ScientistsFindMajorSusceptibilityGenesforCrohn'sDisease
04/16/07--AconsortiumofCanadianandAmericanresearchersledbyDr.JohnD.Rioux,PhD,AssociateProfessorofMedicineattheMontrealHeartInstituteandtheUniversit?deMontr?al,reportintheApril15onlineeditionofNatureGeneticstheresultsfromasearchoftheentirehumangenomeforgeneticriskfactorsleadingtothedevelopmentofCrohn'sdisease.Specifically,usinganovelapproach,theauthorsidentifiedthatthePHOX2B,NCF4andATG16L1genesconstitutegeneticriskfactorsforCrohn'sdisease.Inaddition,theirstudyidentifiedtworegionsofthegenomewheregeneticriskfactorsarelocatedbutnoknowngeneswereimplicated?furtherworkwillbenecessarytoidentifythecausalgenesintheseregions.Morethan1millionAmericansandsome170,000CanadianshaveCrohn'sorcolitis,knowncollectivelyasinflammatoryboweldisease（IBD）.Thestudy'sauthorsrepresenttheIBDGeneticsConsortium,whichisfundedbytheNationalInstituteofDiabetesandDigestiveandKidneyDiseases（NIDDK）oftheNationalInstitutesofHealth.InadditiontotheMontrealHeartInstituteandUniversit?deMontr?al,theConsortium'smemberinstitutionsincludetheCedars-SinaiMedicalCenterinLosAngeles,theUniversityofChicago,theJohnsHopkinsUniversity,theUniversityofPittsburgh,theUniversityofToronto,andYaleUniversity.BecauseIBDtendstoruninfamiliesandismorefrequentincertainethnicpopulations,especiallyAshkenaziJews,scientistshavelongsuspectedasignificantgeneticcomponent.AlthoughpreviousgeneticstudiesfoundalinkbetweenCrohn'sdiseaseandmutationsinageneknownasCARD15,thosemutationsalonearenotconsideredtoaccountfortheentiregeneticcomponentofdisease.ToidentifyadditionalgenesthatareassociatedwithIBD,theinternationalteamofresearchersscannedthegenome?allof22,000orsogenes?bytestingmorethan300,000singlenucleotidepolymorphisms,orSNPs,inpeoplewithCrohn'sdiseaseandinhealthycontrols.ThecomparisonoftheseSNPs（commongeneticvariants）betweenpatientandcontrolgroupsidentifiedmultipleSNPsthatwerestronglyassociatedwithCrohn'sdisease.Thesefindingswerethentestedintwoadditionalsetsofpatientsandhealthycontrolsinordertoconfirmtheirresults.AccordingtothecorrespondingauthorJohnD.Rioux,thefindingshighlightnumerousbiologicalpathwaysnotpreviouslythoughttoplayaroleinCrohn'sdisease."TheidentificationofthePHOX2Bgeneinthisstudy,forexample,mayimplicatearoleforneuroendocrinecellsoftheintestinalepitheliumashavingaroletoplayinCrohn'sDisease.Inaddition,theidentificationoftheNCF4geneindicatesthatalteredreactiveoxygenspecies（ROS）production,importantinthegenerationofaneffectiveanti-microbialresponse,mayleadtoincreasedrisktodevelopingCrohn'sdisease".ThefactthattheauthorsalsofoundstrongassociationoftheATG16L1geneprovidesfurtherevidencethatanindividual'sresponsetomicrobeshasaninfluenceonsusceptibilitytoCrohn'sdisease.Specifically,inadditiontodemonstratingitsassociationtodisease,theseauthorshaveshownthatATG16L1isessentialforthenormalautophagicprocessusedtodegradeworn-outcellularcomponentsandhelpeliminatesomepathogenicbacteria."WeproposethatgeneticvariationintheATG16L1geneleadstoalterationsinhowthebodyusesautophagyandthereforemayresultinincreasedpersistenceofbothcellularandbacterialcomponents,leadingtoinappropriateimmuneactivationandincreasedriskofCrohn'sdisease"addsDr.Rioux.Thefindingsreportedinthisstudyareexpectedtonotonlyimproveonthebiologicalunderstandingofdiseasebutshouldalsohavealong-termimpactonclinicalpractice.AccordingtoDr.Edmond-JeanBernard,co-authorandgastroenterologistattheHotelDieuHospitalinMontrealandtheUniversit?deMontr?al"themultiplegeneticriskfactorswe'veidentifiedprovideimportantmoleculartargetsforcurrentfunctionalstudiesaimedatunderstandingthediseaseandimportanttargetsfordrugdevelopmenttoimprovetherapyofCrohn'sdiseaseinthefuture."Dr.StephenP.James,M.D.,directoroftheDivisionofDigestiveDiseasesandNutritionattheNationalInstitutesofHealth'sNIDDKcontinuedbysayingthat"theseimportantdiscoveriesnotonlyoffernewhopeforbettertherapiesforpatientswithCrohn'sdisease,theyalsohighlightthepromiseofthehumangenomeprojectandsubsequentinvestmentsbytheNIHinlargescale,collaborativeresearchprojectstounravelthecausesof,andhopefullybettertreatmentsforcomplex,enigmaticdiseases".Source:UniversityofMontreal
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