EBioMedicine (Aug 2025)
Genotype and transcript processing of the tumour necrosis factor receptor TNFRSF1A in epithelial cells: implications for survival in cystic fibrosisResearch in context
- 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,
- Josje Altenburg,
- Els Aertgeerts,
- Vera Bauer,
- Johanna M.W. van den Berg,
- Sebastian F.N. Bode,
- Carlo Castellani,
- Raphael Chiron,
- Owen Dempsey,
- Angelika Dübbers,
- Johannes Eder,
- Helmut Ellemunter,
- Mary Herzig,
- Andrea Lakatos-Krepcik,
- Ulrika Lindberg,
- Jan ter Maaten,
- Henry Mazurek,
- Paola Melotti,
- Rita Francesca Padoan,
- Caroline Raynal,
- Sabina Seehofer,
- Nicholas J. Simmonds,
- Christina Smaczny,
- Prasima Srivastava,
- Nathalie Stremler,
- Fiona Thomson,
- Maria Dolores Pastor Vivero,
- Paul Vöhringer,
- Nadine Wollscheid,
- Domenique D. Zomer-van Ommen
Affiliations
- Alexander Uden
- 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
- Inga Dunsche
- Department for Paediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany
- Sabina Janciauskiene
- 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
- Simon Gräber
- 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
- Longhua Feng
- 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
- Stephanie Tamm
- 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
- Silke Hedtfeld
- 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
- Gesa Stege
- Department for Paediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany
- Kirsten Jahn
- Clinic for Psychiatry, Social Psychiatry and Psychotherapy, Molecular Neuroscience Laboratory, Hannover Medical School, Hannover, Germany
- Julia Kontsendorn
- 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
- Nadine Alfeis
- 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
- Iris Kühbandner
- Department of Paediatrics, University Hospital Heidelberg, Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Germany
- Rebecca Minso
- 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
- Christian Dopfer
- Department for Paediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany
- Matthias Griese
- Department of Paediatrics, Ludwig-Maximilians-University, Munich, Germany; Comprehensive Pneumology Center Munich (CPC-M), German Center for Lung Research (DZL), Germany
- Olaf Sommerburg
- Department of Paediatrics, University Hospital Heidelberg, Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Germany
- Felix C. Ringshausen
- 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
- Lutz Nährlich
- Department of Paediatrics, Justus-Liebig-University Giessen, Giessen, Germany; Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Germany
- Gesine Hansen
- 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
- Tobias Welte
- 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
- Peter Braubach
- Institute for Pathology, Hannover Medical School, Hannover, Germany
- Marcus A. Mall
- 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
- Burkhard Tümmler
- 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
- Anna-Maria Dittrich
- 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
- Frauke Stanke
- 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; Corresponding author. Department for Paediatric Pneumology, Allergology and Neonatology; Centre for Paediatrics and Adolescent Medicine; Hannover Medical School; Carl-Neuberg-Strasse 1, Hannover 30625, Germany.
- Josje Altenburg
- Els Aertgeerts
- Vera Bauer
- Johanna M.W. van den Berg
- Sebastian F.N. Bode
- Carlo Castellani
- Raphael Chiron
- Owen Dempsey
- Angelika Dübbers
- Johannes Eder
- Helmut Ellemunter
- Mary Herzig
- Andrea Lakatos-Krepcik
- Ulrika Lindberg
- Jan ter Maaten
- Henry Mazurek
- Paola Melotti
- Rita Francesca Padoan
- Caroline Raynal
- Sabina Seehofer
- Nicholas J. Simmonds
- Christina Smaczny
- Prasima Srivastava
- Nathalie Stremler
- Fiona Thomson
- Maria Dolores Pastor Vivero
- Paul Vöhringer
- Nadine Wollscheid
- Domenique D. Zomer-van Ommen
- DOI
- https://doi.org/10.1016/j.ebiom.2025.105848
- Journal volume & issue
-
Vol. 118
p. 105848
Abstract
Summary: 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
- Cystic fibrosis
- Patient survival
- Genetic association study
- Tumour necrosis factor receptor
- TNFRSF1A
- Alternative transcript
