Abstract
IntroductionCirculating 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.MethodsSerum 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).ResultsOf 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.ConclusionReduced 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.
Highlights
Circulating microRNAs are promising biomarkers for human diseases
Circulating miRNAs are highly stable in the serum [7]. miRNA plasma biomarkers have been proposed for neurological conditions [8], cancer detection/prognosis [9], cardiovascular disease [10], and other conditions including an emerging role in respiratory diseases [11]
Our study investigated the association of circulating miRNA with methacholine PC20 at time of randomization in the Childhood Asthma Management Program (CAMP) [16]
Summary
Circulating microRNAs (miRNA) are promising biomarkers for human diseases. Asthma is a chronic inflammatory respiratory disease that affects greater than 300 million people worldwide [1]. It is characterized by airway obstruction due to a combination of smooth muscle hyperresponsiveness and inflammation [2]. Circulating microRNAs (miRNAs) are promising biomarkers for human diseases [4] and may be helpful in a variety of clinical scenarios from risk assessment to monitoring response to treatment [5]. MiRNA plasma biomarkers have been proposed for neurological conditions [8], cancer detection/prognosis [9], cardiovascular disease [10], and other conditions including an emerging role in respiratory diseases [11]. Translational methods have been applied in order to generate screening tests [12]
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