TGFB1 – Cystic Fibrosis Modifier

Multiple studies have investigated TGFB1 polymorphisms as genetic modifiers of lung disease severity in cystic fibrosis (CF). In a cohort of 329 CF patients, heterozygosity for TGFB1 +869T/C (c.29C>T (p.Pro10Leu)) was associated with a reduced rate of decline in forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) (PMID:19009622). A family-based association study of 472 patient-parent trios stratified by CFTR genotype revealed significant transmission distortion of a haplotype including the -509C allele (rs1800469), c.29C>T (p.Pro10Leu), and rs8179181 C allele, correlating with improved pulmonary function (PMID:18424453).

These findings support a modifier role for TGFB1 variants in CF lung disease, though classic segregation data and CF-specific mechanistic studies are lacking. Based on consistent association in independent cohorts, the clinical validity is categorized as Limited, with Supporting genetic evidence. Functional impact of these variants on TGF-β1 bioactivity in airway models remains to be demonstrated. Key Take-home: TGFB1 c.29C>T (p.Pro10Leu) and linked promoter variants may inform risk stratification for CF lung disease progression.

References

• Pediatric pulmonology | 2008 | Genetic variations in inflammatory mediators influence lung disease progression in cystic fibrosis. PMID:19009622
• Human molecular genetics | 2008 | Interaction between a novel TGFB1 haplotype and CFTR genotype is associated with improved lung function in cystic fibrosis. PMID:18424453

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