Contributors: HAL UVSQ, Équipe; Centre de Recherche Saint-Antoine (CRSA); Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU); Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP); Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU); The University of Western Australia (UWA); Curtin University [Perth]; Planning and Transport Research Centre (PATREC); Hôpital Foch [Suresnes]; Virologie et Immunologie Moléculaires (VIM (UR 0892)); Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE); Service de Pneumologie pédiatrique [CHU Trousseau]; CHU Trousseau [APHP]; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU); Mucoviscidose: physiopathologie et phénogénomique [CRSA]; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU); Sorbonne Université - Faculté de Médecine (SU FM); Sorbonne Université (SU); RF20170501936, RF20180502243, RF20190502451; JM received a doctoral fellowship from the French Ministry of Higher Education, Research and Innovation. MR received a post-doctoral fellowship from the French cystic fibrosis non-profit organization Vaincre la mucoviscidose (RF20180502243 and RF20190502451). LG received a grant from the French cystic fibrosis non-profit organization Vaincre la mucoviscidose (RF20170501936, RF20180502243, and RF20190502451).; CHU Saint-Antoine [AP-HP]; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU); Perth Children's Hospital [Nedlands, WA, Australia]
نبذة مختصرة : Cystic fibrosis (CF), due to pathogenic variants in CFTR 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 CFTR 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 Pseudomonas aeruginosa. In this study, we investigated whether the single nucleotide polymorphism (SNP) rs3788766, located within SLC6A14 promoter, is associated with lung disease severity in a large French cohort of pwCF. We also studied the consequences of this SNP on SLC6A14 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 SLC6A14 rs3788766 SNP is associated with lung disease severity in pwCF (p = 0.020; n = 3,257, pancreatic insufficient, aged 6–40 years old), with the minor allele G being deleterious. In bronchial epithelial cell lines deficient for CFTR, SLC6A14 promoter activity is reduced in the presence of the rs3788766 G allele. SLC6A14 inhibition with a specific pharmacological blocker reduced 3H-arginine transport, mTOR phosphorylation, and bronchial epithelial repair rates in wound healing assays. To conclude, our study highlights that SLC6A14 genotype might affect lung disease severity of people with cystic fibrosis via mTOR and epithelial repair mechanism modulation in the lung.
Processing Request
No Comments.