Zhou Zhenyu, Niu Hongchuan, Xu Shaoqi, Zhang Junze, Liu Yutong, Lei Chengxu, He Shihao, Zhao Yuanli
Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China.
Department of Neurosurgery, Peking University International Hospital, Beijing, China.
Orphanet J Rare Dis. 2025 Jul 28;20(1):385. doi: 10.1186/s13023-025-03945-4.
Moyamoya disease (MMD) is a chronic, progressive occlusive cerebrovascular disease. It causes recurrent cerebrovascular stroke due to vascular closure and proliferation. An unclear pathophysiological mechanism is the most significant obstacle in the diagnosis and treatment of MMD.
This study prospectively included 10 MMD and 3 HC (healthy controls) participants in the discovery cohort. GSE189993 and GSE157628 were downloaded from the Gene Expression Omnibus (GEO) as validation cohorts, which included 32 patients with MMD and 20 HC. Angiogenesis-related genes were downloaded from GENECARD. Hub genes were selected by differential analysis and weighted correlation network analysis. Functional enrichment, immune infiltration, and metabolic pathway analyses and drug prediction mapping (Connectivity Map [CMap]) were performed.
Through differential analysis identified, 198 differentially expressed genes (DEGs), including 85 upregulated genes and 113 downregulated genes. In total, 238 angiogenesis -related genes were identified using WGCNA. Four hub genes were identified: TBC1 domain family member 9B (TBC1D9B), Phosphatidylinositol transfer protein beta (PITPNB), The ANK repeat and PH domain-containing protein 3 (ARAP3), and Ubiquitin-conjugating enzyme E2 E1 (UBE2E1). Four potential drugs were selected: calyculin A, H-9, parbendazole, and velnacrine. The results of multiple immune infiltration analyses collectively depicted the immune microenvironment characteristics of MMD.
This study is the first to explore the mechanism by which angiogenesis related genes are involved in intimal hyperplasia in Moyamoya disease. TBC1D9B and ARAP3 may promote the pathological development of moyamoya disease through immune response, metabolism.
烟雾病（MMD）是一种慢性、进行性闭塞性脑血管疾病。它由于血管闭塞和增生导致复发性脑血管中风。尚不明确的病理生理机制是烟雾病诊断和治疗中最主要的障碍。
本研究前瞻性纳入了发现队列中的10名烟雾病患者和3名健康对照（HC）参与者。从基因表达综合数据库（GEO）下载GSE189993和GSE157628作为验证队列，其中包括32例烟雾病患者和20名健康对照。从GENECARD下载血管生成相关基因。通过差异分析和加权相关网络分析选择枢纽基因。进行功能富集、免疫浸润和代谢途径分析以及药物预测映射（连通性图谱[CMap]）。
通过差异分析鉴定出198个差异表达基因（DEG），包括85个上调基因和113个下调基因。使用加权基因共表达网络分析（WGCNA）总共鉴定出238个血管生成相关基因。鉴定出四个枢纽基因：TBC1结构域家族成员9B（TBC1D9B）、磷脂酰肌醇转移蛋白β（PITPNB）、含ANK重复序列和PH结构域蛋白3（ARAP3）以及泛素结合酶E2 E1（UBE2E1）。选择了四种潜在药物：花萼海绵诱癌素A、H - 9、帕苯达唑和维脑路通。多次免疫浸润分析的结果共同描绘了烟雾病的免疫微环境特征。
本研究首次探索血管生成相关基因参与烟雾病内膜增生的机制。TBC1D9B和ARAP3可能通过免疫反应、代谢促进烟雾病的病理发展。
