Nikhil Prasad Fact checked by:Thailand Medical News Team May 18, 2025 7 hours, 13 minutes ago
Medical News: New Research Uncovers Potential Long COVID Biomarker in Blood Cells
A new study by researchers from several Italian medical institutions has uncovered a possible molecular clue to why some people continue to suffer debilitating symptoms long after recovering from the initial phase of COVID-19. The team, led by experts from the IRCCS Policlinico San Donato, ICS Maugeri IRCCS in Pavia, and IRCCS MultiMedica in Milan, focused on the blood expression levels of a specific long non-coding RNA called LEF1-AS1. Their findings suggest that a persistent drop in this RNA marker could be closely linked to long COVID symptoms, especially those affecting the body physically.
LEF1AS1 Gene Disruption Could Be Driving Long COVID Symptoms in Some Patients
This
Medical News report explores a deeply detailed clinical investigation involving 98 previously hospitalized COVID-19 patients, 18 months after their original illness. Researchers analyzed blood samples for the presence of noncoding RNAs—genetic material that does not produce proteins but plays an important role in regulating gene expression. Among the RNAs examined, LEF1-AS1 stood out for its striking reduction in patients still experiencing major physical symptoms such as fatigue and shortness of breath.
What is LEF1-AS1 and Why Does It Matter
LEF1-AS1, short for “Lymphoid Enhancer-Binding Factor 1 antisense RNA 1,” is a long non-coding RNA located on chromosome 4q25. As an antisense transcript, it's derived from the DNA strand opposite the LEF1 gene. Although it doesn’t code for proteins, LEF1-AS1 has regulatory functions that influence how other genes, including LEF1 itself, behave. It is particularly important in hematopoiesis—the formation of blood cells—and is usually highly expressed in healthy blood stem cells.
In various diseases, especially cancers such as non-small-cell lung cancer, glioma, and colorectal cancer, LEF1-AS1 levels are often abnormally high and contribute to tumor growth. However, in blood disorders like myelodysplastic syndromes and acute myeloid leukemia, its expression drops significantly. This context is vital when considering its newly uncovered role in long COVID.
Symptoms and Scope of Long COVID
Long COVID refers to symptoms that continue or emerge three months after an acute SARS-CoV-2 infection and last for at least two months. While up to 15% of patients worldwide may be affected, long COVID remains poorly understood and hard to diagnose due to the wide range of physical and neurological symptoms it causes. Common complaints include fatigue, brain fog, memory loss, and breathlessness, all of which can severely affect quality of life.
In this Italian study, researchers tracked patients for over a year and a half after hospitalization for COVID-19. Nearly 38% still suffered from persistent fatigue, 34% from breathlessness, and 30% from memory problems.
Digging into the RNA Clues
The scientists focused thei
r attention on a set of small and long noncoding RNAs previously linked to severe COVID-19 outcomes. Among them, LEF1-AS1-202—a specific variant—showed a consistent and significant reduction in patients reporting major physical symptoms (referred to in the study as MPS). This pattern did not appear in those with only major neuropsychological symptoms (MNS) like depression or memory dysfunction.
In addition to LEF1-AS1-202, other variants like LEF1-AS1-207 and several grouped together as “multiple isoforms” were also significantly decreased. Notably, the LEF1 gene itself—which LEF1-AS1 helps regulate—was found to be suppressed in these same patients, suggesting a co-regulatory relationship between the two.
This strong correlation suggests that lowered LEF1-AS1 levels could reflect an impaired immune memory response, possibly disrupting the formation of CD8+ T cells essential for viral clearance and recovery.
Clinical Relevance and Risk Factors
Interestingly, LEF1-AS1 levels negatively correlated with certain blood immune cells such as monocytes and eosinophils, hinting at a lingering low-grade inflammatory state. Furthermore, reduced LEF1-AS1 expression was more common in older patients and former smokers—both already known risk groups for long COVID.
Even after adjusting for age and smoking, reductions in some LEF1-AS1 variants remained statistically significant. These findings reinforce the potential of LEF1-AS1 as a disease biomarker, though the researchers caution that more data is needed.
Understanding the LEF1-AS1 LEF1 Connection
The LEF1 gene encodes a transcription factor that plays a role in immune system regulation, particularly the Wnt/β-catenin pathway. In healthy systems, LEF1 helps develop memory precursor T cells. LEF1-AS1 influences LEF1 through multiple mechanisms. In cancer, LEF1-AS1 can activate LEF1 by recruiting epigenetic modifiers like MLL1 to stimulate transcription. Other LEF1-AS1 isoforms may also “sponge” RNA binding proteins, preventing LEF1 mRNA from being degraded.
In long COVID, reduced LEF1-AS1 could disrupt these processes, weakening immune reprogramming after SARS-CoV-2 infection and possibly contributing to chronic inflammation and persistent physical symptoms.
Limitations and the Road Ahead
The authors acknowledge several limitations. The study was conducted at a single center, and only included patients who had been hospitalized during their acute COVID-19 phase. Therefore, the findings may not apply to people who had milder infections. Also, since participation required a physical return to the hospital, the most severely affected individuals might have been excluded.
Moreover, the study’s power was limited by sample size, and it did not account for post-COVID medications or external treatments. Some data on mental health symptoms relied on patient self-reports rather than clinical assessment.
Despite these limitations, the study presents compelling evidence that LEF1-AS1, particularly its multiple isoforms, could serve as a useful marker for long COVID with physical symptoms.
A Step Closer to Predicting Long COVID
This new discovery not only opens doors for improved diagnosis and patient monitoring but may also point to novel therapeutic targets. If further studies confirm these results in broader and more diverse populations, LEF1-AS1 expression levels could become a part of routine tests used to evaluate lingering post-COVID symptoms.
By providing insight into one of the molecular mechanisms potentially driving long COVID, this research helps demystify a condition that has baffled doctors and debilitated millions. It also paves the way for personalized treatment strategies based on a patient’s unique RNA profile.
The study findings were published in the peer reviewed International Journal of Molecular Sciences
https://www.mdpi.com/1422-0067/26/10/4806
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Medical News.
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