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

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Highlights

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    We studied whether SNPs in cytokine genes modulated cytokine associations with relapse risk in MS.

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    GG genotype of rs32183295 in IL2RB enhanced TNF-α anti-relapse association w/relapse.

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    A allele in rs522807 in TNFRSF1B enhanced TNF-α anti-relapse association w/relapse.

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    G allele of rs25879 of IL3 abrogated IFN-γ association w/relapse.

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    A allele of rs522807 of TNFRSF1B abrogated IFN-γ association w/relapse.

Abstract

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.

Introduction

Multiple sclerosis (MS) is a progressive demyelinating neurological disease of the central nervous system resulting from the effects of both environmental risk factors and susceptibility loci [1]. Its major clinical subtype is relapsing–remitting MS (RRMS), which is characterised by intermittent and irregular relapses followed by periods of relative clinical inactivity (remission). In our previous work, we found that stimulated PBMC-produced TNF-α was associated with a lower risk of relapse, while stimulated PBMC-produced IFN-γ was significantly associated with an increased risk of relapse. We further found that one MS-related SNP, rs1800693, within the TNF-α-receptor gene significantly modified TNF-α association with relapse, such that the secreted form blocked the protective effect of TNF-α [2].

In this paper, we provide further genetic context by assessing whether SNPs within a greater number of genes for cytokines and their receptors significantly modulate the associations of TNF-α and IFN-γ with relapse, thus providing information about the effects of these cytokine and the potential role of these loci in MS.

Section snippets

Study design

The Southern Tasmanian Multiple Sclerosis Longitudinal (MSL) Study followed a cohort of 203 persons with clinically definite MS living in southern Tasmania, Australia over 2002–2005 [3]. This population-based study solicited participants from the sole MS clinic servicing southern Tasmania operating out of the public hospital (19.2%), with additional recruitment from participants in previous studies (80.8%) and via MS Society referral. Accordingly, an estimated 78% (203/259) of eligible cases in

Results

As discussed previously, our cohort was majority female, of middle age and low disability, and a minority had any relapses, both during the study and during the analysis period here, reflecting their largely being on immunomodulatory therapy (Table 1).

Discussion

In this work, we systematically examined the SNPs within a large number of genes for cytokines and their receptors to assess whether there was an interaction with the previously demonstrated associations [2] of TNF-α and IFN-γ with relapse. 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 did not (pinteraction = 5.04 × 10− 5). Carriers of CC genotype of rs522807 (3′ region of TNFRSF1B) and

Contribution statement

BT, IvdM, A-LP, and TD were involved in the conception, planning, and acquisition of funding for the study. BT, IvdM, FP, A-LP, and TD were involved in the acquisition of data for the study. Analysis of peripheral blood mononuclear cell cytokine production by NS. Conception of current analysis by SSJ. Statistical analysis of PBMC–SNP interactive relationship predicting relapse undertaken by YZ under supervision by SSJ, with statistical support by LB and genetic analysis support by JC. YZ, SSJ

Funding statement

The MS Longitudinal Study was funded by a grant from the Australian National Health & Medical Research Council (Project 211308). SSJ is supported by a postdoctoral fellowship from Multiple Sclerosis Research Australia (12051). IvdM is supported by a fellowship from the Australian Research Council (FT100100553).

Conflict of interest

The authors have no conflicts of interest to disclose.

Acknowledgements

We would like to thank all the study participants and the research staff who assisted with this project, particularly our MSL research nurse P Groom.

We also thank Andrew Kemp for the helpful comments on an earlier iteration of this paper.

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