Association analysisofRAC1sin- gle nucleotidepolymorphismswith ulcerativecolitis


خلاصه: number ofpossiblecandidategeneshavebeenidentifiedto play acausativeroleinconferringageneticsusceptibilityto UC, resultinginimmunedysregulation.Recently,Muiseetal. reported anovelgeneticassociationbetweenRAC1withUC, a findingsupportedbyhumangeneticandfunctionalstud- ies andanimalmodelsofcolitis [3]. Administrationofthe RAC1 inhibitorNSC23766,aswellasconditionaldisruption of RAC1 [3], decreasedDSS-inducedneutrophilrecruitment and tissuedamageinthecolon.InhibitionofRAC1wasshown to abolishCXCchemokine-inducedneutrophilchemotaxis and up-regulationofMac-1invitro.Inadditiontoitsessen- tial roleinmodulatingimmuneandinflammatoryresponses, RAC1 playsanessentialroleinwoundhealingandepithe- lial celladhesion/migration/differentiation,whichinvolves Rho GTPase-mediatedcytoskeletonremodelinganddisso- lution andreassemblyofcellularjunctions [4]. Moreover, inflammation- andpathogen-inducedRAC1inactivationpro- motes apoptosisandcontributestomicrobialinfectionand barrier dysfunction. In thepresentstudy,three RAC1 gene variants,previously reported toconfersusceptibilitytoUC [3], werestudies in anIranianpatientpopulation.Ourresultsindicatedthat the allelicfrequenciesoftheseSNPswerenotsignifican- tly differentinUCpatientscomparedtocontrols,which was similartowhatwepreviouslyreportedinpatientswith CD [13]. Thiscanbeinpartexplainedbyheterogeneityof the studiedpopulations,suggestingaroleforepigenetic factors inthecomplexinterplaybetweengenesandenvi- ronment amongdifferentethnicpopulations.Italsoshould be emphasizedthatUCisacomplexdisease,inwhichmul- tiple factorscanaffectdiseasebehaviororseverity.Thus, different studydesigns,controlpopulations,andincomplete phenotype descriptioncouldpotentiallyresultindifferent outcomes. GivenitshigherprevalenceinEuropeandNorth America comparedtotheMiddleEasternregions,itcouldbe hypothesized that RAC1 gene variantsmightbeassociated with UCamongpatientsofEuropeanancestry,althoughit needs furtherinvestigations. In conclusion,ourstudydidnotshowanyassociation between thestudiedRAC1SNPsandUCinIranianpatients, similar towhatwefoundinCD.WhetherRAC1,thoughnota predictive geneticbiomarkerbasedontheassessedSNPsin the presentstudy,isamajorplayerinthepathogenesisof UC inourpatientpopulationneedsfurtherinvestigations. Considering ethnicitydifferencesstudyingimmunemodu- lating genesindifferentpopulationswouldshedlightonthe molecular pathogenesisofUC.Thiswilllaythefoundation for improvedpersonalizedmedicineinUCbasedonpharma- cogenetic approachesandtargetedgenetherapy.Further studies ondifferentpopulationswithlargersamplesizes are requiredtoidentifytheexactroleofRAC1andother contributing genesinUC.