Increased expression of ATP12A proton pump in cystic fibrosis airways

LocusFocus: A web-based colocalization tool for the annotation and functional follow-up of GWAS

“…Investigating colocalization of the GWAS p-values with HNE eQTLs for other genes at the locus indicates no significant eQTLs (ANKRD20A10P, ATP12A, RNF17), or a lack of expression in HNE (RNY1P7, RPL26P34, IRX1P1) (Figure 2a, c). Taken together, while biological studies suggest a role for ATP12A in the lung [17][18][19] and have advocated for ATP12A as an alternative CF therapeutic target [23], our studies in the CF population do not support that common variation in expression of this gene affects lung function outcomes.…”

“…Results support strong colocalization for ATP12A in the pancreas as reported [11]. Interestingly, ATP12A has been proposed as a modifier of lung disease severity via its role in pH regulation, which in turn may influence immune response to infections in the CF lung [17][18][19]. Our GWAS on lung disease severity in CF, however, revealed no association at this locus [20].…”

“…The web server computes the LD matrix with the 1000 Genomes on demand using PLINK v1.90b6.9 [15]. Lines shown on the plot represent a summary of GTEx (v7) and primary human nasal epithelial cells' (HNEs) eQTL p-values for ATP12A, a gene proposed as a modifier for CF [17][18][19] (with corresponding y-axis on the right), with each line representing a tissue (eQTLs for other genes within the region can be selected and the plot re-drawn within the same session). Line traces for some tissues do not appear due to no eQTL data for ATP12A for that tissue (likely due to little or no expression).…”

Niclosamide repurposed for the treatment of inflammatory airway disease

“…Along with Na + hyperabsorption and dehydration of the airway surface liquid (ASL; periciliary fluid layer) covering the airway epithelium, this will lead to an inflammatory airway disease (1,9). Although low ASL pH and airway mucus plugging are believed to cause chronic inflammation in CF, mucus hypersecretion in allergic asthma is due to proinflammatory CD4 + Th2-dependent IL-4/IL-13 signaling (10)(11)(12). Additional local hypoxia, neutrophilic infiltration, accumulation of reactive oxygen species, and bacterial superinfection cause destructive pulmonary inflammation.…”

Discovery of a picomolar potency pharmacological corrector of the mutant CFTR chloride channel

“…Differentiated CF bronchial epithelial cells under air-liquid interface condition were treated for 24 hours with vehicle alone (DMSO) or with ARN23765 (10 nM), 4172 (10 M), or with the combination of ARN23765 plus 4172. At the end of the treatment, cells were incubated (37°C, 5% CO 2 atmosphere) with 75 l of a modified PBS solution with low buffer capacity on the apical side (37). The modified PBS solution had the following composition: 145 mM NaCl, 2.7 mM KCl, 0.81 mM Na 2 HPO 4 , 0.15 mM KH 2 PO 4 , 1 mM CaCl 2 , 0.5 mM MgCl 2 , 100 M CPT-cAMP, and 1 M VX-770 (pH 7.35).…”