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Four missense genetic variants in CUBN are associated with higher levels of eGFR in non-diabetes but not in diabetes mellitus or its subtypes: A genetic association study in Europeans

dc.rights.licenseopenen_US
dc.contributor.authorUGLEBJERG, Nicoline
dc.contributor.authorAHMADIZAR, Fariba
dc.contributor.authorALY, Dina M.
dc.contributor.authorCANADAS-GARRE, Marisa
dc.contributor.authorHILL, Claire
dc.contributor.authorNABER, Annemieke
dc.contributor.authorODDSSON, Asmundur
dc.contributor.authorSINGH, Sunny S.
dc.contributor.authorSMYTH, Laura
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorTREGOUET, David-Alexandre
dc.contributor.authorCHAKER, Layal
dc.contributor.authorGHANBARI, Mohsen
dc.contributor.authorSTEINTHORSDOTTIR, Valgerdur
dc.contributor.authorAHLQVIST, Emma
dc.contributor.authorHADJADJ, Samy
dc.contributor.authorVAN HOEK, Mandy
dc.contributor.authorKAVOUSI, Maryam
dc.contributor.authorMCKNIGHT, Amy Jayne
dc.contributor.authorSIJBRANDS, Eric J.
dc.contributor.authorSTEFANSSON, Kari
dc.contributor.authorSIMONS, Matias
dc.contributor.authorROSSING, Peter
dc.contributor.authorAHLUWALIA, Tarunveer S.
dc.date.accessioned2023-04-18T13:03:36Z
dc.date.available2023-04-18T13:03:36Z
dc.date.issued2023-02-28
dc.identifier.issn1664-2392en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/173071
dc.description.abstractEnAIM: Rare genetic variants in the CUBN gene encoding the main albumin-transporter in the proximal tubule of the kidneys have previously been associated with microalbuminuria and higher urine albumin levels, also in diabetes. Sequencing studies in isolated proteinuria suggest that these variants might not affect kidney function, despite proteinuria. However, the relation of these CUBN missense variants to the estimated glomerular filtration rate (eGFR) is largely unexplored. We hereby broadly examine the associations between four CUBN missense variants and eGFR(creatinine) in Europeans with Type 1 (T1D) and Type 2 Diabetes (T2D). Furthermore, we sought to deepen our understanding of these variants in a range of single- and aggregate- variant analyses of other kidney-related traits in individuals with and without diabetes mellitus. METHODS: We carried out a genetic association-based linear regression analysis between four CUBN missense variants (rs141640975, rs144360241, rs45551835, rs1801239) and eGFR(creatinine) (ml/min/1.73 m(2), CKD-EPI(creatinine(2012)), natural log-transformed) in populations with T1D (n ~ 3,588) or T2D (n ~ 31,155) from multiple European studies and in individuals without diabetes from UK Biobank (UKBB, n ~ 370,061) with replication in deCODE (n = 127,090). Summary results of the diabetes-group were meta-analyzed using the fixed-effect inverse-variance method. RESULTS: Albeit we did not observe associations between eGFR(creatinine) and CUBN in the diabetes-group, we found significant positive associations between the minor alleles of all four variants and eGFR(creatinine) in the UKBB individuals without diabetes with rs141640975 being the strongest (Effect=0.02, P(eGFR_creatinine)=2.2 × 10(-9)). We replicated the findings for rs141640975 in the Icelandic non-diabetes population (Effect=0.026, P(eGFR_creatinine)=7.7 × 10(-4)). For rs141640975, the eGFR(creatinine)-association showed significant interaction with albuminuria levels (normo-, micro-, and macroalbuminuria; p = 0.03). An aggregated genetic risk score (GRS) was associated with higher urine albumin levels and eGFR(creatinine). The rs141640975 variant was also associated with higher levels of eGFR(creatinine-cystatin C) (ml/min/1.73 m(2), CKD-EPI(2021), natural log-transformed) and lower circulating cystatin C levels. CONCLUSIONS: The positive associations between the four CUBN missense variants and eGFR in a large population without diabetes suggests a pleiotropic role of CUBN as a novel eGFR-locus in addition to it being a known albuminuria-locus. Additional associations with diverse renal function measures (lower cystatin C and higher eGFR(creatinine-cystatin C) levels) and a CUBN-focused GRS further suggests an important role of CUBN in the future personalization of chronic kidney disease management in people without diabetes.
dc.language.isoENen_US
dc.rightsAttribution 3.0 United States*
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/us/*
dc.subject.enGenetics
dc.subject.enCUBN
dc.subject.enCubilin
dc.subject.enKidney function
dc.subject.eneGFR
dc.subject.enDiabetes
dc.subject.enNon-diabetes
dc.subject.enChronic kidney disease (CKD)
dc.title.enFour missense genetic variants in CUBN are associated with higher levels of eGFR in non-diabetes but not in diabetes mellitus or its subtypes: A genetic association study in Europeans
dc.title.alternativeFront Endocrinol (Lausanne)en_US
dc.typeArticle de revueen_US
dc.identifier.doi10.3389/fendo.2023.1081741en_US
dc.subject.halSciences du Vivant [q-bio]/Santé publique et épidémiologieen_US
dc.identifier.pubmed36926036en_US
bordeaux.journalFrontiers in Endocrinologyen_US
bordeaux.volume14en_US
bordeaux.hal.laboratoriesBordeaux Population Health Research Center (BPH) - UMR 1219en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.institutionINSERMen_US
bordeaux.teamELEANOR_BPHen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
hal.identifierhal-04073024
hal.version1
hal.date.transferred2023-04-18T13:03:57Z
hal.exporttrue
dc.rights.ccPas de Licence CCen_US
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