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Updated: Apr 18, 2026
High-throughput Quantitative Real-time RT-PCR Assay for Determining Expression Profiles of Types I and III Interferon Subtypes
Published on: March 24, 2015
Genetic variation in PBMC-produced IFN-γ and TNF-α associations with relapse in multiple sclerosis
Yuan Zhou1, Bruce Taylor1, Ingrid van der Mei1
1Menzies Institute for Medical Research, University of Tasmania, Australia.
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.
Insights
Genetic variations in cytokine genes influence multiple sclerosis (MS) relapse risk. Specific single nucleotide polymorphisms (SNPs) in IL2RB, TNFRSF1B, and IL3 genes modify the effects of TNF-α and IFN-γ on MS disease activity.
Area of Science:
- Immunogenetics
- Neuroimmunology
- Genetics of Multiple Sclerosis
Background:
- Peripheral blood mononuclear cell (PBMC) cytokine production differs in multiple sclerosis (MS) patients versus healthy controls.
- Previously, elevated TNF-α was found to be protective against MS relapse, while elevated IFN-γ increased relapse risk.
Purpose of the Study:
- To investigate if single nucleotide polymorphisms (SNPs) in cytokine and cytokine receptor genes modulate the association between TNF-α, IFN-γ, and MS relapse risk.
- To gain further insight into the roles of these genes in MS pathogenesis.
Main Methods:
- Analysis of 361 SNPs within 10 kb of 84 cytokine/cytokine receptor genes in 91 relapsing-remitting MS patients.
- Multilevel mixed-effects linear regression used to identify predictors of PBMC cytokines.
- Cox proportional hazards regression used to predict relapse risk, with Bonferroni correction for multiple testing (p<1.39 × 10(-4) considered significant).
Main Results:
- The GG genotype of rs3218295 (IL2RB) showed a protective effect of TNF-α on relapse, while GA/AA genotypes showed a positive association (pinteraction=5.04 × 10(-5)).
- CC genotype of rs522807 (TNFRSF1B) and AA genotype of rs25879 (IL3) were associated with increased IFN-γ and relapse risk (pinteraction=8.21 × 10(-5) and 1.70 × 10(-5), respectively).
Conclusions:
- Novel modulation of TNF-α and IFN-γ associations with MS relapse by SNPs in key cytokine genes was identified.
- These findings highlight the potential of these genes and their products as therapeutic targets for MS.
