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Reduced monocyte and macrophage TNFSF15/TL1A expression is associated with susceptibility to inflammatory bowel disease.

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cam.issuedOnline2018-09-10
cam.orpheus.successThu Jan 30 10:54:40 GMT 2020 - The item has an open VoR version.
dc.contributor.authorRichard, Arianne C
dc.contributor.authorPeters, James E
dc.contributor.authorSavinykh, Natalia
dc.contributor.authorLee, James C
dc.contributor.authorHawley, Eric T
dc.contributor.authorMeylan, Françoise
dc.contributor.authorSiegel, Richard M
dc.contributor.authorLyons, Paul A
dc.contributor.authorSmith, Kenneth GC
dc.contributor.orcidLee, James C [0000-0001-5711-9385]
dc.contributor.orcidHawley, Eric T [0000-0002-2357-2154]
dc.contributor.orcidMeylan, Françoise [0000-0002-9279-7875]
dc.date.accessioned2018-09-05T12:49:58Z
dc.date.available2018-09-05T12:49:58Z
dc.date.issued2018-09
dc.description.abstractChronic inflammation in inflammatory bowel disease (IBD) results from a breakdown of intestinal immune homeostasis and compromise of the intestinal barrier. Genome-wide association studies have identified over 200 genetic loci associated with risk for IBD, but the functional mechanisms of most of these genetic variants remain unknown. Polymorphisms at the TNFSF15 locus, which encodes the TNF superfamily cytokine commonly known as TL1A, are associated with susceptibility to IBD in multiple ethnic groups. In a wide variety of murine models of inflammation including models of IBD, TNFSF15 promotes immunopathology by signaling through its receptor DR3. Such evidence has led to the hypothesis that expression of this lymphocyte costimulatory cytokine increases risk for IBD. In contrast, here we show that the IBD-risk haplotype at TNFSF15 is associated with decreased expression of the gene by peripheral blood monocytes in both healthy volunteers and IBD patients. This association persists under various stimulation conditions at both the RNA and protein levels and is maintained after macrophage differentiation. Utilizing a "recall-by-genotype" bioresource for allele-specific expression measurements in a functional fine-mapping assay, we localize the polymorphism controlling TNFSF15 expression to the regulatory region upstream of the gene. Through a T cell costimulation assay, we demonstrate that genetically regulated TNFSF15 has functional relevance. These findings indicate that genetically enhanced expression of TNFSF15 in specific cell types may confer protection against the development of IBD.
dc.format.mediumElectronic-eCollection
dc.identifier.doi10.17863/CAM.26979
dc.identifier.eissn1553-7404
dc.identifier.issn1553-7390
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/279608
dc.languageeng
dc.language.isoeng
dc.publisherPublic Library of Science (PLoS)
dc.publisher.urlhttp://dx.doi.org/10.1371/journal.pgen.1007458
dc.rightsCC0 1.0 Universal (CC0 1.0)Public Domain Dedication
dc.rights.urihttps://creativecommons.org/publicdomain/zero/1.0/
dc.subjectAdult
dc.subjectAlleles
dc.subjectCells, Cultured
dc.subjectColitis, Ulcerative
dc.subjectCrohn Disease
dc.subjectFemale
dc.subjectGenetic Predisposition to Disease
dc.subjectHaplotypes
dc.subjectHumans
dc.subjectMacrophages
dc.subjectMale
dc.subjectMiddle Aged
dc.subjectMonocytes
dc.subjectPolymorphism, Single Nucleotide
dc.subjectPrimary Cell Culture
dc.subjectQuantitative Trait Loci
dc.subjectTumor Necrosis Factor Ligand Superfamily Member 15
dc.subjectYoung Adult
dc.titleReduced monocyte and macrophage TNFSF15/TL1A expression is associated with susceptibility to inflammatory bowel disease.
dc.typeArticle
dcterms.dateAccepted2018-06-01
prism.issueIdentifier9
prism.publicationDate2018
prism.publicationNamePLoS Genet
prism.startingPagee1007458
prism.volume14
pubs.funder-project-idWellcome Trust (083650/Z/07/Z)
pubs.funder-project-idMedical Research Council (MR/L019027/1)
pubs.funder-project-idBritish Heart Foundation (None)
rioxxterms.licenseref.startdate2018-09-10
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionofrecord10.1371/journal.pgen.1007458

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