Genetic analysis points to new clues behind pain in cystic fibrosis
Six genes interacting with CFTR emerge from database-driven study
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Researchers in Australia have identified six potential genes that may help explain why people with cystic fibrosis (CF) experience pain — and respond to pain treatments — differently.
The genes — CTRC, SPINK1, TNF, ABCB1, PRSS1, and TGFB1 — were found to interact with CFTR, the gene whose mutations cause CF, and to influence pain mainly through biological pathways involved in inflammation, immune signaling, and responses to treatment.
The findings could guide future research to confirm results in people with CF and explore how these genes shape an individual’s “pain phenotype,” or overall pain profile, the researchers wrote.
The study, “Identification of Novel Modifier Genes Associated With Pain in Cystic Fibrosis: An In Silico Gene Discovery,” was published in Human Mutation.
How cystic fibrosis affects the body and why pain matters
CF causes thick, sticky mucus to build up in the lungs and other organs. While the disease is best known for hallmark symptoms affecting the lungs and digestive system, pain is increasingly recognized as an important aspect of living with CF. Pain can affect the chest, joints, and abdomen, and often interferes with sleep, mood, and everyday activities.
Research suggests that genetics can influence how people perceive and respond to pain, shaping pain sensitivity, responses to treatment, and the risk of chronic pain. These effects may involve modifier genes, which do not cause CF themselves but can influence how severe symptoms are, when they begin, or how the body responds to the disease and its treatments.
However, the genetic factors that contribute to pain in CF remain poorly understood.
To address this gap, researchers used a computer-based, or in silico, approach to identify genes and biological pathways that may influence how pain develops and varies in people with CF.
The team first searched several large genetic databases, identifying 1,516 genes linked to CF and 1,830 linked to pain. Seven genes — CFTR, TNF, TGFB1, ABCB1, PRSS1, CTRC, and SPINK1 — consistently appeared across multiple databases as being linked to both CF and pain.
Among these, CFTR is the gene whose mutations cause CF. TNF and TGFB1 are involved in inflammation and immune signaling, while ABCB1 helps regulate how the body processes certain medications. PRSS1, CTRC, and SPINK1 encode proteins that control the production and activation of digestive enzymes — processes that, when disrupted, can contribute to pancreatic inflammation and pain.
When the researchers compared their findings with previously published studies, they found that CTRC and PRSS1 had already been identified as CF modifier genes, while ABCB1 and TGFB1 had been linked to pain. Only TNF appeared consistently across every source, suggesting it may represent a key link between inflammation, CF biology, and pain.
Mapping gene interactions linked to pain in cystic fibrosis
To better understand how TNF, TGFB1, and ABCB1 may work together, the researchers used computer-based tools to map how these genes and their proteins interact — essentially identifying which genes “communicate” with one another and participate in shared biological processes.
The analysis showed that TNF and TGFB1 were active in 26 shared biological pathways. When compared with CFTR, all three genes were linked through a common biological process known as signal transduction — the mechanism by which cells convert chemical or physical signals into molecular responses.
The team also examined a broader network of protein interactions that included CTRC, SPINK1, PRSS1, and CFTR. Within this network, TNFRSF1A, a receptor that binds TNF, appeared as a central hub, reinforcing the idea that TNF-driven inflammatory signaling may play an important role in linking CF biology to pain perception.
Finally, using databases that predict interactions between genes (or their proteins) and medications, the researchers found that ABCB1 was linked to nine pain-relief drugs, while CFTR, TGFB1, and TNF were each linked to one pain-related medication.
The study “highlights potential genes and biochemical pathways implicated in pain pathways that could significantly impact pain perception in people living with CF and their response to prescribed therapies,” the researchers wrote.
The researchers also wrote that studies involving people with CF will be needed to confirm these findings and better understand how genetic differences may shape individual pain experiences and responses to treatment.
