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dc.contributor.authorNurnberg, Sylvia Ten
dc.contributor.authorGuerraty, Marie Aen
dc.contributor.authorWirka, Robert Cen
dc.contributor.authorRao, H Shankeren
dc.contributor.authorPjanic, Milosen
dc.contributor.authorNorton, Scotten
dc.contributor.authorSerrano, Felipeen
dc.contributor.authorPerisic, Ljubicaen
dc.contributor.authorElwyn, Susannahen
dc.contributor.authorPluta, Johnen
dc.contributor.authorZhao, Weien
dc.contributor.authorTesta, Stephanieen
dc.contributor.authorPark, YoSonen
dc.contributor.authorNguyen, Trieuen
dc.contributor.authorKo, Yi-Anen
dc.contributor.authorWang, Tingen
dc.contributor.authorHedin, Ulfen
dc.contributor.authorSinha, Sanjayen
dc.contributor.authorBarash, Yosephen
dc.contributor.authorBrown, Christopher Den
dc.contributor.authorQuertermous, Thomasen
dc.contributor.authorRader, Daniel Jen
dc.date.accessioned2019-11-29T00:30:49Z
dc.date.available2019-11-29T00:30:49Z
dc.date.issued2020-01-09en
dc.identifier.issn1553-7390
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/299435
dc.description.abstractGenome-wide association studies have identified multiple novel genomic loci associated with vascular diseases. Many of these loci are common non-coding variants that affect the expression of disease-relevant genes within coronary vascular cells. To identify such genes on a genome-wide level, we performed deep transcriptomic analysis of genotyped primary human coronary artery smooth muscle cells (HCASMCs) and coronary endothelial cells (HCAECs) from the same subjects, including splicing Quantitative Trait Loci (sQTL), allele-specific expression (ASE), and colocalization analyses. We identified sQTLs for TARS2, YAP1, CFDP1, and STAT6 in HCASMCs and HCAECs, and 233 ASE genes, a subset of which are also GTEx eGenes in arterial tissues. Colocalization of GWAS association signals for coronary artery disease (CAD), migraine, stroke and abdominal aortic aneurysm with GTEx eGenes in aorta, coronary artery and tibial artery discovered novel candidate risk genes for these diseases. At the CAD and stroke locus tagged by rs2107595 we demonstrate colocalization with expression of the proximal gene TWIST1. We show that disrupting the rs2107595 locus alters TWIST1 expression and that the risk allele has increased binding of the NOTCH signaling protein RBPJ. Finally, we provide data that TWIST1 expression influences vascular SMC phenotypes, including proliferation and calcification, as a potential mechanism supporting a role for TWIST1 in CAD.
dc.format.mediumElectronic-eCollectionen
dc.languageengen
dc.publisherPublic Library of Science (PLoS)
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectCoronary Vesselsen
dc.subjectEndothelium, Vascularen
dc.subjectCells, Cultureden
dc.subjectEndothelial Cellsen
dc.subjectMyocytes, Smooth Muscleen
dc.subjectHumansen
dc.subjectVascular Diseasesen
dc.subjectNuclear Proteinsen
dc.subjectProtein Bindingen
dc.subjectPolymorphism, Single Nucleotideen
dc.subjectImmunoglobulin J Recombination Signal Sequence-Binding Proteinen
dc.subjectTranscriptomeen
dc.subjectTwist-Related Protein 1en
dc.titleGenomic profiling of human vascular cells identifies TWIST1 as a causal gene for common vascular diseases.en
dc.typeArticle
prism.issueIdentifier1en
prism.publicationDate2020en
prism.publicationNamePLoS geneticsen
prism.startingPagee1008538
prism.volume16en
dc.identifier.doi10.17863/CAM.46504
dcterms.dateAccepted2019-11-25en
rioxxterms.versionofrecord10.1371/journal.pgen.1008538en
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2020-01-09en
dc.contributor.orcidNurnberg, Sylvia T [0000-0002-0869-484X]
dc.contributor.orcidGuerraty, Marie A [0000-0002-0766-1253]
dc.contributor.orcidWirka, Robert C [0000-0001-9131-9508]
dc.contributor.orcidRao, H Shanker [0000-0001-6827-1470]
dc.contributor.orcidNorton, Scott [0000-0002-1366-0628]
dc.contributor.orcidPluta, John [0000-0002-8941-6242]
dc.contributor.orcidZhao, Wei [0000-0002-8301-9297]
dc.contributor.orcidPark, YoSon [0000-0002-0465-4744]
dc.contributor.orcidNguyen, Trieu [0000-0001-5647-1301]
dc.contributor.orcidHedin, Ulf [0000-0001-9212-3945]
dc.contributor.orcidSinha, Sanjay [0000-0001-5900-1209]
dc.contributor.orcidBarash, Yoseph [0000-0003-3005-5048]
dc.contributor.orcidBrown, Christopher D [0000-0002-3785-5008]
dc.contributor.orcidQuertermous, Thomas [0000-0002-7645-9067]
dc.contributor.orcidRader, Daniel J [0000-0002-9245-9876]
dc.identifier.eissn1553-7404
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idBritish Heart Foundation (RG/17/5/32936)
cam.orpheus.successMon Jun 08 08:21:46 BST 2020 - The item has an open VoR version.*
rioxxterms.freetoread.startdate2100-01-01


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