Gaberino Courtney L, Segnitz R Max, Dill-McFarland Kimberly A, Bacharier Leonard B, Calatroni Agustin, Gill Michelle A, Stokes Jeffrey, Liu Andrew H, Cohen Robyn T, Kumar Rajesh, Lang Abigail, Khurana Hershey Gurjit K, Sherenian Michael G, Zoratti Edward M, Teach Stephen J, Kattan Meyer, Becker Patrice M, Togias Alkis, Busse William W, Jackson Daniel J, Altman Matthew C
Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Department of Medicine, University of Washington, Seattle, WA, USA.
Nat Commun. 2025 Sep 2;16(1):8191. doi: 10.1038/s41467-025-63629-2.
Mepolizumab (anti-IL5 therapy) reduces asthma exacerbations in urban children with exacerbation-prone eosinophilic asthma. We previously utilized nasal transcriptomics to identify inflammatory pathways (gene co-expression modules) associated with asthma exacerbations despite this therapy. In this study, we applied differential gene correlation analysis on these targeted gene co-expression modules to gain better insight into the treatment effects on correlation structure within gene networks. Mepolizumab treatment resulted in loss of correlation amongst eosinophil-specific genes but conservation and even strengthening of correlation amongst mast cell-specific genes, T2 cytokines, and airway epithelial inflammatory genes. Notably, mepolizumab induced significant gain in correlation of genes associated with multiple aspects of airway epithelial inflammation including those related to extracellular matrix production and nitric oxide synthesis, and this change was associated with a poor clinical response to mepolizumab. These findings highlight that using differential gene correlation analysis offers insight into the molecular regulatory effects of treatment on gene interactions and may lead to better understanding of disease mechanisms and therapeutic responses. ClinicalTrials.gov ID: NCT03292588.
美泊利珠单抗（抗白细胞介素-5疗法）可减少城市中易发作的嗜酸性粒细胞性哮喘儿童的哮喘发作。尽管采用了这种疗法，我们之前利用鼻腔转录组学来识别与哮喘发作相关的炎症途径（基因共表达模块）。在本研究中，我们对这些靶向基因共表达模块应用差异基因相关性分析，以更好地了解治疗对基因网络内相关性结构的影响。美泊利珠单抗治疗导致嗜酸性粒细胞特异性基因之间的相关性丧失，但肥大细胞特异性基因、2型细胞因子和气道上皮炎症基因之间的相关性得以保留甚至增强。值得注意的是，美泊利珠单抗使与气道上皮炎症多个方面相关的基因之间的相关性显著增加，包括与细胞外基质产生和一氧化氮合成相关的基因，并且这种变化与对美泊利珠单抗的临床反应不佳有关。这些发现突出表明，使用差异基因相关性分析可深入了解治疗对基因相互作用的分子调节作用，并可能有助于更好地理解疾病机制和治疗反应。临床试验注册号：NCT03292588。
