Association of a Functional Variant in the Wnt Co-Receptor LRP6 with Early Onset Ileal Crohns Disease 英文参考文献.docVIP
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Association of a Functional Variant in the Wnt Co-Receptor LRP6 with Early Onset Ileal Crohns Disease 英文参考文献
AssociationofaFunctionalVariantintheWntCo-
ReceptorLRP6withEarlyOnsetIlealCrohn’sDisease
MaureenJ.Koslowski1,ZoraTeltschik1,JuliaBeisner1,ElkeSchaeffeler1,GuoxingWang1 ,Irmgard
Ku¨bler2,MichaelGersemann1,2,RachelCooney3,DerekJewell3,WalterReinisch4,Se′verineVermeire5,
PaulRutgeerts5,MatthiasSchwab1,6,EduardF.Stange2,JanWehkamp1,2*
1Dr.Margarete-Fischer-BoschInstituteforClinicalPharmacologyandUniversityofTu¨bingen,Stuttgart,Germany,2Robert-Bosch-HospitalStuttgart,Stuttgart,Germany,
3MedicalScienceDivision,JohnRadcliffeHospital,Oxford,UnitedKingdom,4DepartmentofInternalMedicineIII,DivisionofGastroenterologyandHepatology,Medical
UniversityVienna,Vienna,Austria,5DivisionofGastroenterology,UniversityHospitalGasthuisberg,Leuven,Belgium,6DepartmentofClinicalPharmacology,Instituteof
ExperimentalandClinicalPharmacologyandToxicology,UniversityHospital,Tu¨bingen,Germany
Abstract
Ileal Crohn’s Disease (CD), a chronic small intestinal inflammatory disorder, is characterized by reduced levels of the
antimicrobialpeptidesDEFA5(HD-5)andDEFA6(HD-6).Bothofthesea-defensinsareexclusivelyproducedinPanethcells
(PCs) at small intestinal crypt bases. Different ileal CD–associated genes including NOD2, ATG16L1, and recently the b-
catenin–dependant Wnt transcription factor TCF7L2 have been linked to impaired PC antimicrobial function. The Wnt
pathwayinfluencesgutmucosalhomeostasisandPCmaturation,besidesdirectlycontrollingHD-5/6geneexpression.The
hereinreportedcandidategenestudyfocusesonanothercrucialWntfactor,theco-receptorlowdensitylipoproteinreceptor-
relatedprotein6(LRP6).Weanalysedexonicsinglenucleotidepolymorphisms(SNPs)inalargecohort(Oxford:n=1,893)and
prospectivelytested2additionalEuropeansamplesets(Leuven:n=688,Vienna:n=1,628).Werevealedanassociationofa
non-synonymousSNP(rs2302685;Ile1062Val)withearlyonsetilealCD(OR1.8;p=0.00034;forhomozygouscarriers:OR4.1;
p=0.00004)andadditionallywithpenetratingilealCDbehaviour(OR1.3;p=0.00917).Incontrast,itwasnotlinkedtoadult
onsetilealCD,colon
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