Modifier genes

Question

Hello, could you tell me what are the cystic fibrosis modifier genes? Do we know how to identify them if necessary? If yes, could you give me some examples of modifier genes? Thank you

Answer

Hello,

One characteristics of cystic fibrosis is the clinical heterogeneity, that is the variability in the severity of the organs’ disease from a patient to another. This variability is neither explained by the CFTR gene mutations, nor by the environmental factors. Indeed, some patients having the same CFTR mutations (F508del homozygotes for example) or a similar environment (particularly in sibs) can have a variable disease severity. These observations suggest the influence of genes others than CFTR, named "modifier genes".

For example for the respiratory disease, the severity is particularly estimated by the regular measure of the respiratory function, and more specifically by the FEV1. It is recognized that CF patients’ FEV1 decreases with age, but its decline’s slope is variable from a patient to another (see the national French registry, www.vaincrelamuco.org/e_upload/div/registrefrancais__de_la_mucoviscidose_version2011.pdf). This variability is, at least partially, due to the intervention of these “modifier genes”, that could have a positive effect (with a less steep slope), or, on the contrary, a negative impact (with an increased slope of decline).

Thus, the characterization of these genes seems important to allow the early identification of the patients at risk of developing a more severe disease (in particular with the CF neonatal screening), and to improve the patients’ care by proposing “adapted”, “targeted” therapeutic strategies. The overall purpose is to develop a "personalized medicine ", that is adapted to each patient. Moreover, the identification of these genes would also allow the discovery of new CF therapeutic targets.

Nowadays, the identification of the modifier genes is still a research area and is not performed in a routine basis for the patient care. Several genes have been identified possibly associated with the respiratory disease, the CF related liver disease or the CF related diabetes, but studies are still ongoing to confirm those genes. One major problem in the modifier genes research is indeed the necessity of investigating a large number of patients. So, large consortiums have emerged, mainly in Europe (www.ecfs.eu/ecfs-working-groups/ecfs-gene-modifier-working-group) and in North America. In France, a project is in progress and more than 4200 French patients already participate, with results that should be available in 2014.

I hope to have answered your questions, but do not hesitate to re-ask for more details if necessary,

Sincerely

Harriet Corvol

16.12.2013