Nikhil Prasad Fact checked by:Thailand Medical News Team May 22, 2025 6 hours, 52 minutes ago
Medical News: A groundbreaking international genetic study has identified a specific genetic variation in the FOXP4 gene that increases the risk of developing long COVID. The discovery, made through a global collaboration involving data from over 1.8 million people across 19 countries, sheds light on why some individuals continue to suffer from persistent symptoms months after recovering from a SARS-CoV-2 infection.
FOXP4 Gene Variant Uncovered as Key Driver of Long COVID Globally
The study, conducted by the COVID-19 Host Genetics Initiative and led by researchers from institutions including Karolinska Institutet in Sweden, the University of Helsinki in Finland, and the Broad Institute in the United States, is one of the largest to date investigating the genetic underpinnings of long COVID. This
Medical News report explores how their work reveals that certain people may be genetically predisposed to lingering COVID symptoms due to variations in the FOXP4 gene.
The Global Search for Genetic Clues Behind Long COVID
The researchers carried out a genome-wide association study (GWAS), comparing the genetic profiles of 15,950 individuals with long COVID to nearly 1.9 million people without the condition. Long COVID, also known as post-acute sequelae of COVID-19 (PASC), is a condition where symptoms such as fatigue, shortness of breath, memory issues, and chest pain persist for months after the acute infection has passed.
Through meticulous analysis, the team identified a genetic variant located at chromosome 6—specifically, the FOXP4 locus—that was strongly associated with a higher risk of developing long COVID. The lead variant identified, rs9367106-C, was linked with a 63% increase in the odds of developing long COVID, according to their strictest case and control definitions. This signal was confirmed in replication cohorts comprising more than 5,000 additional cases.
FOXP4 Expression Tied to Long-Term Lung Dysfunction
FOXP4 is a transcription factor that plays a critical role in lung development and immune response. The researchers found that this gene is especially active in alveolar type 2 cells in the lungs—cells essential for lung repair and immune defense. Individuals with the risk variant had higher expression levels of FOXP4 in both lung tissue and blood samples, indicating a possible biological mechanism connecting FOXP4 activity to prolonged COVID symptoms.
Further studies showed that the FOXP4 variant also increased the risk of lung cancer, particularly in East Asian populations where the variant is more common. Colocalization analyses supported that the same genetic signal underlies both long COVID and lung cancer associations. This dual link suggests FOXP4 may play a broader role in respiratory health and disease.
A Complex Genetic Signature That Goes Beyond Severity
While severe COVID-19 is known to increase the likelihood of developing long COVID, the researchers discovered that the FOXP4 variant’s effect was stronger than expect
ed based on severity alone. Even after adjusting for hospitalization, vaccination status, and variant strain, the genetic association with long COVID remained statistically significant.
Interestingly, the FOXP4 signal remained consistent across ancestries and appeared to be more potent in infections caused by the original and Alpha variants of SARS-CoV-2. The risk was also elevated in individuals who were homozygous for the FOXP4 risk allele—meaning they inherited the variant from both parents.
FOXP4 and the Variety of Long COVID Symptoms
The researchers also looked at how the FOXP4 variant correlated with specific long COVID symptoms. Data from the Finnish FinnGen project and the US-based Million Veteran Program showed consistent associations between FOXP4 and symptoms such as fatigue, asthma, and the use of medications for acid reflux and heart conditions. These associations suggest that FOXP4’s role in long COVID may extend beyond the lungs, possibly affecting systemic immune and neurological pathways.
Implications for the Future of Long COVID Research
This study provides robust evidence that a specific genetic variant in FOXP4 contributes independently to the risk of long COVID. It adds to a growing body of evidence suggesting that long COVID is not a single disease but a complex condition influenced by a variety of genetic and environmental factors.
Importantly, the researchers caution that the data used for this analysis was mostly collected before the widespread rollout of COVID-19 vaccines and before the dominance of the Omicron variant. They note that genetic associations may vary with different viral strains and in vaccinated populations.
Conclusion
The identification of FOXP4 as a risk gene for long COVID opens new avenues for research into treatments and preventative strategies. It also underscores the importance of personalized medicine—understanding individual genetic profiles could one day help predict who is at higher risk for long-term complications from COVID-19. These findings offer hope that as we unravel the genetic architecture of post-viral syndromes, more targeted therapies and diagnostics can be developed to help the millions suffering from long COVID.
The study findings were published in the peer reviewed journal: Nature Genetics.
https://link.springer.com/article/10.1038/s41588-025-02100-w
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