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

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cam.issuedOnline2022-03-09
dc.contributor.authorStacey, David
dc.contributor.authorChen, Lingyan
dc.contributor.authorStanczyk, Paulina J
dc.contributor.authorHowson, Joanna MM
dc.contributor.authorMason, Amy M
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.authorDehghan, Abbas
dc.contributor.authorHeath, Adam S
dc.contributor.authorMorrison, Alanna C
dc.contributor.authorReiner, Alex P
dc.contributor.authorJohnson, Andrew
dc.contributor.authorRichmond, Anne
dc.contributor.authorPeters, Annette
dc.contributor.authorvan Hylckama Vlieg, Astrid
dc.contributor.authorMcKnight, Barbara
dc.contributor.authorPsaty, Bruce M
dc.contributor.authorHayward, Caroline
dc.contributor.authorWard-Caviness, Cavin
dc.contributor.authorO’Donnell, Christopher
dc.contributor.authorChasman, Daniel
dc.contributor.authorStrachan, David P
dc.contributor.authorTregouet, David A
dc.contributor.authorMook-Kanamori, Dennis
dc.contributor.authorGill, Dipender
dc.contributor.authorThibord, Florian
dc.contributor.authorAsselbergs, Folkert W
dc.contributor.authorLeebeek, Frank WG
dc.contributor.authorRosendaal, Frits R
dc.contributor.authorDavies, Gail
dc.contributor.authorHomuth, Georg
dc.contributor.authorTemprano, Gerard
dc.contributor.authorCampbell, Harry
dc.contributor.authorTaylor, Herman A
dc.contributor.authorBressler, Jan
dc.contributor.authorHuffman, Jennifer E
dc.contributor.authorRotter, Jerome I
dc.contributor.authorYao, Jie
dc.contributor.authorWilson, James F
dc.contributor.authorBis, Joshua C
dc.contributor.authorHahn, Julie M
dc.contributor.authorDesch, Karl C
dc.contributor.authorWiggins, Kerri L
dc.contributor.authorRaffield, Laura M
dc.contributor.authorBielak, Lawrence F
dc.contributor.authorYanek, Lisa R
dc.contributor.authorKleber, Marcus E
dc.contributor.authorMueller, Martina
dc.contributor.authorKavousi, Maryam
dc.contributor.authorMangino, Massimo
dc.contributor.authorConomos, Matthew P
dc.contributor.authorLiu, Melissa
dc.contributor.authorBrown, Michael R
dc.contributor.authorJhun, Min-A
dc.contributor.authorChen, Ming-Huei
dc.contributor.authorde Maat, Moniek PM
dc.contributor.authorPeyser, Patricia A
dc.contributor.authorElliot, Paul
dc.contributor.authorWei, Peng
dc.contributor.authorWild, Philipp S
dc.contributor.authorMorange, Pierre E
dc.contributor.authorvan der Harst, Pim
dc.contributor.authorYang, Qiong
dc.contributor.authorLe, Ngoc-Quynh
dc.contributor.authorMarioni, Riccardo
dc.contributor.authorLi, Ruifang
dc.contributor.authorDamrauer, Scott M
dc.contributor.authorCox, Simon R
dc.contributor.authorTrompet, Stella
dc.contributor.authorFelix, Stephan B
dc.contributor.authorVölker, Uwe
dc.contributor.authorKoenig, Wolfgang
dc.contributor.authorJukema, J Wouter
dc.contributor.authorGuo, Xiuqing
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 S
dc.contributor.orcidChen, Lingyan [0000-0003-3750-6761]
dc.contributor.orcidHowson, Joanna MM [0000-0001-7618-0050]
dc.contributor.orcidMason, Amy M [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.orcidPaul, Dirk S [0000-0002-8230-0116]
dc.date.accessioned2022-03-09T16:01:46Z
dc.date.available2022-03-09T16:01:46Z
dc.date.issued2022-12
dc.date.submitted2020-03-30
dc.date.updated2022-03-09T16:01:45Z
dc.description.abstract<jats:title>Abstract</jats:title><jats:p>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 <jats:italic>PROCR</jats:italic> locus, associated with lower coronary artery disease (CAD) risk but higher venous thromboembolism (VTE) risk. We identify <jats:italic>PROCR</jats:italic>-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 <jats:italic>PROCR</jats:italic>-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 <jats:italic>PROCR</jats:italic>-219Gly with an increased pro-thrombotic state via coagulation factor VII, a ligand of EPCR. Our study, which links <jats:italic>PROCR</jats:italic>-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.</jats:p>
dc.identifier.doi10.17863/CAM.82241
dc.identifier.eissn2041-1723
dc.identifier.others41467-022-28729-3
dc.identifier.other28729
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/334809
dc.languageen
dc.publisherSpringer Science and Business Media LLC
dc.publisher.urlhttp://dx.doi.org/10.1038/s41467-022-28729-3
dc.subjectArticle
dc.subject/631/208/212/2301
dc.subject/692/4019/592/2727
dc.subject/45/43
dc.subject/45/88
dc.subject/13/31
dc.subject/13/106
dc.subject/13/1
dc.subjectarticle
dc.titleElucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus
dc.typeArticle
dcterms.dateAccepted2022-02-08
prism.issueIdentifier1
prism.publicationNameNature Communications
prism.volume13
pubs.funder-project-idBritish Heart Foundation (BHF) (RE/13/6/30180)
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1038/s41467-022-28729-3
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