Gene dysregulation in peripheral blood of moyamoya disease and comparison with other vascular disorders

Objective Moyamoya disease (MMD) is a chronic occlusive cerebrovascular disease with unknown etiology, sharing many similar clinical symptoms with other vascular disorders. This study aimed to investigate gene dysregulation in peripheral blood of MMD and compare it with other vascular disorders. Methods Transcriptomic profiles of 12 MMD patients and 8 healthy controls were obtained using RNA sequencing. Differentially expressed genes (DEGs) were identified and several were validated by quantitative real-time PCR in independent samples. Biological pathway enrichment analysis of DEGs and deconvolution of leukocyte subsets in peripheral blood were performed. Expression profiles for other vascular diseases were downloaded from public database and consistent DEGs were calculated. Gene set enrichment analysis (GSEA) was conducted to compare gene dysregulation pattern between MMD and other vascular diseases. Results A total of 533 DEGs were identified for MMD. Up-regulated genes were mainly involved in extracellular matrix (ECM) organization, whereas down-regulated genes were primarily associated with inflammatory and immune responses. As for cell populations, significantly increased naïve B cells and naïve CD4 cells as well as obviously decreased resting natural killer cells were observed in peripheral blood of MMD patients. GSEA analysis indicated that only up-regulated genes of ischemic stroke and down-regulated genes of coronary artery disease and myocardial infarction were enriched in up-regulated and down-regulated genes of MMD, respectively. Conclusion Dysregulated genes in peripheral blood of MMD mainly played key roles in ECM organization, inflammatory and immune responses. This gene dysregulation pattern was specific compared with other vascular diseases. Besides, naïve B cells, naïve CD4 cells and resting natural killer cells were aberrantly disrupted in peripheral blood of MMD patients. These results will help elucidate the complicated pathogenic mechanism of MMD.研究背景与目的 烟雾病（Moyamoya disease, MMD）是一种病因不明的慢性闭塞性脑血管疾病，其临床症状与多种其他血管性疾病存在诸多相似之处。本研究旨在探究烟雾病患者外周血中的基因表达失调情况，并将其与其他血管性疾病进行对比分析。 研究方法 本研究通过RNA测序获取了12例烟雾病患者与8例健康对照者的转录组图谱。筛选得到差异表达基因（differentially expressed genes, DEGs），并在独立样本中通过实时定量聚合酶链式反应（quantitative real-time PCR, qRT-PCR）对部分差异基因进行了验证。此外，本研究对差异表达基因开展了生物学通路富集分析，并对外周血白细胞亚群进行了反卷积分析。从公共数据库下载其他血管性疾病的表达谱数据，计算得到共有的差异表达基因。通过基因集富集分析（gene set enrichment analysis, GSEA）对比烟雾病与其他血管性疾病的基因表达失调模式。 研究结果 本研究共筛选得到533个烟雾病相关差异表达基因。其中上调基因主要参与细胞外基质（extracellular matrix, ECM）组织过程，而下调基因则主要与炎症及免疫应答相关。在细胞群体层面，烟雾病患者外周血中初始B细胞、初始CD4阳性T细胞比例显著升高，而静息自然杀伤细胞比例明显降低。基因集富集分析结果显示，缺血性卒中的上调基因集、冠状动脉疾病与心肌梗死的下调基因集分别显著富集于烟雾病的上调与下调基因集中。 研究结论 烟雾病患者外周血中的失调基因主要在细胞外基质组织、炎症与免疫应答过程中发挥关键作用。与其他血管性疾病相比，该基因表达失调模式具有特异性。此外，烟雾病患者外周血中的初始B细胞、初始CD4阳性T细胞与静息自然杀伤细胞比例存在异常改变。本研究结果有助于进一步阐明烟雾病复杂的发病机制。