We did not prove the association of TGF-beta1 polymorphisms and lung function in CF, however, the TT (codon 10)/GG (codon 25) genotype was preferentially associated with CF-related liver disease and diabetes.
These results demonstrate that TGFB1 is a modifier of CF lung disease and reveal a previously unrecognized beneficial effect of TGFB1 variants upon the pulmonary phenotype.
In this issue of the JCI, Dorfman et al. demonstrate in a large, population-based study that two previously studied modifier genes, coding for mannose-binding lectin 2 and TGF-beta1, influence pulmonary outcome in pediatric CF patients (see the related article beginning on page 1040).
In conclusion, the role of TGFbeta1 as a CF modulator, suggested from studies with a case-control setting, needs to be interpreted with caution unless family-based analysis is carried out to identify parental genetic and non-genetic effects.
The present results demonstrated that osthole could inhibit the collagen I and III expressions and their ratio in CFs treated with TGF-β1 via Smad signaling pathway, which might be one of its anti-fibrotic action mechanisms.
Additionally, it was demonstrated that cell population of CFs treated with NRG in the S-phase became smaller whereas that of CFs in the G0/G1-phase increased when compared with the TGF-β1 group.
To assess whether any of 9 polymorphisms in 5 candidate genes (alpha(1)-antitrypsin or alpha(1)-antiprotease [SERPINA1], angiotensin-converting enzyme [ACE], glutathione S-transferase [GSTP1], mannose-binding lectin 2 [MBL2], and transforming growth factor beta1 [TGFB1]) are associated with severe liver disease in patients with CF.
On 19q13, TGFB1 and the cystic fibrosis modifier 1 locus (CFM1) have been identified as modifiers of the course of the monogenic disease cystic fibrosis (CF).
Therefore, we propose that TGF-β1-induced mucociliary dysfunction in CF airways is associated with BK inactivation related to a LRRC26 decrease and is amenable to treatment with clinically useful TGF-β1 inhibitors.
We conclude that a CF-related reduction in Smad3 protein expression selectively alters TGF- beta1-mediated signaling in CF epithelium, potentially contributing to aggressive inflammatory responses.
Pulmonary TGFβ1 expression was sufficient to produce pulmonary remodeling and abnormalities in lung mechanics that were associated with both shared and unique cell signaling pathway activation in CF and non-CF mice.
These results demonstrate that TGFB1 is a modifier of CF lung disease and reveal a previously unrecognized beneficial effect of TGFB1 variants upon the pulmonary phenotype.