Expression of the Multiple Sclerosis-Associated MHC Class II Allele HLA-DRB11501 Is Regulated by Vitamin D 英文参考文献.docVIP

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Expression of the Multiple Sclerosis-Associated MHC Class II Allele HLA-DRB11501 Is Regulated by Vitamin D 英文参考文献.doc

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Expression of the Multiple Sclerosis-Associated MHC Class II Allele HLA-DRB11501 Is Regulated by Vitamin D 英文参考文献

ExpressionoftheMultipleSclerosis-AssociatedMHC ClassIIAlleleHLA-DRB1*1501IsRegulatedbyVitaminD SreeramV.Ramagopalan1,2.,NarelleJ.Maugeri1.,LahiruHandunnetthi1,2,MatthewR.Lincoln1,2 ,Sarah- MichelleOrton1,2,DavidA.Dyment1,2,GabrieleC.DeLuca1,2,BlancaM.Herrera1,2,MichaelJ.Chao1,2 ,A. DessaSadovnick3,4,GeorgeC.Ebers1,2*,JulianC.Knight1* 1Wellcome TrustCentrefor HumanGenetics,University ofOxford, Oxford, United Kingdom, 2Department ofClinical Neurology, University ofOxford, JohnRadcliffe Hospital,Oxford,UnitedKingdom,3DepartmentofMedicalGenetics,DivisionofNeurology,UniversityofBritishColumbia,UBCHospital,Vancouver,BritishColumbia, Canada,4FacultyofMedicine,DivisionofNeurology,UniversityofBritishColumbia,UBCHospital,Vancouver,BritishColumbia,Canada Abstract Multiplesclerosis(MS)isacomplextraitinwhichallelicvariationintheMHCclassIIregionexertsthesinglestrongesteffect ongeneticrisk.EpidemiologicaldatainMSprovidestrongevidencethatenvironmentalfactorsactatapopulationlevelto influencetheunusualgeographicaldistributionofthisdisease.GrowingevidenceimplicatessunlightorvitaminDasakey environmentalfactorinaetiology.Wehypothesisedthatthisenvironmentalcandidatemightinteractwithinheritedfactors andsoughtresponsiveregulatoryelementsintheMHCclassIIregion.SequenceanalysislocalisedasingleMHCvitaminD response element (VDRE) to the promoter region of HLA-DRB1. Sequencing of this promoter in greater than 1,000 chromosomes from HLA-DRB1 homozygotes showed absolute conservation of this putative VDRE on HLA-DRB1*15 haplotypes. In contrast, there was striking variation among non–MS-associated haplotypes. Electrophoretic mobility shift assays showed specific recruitment of vitamin D receptor to the VDRE in the HLA-DRB1*15 promoter, confirmed by chromatin immunoprecipitation experiments using lymphoblastoid cells homozygous for HLA-DRB1*15 . Transient transfection using a luciferase reporter assay showed a functional role for this VDRE. B cells transiently transfected with the HLA-DRB1*15