Plasma microRNA levels in male and female children with cystic fibrosis

Abstract

A gender gap exists in cystic fibrosis (CF). Here we investigate whether plasma microRNA expression profiles differ between the sexes in CF children. MicroRNA expression was quantified in paediatric CF plasma (n = 12; six females; Age range:1-6; Median Age: 3; 9 p.Phe508del homo-or heterozygotes) using TaqMan OpenArray Human miRNA Panels. Principal component analysis indicated differences in male versus female miRNA profiles. The miRNA array analysis revealed two miRNAs which were significantly increased in the female samples (miR-885-5p; fold change (FC):5.07, adjusted p value: 0.026 and miR-193a-5p; FC:2.6, adjusted p value: 0.031), although only miR-885-5p was validated as increased in females using specific qPCR assay (p < 0.0001). Gene ontology analysis of miR-885-5p validated targets identified cell migration, motility and fibrosis as processes potentially affected, with RAC1-mediated signalling featuring significantly. There is a significant increase in miR-885-5p in plasma of females versus males with CF under six years of age. Cystic fibrosis (CF) is an autosomal recessive genetic disorder arising from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene 1. CFTR is a crucial chloride ion channel expressed by epithelial cells in the lung and other organs. The consequences of defective CFTR are most severely manifested in the lung, where the imbalanced ion homeostasis results in chronic airway inflammation, which leads to a progressive and ultimately fatal decline in lung function. Despite improved therapies and increased life expectancy for both males and females with CF in recent years, a gender dichotomy persists whereby females are at a clinical disadvantage e.g. poorer lung function, earlier colonisation by chronic mucoid Pseudomonas aeruginosa, greater frequency of exacerbations, and lower median survival age 2-7. Whether sex differences exist in children with CF remains controversial 8,9. The ability to measure and monitor lung disease in children via a non-invasive method would be highly beneficial for CF clinical care. Molecular biomarkers that are prognostic for lung disease progression could serve, in support of clinical examination, to allow earlier and hence more effective intervention strategies. Ideally these would be molecules that are stable in body fluids (e.g. plasma), able to be quantified with reliance and accuracy, and mechanistically linked to pulmonary infection and/or inflammation. MicroRNAs are small non-coding RNAs that bind specific target mRNA sequences to inhibit their expression. As well as being expressed within cells/tissues, miRNAs are also present extracellularly, and are readily detectable in body fluids such as serum and plasma. In contrast to mRNA, miRNAs circulating in plasma are surprisingly resistant to RNase degradation due to the fact they are found either packaged inside microvesicles e.g. exosomes, or associated with protein/lipid complexes e.g. argonaute 2 or high density lipoprotein 10. Although the role of circulating miRNAs is not...

Chronic inflammation and the growth hormone/insulin-like growth factor-1 axis

“…In light of the studies conducted in the last few years, it should also be emphasised that changes in the miRNAs seem to be additional factors linking chronic inflammation and growth retardation observed in childhood-onset chronic inflammatory diseases [1,8]. Numerous studies indicate that miRNAs, as post-transcriptional regulators of gene expression, could impact a number of proteins and cytokines, which are involved in the control of the GH/ IGF-1 axis [98][99][100][101][102]. The mechanisms of those associations, their biological role, and clinical utility requires further investigation.…”

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“…Women are affected by poorer lung function as well as lower median survival. To study this gender gap, circulating miRNAs were profiled in male and female pediatric CF plasma samples [ 99 ]. miR-885 was increased in samples from girls under six years.…”

“…Moreover, in silico analyses suggested that the severity of the disease in CF females could be related to a Ras-related C3 botulinum toxin substrate 1 (RAC1)-mediated process. However, functional experiments need to validate these theoretical predictions [ 99 ].…”

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“…A potential alternative non-CFTR therapeutic in CF are microRNAs. 140,141 MicroRNAs are small noncoding, 21 to 23 nucleotide RNAs capable of suppressing the expression of target genes. Numerous microRNAs are differentially expressed CF females compared to males.…”