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Association of Coding Variants in Hydroxysteroid 17-beta Dehydrogenase 14 (HSD17B14) with Reduced Progression to End Stage Kidney Disease in Type 1 Diabetes

dc.rights.licenseopenen_US
dc.contributor.authorMYCHALECKYJ, Josyf C.
dc.contributor.authorVALO, Erkka
dc.contributor.authorICHIMURA, Takaharu
dc.contributor.authorAHLUWALIA, Tarunveer S.
dc.contributor.authorDINA, Christian
dc.contributor.authorMILLER, Rachel G.
dc.contributor.authorSHABALIN, Ivan G.
dc.contributor.authorGYORGY, Beata
dc.contributor.authorCAO, Jingjing
dc.contributor.authorONENGUT-GUMUSCU, Suna
dc.contributor.authorSATAKE, Eiichiro
dc.contributor.authorSMILES, Adam M.
dc.contributor.authorHAUKKA, Jani K.
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorTREGOUET, David-Alexandre
dc.contributor.authorCOSTACOU, Tina
dc.contributor.authorO'NEIL, Kristina
dc.contributor.authorPATERSON, Andrew D.
dc.contributor.authorFORSBLOM, Carol
dc.contributor.authorKEENAN, Hillary A.
dc.contributor.authorPEZZOLESI, Marcus G.
dc.contributor.authorPRAGNELL, Marlon
dc.contributor.authorGALECKI, Andrzej
dc.contributor.authorRICH, Stephen S.
dc.contributor.authorSANDHOLM, Niina
dc.contributor.authorKLEIN, Ronald
dc.contributor.authorKLEIN, Barbara E.
dc.contributor.authorSUSZTAK, Katalin
dc.contributor.authorORCHARD, Trevor J.
dc.contributor.authorKORSTANJE, Ron
dc.contributor.authorKING, George L.
dc.contributor.authorHADJADJ, Samy
dc.contributor.authorROSSING, Peter
dc.contributor.authorBONVENTRE, Joseph V.
dc.contributor.authorGROOP, Per-Henrik
dc.contributor.authorWARRAM, James H.
dc.contributor.authorKROLEWSKI, Andrzej S.
dc.date.accessioned2021-12-06T08:29:23Z
dc.date.available2021-12-06T08:29:23Z
dc.date.issued2021-10
dc.identifier.issn1533-3450 (Electronic) 1046-6673 (Linking)en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/123983
dc.description.abstractEnBACKGROUND: Rare variants in gene coding regions likely have a greater impact on disease-related phenotypes than common variants through disruption of their encoded protein. We searched for rare variants associated with onset of ESKD in individuals with type 1 diabetes at advanced kidney disease stage. METHODS: Gene-based exome array analyses of 15,449 genes in five large incidence cohorts of individuals with type 1 diabetes and proteinuria were analyzed for survival time to ESKD, testing the top gene in a sixth cohort (n=2372/1115 events all cohorts) and replicating in two retrospective case-control studies (n=1072 cases, 752 controls). Deep resequencing of the top associated gene in five cohorts confirmed the findings. We performed immunohistochemistry and gene expression experiments in human control and diseased cells, and in mouse ischemia reperfusion and aristolochic acid nephropathy models. RESULTS: Protein coding variants in the hydroxysteroid 17-beta dehydrogenase 14 gene (HSD17B14), predicted to affect protein structure, had a net protective effect against development of ESKD at exome-wide significance (n=4196; P value=3.3 x 10(-7)). The HSD17B14 gene and encoded enzyme were robustly expressed in healthy human kidney, maximally in proximal tubular cells. Paradoxically, gene and protein expression were attenuated in human diabetic proximal tubules and in mouse kidney injury models. Expressed HSD17B14 gene and protein levels remained low without recovery after 21 days in a murine ischemic reperfusion injury model. Decreased gene expression was found in other CKD-associated renal pathologies. CONCLUSIONS: HSD17B14 gene is mechanistically involved in diabetic kidney disease. The encoded sex steroid enzyme is a druggable target, potentially opening a new avenue for therapeutic development.
dc.language.isoENen_US
dc.subject.enType 1 diabetes
dc.subject.enHydroxysteroid 17-beta dehydrogenase 14
dc.subject.enEnd stage kidney disease
dc.subject.enGene-based tests
dc.subject.enRare variants
dc.subject.enDiabetic nephropathy
dc.subject.enDiabetic kidney disease
dc.title.enAssociation of Coding Variants in Hydroxysteroid 17-beta Dehydrogenase 14 (HSD17B14) with Reduced Progression to End Stage Kidney Disease in Type 1 Diabetes
dc.typeArticle de revueen_US
dc.identifier.doi10.1681/ASN.2020101457en_US
dc.subject.halSciences du Vivant [q-bio]/Santé publique et épidémiologieen_US
dc.identifier.pubmed34261756en_US
bordeaux.journalJournal of the American Society of Nephrologyen_US
bordeaux.page2634-2651en_US
bordeaux.volume32en_US
bordeaux.hal.laboratoriesBordeaux Population Health Research Center (BPH) - UMR 1219en_US
bordeaux.issue10en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.institutionINSERMen_US
bordeaux.teamVINTAGEen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
hal.identifierhal-03466624
hal.version1
hal.date.transferred2021-12-06T08:29:27Z
hal.exporttrue
dc.rights.ccPas de Licence CCen_US
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