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dc.contributor.authorLi, Yong
dc.contributor.authorCheng, Yurong
dc.contributor.authorConsolato, Francesco
dc.contributor.authorSchiano, Guglielmo
dc.contributor.authorChong, Michael R
dc.contributor.authorPietzner, Maik
dc.contributor.authorNguyen, Ngoc Quynh H
dc.contributor.authorScherer, Nora
dc.contributor.authorBiggs, Mary L
dc.contributor.authorKleber, Marcus E
dc.contributor.authorHaug, Stefan
dc.contributor.authorGöçmen, Burulça
dc.contributor.authorPigeyre, Marie
dc.contributor.authorSekula, Peggy
dc.contributor.authorSteinbrenner, Inga
dc.contributor.authorSchlosser, Pascal
dc.contributor.authorJoseph, Christina B
dc.contributor.authorBrody, Jennifer A
dc.contributor.authorGrams, Morgan E
dc.contributor.authorHayward, Caroline
dc.contributor.authorSchultheiss, Ulla T
dc.contributor.authorKrämer, Bernhard K
dc.contributor.authorKronenberg, Florian
dc.contributor.authorPeters, Annette
dc.contributor.authorSeissler, Jochen
dc.contributor.authorSteubl, Dominik
dc.contributor.authorThen, Cornelia
dc.contributor.authorWuttke, Matthias
dc.contributor.authorMärz, Winfried
dc.contributor.authorEckardt, Kai-Uwe
dc.contributor.authorGieger, Christian
dc.contributor.authorBoerwinkle, Eric
dc.contributor.authorPsaty, Bruce M
dc.contributor.authorCoresh, Josef
dc.contributor.authorOefner, Peter J
dc.contributor.authorPare, Guillaume
dc.contributor.authorLangenberg, Claudia
dc.contributor.authorScherberich, Jürgen E
dc.contributor.authorYu, Bing
dc.contributor.authorAkilesh, Shreeram
dc.contributor.authorDevuyst, Olivier
dc.contributor.authorRampoldi, Luca
dc.contributor.authorKöttgen, Anna
dc.date.accessioned2022-07-01T23:31:17Z
dc.date.available2022-07-01T23:31:17Z
dc.date.issued2022-05-23
dc.identifier.issn2379-3708
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/338691
dc.description.abstractUromodulin (UMOD) is a major risk gene for monogenic and complex forms of kidney disease. The encoded kidney-specific protein uromodulin is highly abundant in urine and related to chronic kidney disease, hypertension, and pathogen defense. To gain insights into potential systemic roles, we performed genome-wide screens of circulating uromodulin using complementary antibody-based and aptamer-based assays. We detected 3 and 10 distinct significant loci, respectively. Integration of antibody-based results at the UMOD locus with functional genomics data (RNA-Seq, ATAC-Seq, Hi-C) of primary human kidney tissue highlighted an upstream variant with differential accessibility and transcription in uromodulin-synthesizing kidney cells as underlying the observed cis effect. Shared association patterns with complex traits, including chronic kidney disease and blood pressure, placed the PRKAG2 locus in the same pathway as UMOD. Experimental validation of the third antibody-based locus, B4GALNT2, showed that the p.Cys466Arg variant of the encoded N-acetylgalactosaminyltransferase had a loss-of-function effect leading to higher serum uromodulin levels. Aptamer-based results pointed to enzymes writing glycan marks present on uromodulin and to their receptors in the circulation, suggesting that this assay permits investigating uromodulin's complex glycosylation rather than its quantitative levels. Overall, our study provides insights into circulating uromodulin and its emerging functions.
dc.format.mediumElectronic
dc.publisherAmerican Society for Clinical Investigation
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectChronic kidney disease
dc.subjectGenetics
dc.subjectNephrology
dc.subjectPopulation genetics
dc.subjectBlood Pressure
dc.subjectGenome-Wide Association Study
dc.subjectHumans
dc.subjectHypertension
dc.subjectRenal Insufficiency, Chronic
dc.subjectUromodulin
dc.titleGenome-wide studies reveal factors associated with circulating uromodulin and its relationships to complex diseases.
dc.typeArticle
dc.publisher.departmentMrc Epidemiology Unit
dc.date.updated2022-07-01T14:48:22Z
prism.issueIdentifier10
prism.numberARTN e157035
prism.publicationDate2022
prism.publicationNameJCI Insight
prism.startingPagee157035
prism.volume7
dc.identifier.doi10.17863/CAM.86104
dcterms.dateAccepted2022-04-07
rioxxterms.versionofrecord10.1172/jci.insight.157035
rioxxterms.versionVoR
dc.contributor.orcidPietzner, Maik [0000-0003-3437-9963]
dc.contributor.orcidLangenberg, Claudia [0000-0002-5017-7344]
dc.identifier.eissn2379-3708
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMRC (MC_UU_00006/1)
cam.issuedOnline2022-05-23
cam.depositDate2022-07-01
pubs.licence-identifierapollo-deposit-licence-2-1
pubs.licence-display-nameApollo Repository Deposit Licence Agreement


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