Pharmacogenomics of interferon-beta therapy in multiple sclerosis: baseline IFN signature determines pharmacological differences between patients
| Autor: | Chris H. Polman, Cornelis L. Verweij, Joep Killestein, Lisa G. M. van Baarsen, J.M. Baggen, Saskia Vosslamber, Laura F. van der Voort, Tineke C. T. M. van der Pouw Kraan, Marianne Tijssen |
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| Přispěvatelé: | Pathology, Molecular cell biology and Immunology, Neurology, CCA - Disease profiling, Neuroscience Campus Amsterdam 2008, Clinical Immunology and Rheumatology, Experimental Immunology |
| Rok vydání: | 2008 |
| Předmět: |
Adult
Male Time Factors Science Genetics and Genomics/Pharmacogenomics Immunology/Autoimmunity Neurological Disorders/Multiple Sclerosis and Related Disorders Peripheral blood mononuclear cell Cohort Studies Multiple Sclerosis Relapsing-Remitting medicine Humans Cell Biology/Gene Expression Oligonucleotide Array Sequence Analysis Regulation of gene expression Multidisciplinary business.industry Reverse Transcriptase Polymerase Chain Reaction Multiple sclerosis Genetics and Genomics/Functional Genomics Genetics and Genomics/Gene Expression Interferon-beta Middle Aged medicine.disease Gene expression profiling Real-time polymerase chain reaction Gene Expression Regulation Pharmacogenetics Pharmacogenomics Immunology Significance analysis of microarrays Immunology/Immune Response Leukocytes Mononuclear Medicine Biomarker (medicine) Female Interferons business Pharmacology/Personalized Medicine Research Article |
| Zdroj: | van Baarsen, L G, Vosslamber, S, Tijssen, M, Baggen, J M, van, D V, Killestein, J, van der Pouw Kraan, C T M, Polman, C H & Verweij, C L 2008, ' Pharmacogenomics of interferon-beta therapy in multiple sclerosis: baseline IFN signature determines pharmacological differences between patients ', PLoS ONE, vol. 3, no. 4, pp. e1927 . https://doi.org/10.1371/journal.pone.0001927 PLoS ONE PLoS ONE, 3(4). Public Library of Science PLoS ONE, Vol 3, Iss 4, p e1927 (2008) |
| ISSN: | 1932-6203 |
| Popis: | Background: Multiple sclerosis (MS) is a heterogeneous disease. In order to understand the partial responsiveness to IFNs in Relapsing Remitting MS (RRMS) we studied the pharmacological effects of IFNs therapy. Methodology: Large scale gene expression profiling was performed on peripheral blood of 16 RRMS patients at baseline and one month after the start of IFNs therapy. Differential gene expression was analyzed by Significance Analysis of Microarrays. Subsequent expression analyses on specific genes were performed after three and six months of treatment. Peripheral blood mononuclear cells (PBMC) were isolated and stimulated in vitro with IFNs. Genes of interest were measured and validated by quantitative realtime PCR. An independent group of 30 RRMS patients was used for validation. Principal Findings: Pharmacogenomics revealed a marked variation in the pharmacological response to IFNs 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 IFNs 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) months of treatment, as determined by gene expression levels of the most significant correlating gene. Similar results were obtained in an independent group of patients (n=30; R= 20.4719; p=0.0085). Moreover, the ex vivo results could be confirmed by in vitro stimulation of purified PBMCs at baseline with IFNs indicating that differential responsiveness to IFNs is an intrinsic feature of peripheral blood cells at baseline. Conclusion: These data imply that the expression levels of IFN response genes in the peripheral blood of MS patients prior to treatment could serve a role as biomarker for the differential clinical response to IFNs. Citation: van Baarsen LGM, Vosslamber S, Tijssen M, Baggen JMC, van der Voort LF, et al. (2008) Pharmacogenomics of Interferon-s Therapy in Multiple Sclerosis |
| Databáze: | OpenAIRE |
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