A Common Polymorphism in the Promoter Region of the TNFSF4 Gene Is Associated with Lower Allele-Specific Expression and Risk of Myocardial Infarction 英文参考文献.docVIP

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A Common Polymorphism in the Promoter Region of the TNFSF4 Gene Is Associated with Lower Allele-Specific Expression and Risk of Myocardial Infarction 英文参考文献.doc

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A Common Polymorphism in the Promoter Region of the TNFSF4 Gene Is Associated with Lower Allele-Specific Expression and Risk of Myocardial Infarction 英文参考文献

ACommonPolymorphisminthePromoterRegionofthe TNFSF4GeneIsAssociatedwithLowerAllele-Specific ExpressionandRiskofMyocardialInfarction MassimilianoRia1*¤,JacobLagercrantz1,AnnSamnega?rd2,SusannaBoquist1,AndersHamsten1 ,Per Eriksson1 1Atherosclerosis Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska University Hospital Solna, Stockholm, Sweden, 2Division of CardiovascularMedicine,DepartmentofClinicalSciences,DanderydHospital,KarolinskaInstitutet,Stockholm,Sweden Abstract Background:TheTNFSF4/TNFRSF4system,alongwithseveralotherreceptor-ligandpairs,isinvolvedintherecruitmentand activation of T-cells and is therefore tentatively implicated in atherosclerosis and acute coronary syndromes. We have previouslyshownthatgeneticvariantsinTNFSF4areassociatedwithmyocardialinfarction(MI)inwomen.Thisprompted functionalstudiesofTNFSF4expression. MethodsandResults:BasedonascreeningoftheTNFSF4genomicregion,apromoterpolymorphism(rand a haplotype were identified, conceivably involved in gene regulation. The r-allele, in agreement with the linked rs3850641G-allele, proved to be associated with increased risk of MI in women. Haplotype-specific chromatin immunoprecipitation of activated polymerase II, as a measure of transcriptional activity in vivo, suggested that the haplotype including the rand rs3850641 polymorphisms is functionally important, the r- and rs3850641G-allelesbeingassociatedwithlowertranscriptionalactivityincellsheterozygousforbothpolymorphisms.The functional role of ron transcriptional levels of TNFSF4 was clarified by luciferase reporter assays, where the r-alleledecreasedgeneexpressionwhencomparedwithther-allele,whilethers3850641SNPdid nothaveanyeffectonTNFSF4promoteractivity.Electromobilityshiftassayshowedthattherolymorphism,but notrs3850641,affectsthebindingofnuclearfactors,thussuggestingthatthelowertranscriptionalactivityisattributedto bindingofoneormoretrans