At the core of the study lies the question of how genetic variants of the TNFRSF1A gene (TNFR1), which encodes the tumour necrosis factor receptor 1, influence survival in patients with cystic fibrosis (CF). Previous research had already suggested that TNFR1 polymorphisms might modulate disease progression. The aim of the current study was to confirm these observations in independent cohorts while simultaneously shedding light on possible functional mechanisms.

To this end, three independent long-term cohorts of CF patients were analyzed, including sibling pairs. The analyses revealed that certain TNFR1 genotypes are associated with substantial differences in survival—up to ten years between groups. Remarkably, these differences were reproducible both in population-based cohorts and within families, providing strong evidence for the influence of genetic factors.

Furthermore, the researchers conducted functional studies in primary human airway epithelial cells. They identified an alternative transcript variant, TNFR1delEx2, whose expression is directly linked to the TNFR1 genotype. This variant provides a plausible molecular explanation for how different genotypes can affect TNFR1 signaling pathways and, in turn, modulate disease progression in CF. By integrating genetic, epidemiological, and molecular data, the study was able to mechanistically substantiate the link between genotype and survival for the first time.

“Our study highlights that genetic modifiers such as TNFR1 variants are not merely statistical associations but can exert functional effects on disease progression through specific transcript variants. This knowledge opens new perspectives for personalized prognosis and potentially for future therapeutic strategies in cystic fibrosis,” explains Prof. Dr. Anna-Maria Dittrich, senior author and BREATH scientist.

The work carries significant translational relevance. On one hand, the findings suggest that genotype-based risk stratification could play a role in the future clinical management of CF patients. On the other hand, the identification of TNFR1delEx2 as a functionally relevant transcript variant establishes a new foundation for exploring therapeutic approaches targeting TNF signaling pathways. This combination of basic research and clinical relevance illustrates how genetic insights can contribute to more personalized and improved patient care in the future.

The publication is a striking example of how cross-site and international collaboration can uncover new mechanisms in the pathophysiology of cystic fibrosis. It underscores the added value of pooling expertise and resources within the DZL for developing innovative, patient-centered research approaches.

The original publication can e found here.

Text: BREATH/ AB