Department of Clinical Neurosciences and Hotchkiss Brain Institute, University of Calgary, Calgary, AB.
Department of Community Health Sciences, University of Calgary, Calgary, AB.
Eur J Neurol. 2018 Apr;25(4):651-658. doi: 10.1111/ene.13565. Epub 2018 Feb 13.
Genetic research in multiple sclerosis (MS) mostly compares patients with MS with healthy controls, but does not differentiate between MS disease courses. We compared peripheral blood gene expression patterns between extremes of MS phenotypes, i.e. patients with mild relapsing-remitting MS (mRRMS) and primary progressive MS (PPMS).
We analyzed global gene expression profiles of peripheral blood samples of age- and gender-matched patients with mRRMS and PPMS. Detailed bioinformatic and gene set enrichment analysis, pathway and principle component analyses were used to identify differentially expressed genes and pathways.
A total of 84 genes were significantly deregulated between the groups. Of those, 19 had been previously reported to be deregulated in patients with MS as compared with healthy controls, including major histocompatibility complex, interferon receptor 2 and interleukin 6 receptor. Detailed molecular pathway analysis revealed significant up-regulation of antigen processing and presentation, leukocyte transendothelial migration, nucleotide-binding oligomerization domain-like receptor signaling, chemokine signaling and down-regulation of RNA transport, spliceosome and aminoacyl-tRNA biosynthesis pathways in PPMS compared with mRRMS.
Our analyses show significant differences between mRRMS and PPMS gene expression. Surprisingly, the differentially expressed genes were mostly involved in immunological and inflammatory pathways, suggesting that the difference in MS phenotypes is caused primarily by a difference in immune responses. It should be kept in mind that our analyses were in peripheral blood only, and that the observed differences in inflammatory pathways may be a substrate of the analysed tissue. Further research into gene expression differences between disease courses including analyses in central nervous system tissue is warranted.
多发性硬化症（MS）的遗传研究大多将 MS 患者与健康对照进行比较，但并未区分 MS 疾病病程。我们比较了 MS 表型两端（即轻度复发缓解型 MS（mRRMS）和原发性进展型 MS（PPMS））患者外周血的基因表达模式。
我们分析了年龄和性别匹配的 mRRMS 和 PPMS 患者外周血样本的全基因组表达谱。采用详细的生物信息学和基因集富集分析、通路和主成分分析，鉴定差异表达基因和通路。
两组间共有 84 个基因显著失调。其中，19 个基因已被报道在 MS 患者与健康对照之间失调，包括主要组织相容性复合体、干扰素受体 2 和白细胞介素 6 受体。详细的分子通路分析显示，PPMS 中抗原加工和呈递、白细胞跨内皮迁移、核苷酸结合寡聚化结构域样受体信号、趋化因子信号通路显著上调，而 mRRMS 中 RNA 转运、剪接体和氨酰-tRNA 生物合成通路显著下调。
我们的分析显示 mRRMS 和 PPMS 之间的基因表达存在显著差异。令人惊讶的是，差异表达的基因主要涉及免疫和炎症通路，这表明 MS 表型的差异主要是由免疫反应的差异引起的。需要注意的是，我们的分析仅在外周血中进行，观察到的炎症通路差异可能是分析组织的基础。需要进一步研究包括中枢神经系统组织在内的疾病病程之间的基因表达差异。
