Zhou Yuan, Taylor Bruce, van der Mei Ingrid, Stewart Niall, Charlesworth Jac, Blizzard Leigh, Ponsonby Anne-Louise, Dwyer Terence, Pittas Fotini, Simpson Steve
Menzies Institute for Medical Research, University of Tasmania, Australia.
School of Pharmacy, University of Tasmania, Australia; School of Medicine, University of Tasmania, Australia.
J Neurol Sci. 2015 Feb 15;349(1-2):40-4. doi: 10.1016/j.jns.2014.12.022. Epub 2014 Dec 19.
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.
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.
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.
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).
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.
与健康对照相比，多发性硬化症（MS）患者外周血单个核细胞（PBMC）细胞因子产生存在改变。我们之前发现，受刺激的PBMC产生的肿瘤坏死因子-α（TNF-α）和干扰素-γ（IFN-γ）可调节MS复发风险，即升高的TNF-α具有保护作用，而升高的IFN-γ会增加复发风险。
评估相关细胞因子及其受体基因内的单核苷酸多态性（SNP）是否调节TNF-α和IFN-γ与复发的关联，从而提供有关这些细胞因子作用以及这些基因在MS中的作用的更多信息。
对91例复发缓解型MS患者进行前瞻性队列研究，并收集细胞因子和基因型数据。选择每个细胞因子/细胞因子受体基因（共84个）周围10 kb窗口内的SNP（共361个）进行分析。通过多级混合效应线性回归评估PBMC细胞因子的预测因素。通过Cox比例风险回归评估复发的预测因素。采用Bonferroni校正进行多重检验校正；因此，p<1.39×10⁻⁴被定义为具有显著性。
rs3218295（位于IL2RB基因内）的GG基因型个体中，TNF-α对复发具有显著保护作用，而GA/AA基因型个体则显示出显著正相关（交互作用p=5.04×10⁻⁵）。rs522807（TNFRSF1B的3'区域）的CC基因型携带者以及rs25879（IL3的5'区域）的AA基因型携带者中，IFN-γ与复发风险增加之间存在强关联（交互作用p分别为8.21×10⁻⁵和1.70×10⁻⁵）。
我们的结果显示，主要细胞因子中的SNP对TNF-α和IFN-γ与复发的关联具有新的调节作用。这些发现提示这些基因和/或其产物作为MS潜在治疗靶点的可能性。
