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pediatric asthma. miR-21 was previously described as increased in allergic airway models in mice [47,67] ,
[68]
thus Sawant et al. set out to determine if this was also true in asthmatic children. Using serum samples,
they found that miR-21 was specifically increased in children with asthma and that this increase was not
correlated to IgE levels, indicating that miR-21 may be usable as a biomarker for asthma independent of
atopic status. Other recent studies have also shown the potential of miR-21 as a biomarker in pediatric
[69]
[69]
asthma, but this time in plasma . Hammad et al. explored the potential of two suggested asthma
biomarker miRNAs and whether they played a role in predicting asthma outcome following treatment
with inhaled corticosteroids (ICS). They found that both miR-21 and miR-146a were upregulated in plasma
from asthmatic children and showed a correlation to forced expiratory volume in 1 second following ICS
treatment, suggesting that they may play a role in determining the outcome of asthma after treatment.
As mentioned above, miR-21 was also found to be associated with very young children with recurrent
[66]
[70]
wheeze . As pulmonary function tests are difficult to perform in young children , it would be interesting
to see if high miR-21 and -146a levels can be used as a predictor of future lung function.
[71]
Although most studies in pediatric asthma use a general “allergic” definition for their subjects, Dong et al.
focused specifically on dust-mite induced mild asthmatic children. The group isolated total RNA from
peripheral blood of 124 age- and gender-matched asthmatic and non-asthmatic children and performed a
microarray-based analysis to determine altered expression levels. They went on to identify 122 differentially
expressed miRNAs and found three downregulated miRNAs, miR-22-3p, -513a-5p, -625-5p, to be not only
statistically significant, but functionally linked to inflammation by web-based bioinformatics analysis.
Through a series of filtering processes, CBL, PPARGC1B and ESR1 were identified targets of the three
aforementioned miRNAs. Furthermore, the predicted target genes were differentially expressed in their
asthmatic group and were associated with PI3K and nuclear factor κB (NF-κB) signaling pathways as well
as T and B cell differentiation and inflammatory factor signaling using Kyoto Encyclopedia of Genes and
Genomes and Gene Ontology analysis. Additionally, they showed a correlation between these three miRNAs
and their predicted mRNA targets, as well as a suggestion for how they regulate their predicted signaling
pathways, thus, putting forth potentially important mechanistic roles for these miRNAs in pediatric asthma.
[72]
Again, apart from studying pediatric asthma as mainly an allergic disease, Midyat et al. explored the
relationship between miRNA expression and the severity of childhood asthma. Using a relatively wide
age range (6-18 years), approximately 100 asthmatic children, half exhibiting intermittent asthma and half
exhibiting severe asthma, were examined in comparison to age-matched controls. miRNA expression from
blood lymphocytes were examined by microarray and ten miRNAs were found to significantly increase their
expression as asthma severity increased. miRNAs let-7e, miR-98 and miR-497 were found to be significantly
increased in the intermittent asthma group compared to controls, but not severe asthma. As mentioned
[40]
above, the let-7e/miR-98 family has been suggested to target the IL13 gene . Together, these findings further
drive home the complexity of the asthmatic phenotype, with differing asthma severity exhibiting alterations
[73]
to miRNA repertoire. Finally, Nakano et al. took an alternative approach to identifying potential miRNA
biomarkers. They focused on the mRNA vascular endothelial growth factor A (VEGFA), which was
identified as a key molecule in asthma pathogenesis and had previously been shown to be overexpressed in
the serum and sputum of asthmatic subjects of all ages [74-76] . Through in silico analysis, the group selected
12 miRNAs predicted to bind the 3’ UTR of VEGFA and examined their expression in CD4+ T cells, which
are a major serum source of VEGFA, from pediatric subjects. They found that three miRNAs, miR-15a, -15b,
and -20a, exhibited lower expression when VEGFA levels were increased, but only miR-15a and VEGFA were
significantly correlated. Finally, they showed through luciferase reporter assays that the binding of miR-15a
led to decreased expression of VEGFA, thus reporting one of the first instances of miRNA-target binding in
pediatric asthma patients.

Recently, several studies from the Tantisira group, using the Childhood Asthma Management Program
(CAMP) cohort of asthmatic children, have shown the potential for not only array screening for miRNAs
as biomarkers, but the potential downstream applications and analysis needed to move the asthma field