Ivacaftor results in a sustained increase in FeNO in children and adults with CF. The increase in FeNO may be related to changes in airway NO metabolism by myeloperoxidase. Lumacaftor–ivacaftor therapy does not have an immediate effect on FeNO.http://bit.ly/2mzqhds
1 Abstract Background While cystic fibrosis is caused by loss-of-function variants in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) , other modifier genes have been shown to associate with disease severity. Co-expression of modifiers with CFTR in normal tissue indicates a cooperative relationship and suggests the potential for compensation in the presence of CFTR dysfunction. We examined the co-expression relationships with CFTR in the lung using single cell RNA sequencing to pinpoint cell types and their modifiers involved in the forced expiratory volume in 1 second (FEV1)-based cystic fibrosis lung phenotype and support target cell-type prioritization for therapy 1 . Methods SmartSeq2 single cell RNA sequencing data from non-cystic fibrosis lung tissue was used for evaluation of co-expression with CFTR and modifier genes. Zero-inflated negative binomial model was used to formally test the co-expression association. 10X Chromium based single cell RNA sequencing data from both cystic fibrosis and non-cystic fibrosis studies were assessed graphically to confirm conclusions from the SmartSeq2 primary analysis. Results Differentiating basal, club and alveolar epithelial type 2 cells were found to have high proportions of cells expressing CFTR as well as the greatest number of significant co-expression relationships with the modifiers. In particular, among alveolar epithelial type 2 cells, we observed a strong co-expression trio relationship between CFTR, SLC6A14 and SLC26A9 (p < 0.05). Conclusions CFTR-modifier gene co-expression suggests basal, club and alveolar epithelial type 2 cells show coordinated expression. Alveolar epithelial type 2 cells showed strong co-expression evidence with two of the most established cystic fibrosis modifier genes.
Cystic fibrosis (CF) is the most common autosomal recessive disorder in Caucasians, affecting ∼1:2500 children, with a carrier frequency of 1:25. The causative gene, named CF transmembrane conductance regulator (CFTR), encodes a chloride channel in epithelial cells. Abnormal transport of chloride and sodium ions affects water movement across epithelia, leading to pathophysiological consequences in various organs including the respiratory, gastrointestinal and reproductive tract, the pancreas, and liver. The CF phenotype is rather heterogeneous due to many different mutations in CFTR and the influence of modifier genes. Chronic bacterial lung infections stimulate inflammatory defense mechanisms, leading to extensive tissue remodeling. The resulting emphysema and fibrosis mainly determine the reduced life expectancy in individuals with CF. Owing to improved symptomatic treatment strategies, including better nutrition and antibiotic therapy, the prognosis of CF individuals has considerably improved and many children now reach adult life. Research is focused on the development of pharmacological drugs correcting ion channel dysfunction, anti-inflammatory drugs and vaccines to prevent airway infections. The causative gene replacement therapy has not yet been successfully applied in CF patients.
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