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BACKGROUND: Alterations 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. OBJECTIVE: To 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. METHODS: Prospective 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. RESULTS: Individuals 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). CONCLUSIONS: Our 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.

Original publication

DOI

10.1016/j.jns.2014.12.022

Type

Journal article

Journal

J Neurol Sci

Publication Date

15/02/2015

Volume

349

Pages

40 - 44

Keywords

Epidemiology, Interferon-gamma, Multiple sclerosis, Peripheral blood mononuclear cell, Relapse, Tumour necrosis factor alpha, Adult, Aged, Cohort Studies, Female, Genetic Predisposition to Disease, Genotype, Humans, Interferon-gamma, Leukocytes, Mononuclear, Male, Middle Aged, Multiple Sclerosis, Relapsing-Remitting, Polymorphism, Single Nucleotide, Prospective Studies, Risk Factors, Tumor Necrosis Factor-alpha, Young Adult