Pharmacogenomic analysis of interferon receptor polymorphisms in multiple sclerosis

Abstract

Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system characterized by progressive neurological dysfunction. No curative therapy is currently available, and approximately 80-90% of afflicted individuals are ultimately disabled. Interferon beta (IFNb) has been shown to decrease clinical relapses, reduce brain disease activity, and possibly slow progression of disability. However, the overall effect of treatment is partial and a substantial number of patients are considered poor or nonresponders. For this report, we tested the pharmacogenomic effects of eight polymorphisms in the interferon receptor genes (IFNAR1 and IFNAR2) in a group of 147 patients undergoing open-label IFNb therapy. Overall, no significant differences in the distribution of responders and nonresponders, classified based on prospectively acquired primary and secondary clinical end points, were observed when stratified by any of the studied IFNAR gene polymorphisms. A trend detected with a single nucleotide polymorphism SNP 16469 (A/T) located at the third intron of the IFNAR1 gene, suggesting modest association with relapse-free status, will require confirmation in an independent data set. In addition, no significant association was observed of any of the IFNAR gene polymorphisms with susceptibility to MS, as studied by a family-based association analysis.

Genome-wide Scan of 500 000 Single-Nucleotide Polymorphisms Among Responders and Nonresponders to Interferon Beta Therapy in Multiple Sclerosis

“…This study, in which the Centre d'Esclerosi Mú ltiple de Catalunya was one of 4 collaborating centers, aimed to identify genes associated with response to interferon beta therapy and was performed among responder and nonresponder DNA pools using genotyping arrays (Affymetrix 100K). Although previously reported genetic associations [5][6][7][8][9][10][11] were not confirmed, the study identified candidate genes and underscored the genetic heterogeneity underlying response to interferon beta therapy in MS.…”

Clinical Parameters to Predict Response to Interferon in Relapsing Multiple Sclerosis

“…Nevertheless, the frequency of relapses appears to be the least unreliable clinical predictor of a response to therapy but only for the year before treatment onset. Other non-clinical markers, such as those provided by non-conventional MRI, and especially pharmacogenetic markers could help to answer the question [30,31] .…”

Multiple sclerosis genetics: leaving no stone unturned

“…89,116 The analysis of eight SNPs in the interferon receptor genes failed to show significant evidence of pharmacogenomic influences. 117 More recently, we applied advanced data-mining and predictive modeling tools to a longitudinal gene expression data set generated from MS patients treated with IFNb in order to discover higher-order predictive patterns associated with treatment outcome. 118 We identified nine sets of gene triplets whose expression, when tested before the initiation of therapy, can predict favorable response to with up to 87% accuracy.…”