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

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dc.contributor.authorStacey, D.
dc.contributor.authorChen, L.
dc.contributor.authorStanczyk, P.J.
dc.contributor.authorHowson, J.M.M.
dc.contributor.authorMason, A.M.
dc.contributor.authorBurgess, S.
dc.contributor.authorMacDonald, S.
dc.contributor.authorLangdown, J.
dc.contributor.authorMcKinney, H.
dc.contributor.authorDownes, K.
dc.contributor.authorFarahi, N.
dc.contributor.authorPeters, J.E.
dc.contributor.authorBasu, S.
dc.contributor.authorPankow, J.S.
dc.contributor.authorTang, W.
dc.contributor.authorPankratz, N.
dc.contributor.authorSabater-Lleal, M.
dc.contributor.authorde Vries, P.S.
dc.contributor.authorSmith, N.L.
dc.contributor.authorGelinas, A.D.
dc.contributor.authoret al.
dc.date.issued2022
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.identifier.citationNature Communications, 2022; 13(1)
dc.identifier.doi10.1038/s41467-022-28729-3
dc.identifier.issn2041-1723
dc.identifier.issn2041-1723
dc.identifier.urihttps://hdl.handle.net/11541.2/36761
dc.language.isoen
dc.publisherSpringer Science and Business Media LLC
dc.relation.fundingDepartment of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates
dc.relation.fundingEU/EFPIA 116074
dc.relation.fundingSpanish Health Institute (ISCIII) CP17/00142
dc.relation.fundingNIHR133788
dc.relation.fundingUK Medical Research Council, Engineering and Physical Sciences Research Council
dc.relation.fundingVan Geest Heart and Cardiovascular Diseases Research Fund and Health Data Research UK
dc.relation.fundingNIH HHSN268200625226C
dc.relation.fundingNational Heart, Lung, and Blood Institute (NHLBI) R01HL059367, R01HL086694, R01HL087641, R01HL134894
dc.relation.fundingNational Human Genome Research Institute (NHGRI) U01HG004402
dc.relation.fundingNational Center for Research Resources (NCRR) UL1RR025005
dc.relation.fundingAmerican Heart Association (AHA) 18CDA34110116
dc.relation.fundingAstraZeneca
dc.relation.fundingMerck Sharp and Dohme (MSD)
dc.relation.fundingWellcome Trust (WT) RG/16/4/32218
dc.relation.fundingUK Research and Innovation (UKRI) MR/S004068/2
dc.relation.fundingMedical Research Council (MRC) MR/L003120/1, MR/P502091/1, RG/13/13/30194, RG/18/13/33946
dc.relation.fundingEconomic and Social Research Council (ESRC)
dc.relation.fundingCambridge Biomedical Research Centre (NIHR) BRC-1215-20014, RG/19/9/34655, SP/19/2/344612
dc.relation.fundingHealth and Social Care Research and Development Division (HCS R&D)
dc.relation.fundingEuropean Social Fund (ESF)
dc.relation.fundingPublic Health Agency (PHA)
dc.relation.fundingNational Heart and Lung Institute (NHLI) HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I, HHSN268201700005I
dc.relation.fundingBritish Heart Foundation (BHF) RE/13/6/30180
dc.relation.fundingNational Institute for Health and Care Research (NIHR)
dc.rightsCopyright 2022 The Authors. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. (http://creativecommons.org/licenses/by/4.0/)
dc.source.urihttps://doi.org/10.1038/s41467-022-28729-3
dc.subjectCHARGE Hemostasis Working Group
dc.subjectEndothelial Cells
dc.subjectHumans
dc.subjectThrombosis
dc.subjectProtein C
dc.subjectReceptors, Cell Surface
dc.subjectAntigens, CD
dc.subjectCrosses, Genetic
dc.subjectVenous Thromboembolism
dc.subjectEndothelial Protein C Receptor
dc.titleElucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus
dc.typeJournal article
pubs.publication-statusPublished
ror.mmsid9916807829801831

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