Pharmacogenomics of Interferon-ß Therapy in Multiple Sclerosis: Baseline IFN Signature Determines Pharmacological Differences between Patients

Abstract

BackgroundMultiple sclerosis (MS) is a heterogeneous disease. In order to understand the partial responsiveness to IFNß in Relapsing Remitting MS (RRMS) we studied the pharmacological effects of IFNß therapy.MethodologyLarge scale gene expression profiling was performed on peripheral blood of 16 RRMS patients at baseline and one month after the start of IFNß 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 IFNß. Genes of interest were measured and validated by quantitative realtime PCR. An independent group of 30 RRMS patients was used for validation.Principal FindingsPharmacogenomics revealed a marked variation in the pharmacological response to IFNß 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 IFNß 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 IFNß indicating that differential responsiveness to IFNß is an intrinsic feature of peripheral blood cells at baseline.ConclusionThese 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 IFNß.

Gene expression profiles in human peripheral blood mononuclear cells as biomarkers for nutritional in vitro and in vivo investigations

“…Since nearly all investigated drug metabolism and biotransformation enzymes are expressed on mRNA-level in PBMC and some genes could be modulated by food ingredients, PBMC seem to be a suitable tool for in vitro and ex vivo gene expression investigations. This hypothesis is also supported by a study by van Baarsen et al [44] that could show that responses of in vitro stimulated PBMC isolated prior to treatment are consistent with those of the ex vivo results. A critical question is whether these effects in PBMC at gene expression level are comparable to that in the target organs.…”

Molecular subtypes of systemic sclerosis in association with anti-centromere antibodies and digital ulcers

“…10,13,15 For multiple sclerosis, we have shown earlier that an increased expression of the type I IFN response program is associated with unresponsiveness towards IFNb therapy. 18 Here, we observed significantly increased type I IFN response and the occurrence of digital ulcers. The occurrence of digital ulcers is believed to be a reflection of an imbalanced angiogenesis.…”

Interferon regulatory factor 5 gene variants and pharmacological and clinical outcome of Interferonβ therapy in multiple sclerosis

“…6 Previously, we and others showed that levels of IFN activity in untreated patients negatively correlated with the pharmacological and clinical response towards IFNb. 6,7 In systemic lupus erythematosus, an autoimmune disease in which type I IFN is associated with development and severity of the disease, a clear link between IRF5 polymorphisms, among these rs2004640, and disease has been shown.…”

“…6 Previously, we and others showed that levels of IFN activity in untreated patients negatively correlated with the pharmacological and clinical response towards IFNb. 6,7 In systemic lupus erythematosus, an autoimmune disease in which type I IFN is associated with development and severity of the disease, a clear link between IRF5 polymorphisms, among these rs2004640, and disease has been shown. 11,16 Besides a role for rs2004640 in IFNb pharmacogenetics in multiple sclerosis S Vosslamber et al conferring risk to systemic lupus erythematosus, we here provide evidence for a role of this SNP in determining the responsiveness towards IFNb in RRMS.…”

“…5 Non-responders to IFNb treatment were characterized by an increased expression of IFN response genes before the start of therapy and a lack of a pharmacologically induced increase in IFN response gene activity. 6 Accordingly, the expression of IFN response genes before the start of IFNb therapy was shown to be related to the clinical response. 7 In search for genetic polymorphisms as predictors of drug response, we focused on regulators of the IFN pathway that could influence IFN-activity and downstream signaling and gene activation events.…”