Purpose of review: Cystic fibrosis is a recessive genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, but there is great heterogeneity of lung-disease severity. If we could understand non-CFTR genetic factors (modifier genes) that contribute to the severity of lung disease, we could develop novel therapies. Early studies were small and/or phenotyping methodologies were limited; consequently, most findings have not been replicated.
Recent findings: Several large gene-modifier studies have been established. These studies are complementary in terms of design and the types of patient, and employ specialized approaches to quantitate pulmonary disease severity. Emerging data indicate that non-CFTR genetic variants contribute to at least half the variability in pulmonary disease severity, and genetic variation in transforming growth factor beta1 clearly modifies the severity of cystic fibrosis lung disease.
Summary: The cystic fibrosis community is working to identify the most important gene modifiers for lung disease. Candidate genes are currently being tested, and high-resolution, whole-genome scans are now affordable. For cystic fibrosis, several hundred thousand genetic markers (single-nucleotide polymorphisms) will identify key chromosomal regions and genes. If successful, these studies will provide the opportunity for novel approaches and therapies for cystic fibrosis lung disease.