295: CFTR deltaF508 and CF-risk variants protect against IBD in large exome study

Yu M et al., Cell Genomics, 6 (2026) 101071. doi:10.1016/j.xgen.2025.101071 - 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. Key terms: CFTR, deltaF508, inflammatory bowel disease, exome sequencing, rare-variant burden test.

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.

Music:
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Article title:
Cystic fibrosis risk variants confer protection against inflammatory bowel disease

First author:
Yu M

Journal:
Cell Genomics, 6 (2026) 101071. doi:10.1016/j.xgen.2025.101071

DOI:
10.1016/j.xgen.2025.101071

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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QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-02-19.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the Results and Discussion segments of the transcript, including the DeltaF508 association with IBD, CFTR2-based burden tests, replication across ancestries, AlphaMissense evaluation and mechanistic discussion about mucus and BEST4+ enterocytes, and therapeutic implications.
- transcript topics: CFTR deltaF508 single-variant association with IBD; CFTR2-based rare-variant burden test; negative control with non-CF-risk variants; ancestry-adjusted analysis and replication (EUR, AFR.AMR, EAS); CFTR variant prioritization: AlphaMissense vs CFTR2; mechanistic discussion: mucus hydration and BEST4+ enterocytes

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 8
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- CFTR deltaF508 single-variant protective effect against IBD (OR 0.82; p 8.96E-11)
- CF-risk variants burden test shows protective effect against IBD (OR 0.85; p 3.9E-07)
- CD/UC subtype effects: deltaF508 protective stronger for CD (OR ~0.79) than UC (OR ~0.87)
- Exclusion of homozygous deltaF508 to avoid CF misclassification
- Cross-ancestry replication across AFR.AMR and EAS groups
- CFTR2-based burden variants outperform AlphaMissense for burden tests

QC result: Pass.