modifier genes

Question

Definition?
Could these genes have a negative or positive influence on the diagnosed mutations 1) homozygotes 2 ) heterozygotes? Thanks, M. H.

Answer

Hello,

One characteristic of Cystic Fibrosis is the clinical heterogenity, 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 (in a sibship in particular) 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 known that CF patients’ FEV1 decreases with age, but its decline’s slope is variable from a patient to another (see national registry, http: // www.vaincrelamuco.org/e_upload/div/regi strefrancais __ 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 slope less steep), or, on the contrary, a negative impact (with an increased slope of decline).

Thus, the characterization of these genes appears as essential 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.

One major problem in the modifier genes research is 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 4000 French patients already participate, with results that should be available this year.

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

Sincerely

Harriet Corvol

15.03.2013