• J. Neurol. Sci. · Feb 2015

    Genetic variation in PBMC-produced IFN-γ and TNF-α associations with relapse in multiple sclerosis.

    • Yuan Zhou, Bruce Taylor, Ingrid van der Mei, Niall Stewart, Jac Charlesworth, Leigh Blizzard, Anne-Louise Ponsonby, Terence Dwyer, Fotini Pittas, and Steve Simpson.
    • Menzies Institute for Medical Research, University of Tasmania, Australia.
    • J. Neurol. Sci. 2015 Feb 15;349(1-2):40-4.

    BackgroundAlterations in peripheral blood mononuclear cell (PBMC) cytokine production have been found in multiple sclerosis (MS) compared to healthy controls. We have previously found that stimulated PBMC-produced TNF-α and IFN-γ modulated MS relapse risk, such that raised TNF-α was protective, while raised IFN-γ increased relapse risk.ObjectiveTo assess whether SNPs within genes for relevant cytokines and their receptors modulate the associations of TNF-α and IFN-γ with relapse, thus providing additional information about these cytokine effects and the roles of these genes in MS.MethodsProspective cohort of 91 participants with relapsing-remitting MS and cytokine and genotype data. SNPs (N=361) within a window of 10 kb around each cytokine/cytokine receptor gene (N=84) were selected for analysis. Predictors of PBMC cytokines were evaluated by multilevel mixed-effects linear regression. Predictors of relapse were evaluated by Cox proportional hazards regression. Bonferroni correction was used to adjust for multiple testing; thus p<1.39 × 10(-4) was defined as significant.ResultsIndividuals of GG genotype of rs3218295 (within the gene IL2RB) demonstrated a significant protective effect of TNF-α on relapse while those of GA/AA genotype showed a significant positive association (pinteraction=5.04 × 10(-5)). Carriers of CC genotype of rs522807 (3' region of TNFRSF1B) and the AA genotype of rs25879 (5' region of IL3) showed a strong association between IFN-γ and increased relapse risk (pinteraction=8.21 × 10(-5) and 1.70 × 10(-5), respectively).ConclusionsOur results show novel modulation of TNF-α and IFN-γ associations with relapse by SNPs in major cytokines. These findings suggest the potential for these genes and/or their products as potential therapeutic targets in MS.Copyright © 2014 Elsevier B.V. All rights reserved.

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