Identification of inter-individual and gene-specific variances in mRNA expression profiles in the RA SM

Background. Rheumatoid arthritis (RA) is a chronic inflammatory and destructive joint disease, characterized by overexpression of pro-inflammatory/-destructive genes and other activating genes (e.g., proto-oncogenes) in the synovial membrane (SM). The gene expression in disease is often characterized by significant inter-individual variances via specific synchronization/ desynchronization of gene expression. To elucidate the contribution of the variance to the pathogenesis of disease, expression variances were tested in SM samples of RA patients, osteoarthritis (OA) patients, and normal controls (NC). Results. For the comparison between RA and NC, 568 genes with significantly different variances in the 2 groups (p < 0.05; Bonferroni/Holm corrected Brown-Forsythe version of the Levene-Test) were selected. For the comparison between RA and OA, 333 genes were selected. Using the Kyoto encyclopedia of genes and genomes (KEGG), 10 pathways/complexes significantly affected by higher gene expression variances were identified in RA compared to NC, including cytokine – cytokine receptor interactions, the TGF-pathway, and anti-apoptosis. Compared to OA, 3 pathways with significantly higher variances were identified in RA (e.g., B cell receptor signaling, VEGF signaling). Functionally, the majority of the identified pathways is involved in the regulation of inflammation, proliferation, cell survival, and angiogenesis. Conclusion. In RA, a number of disease-relevant or even disease-specific pathways/complexes are characterized by broad intra-group, inter-individual expression variances. This indicates that RA pathogenesis in different individuals may depend to a lesser extent on common alterations of the expression of specific key genes, but on individual-specific alterations of different genes resulting in common disturbances of key pathways. Expression variances were tested in synovial membrane samples of rheumatoid arthritis patients, osteoarthritis patients, and normal controls (see publication for further details).

背景：类风湿关节炎（Rheumatoid arthritis, RA）是一种慢性炎症性破坏性关节疾病，其特征为滑膜（synovial membrane, SM）内促炎/破坏基因及其他激活基因（如原癌基因（proto-oncogenes））过表达。该疾病的基因表达通常呈现显著的个体间异质性，该异质性源于基因表达的特异性同步化与去同步化调控。为阐明该表达异质性在疾病发病机制中的作用，本研究对RA患者、骨关节炎（osteoarthritis, OA）患者及正常对照（normal controls, NC）的滑膜样本进行了基因表达异质性检测。
结果：在RA与正常对照的比较中，筛选出两组间表达异质性存在显著差异的基因共568个（p < 0.05；经Bonferroni/Holm校正的Levene检验Brown-Forsythe修正版本）。在RA与OA的比较中，共筛选出333个差异表达异质性基因。借助京都基因与基因组百科全书（Kyoto Encyclopedia of Genes and Genomes, KEGG）数据库，本研究在RA与正常对照的比较中，鉴定出10个受基因表达异质性显著上调影响的通路/复合体，包括细胞因子-细胞因子受体相互作用、转化生长因子（TGF）通路及抗凋亡通路。相较于OA，本研究在RA中鉴定出3个表达异质性显著升高的通路（如B细胞受体信号通路（B cell receptor signaling）、血管内皮生长因子（VEGF）信号通路）。功能富集分析显示，大部分鉴定得到的通路均参与炎症调控、细胞增殖、细胞存活及血管生成过程。
结论：在RA中，诸多疾病相关甚至疾病特异性的通路/复合体均表现出显著的组内个体间基因表达异质性。这提示，不同个体的RA发病机制，较少依赖于特定关键基因表达的共性异常，而更多由不同个体的特异性基因表达改变所介导，最终引发关键通路的共性紊乱。本研究对类风湿关节炎患者、骨关节炎患者及正常对照的滑膜样本进行了基因表达异质性检测（详细信息请参见已发表文献）。