Li Niannian, Gao Zhenfei, Shen Jinhong, Liu Yuenan, Wu Kejia, Yang Jundong, Wang Shengming, Zhang Xiaoman, Zhu Yaxin, Zhu Jingyu, Guan Jian, Liu Feng, Yin Shankai
Department of Otolaryngology Head and Neck Surgery & Center of Sleep Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai, China.
Front Genet. 2022 Apr 26;13:862972. doi: 10.3389/fgene.2022.862972. eCollection 2022.
Obstructive sleep apnea (OSA) is the most common type of sleep apnea that impacts the development or progression of many other disorders. Abnormal expression of N6-methyladenosine (m6A) RNA modification regulators have been found relating to a variety of human diseases. However, it is not yet known if m6A regulators are involved in the occurrence and development of OSA. Herein, we aim to explore the impact of m6A modification in severe OSA. We detected the differentially expressed m6A regulators in severe OSA microarray dataset GSE135917. The least absolute shrinkage and selection operator (LASSO) and support vector machines (SVM) were used to identify the severe OSA-related m6A regulators. Receiver operating characteristic (ROC) curves were performed to screen and verify the diagnostic markers. Consensus clustering algorithm was used to identify m6A patterns. And then, we explored the character of immune microenvironment, molecular functionals, protein-protein interaction networks and miRNA-TF coregulatory networks for each subcluster. Finally, the Connectivity Map (CMap) tools were used to tailor customized treatment strategies for different severe OSA subclusters. An independent dataset GSE38792 was used for validation. We found that HNRNPA2B1, KIAA1429, ALKBH5, YTHDF2, FMR1, IGF2BP1 and IGF2BP3 were dysregulated in severe OSA patients. Among them, IGF2BP3 has a high diagnostic value in both independent datasets. Furthermore, severe OSA patients can be accurately classified into three m6A patterns (subcluster1, subcluster2, subcluster3). The immune response in subcluster3 was more active because it has high M0 Macrophages and M2 Macrophages infiltration and up-regulated human leukocyte antigens (HLAs) expression. Functional analysis showed that representative genes for each subcluster in severe OSA were assigned to histone methyltransferase, ATP synthesis coupled electron transport, virus replication, RNA catabolic, multiple neurodegeneration diseases pathway, et al. Moreover, our finding demonstrated cyclooxygenase inhibitors, several of adrenergic receptor antagonists and histamine receptor antagonists might have a therapeutic effect on severe OSA. Our study presents an overview of the expression pattern and crucial role of m6A regulators in severe OSA, which may provide critical insights for future research and help guide appropriate prevention and treatment options.
阻塞性睡眠呼吸暂停（OSA）是最常见的睡眠呼吸暂停类型，会影响许多其他疾病的发生或发展。已发现N6-甲基腺苷（m6A）RNA修饰调节因子的异常表达与多种人类疾病有关。然而，尚不清楚m6A调节因子是否参与OSA的发生和发展。在此，我们旨在探讨m6A修饰在重度OSA中的作用。我们在重度OSA微阵列数据集GSE135917中检测了差异表达的m6A调节因子。使用最小绝对收缩和选择算子（LASSO）和支持向量机（SVM）来识别与重度OSA相关的m6A调节因子。绘制受试者工作特征（ROC）曲线以筛选和验证诊断标志物。使用共识聚类算法识别m6A模式。然后，我们探讨了每个亚群的免疫微环境特征、分子功能、蛋白质-蛋白质相互作用网络和miRNA-TF共调节网络。最后，使用连通性图谱（CMap）工具为不同的重度OSA亚群定制治疗策略。使用独立数据集GSE38792进行验证。我们发现重度OSA患者中HNRNPA2B1、KIAA1429、ALKBH5、YTHDF2、FMR1、IGF2BP1和IGF2BP3表达失调。其中，IGF2BP3在两个独立数据集中均具有较高的诊断价值。此外，重度OSA患者可准确分为三种m6A模式（亚群1、亚群2、亚群3）。亚群3中的免疫反应更为活跃，因为它有高M0巨噬细胞和M2巨噬细胞浸润以及上调的人类白细胞抗原（HLA）表达。功能分析表明，重度OSA中每个亚群的代表性基因被归类为组蛋白甲基转移酶、ATP合成偶联电子传递、病毒复制、RNA分解代谢、多种神经退行性疾病途径等。此外，我们的研究表明环氧合酶抑制剂、几种肾上腺素能受体拮抗剂和组胺受体拮抗剂可能对重度OSA有治疗作用。我们的研究概述了m6A调节因子在重度OSA中的表达模式和关键作用，这可能为未来的研究提供重要见解，并有助于指导适当的预防和治疗方案。
