Checking 1 gene’s activity may aid in sleep apnea detection in IPF
Potential biomarker might help ID patients needing sleep studies
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Lower activity of a gene called ZNF331 may help identify obstructive sleep apnea (OSA), marked by repeated stops and starts in breathing during sleep, in people with idiopathic pulmonary fibrosis (IPF), according to a new study by researchers in China.
The team found that ZNF331 activity was lowest among people who had both IPF and OSA — a condition in which the throat muscles relax and block the airway — and enabled accurate distinction from those with IPF alone. In fact, it performed better in that distinction than two commonly used questionnaires assessing daytime sleepiness and sleep quality, the researchers noted.
While further study is needed to confirm the gene’s use as a marker of this sleep-related condition in IPF, the early data are “promising,” per the team.
“A simple blood-based biomarker could facilitate the prioritization of patients with IPF requiring formal [sleep studies],” the researchers wrote, noting that “therapeutic intervention for OSA represents a viable pathway for improving functional status in these patients.”
The study, “Identification of ZNF331 as a Biomarker for Obstructive Sleep Apnea in Idiopathic Pulmonary Fibrosis Through Integrated Bioinformatics Analysis and Clinical Validation,” was published in the journal Lung.
IPF is a lung disease of unknown origin marked by the buildup of scar tissue, or fibrosis, in the lungs, which leads to worsening symptoms of shortness of breath and declining lung function. While antifibrotic treatments can slow disease progression, managing other conditions that occur alongside IPF remains an important part of care.
Sleep apnea affects up to 90% with IPF, but remains hard to detect
OSA is one of the most common of these conditions. Previous studies have estimated that sleep apnea affects about 60% to 90% of people with IPF. Also, nighttime oxygen level reduction, which can happen in OSA, has been linked to worse outcomes for IPF patients.
Still, OSA can be difficult to diagnose in people with IPF. The sleep disruptions these patients already experience make symptom-based tools such as the Epworth Sleepiness Scale of daytime sleepiness unreliable, the scientists noted. Further, formal overnight sleep testing also may not always be easy to implement, particularly in people with substantial heart or lung disease.
But “managing [coexisting] OSA may alleviate symptoms and improve quality of life in patients with chronic respiratory disorders, further underscoring the importance of early identification,” the investigators wrote.
While blood-based biomarkers of OSA have been identified for the general population, whether such tools can be used in the context of IPF with OSA is still a matter of debate. Now, a team from Tianjin Medical University General Hospital set out to address this unmet clinical need.
The researchers analyzed two publicly available gene expression (activity) datasets, each with its own control group: one comparing 93 people with IPF with 30 healthy people, who served as controls, and another comparing 28 untreated people with OSA with six individuals with primary snoring.
First, the investigators identified genes whose activity differed from that of controls in each data set. Of these, 51 genes overlapped in the two datasets. Further analysis narrowed this number down to two: the genes ZNF331 and NIF3L1.
ZNF331 was selected for clinical validation because its activity showed a more consistent downward pattern across the IPF and OSA datasets, according to the researchers.
Assessing ZNF331 activity worked better than 2 often used tests
Computer analyses implicated pathways related to inflammation, cellular stress, and tissue remodeling, and linked ZNF331 with changes in several immune cell populations. Tissue remodeling broadly refers to structural and functional alterations in existing tissues, and is implicated in respiratory diseases.
The researchers next evaluated the diagnostic relevance of ZNF331 in an independent group of patients. In the group were healthy indiviuals, people with OSA, people with IPF alone, and people with both IPF and OSA. The analysis focused on people with relatively early-stage IPF who were not dependent on long-term oxygen therapy. All underwent overnight respiratory monitoring.
Among the IPF participants, 30 had IPF alone, while 30 also had OSA; the mean age of patients in both groups was in the mid 50s. Of those with OSA, 16 had mild disease, eight had moderate OSA, and six had severe OSA.
ZNF331 gene activity showed an overall decline from healthy controls through the OSA and IPF groups, and reached its lowest in people with both IPF and OSA.
The researchers next calculated the area under the curve (AUC), a measure of how well a marker distinguishes between two groups. An AUC of 1 represents perfect discrimination.
ZNF331 achieved an AUC of 0.932. In comparison, the Epworth Sleepiness Scale had an AUC of 0.587 and the Pittsburgh Sleep Quality Index, another questionnaire used to assess sleep, had an AUC of 0.480, the data showed.
After accounting for potential confounding factors, including age, sex, body mass index (a measure of body fat based on weight and height), and IPF severity, the researchers found that ZNF331 remained significantly lower in people with IPF and OSA.
Overall, these early findings “support ZNF331 as a potential blood-based screening biomarker” of OSA in patients with IPF, the researchers wrote. However, further validation in larger studies is warranted, the team concluded.
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