|Geneticist, Garry Cutting, M.D.|
Geneticist Garry Cutting, M.D.
Although cystic fibrosis is caused by mutations in the gene that makes a protein called CFTR (cystic fibrosis transmembrane conductance regulator), a broad spectrum of disease severity exists. Some patients with CF die early in childhood while others live well into adulthood with only mild lung or liver disease. Evidence is accumulating that shows the CFTR genotype alone does not account for this wide diversity. Rather, it is the interaction of the environment and other non-CFTR "modifier" genes that determines the clinical course of CF.
What are gene modifiers?
In terms of cystic fibrosis, modifier genes are genes other than the CF gene (CFTR) that may have an effect on how the body responds to the conditions that develop as the result of defective CFTR.
Have any gene modifiers been identified?
Researchers have studied a number of potential CF gene modifiers; however, none have been clearly substantiated. Potential modifiers of CF are chosen to reflect the known pathophysiology of CF, including genes involved in the patient’s response to infection and CF complications such as intestinal obstruction, diabetes, and liver disease. The general classes of potential modifier genes include inflammatory and anti-inflammatory mediators, antioxidants, mediators of airway reactivity, molecules involved in CFTR trafficking, and alternative ion channels. The best-studied CF candidate modifiers include mannose-binding lectin (MBL), glutathione-S-transferase, transforming growth factor-beta1 (TGF-ß1), tumor necrosis factor-? (TNF-?), adrenegic receptor, and HLA class II antigens.
In a preliminary study, Johns Hopkins researchers have identified two genes associated with CF survival—MBL and TNF-?—although these findings have yet to be confirmed by other studies. If confirmed, researchers say it may be possible to type patients for these genes in order to provide a better idea of outcome. Targeted gene therapies could also be developed.