John
dc.contributor.authorPaul, Dirk
dc.date.accessioned2022-02-11T00:30:59Z
dc.date.available2022-02-11T00:30:59Z
dc.date.issued2022-03-09
dc.identifier.issn2041-1723
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/333874
dc.description.abstractMany 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.
dc.publisherNature Research
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.titleElucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus.
dc.typeArticle
dc.publisher.departmentDepartment of Public Health And Primary Care, Cardiovascular Epidemiology Unit
dc.date.updated2022-02-09T16:13:35Z
prism.publicationNameNat Commun
dc.identifier.doi10.17863/CAM.81290
dcterms.dateAccepted2022-02-08
rioxxterms.versionofrecord10.1038/s41467-022-28729-3
rioxxterms.versionAM
dc.contributor.orcidChen, Lingyan [0000-0003-3750-6761]
dc.contributor.orcidHowson, Joanna MM [0000-0001-7618-0050]
dc.contributor.orcidMason, Amy [0000-0002-8019-0777]
dc.contributor.orcidBurgess, Stephen [0000-0001-5365-8760]
dc.contributor.orcidPeters, James E [0000-0002-9415-3440]
dc.contributor.orcidPankow, James S [0000-0001-7076-483X]
dc.contributor.orcidPankratz, Nathan [0000-0001-5958-693X]
dc.contributor.orcidSabater-Lleal, Maria [0000-0002-0128-379X]
dc.contributor.orcidSchneider, Daniel J [0000-0001-6830-0905]
dc.contributor.orcidSamani, Nilesh J [0000-0002-3286-8133]
dc.contributor.orcidYe, Shu [0000-0002-4126-4278]
dc.contributor.orcidSummers, Charlotte [0000-0002-7269-2873]
dc.contributor.orcidChilvers, Edwin R [0000-0002-4230-9677]
dc.contributor.orcidDanesh, John [0000-0003-1158-6791]
dc.contributor.orcidPaul, Dirk [0000-0002-8230-0116]
dc.identifier.eissn2041-1723
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMedical Research Council (MR/L003120/1)
pubs.funder-project-idBritish Heart Foundation (None)
pubs.funder-project-idBritish Heart Foundation (None)
pubs.funder-project-idBritish Heart Foundation (RG/16/4/32218)
pubs.funder-project-idBritish Heart Foundation (RG/18/13/33946)
pubs.funder-project-idNational Institute for Health Research (NIHRDH-IS-BRC-1215-20014)
cam.orpheus.counter1
cam.depositDate2022-02-09
pubs.licence-identifierapollo-deposit-licence-2-1
pubs.licence-display-nameApollo Repository Deposit Licence Agreement
rioxxterms.freetoread.startdate2025-02-10


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International