New Group of Modifier Genes in CF Patients with F508del Mutation May Explain Disease Variability, Study Suggests

European researchers have identified a group of genes that behave as potential modifiers in cystic fibrosis (CF) patients with a F508del mutation in the CFTR gene — a discovery that may lead to new ways to treat the disease.

Their study, “Transcriptomic profile of cystic fibrosis patients identifies type I interferon response and ribosomal stalk proteins as potential modifiers of disease severity,” appeared in the journal PLOS One.

CF is caused by mutations in the cystic fibrosis transmembrane and conductance regulator (CFTR) gene. This affects the ability of organs including the lungs, intestines and pancreas to transport chloride, an important ion. Even so, the leading cause for morbidity and mortality in CF patients is chronic progressive lung disease.

“However, disease severity is immensely variable even among patients with similar CFTR mutations due to the possible effect of ‘modifier genes,’” authors wrote. Modifier genes can affect other genes — in this case the mutated gene of CF — giving them the power to influence the severity of CF lung disease.

Researchers aimed to identify gene modifiers in CF by analyzing global gene expression through use of a technique called RNA-sequencing (RNA-seq).

The team used blood samples from CF patients recruited at University Children’s Hospital in Tuebingen, Germany and the Division of Pediatric Respiratory Medicine at Switzerland’s University of Bern. Patients were divided into mild and severe CF groups.

Researchers first assessed if blood cells — specifically blood leukocytes — presented a similar gene expression profile, or transcriptome, to cells of the respiratory tract, namely nasal, tracheal and bronchial epithelial cells. Results confirmed that blood cells’ transcriptome was a good surrogate for both upper and lower airway respiratory cells in CF.

RNA-seq identified a marked difference in gene expression between the mild and severe pulmonary phenotype of CF. The expression of 74 out of 88 genes was higher in mild CF than in severe CF, with only 14 genes found up-regulated in this group of patients.

The analysis revealed that the genes of a particular pathway, called type I interferon response — a key response of the immune system against pathogens — was highly enriched in the mild CF group. These results confirm the role of the type I IFN pathway in modifying CF, which was previously suggested in other studies.

“It is rational to hypothesize that due to the enhanced Type I IFN signaling, mild CF individuals kept their infections and lung function decline in control,” the team wrote. “This hypothesis can be further supported by the anti-bacterial effect of the type I IFN response in lung epithelium and the respiratory tract.”

A second group of genes that was higher in mild CF coded for ribosomal stalk proteins, specifically RPL31, RPL34 and RPS24. Previous studies showed that these proteins, which regulate protein trafficking inside cells, were linked to the function of the CFTR channel.

“As the F508del mutation is related to protein trafficking and early degradation in endoplasmic reticulum (ER), these ribosomal stalk proteins are attractive for further research,” researchers noted.

Overall, the team concluded that their “Global gene expression and enrichment analyses revealed that genes of the type I interferon response and ribosomal stalk proteins are potential modifiers of CF related lung dysfunction. The results provide a new set of CF modifier genes with possible implications as new therapeutic targets for the treatment of CF.”