RHOA Is a Modulator of the Cholesterol-Lowering Effects of Statin 英文参考文献.docVIP

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RHOA Is a Modulator of the Cholesterol-Lowering Effects of Statin 英文参考文献.doc

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RHOA Is a Modulator of the Cholesterol-Lowering Effects of Statin 英文参考文献

RHOAIsaModulatoroftheCholesterol-LoweringEffects ofStatin MarisaW.Medina1*,ElizabethTheusch1,DeveshNaidoo1,FrederickBauzon1,KristenStevens1, LaraM.Mangravite2,Yu-LinKuang1,RonaldM.Krauss1* 1Children’sHospitalOaklandResearchInstitute,Oakland,California,UnitedStatesofAmerica,2SageBionetworks,Seattle,Washington,UnitedStatesofAmerica Abstract AlthoughstatindrugsaregenerallyefficaciousforloweringplasmaLDL-cholesterollevels,thereisconsiderablevariabilityin response. To identify candidate genes that may contribute to this variation, we used an unbiased genome-wide filter approachthatwasappliedto10,149genesexpressedinimmortalizedlymphoblastoidcelllines(LCLs)derivedfrom480 participants of the Cholesterol and Pharmacogenomics (CAP) clinical trial of simvastatin. The criteria for identification of candidates included genes whose statin-induced changes in expression were correlated with change in expression of HMGCR,akeyregulatorofcellularcholesterolmetabolismandthetargetofstatininhibition.Thisanalysisyielded45genes, fromwhichRHOAwasselectedforfollow-upbecauseithasbeenfoundtoparticipateinmediatingthepleiotropicbutnot thelipid-loweringeffectsofstatintreatment.RHOAknock-downinhepatomacelllinesreducedHMGCR,LDLR,andSREBF2 mRNAexpressionandincreasedintracellularcholesterolestercontentaswellasapolipoproteinB(APOB)concentrationsin theconditionedmedia.Furthermore,inter-individualvariationinstatin-inducedRHOAmRNAexpressionmeasuredinvitro inCAPLCLswascorrelatedwiththechangesinplasmatotalcholesterol,LDL-cholesterol,andAPOBinducedbysimvastatin treatment (40mg/d for 6wk) of the individuals from whom these cell lines were derived. Moreover, the minor allele of raSNPlocatedinanovelcrypticRHOAexon,dramaticallyincreasedinclusionoftheexoninRHOAtranscripts during splicing and was associated with a smaller LDL-cholesterol reduction in response to statin treatment in 1,886 participantsfromtheCAPandPravastatinInflamationandCRPEvaluation(PRINCE;pravastatin40mg/d)statinclinicaltrials. Thus