Yu M et al., Cell Genomics. 6 ( - Large-scale exome sequencing shows CFTR risk variants, including deltaF508, reduce susceptibility to inflammatory bowel disease, suggesting targeted CFTR modulation as a potential IBD therapy.

Study Highlights:
The authors analyzed large-scale human exome and genome sequencing data (38,558 cases and 66,945 controls in European discovery; 42,475 cases and 192,050 controls in replication across ancestries) using single-variant tests and gene-based rare-variant burden tests. They report a protective single-variant association for CFTR deltaF508 with IBD (meta-analysis p = 8.96E-11, OR = 0.82) and a significant protective gene-level burden of clinically annotated CF-risk variants (meta-analysis p = 3.9E-7, OR = 0.85). The study also compared variant prioritization methods and found clinically curated CFTR2 annotations outperform in silico predictors such as AlphaMissense for powering burden tests. Replication signals were observed in non-European groups at nominal significance and the results support exploration of selective, tissue-targeted CFTR modulators as a potential therapeutic implication.

Conclusion:
Clinically annotated CFTR risk variants, including deltaF508, confer a reproducible protective effect against IBD in large sequencing cohorts, supporting investigation of selective tissue-targeted CFTR modulation while balancing cystic fibrosis risks.

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Reference:
Yu M., Zhang Q., Yuan K., Sazonovs A., Stevens C.R., Fachal L., et al. Cystic fibrosis risk variants confer protection against inflammatory bowel disease. Cell Genomics. 6 (2026) 101071. https://doi.org/10.1016/j.xgen.2025.101071

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/

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