TNFR1 gene variants influence survival in cystic fibrosis

A new DZL study shows that genetic variants of the TNFRSF1A gene (TNFR1) can significantly influence survival in people with cystic fibrosis (CF). The study was led by researchers at the DZL site BREATH in close collaboration with DZL scientists from the sites CPC-M, TLRC, and UGMLC, as well as the CF teams of the European CF Twin and Sibling Study.

The researchers analyzed three independent long-term cohorts of individuals with CF, including sibling pairs. Their analyses revealed that specific TNFR1 genotypes are associated with differences in survival of up to ten years. These findings were reproducible both in population-based cohorts and within families – providing strong evidence for the impact of genetic factors.

In functional studies using human airway epithelial cells, the team identified an alternative transcript variant, TNFR1delEx2, whose expression is directly linked to the TNFR1 genotype. This discovery offers a plausible molecular explanation for how different genotypes modulate TNFR1 signaling pathways and, consequently, disease progression. “Our study highlights that genetic modifiers such as TNFR1 variants are not merely statistical associations but can have functional consequences on disease course through specific transcript variants. This knowledge opens new perspectives for personalized prognosis and potentially for future therapeutic approaches in cystic fibrosis,” explains Prof. Dr. Anna-Maria Dittrich, senior author of the study and head of the pediatric cystic fibrosis section at Hannover Medical School.

The findings suggest that genotype-based risk stratification may become relevant in the clinical management of CF patients. Moreover, the identification of TNFR1delEx2 provides a new foundation for exploring therapeutic strategies targeting TNF signaling pathways.

This work underscores how the close collaboration between DZL sites contributes to a deeper understanding of cystic fibrosis mechanisms and the development of patient-oriented solutions.

Source: Cooperative DZL study identifies alternative TNFR1 transcript variant as key to prognosis in CF

Original publication: Uden A, Dunsche I, Janciauskiene Set al. Genotype and transcript processing of the tumour necrosis factor receptor TNFRSF1A in epithelial cells: implications for survival in cystic fibrosis. EBioMedicine. 2025 Aug;118:105848. doi: 10.1016/j.ebiom.2025.105848. Epub 2025 Jul 10. PMID: 40645008; PMCID: PMC12275981.