Genotype and transcript processing of the tumour necrosis factor receptor TNFRSF1A in epithelial cells: implications for survival in cystic fibrosis

Alexander Uden; Inga Dunsche; Sabina Janciauskiene; Simon Gräber; Longhua Feng; Stephanie Tamm; Silke Hedtfeld; Gesa Stege; Kirsten Jahn; Julia Kontsendorn; Nadine Alfeis; Iris Kühbandner; Rebecca Minso; Christian Dopfer; Matthias Griese; Olaf Sommerburg; Felix C Ringshausen; Lutz Nährlich; Gesine Hansen; Tobias Welte; Peter Braubach; Marcus A Mall; Burkhard Tümmler; Anna-Maria Dittrich; Frauke Stanke; CF teams from the European CF Twin and Sibling Study

doi:10.1016/j.ebiom.2025.105848

Genotype and transcript processing of the tumour necrosis factor receptor TNFRSF1A in epithelial cells: implications for survival in cystic fibrosis

EBioMedicine. 2025 Jul 10:118:105848. doi: 10.1016/j.ebiom.2025.105848. Online ahead of print.

Authors

Alexander Uden¹, Inga Dunsche², Sabina Janciauskiene³, Simon Gräber⁴, Longhua Feng¹, Stephanie Tamm¹, Silke Hedtfeld¹, Gesa Stege², Kirsten Jahn⁵, Julia Kontsendorn¹, Nadine Alfeis¹, Iris Kühbandner⁶, Rebecca Minso¹, Christian Dopfer², Matthias Griese⁷, Olaf Sommerburg⁶, Felix C Ringshausen⁸, Lutz Nährlich⁹, Gesine Hansen¹⁰, Tobias Welte³, Peter Braubach¹¹, Marcus A Mall⁴, Burkhard Tümmler¹, Anna-Maria Dittrich¹, Frauke Stanke¹²; CF teams from the European CF Twin and Sibling Study

Collaborators

Affiliations

¹ Department for Paediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Germany.
² Department for Paediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany.
³ Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Germany; Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School, Hannover, Germany.
⁴ Department of Paediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität, Berlin, Germany; German Centre for Lung Research (DZL), Associated Partner Site, Berlin, Germany; German Center for Child and Adolescent Health (DZKJ), partner site Berlin, Berlin, Germany.
⁵ Clinic for Psychiatry, Social Psychiatry and Psychotherapy, Molecular Neuroscience Laboratory, Hannover Medical School, Hannover, Germany.
⁶ Department of Paediatrics, University Hospital Heidelberg, Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Germany.
⁷ Department of Paediatrics, Ludwig-Maximilians-University, Munich, Germany; Comprehensive Pneumology Center Munich (CPC-M), German Center for Lung Research (DZL), Germany.
⁸ Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Germany; Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School, Hannover, Germany; European Reference Network on Rare and Complex Respiratory Diseases (ERN-LUNG), Frankfurt, Germany.
⁹ Department of Paediatrics, Justus-Liebig-University Giessen, Giessen, Germany; Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Germany.
¹⁰ Department for Paediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Germany; Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Germany.
¹¹ Institute for Pathology, Hannover Medical School, Hannover, Germany.
¹² Department for Paediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Germany. Electronic address: mekus.frauke@mh-hannover.de.

PMID: 40645008
DOI: 10.1016/j.ebiom.2025.105848

Abstract

Background: Cystic fibrosis is caused by mutations of the cystic fibrosis transmembrane conductance regulator, CFTR, an epithelial anion transport protein, responsible for, inter alia, sputum viscoelasticity in the lung. We previously identified the TNF receptor superfamily 1A TNFRSF1A (TNFR1) as a genetic modifier of CFTR function and disease severity in the CF twin and sibling study population. We aimed to replicate our findings in independent cohorts, assess the role of TNFR1 for patient survival and identify functional changes associated with TNFR1 polymorphisms.

Methods: We incorporated data from three independent long-term mono- and multicentric cohorts of people with cystic fibrosis (pwCF) to confirm the previously described association of TNFR1 with CFTR function and to extend our study to include survival data for our local cohort and a pan-European cohort of pwCF. We studied TNFR1 transcripts obtained from primary airway epithelia grown as air-liquid interface cultures to address possible mechanisms involved in up-stream and down-stream effects of TNFR1.

Findings: Survival differed by more than a decade when comparing carriers of contrasting TNFR1 genotypes among unrelated pwCF as well as among CF siblings pairs. The presence of the TNFR1 transcript variant TNFR1delEx2 in primary airway epithelia was associated with TNFR1 genotype.

Interpretation: The association of the TNFR1 transcript variant TNFR1delEx2 associates with the TNFR1 genotype, possibly mediating the genotype-survival association we found regarding TNFR1 genotype and patient survival in cystic fibrosis.

Funding: Supported by the German Ministry for Education and Research (BMBF) (82DZL009B1 to MAM and 82DZL002A1, to GH, BT, AMD, FS) and the Mukoviszidose Institut gGmbH (MI-2002, to LN, AMD, FS).

Keywords: Alternative transcript; Cystic fibrosis; Genetic association study; Patient survival; TNFRSF1A; Tumour necrosis factor receptor.