Zhou, Y and Taylor, B and van der Mei, I and Stewart, N and Charlesworth, J and Blizzard, L and Ponsonby, AL and Dwyer, T and Pittas, F and Simpson Jr, S, Genetic variation in PBMC-produced IFN-γ and TNF-α associations with relapse in multiple sclerosis, Journal of The Neurological Sciences, 349, (1-2) pp. 40-44. ISSN 0022-510X (2015) [Refereed Article]
Copyright 2015 Elsevier
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.
|Item Type:||Refereed Article|
|Keywords:||epidemiology, interferon-gamma, multiple sclerosis, peripheral blood mononuclear cell, relapse, tumour necrosis factor alpha|
|Research Division:||Medical and Health Sciences|
|Research Field:||Central Nervous System|
|Objective Group:||Clinical Health (Organs, Diseases and Abnormal Conditions)|
|Objective Field:||Nervous System and Disorders|
|Author:||Zhou, Y (Mr Yuan Zhou)|
|Author:||Taylor, B (Professor Bruce Taylor)|
|Author:||van der Mei, I (Associate Professor Ingrid van der Mei)|
|Author:||Stewart, N (Dr Niall Stewart)|
|Author:||Charlesworth, J (Dr Jac Charlesworth)|
|Author:||Blizzard, L (Professor Leigh Blizzard)|
|Author:||Pittas, F (Dr Fotini Pittas)|
|Author:||Simpson Jr, S (Dr Steve Simpson JR)|
|Deposited By:||Menzies Institute for Medical Research|
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