Pharmacogenomics of Interferon-？ Therapy in Multiple Sclerosis Baseline IFN Signature Determines Pharmacological Differences between Patients 英文参考文献.docVIP

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Pharmacogenomics of Interferon-？ Therapy in Multiple Sclerosis Baseline IFN Signature Determines Pharmacological Differences between Patients 英文参考文献.doc

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Pharmacogenomics of Interferon-？ Therapy in Multiple Sclerosis Baseline IFN Signature Determines Pharmacological Differences between Patients 英文参考文献

PharmacogenomicsofInterferon-?TherapyinMultiple Sclerosis:BaselineIFNSignatureDetermines PharmacologicalDifferencesbetweenPatients LisaG.M.vanBaarsen1,2.,SaskiaVosslamber1,2.,MarianneTijssen2,JosefienM.C.Baggen1,LauraF. vanderVoort3,JoepKillestein3,TinekeC.T.MvanderPouwKraan1,ChrisH.Polman3,CornelisL. Verweij1,2 * 1DepartmentofMolecularCellBiologyandImmunology,VUMedicalCenter,Amsterdam,TheNetherlands,2DepartmentofPathology,VUMedicalCenter,Amsterdam, TheNetherlands,3DepartmentofNeurology,VUMedicalCenter,Amsterdam,TheNetherlands Abstract Background:Multiplesclerosis(MS)isaheterogeneousdisease.InordertounderstandthepartialresponsivenesstoIFN?in RelapsingRemittingMS(RRMS)westudiedthepharmacologicaleffectsofIFN?therapy. Methodology:Largescalegeneexpressionprofilingwasperformedonperipheralbloodof16RRMSpatientsatbaseline and one month after the start of IFN? therapy. Differential gene expression was analyzed by Significance Analysis of Microarrays.Subsequentexpressionanalysesonspecificgeneswereperformedafterthreeandsixmonthsoftreatment. Peripheral blood mononuclear cells (PBMC) were isolated and stimulated in vitro with IFN?. Genes of interest were measuredandvalidatedbyquantitativerealtimePCR.Anindependentgroupof30RRMSpatientswasusedforvalidation. Principal Findings: Pharmacogenomics revealed a marked variation in the pharmacological response to IFN? between patients. A total of 126 genes were upregulated in a subset of patients whereas in other patients these genes were downregulated or unchanged after one month of IFN? therapy. Most interestingly, we observed that the extent of the pharmacological response correlates negatively with the baseline expression of a specific set of 15 IFN response genes (R=20.7208; p=0.0016). The negative correlation was maintained after three (R=20.7363; p=0.0027) and six (R=20.8154;p=0.0004)monthsoftreatment,asdeterminedbygeneexpressionlevelsofthemostsignificantcorrelating gene.Similarresultswereobtainedinanindependentgroupofpatients