Chemical changes affecting genes help explain differences in CF, per study
Distinct patterns uncovered, tied to lung function, CF-related diabetes
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French scientists have found that distinct patterns of DNA methylation — a type of chemical change that influences how genes are used without altering the underlying DNA sequence — are associated with cystic fibrosis (CF), and are also tied to lung function and CF-related diabetes in people with the inherited disease.
According to the research team, changes in methylation were particularly prominent in genes involved in inflammation, supporting the idea that chronic, body-wide (systemic) inflammation characterizes CF.
These findings also help explain differences in disease severity among people with the genetic disease, the scientists say.
“While the genetic basis of cystic fibrosis is well-established, [it] alone does not explain the substantial inter-individual variability in disease [manifestations], particularly in pulmonary [lung and respiratory system] outcomes,” the team wrote. The scientists said their findings “highlight the biological relevance” of methylation changes in CF and provide new evidence on the mechanisms underlying the disease.
The study, “Epigenome-wide association study and functional analyses reveal regulatory loci linked to lung function and diabetes in cystic fibrosis,” was published in the journal Respiratory Research.
CF is caused by mutations in the CFTR gene that lead to a defective or absent CFTR protein. As a consequence, people with CF produce abnormally thick, sticky mucus that builds up in various organs, most notably the lungs, and drives most CF symptoms.
However, the researchers noted that the substantial variability of disease courses in CF indicates that symptoms are not solely explained by the specific CFTR mutation a patient has.
Progressive lung disease in CF is driven in part by repeated airway infections and persistent inflammation. Meanwhile, nearly half of affected adults develop diabetes — specifically called CF-related diabetes, or CFRD — as a result of the disease.
Investigating changes that regulate gene activity in CF
One possible explanation for this variability is epigenetics, or changes that regulate gene activity without changing the DNA code itself. One such mechanism is DNA methylation, in which chemical tags called methyl groups are attached to DNA.
The scientists, from institutions across France, previously found altered DNA methylation in cells lining the noses of people with CF. Some of these methylation patterns differed between people with mild and severe lung disease and were linked to immune and inflammatory pathways.
Now, the team sought to determine whether DNA methylation changes could be detected in blood samples — and whether they were associated with CF status, lung function, CFRD, and body mass index (BMI), a measure of weight to height. Lung function was assessed using the forced expiratory volume in one second as a percent of the predicted value (FEV1pp), a measure of how much air a person can forcefully exhale in one second compared with the expected amount.
Additionally, the researchers performed lab and computer-based analyses to investigate links between some of the methylation signals and body-wide and pulmonary complications of CF.
The now-completed study (NCT02884622) involved 45 people with CF and 19 healthy individuals, who served as controls. All of the CF patients had two copies of F508del, the most common disease-causing mutation. None had received treatment with any CFTR modulator.
More changes at 1 site linked to CF-related diabetes
The results showed that a total of 636 methylation sites, located at 377 genes, were significantly associated with CF disease status, FEV1pp, BMI, or CF-related diabetes. Four genes in particular — CSGALNACT1, NRXN2, and SOCS3 — showed associations with CF status, FEV1pp, and BMI.
Further analyses identified two biological processes linked to the methylation changes: cellular responses to a signaling molecule called leukemia inhibitory factor and the JAK/STAT pathway, an important system through which cells respond to inflammatory signals.
Regions with altered methylation also had more binding sites for IRF1, a protein involved in immune responses and tumor suppression. Binding sites for two other proteins, NRF1 and NFIL3, were also enriched in these regions.
Together, these findings pointed to immune and inflammatory signaling as a major feature of the methylation differences seen in CF, the team noted.
The researchers then retested six of the strongest methylation sites in samples from 51 people with CF, including 19 with CF-related diabetes, and 24 healthy controls. All except one of the methylation sites showed a significant correlation with clinical traits.
One signal of particular interest was in the promoter region of RGS1, a part of DNA that helps control gene activity.
Higher methylation at this site was associated with CF-related diabetes. A DNA variant near RGS1 explained about 30% of the variation in methylation at the site, while the number of neutrophils — immune cells that respond to inflammation — accounted for another 12%.
These findings suggest that RGS1 methylation may be influenced by both inherited genetics and noninherited factors such as inflammation, the investigators said.
Beyond CF, methylation sites in SOCS3, SBNO2, and RGS1 overlapped with changes previously observed in chronic obstructive pulmonary disease and rheumatoid arthritis. This suggests “shared systemic inflammatory mechanisms” between these conditions, the scientists wrote.
Overall, according to the team, these “findings not only expand our understanding of [CF-related changes in the body], but also corroborate and strengthen previous results.” The team added this work “showed that DNA methylation was significantly altered in [specific] genes.”
Future work should examine whether treatment with Trikafta (lexacaftor/tezacaftor/ivacaftor) changes these epigenetic patterns, the scientists added.
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