Davis Joshua S, Sun Maoyun, Kho Alvin T, Moore Kip G, Sylvia Jody M, Weiss Scott T, Lu Quan, Tantisira Kelan G
Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
Molecular and Integrative Physiological Sciences Program, Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America.
PLoS One. 2017 Jul 27;12(7):e0180329. doi: 10.1371/journal.pone.0180329. eCollection 2017.
Circulating microRNAs (miRNA) are promising biomarkers for human diseases. Our study hypothesizes that circulating miRNA would reveal candidate biomarkers related to airway hyperresponsiveness (AHR) and provide biologic insights into asthma epigenetic influences.
Serum samples obtained at randomization for 160 children in the Childhood Asthma Management Program were profiled using a TaqMan miRNA array set. The association of the isolated miRNA with methacholine PC20 was assessed. Network and pathway analyses were performed. Functional validation of two significant miRNAs was performed in human airway smooth muscle cells (HASMs).
Of 155 well-detected circulating miRNAs, eight were significantly associated with PC20 with the strongest association with miR-296-5p. Pathway analysis revealed miR-16-5p as a network hub, and involvement of multiple miRNAs interacting with genes in the FoxO and Hippo signaling pathways by KEGG analysis. Functional validation of two miRNA in HASM showed effects on cell growth and diameter.
Reduced circulatory miRNA expression at baseline is associated with an increase in PC20. These miRNA provide biologic insights into, and may serve as biomarkers of, asthma severity. miR-16-5p and -30d-5p regulate airway smooth muscle phenotypes critically involved in asthma pathogenesis, supporting a mechanistic link to these findings. Functional ASM phenotypes may be directly relevant to AHR.
循环微小RNA（miRNA）有望成为人类疾病的生物标志物。我们的研究假设，循环miRNA将揭示与气道高反应性（AHR）相关的候选生物标志物，并为哮喘的表观遗传影响提供生物学见解。
使用TaqMan miRNA阵列对儿童哮喘管理项目中160名儿童随机分组时采集的血清样本进行分析。评估分离出的miRNA与乙酰甲胆碱PC20的相关性。进行网络和通路分析。在人气道平滑肌细胞（HASMs）中对两种重要的miRNA进行功能验证。
在155种检测良好的循环miRNA中，有8种与PC20显著相关，其中与miR-296-5p的相关性最强。通路分析显示miR-16-5p是一个网络枢纽，通过KEGG分析发现多个miRNA与FoxO和Hippo信号通路中的基因相互作用。在HASM中对两种miRNA的功能验证显示其对细胞生长和直径有影响。
基线时循环miRNA表达降低与PC20升高有关。这些miRNA为哮喘严重程度提供了生物学见解，并可能作为其生物标志物。miR-16-5p和-30d-5p对哮喘发病机制中至关重要的气道平滑肌表型进行调控，支持了这些发现的机制联系。功能性ASM表型可能与AHR直接相关。
