Progressive lung disease is an important cause of mortality and morbidity in patients with cystic fibrosis (CF). The severity and progression of lung disease, which has a poor correlation with CF transmembrane conductance regulator (CFTR) genotype, is thought to be modulated by secondary genetic factors known as CF modifiers. Mannose binding lectin 2 (MBL2) and transforming growth factor β1 (TGFβ1) genes are among the pulmonary modifiers associated with an earlier onset of lung infection and a more rapid decline in lung function. The objectives of this study were to evaluate the role of MBL2 and TGFβ1 as pulmonary modifiers and to analyse interactions between them.

A cohort of 1019 patients with CF, representative of the general CF population in Canada, were recruited from specialised CF clinics from 2003 to 2006. At every clinic visit sputum cultures and lung function tests were performed and the age at the time of the first positive respiratory culture for Pseudomonas aeruginosa was recorded. Plasma and DNA samples were obtained for measurement of MBL2 protein levels and for MBL2 and TGFβ1 genotyping.

The study showed that children with CF with MBL2 deficiency acquired Pseudomonas infection earlier and also had a faster rate of decline in lung function than those with intermediate or high levels of MBL2. Those who had high expressing variant of TGFβ1 genotype had more severe lung disease, suggesting a complex interaction between these two genes.

Further studies are needed to evaluate the effects of other pulmonary modifiers and their interactions in what is an increasingly complex genetic disease. It is also not known how these modifiers affect other aspects of CF. Gaining insight into the mechanism of interaction between these and other pulmonary modifiers will help in developing modifier-based therapies.

Dorfman R, Sandford A, Taylor C, et al. Complex two-gene modulation of lung disease severity in children with cystic fibrosis. J Clin Invest 2008;118:1040–9