Cerebral Artery Overexpression of the NMUR1 Gene Is Associated with Moyamoya Disease: A Weighted Gene Co-Expression Network Analysis

Abstract

<b><i>Introduction:</i></b> This study aimed to elucidate mechanisms underlying moyamoya disease (MMD) pathogenesis and to identify potential novel biomarkers. We utilized gene co-expression networks to identify hub genes associated with the disease. <b><i>Methods:</i></b> Twenty-one middle cerebral artery (MCA) samples from MMD patients and 11 MCA control samples were obtained from the Gene Expression Omnibus (GEO) dataset, GSE189993. To discover functional pathways and potential biomarkers, weighted gene co-expression network analysis (WGCNA) was employed. The hub genes identified were re-assessed through differential gene expression analysis (DGEA) via DESeq2 for further reliability verification. Additional 4 samples from the superficial temporal arteries (STAs) from MMD patients were obtained from GSE141025, and a subgroup analysis stratified by arterial type (MCA vs. STA) DGEA was performed to assess if the hub genes associated with MMD are expressed significantly greater on the affected arteries compared to healthy ones in MMD. <b><i>Results:</i></b> WGCNA revealed a predominant module encompassing 139 hub genes, predominantly associated with the neuroactive ligand-receptor interaction (NLRI) pathway. Of those, 17 genes were validated as significantly differentially expressed. Neuromedin U receptor 1 (NMUR1) and thyrotropin-releasing hormone were 2 out of the 17 hub genes involved in the NLRI pathway (log fold change [logFC]: 1.150, <i>p</i> = 0.00028; logFC: 1.146, <i>p</i> = 0.00115, respectively). MMD-only subgroup analysis stratified by location showed that NMUR1 is significantly overexpressed in the MCA compared to the STA (logFC: 1.962; <i>p</i> = 0.00053) which further suggests its possible localized involvement in the progressive stenosis seen in the cerebral arteries in MMD. <b><i>Conclusion:</i></b> This is the first study to have performed WGCNA on samples directly affected by MMD. NMUR1 expression is well known to induce localized arterial smooth muscle constriction and, recently, type 2 inflammation which can predispose to arterial stenosis potentially advancing the symptoms and progression of MMD. Further validation and functional studies are necessary to understand the precise role of NMUR1 upregulation in MMD and its potential implications.