Pharmacogenomics of interferon-beta therapy in multiple sclerosis: baseline IFN signature determines pharmacological differences between patients.

<h4>Background</h4>Multiple sclerosis (MS) is a heterogeneous disease. In order to understand the partial responsiveness to IFNbeta in Relapsing Remitting MS (RRMS) we studied the pharmacological effects of IFNbeta therapy.<h4>Methodology</h4>Large scale gene expression profi...

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Autores principales:	Lisa G M van Baarsen, Saskia Vosslamber, Marianne Tijssen, Josefien M C Baggen, Laura F van der Voort, Joep Killestein, Tineke C T M van der Pouw Kraan, Chris H Polman, Cornelis L Verweij
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2008
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/540228089a5342948db5eca8f6d61378
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spelling	oai:doaj.org-article:540228089a5342948db5eca8f6d613782021-11-25T06:12:53ZPharmacogenomics of interferon-beta therapy in multiple sclerosis: baseline IFN signature determines pharmacological differences between patients.1932-620310.1371/journal.pone.0001927https://doaj.org/article/540228089a5342948db5eca8f6d613782008-04-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18382694/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Multiple sclerosis (MS) is a heterogeneous disease. In order to understand the partial responsiveness to IFNbeta in Relapsing Remitting MS (RRMS) we studied the pharmacological effects of IFNbeta therapy.<h4>Methodology</h4>Large scale gene expression profiling was performed on peripheral blood of 16 RRMS patients at baseline and one month after the start of IFNbeta 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 IFNbeta. Genes of interest were measured and validated by quantitative realtime PCR. An independent group of 30 RRMS patients was used for validation.<h4>Principal findings</h4>Pharmacogenomics revealed a marked variation in the pharmacological response to IFNbeta 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 IFNbeta 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 = -0.7208; p = 0.0016). The negative correlation was maintained after three (R = -0.7363; p = 0.0027) and six (R = -0.8154; 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 = -0.4719; p = 0.0085). Moreover, the ex vivo results could be confirmed by in vitro stimulation of purified PBMCs at baseline with IFNbeta indicating that differential responsiveness to IFNbeta is an intrinsic feature of peripheral blood cells at baseline.<h4>Conclusion</h4>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 IFNbeta.Lisa G M van BaarsenSaskia VosslamberMarianne TijssenJosefien M C BaggenLaura F van der VoortJoep KillesteinTineke C T M van der Pouw KraanChris H PolmanCornelis L VerweijPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 3, Iss 4, p e1927 (2008)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Lisa G M van Baarsen Saskia Vosslamber Marianne Tijssen Josefien M C Baggen Laura F van der Voort Joep Killestein Tineke C T M van der Pouw Kraan Chris H Polman Cornelis L Verweij Pharmacogenomics of interferon-beta therapy in multiple sclerosis: baseline IFN signature determines pharmacological differences between patients.
description	<h4>Background</h4>Multiple sclerosis (MS) is a heterogeneous disease. In order to understand the partial responsiveness to IFNbeta in Relapsing Remitting MS (RRMS) we studied the pharmacological effects of IFNbeta therapy.<h4>Methodology</h4>Large scale gene expression profiling was performed on peripheral blood of 16 RRMS patients at baseline and one month after the start of IFNbeta 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 IFNbeta. Genes of interest were measured and validated by quantitative realtime PCR. An independent group of 30 RRMS patients was used for validation.<h4>Principal findings</h4>Pharmacogenomics revealed a marked variation in the pharmacological response to IFNbeta 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 IFNbeta 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 = -0.7208; p = 0.0016). The negative correlation was maintained after three (R = -0.7363; p = 0.0027) and six (R = -0.8154; 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 = -0.4719; p = 0.0085). Moreover, the ex vivo results could be confirmed by in vitro stimulation of purified PBMCs at baseline with IFNbeta indicating that differential responsiveness to IFNbeta is an intrinsic feature of peripheral blood cells at baseline.<h4>Conclusion</h4>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 IFNbeta.
format	article
author	Lisa G M van Baarsen Saskia Vosslamber Marianne Tijssen Josefien M C Baggen Laura F van der Voort Joep Killestein Tineke C T M van der Pouw Kraan Chris H Polman Cornelis L Verweij
author_facet	Lisa G M van Baarsen Saskia Vosslamber Marianne Tijssen Josefien M C Baggen Laura F van der Voort Joep Killestein Tineke C T M van der Pouw Kraan Chris H Polman Cornelis L Verweij
author_sort	Lisa G M van Baarsen
title	Pharmacogenomics of interferon-beta therapy in multiple sclerosis: baseline IFN signature determines pharmacological differences between patients.
title_short	Pharmacogenomics of interferon-beta therapy in multiple sclerosis: baseline IFN signature determines pharmacological differences between patients.
title_full	Pharmacogenomics of interferon-beta therapy in multiple sclerosis: baseline IFN signature determines pharmacological differences between patients.
title_fullStr	Pharmacogenomics of interferon-beta therapy in multiple sclerosis: baseline IFN signature determines pharmacological differences between patients.
title_full_unstemmed	Pharmacogenomics of interferon-beta therapy in multiple sclerosis: baseline IFN signature determines pharmacological differences between patients.
title_sort	pharmacogenomics of interferon-beta therapy in multiple sclerosis: baseline ifn signature determines pharmacological differences between patients.
publisher	Public Library of Science (PLoS)
publishDate	2008
url	https://doaj.org/article/540228089a5342948db5eca8f6d61378
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Pharmacogenomics of interferon-beta therapy in multiple sclerosis: baseline IFN signature determines pharmacological differences between patients.

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