Association Analysis of Canonical Wnt Signalling Genes in Diabetic Nephropathy 英文参考文献.docVIP

AssociationAnalysisofCanonicalWntSignallingGenes inDiabeticNephropathy DavidH.Kavanagh1,DavidA.Savage2,ChristopherC.Patterson3,AmyJayneMcKnight1,JohnK. Crean4,AlexanderP.Maxwell1,GarethJ.McKay1*,theWarren3/UKGoKinDStudyGroup 1NephrologyResearchGroup,CentreforPublicHealth,Queen’sUniversityBelfast,Belfast,UnitedKingdom,2HistocompatibilityandImmunogeneticsLaboratory,Blood TransfusionService,BelfastCityHospital,Belfast,UnitedKingdom,3EpidemiologyResearchGroup,CentreforPublicHealth,Queen’sUniversityBelfast,Belfast,United Kingdom,4ConwayInstitute,UniversityCollegeDublin,Dublin,Ireland Abstract Aims/Hypothesis: Several studies have provided compelling evidence implicating the Wnt signalling pathway in the pathogenesis of diabetic nephropathy. Gene expression profiles associated with renal fibrosis have been attenuated throughWntpathwaymodulationinmodelsystemsimplicatingWntpathwaymembersaspotentialtherapeutictargetsfor thetreatmentofdiabeticnephropathy.Weassessedtagandpotentiallyfunctionalsinglenucleotidepolymorphisms(SNPs; n=31)infourkeyWntpathwaygenes(CTNNB1,AXIN2,LRP5andLRP6)forassociationwithdiabeticnephropathyusinga case-controldesign. Methods:SNPsweregenotypedusingSequenomorTaqmantechnologiesin1351individualswithtype1diabetes(651 caseswithnephropathyand700controlswithoutnephropathy).CasesandcontrolswerewhiteandrecruitedfromtheUK andIreland.AssociationanalyseswereperformedusingPLINK,tocomparealleleandhaplotypefrequenciesincasesand controls.Adjustmentformultipletestingwasperformedbypermutationtesting. Results: Following logistic regression analysis adjusted by collection centre, duration of T1D, and average HbA1c as covariates, a single SNP in LRP6 (rs1337791) was significantly associated with DN (OR=0.74; CI: 0.57–0.97; P=0.028), although this was not maintained following correction for multiple testing. Three additional SNPs (rs2075241 in LRP6; rs3736228andrs491347bothinLRP5)weremarginallyassociatedwithdiabeticnephropathy,butnoneoftheassociations werereplicatedinani