Abstract
Altered microRNA expression patterns in bronchial brushings from people with versus without cystic fibrosis (CF) relate to functional changes and disease pathophysiology. The expression of microRNAs encoded on the X chromosome is also altered in peripheral blood monocytes of p. Phe508del homozygous versus non-CF individuals. Here we investigate whether levels of the top seven X-linked microRNAs (miR-224-5p, miR-452-5p, miR-450b-5p, miR-542-3p, miR-450a-5p, miR-424-5p, and miR-545-5p) that are significantly increased over 1.5 fold in CF versus non-CF monocytes correlate with lung function. CD14+ monocytes were isolated from males and females with (n = 12) and without cystic fibrosis (n = 12) and examined for the expression of X-linked microRNAs by qRT-PCR array. MicroRNA target mRNA levels were quantified using qRT-PCR. Clinical correlations with lung function data were analysed in the CF cohort. Increasing levels of miR-545-5p correlated moderately with FEV1% predicted (r = -0.4553, p > 0.05) and strongly with exacerbation rate (r = 0.5858, p = 0.0483). miR-224-5p levels were significantly higher in the severe (FEV1 <40%) versus mild (FEV1 ≥80%, p = 0.0377) or moderate (FEV1 40–79%, p = 0.0350) groups. MiR-224-5p expression inversely correlated with lung function (FEV1%: r = -0.5944, p = 0.0457) and positively correlated with exacerbation rates (r = 0.6139, p = 0.0370). These data show that peripheral blood monocyte miR-545-5p and miR-224-5p levels correlate with exacerbation rate, whilst miR-224-5p levels also correlate with lung function in cystic fibrosis.
Highlights
Cystic Fibrosis (CF) is an autosomal recessive disease caused by mutations in the gene encoding cystic fibrosis transmembrane conductance regulator (CFTR), a chloride ion channel
It is known that altered miRNA expression in CF bronchial brushings relates to functional changes that can contribute to CF lung disease pathophysiology
Prior to the present study, it was unknown whether expression levels of miRNA encoded on the X chromosome are associated with CF lung disease
Summary
Cystic Fibrosis (CF) is an autosomal recessive disease caused by mutations in the gene encoding cystic fibrosis transmembrane conductance regulator (CFTR), a chloride ion channel. The most prevalent CFTR mutation is p. Phe508del, which results in protein misfolding, retention in the endoplasmic reticulum, and reduced functional CFTR at the cell surface. In addition to the primary CFTR defect there are other important factors that can contribute to CF lung disease pathology including, for example, intrapulmonary proteases, mucus hypersecretion and microRNA (miRNA) expression in bronchial epithelium (Cantin et al, 1989; Voynow et al, 1998; Voynow et al, 1999; Oglesby et al, 2010), amongst others. Altered miRNA expression profiles are evident in people with CF and in vitro CF cell models (De Santi et al, 2020) and have been reviewed elsewhere (Glasgow et al, 2018)
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