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 (p_interaction = 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 (p_interaction = 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.