SLC6A14 Impacts Cystic Fibrosis Lung Disease Severity mTOR and Epithelial Repair Modulation.

Cystic fibrosis (CF), due to pathogenic variants in gene, is associated with chronic infection/inflammation responsible for airway epithelium alteration and lung function decline. Modifier genes induce phenotype variability between people with CF (pwCF) carrying the same variants. Among these, the gene encoding for the amino acid transporter SLC6A14 has been associated with lung disease severity and age of primary airway infection by the bacteria . In this study, we investigated whether the single nucleotide polymorphism (SNP) rs3788766, located within promoter, is associated with lung disease severity in a large French cohort of pwCF. We also studied the consequences of this SNP on promoter activity using a luciferase reporter and the role of SLC6A14 in the mechanistic target of rapamycin kinase (mTOR) signaling pathway and airway epithelial repair. We confirm that rs3788766 SNP is associated with lung disease severity in pwCF ( = 0.020; = 3,257, pancreatic insufficient, aged 6-40 years old), with the minor allele G being deleterious. In bronchial epithelial cell lines deficient for , promoter activity is reduced in the presence of the rs3788766 G allele. SLC6A14 inhibition with a specific pharmacological blocker reduced H-arginine transport, mTOR phosphorylation, and bronchial epithelial repair rates in wound healing assays. To conclude, our study highlights that genotype might affect lung disease severity of people with cystic fibrosis mTOR and epithelial repair mechanism modulation in the lung.