Genetic variation in IFN signaling is associated with responsiveness to IFN-b in multiple sclerosis

• Published in: Multiple sclerosis Vol. 14; p. S291
• Main Authors: Vosslamber, S, van der Voort, LF, van Baarsen, L, Heijmans, R, Crusius, JBA, Killestein, J, Polman, C, Verweij, CL
• Format: Journal Article
• Language: English
• Published: 01.09.2008
• ISSN: 1352-4585

Background: Previously, we showed that baseline status of the IFN type-I activity negatively correlates with pharmacological effects of IFN-b treatment. Objective: It is hypothesized that inter-individual differences in the IFN type-I response program at baseline, and concomitant variation in IFN-b responsiveness may be the result of inter-individual variation in IFN-b biology. In this study we investigated the role of genetic variation in IFN signaling components in relation to heterogeneous pharmacological response to IFN-b. Methods: To determine biological response, peripheral blood was collected from 30 relapsing-remitting multiple sclerosis (RRMS) patients before and during IFN-b therapy. From 20 untreated RRMS patients peripheral blood was collected at two time points over a 3 to 12 month time period to analyze stability of baseline values over time. Baseline stability and biological response-rate, were analyzed by Taqman low-density arrays using the mean gene-expression level of a set of 10 IFN type-I response genes. Genetic variation was determined in several components of the IFN signaling cascade using Taqman genotyping assays and conventional genomic polymerase chain reaction (PCR). The ratios of gene-expression levels before and during therapy were compared with occurrence of genetic variation in components of the IFN signaling pathway. Results: The extent of biological response correlated negatively with baseline expression of the type-I IFN response gene-set (R=-0.3891; p=0.0336). Baseline stability over time was reflected by a correlation efficient of r=0.54; P=0.029 (n=20). Next we determined the association of genetic variation in IFN signalling components with IFN type-I response gene activity at baseline and after pharmacological intervention with IFN-b. This analysis revealed a significant association between genetic variation in one of the IFN signaling components and baseline IFN type-I response gene expression (P=0.0198). Accordingly, a significant reduced biological response was observed for patients who contained the genetic variant (P=0.0057). Conclusions: Variation in IFN signaling may determine (part) of the heterogeneity in pharmacological and clinical response to IFN-b in RRMS.