Analysis of CF patient survival confirms STAT3 as a CF-modifying gene with changing impact over time.

Autor:	Dunsche I; Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, D-30625 Hannover, Germany., Raddatz EL; Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, D-30625 Hannover, Germany.; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research, Hannover Medical School, Hannover D-30625, Germany., Ismer H; Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, D-30625 Hannover, Germany., Hedtfeld S; Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, D-30625 Hannover, Germany., Tamm S; Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, D-30625 Hannover, Germany.; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research, Hannover Medical School, Hannover D-30625, Germany., Moser S; Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, D-30625 Hannover, Germany., Kontsendorn J; Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, D-30625 Hannover, Germany.; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research, Hannover Medical School, Hannover D-30625, Germany., Tümmler B; Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, D-30625 Hannover, Germany.; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research, Hannover Medical School, Hannover D-30625, Germany., Janciauskiene S; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research, Hannover Medical School, Hannover D-30625, Germany.; Department of Respiratory Medicine, Hannover Medical School, D-30625 Hannover, Germany., Dittrich AM; Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, D-30625 Hannover, Germany.; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research, Hannover Medical School, Hannover D-30625, Germany., Stanke F; Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, D-30625 Hannover, Germany.; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research, Hannover Medical School, Hannover D-30625, Germany.
Jazyk:	angličtina
Zdroj:	Human molecular genetics [Hum Mol Genet] 2023 Jan 27; Vol. 32 (4), pp. 543-550.
DOI:	10.1093/hmg/ddac221
Abstrakt:	Introduction and Aim: The signal transducer and activator of transcription 3 (STAT3) has been identified as one of the cystic fibrosis (CF) modifying genes. In this study, we aimed to assess the association between STAT3 genotype and CF patient survival over several decades and to investigate the effect of STAT3 inhibition on epithelial CFTR expression. Methods: We analyzed the informative genetic marker STAT3Sat for its association with survival in 174 p.Phe508del-CFTR homozygous CF patients treated at the CF center in Hannover spanning birth cohorts from >3 decades (1959-1994). Furthermore, we treated two epithelial cell lines with STAT3 inhibitors and monitored changes of CFTR protein expression by western blot. Results: Only for p.Phe508del-CFTR homozygous patients born prior to 1975, survival was significantly influenced by STAT3sat genotype (P = 0.023). The expression levels of STAT3 and CFTR positively correlated in epithelial cell lines (P = 0.01). Conclusions: Our results in different birth cohorts identified a time-dependent impact of STAT3 genotype on CF patients' survival and found that improved symptomatic treatment of later-born CF patients obviates STAT3's modifying influence. Consistent with our previous results, STAT3-specific inhibition resulted in increased CFTR expression in the epithelial cell line 16HBE14o-. Thus, care should be taken when CF-modifying genes are studied in cross-sectional cohorts as the impact of modifying genes might not be invariant in the light of changing therapeutic regimens. (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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