Research Article: Circulating microRNAs and association with methacholine PC20 in the Childhood Asthma Management Program (CAMP) cohort

Date Published: July 27, 2017

Publisher: Public Library of Science

Author(s): Joshua S. Davis, Maoyun Sun, Alvin T. Kho, Kip G. Moore, Jody M. Sylvia, Scott T. Weiss, Quan Lu, Kelan G. Tantisira, Christophe Leroyer.

http://doi.org/10.1371/journal.pone.0180329

Abstract

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.

Partial Text

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]. The economic costs for asthma including drug therapy and hospitalizations is significant [3]. It remains challenging to generate risk assessment, predict prognosis, and determine optimal treatment response in asthmatics.

CAMP (Clinicaltrials.gov register: NCT00000575) was a multi-center, randomized, double-blinded clinical trial evaluating safety and efficacy of inhaled budesonide vs. nedocromil vs. placebo in 1041 pediatric patients over a mean 4.3 years. Trial design and methodology have been detailed [18]. Inclusion criteria were notable for children aged 5–12 years, chronic asthma symptoms, and PC20 < 12.5 mg/mL. Children were excluded if their asthma was severe, for a confounding or complicating condition, or if the child could not perform acceptable spirometry or methacholine challenge. Methacholine challenge was performed 2 weeks prior to randomization [16]. In this study, we examined serum samples from 160 CAMP asthmatics and found 8 miRNA significantly associated with PC20, a defining measure of airways hyperresponsiveness. Based on prior literature, five of the eight miRNA (63%) had evidence of differential expression related to human asthma, but not PC20, with a good portion of these in case-control studies of human bronchial epithelial cells. Three novel miRNAs were identified, including our strongest association, miR-296-5p. Pathway analysis of the miRNA targets implicates effects of both the Hippo and FoxO signaling pathways with both pathways implicated in airways hyperresponsiveness [30, 31]. Lastly, functional validation demonstrated that miR-16-5p resulted in decreased airway smooth muscle cell growth and miR-30d-5p increased airway smooth muscle cell size compared to scramble controls.   Source: http://doi.org/10.1371/journal.pone.0180329

 

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