The role of lung dysfunction and COVID-19 severity in the development of long-term COVID

In a study published in the medRxiv* preprint server, a team of interdisciplinary research groups has identified a genome-wide significant association (GWAS) for long-term coronavirus disease (COVID) at the FOXP4 locus, which has previously been associated with cancer, severe COVID 2019 ( COVID-19) and lung function.

Study: Genome-wide association study of long COVID. Image Credit: NiphonSubsri/Shutterstock.com

*Important Notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be considered conclusive, guide clinical practice/health-related behavior, or treated as established information.

Background

Long COVID is also called post-acute sequelae of COVID-19. It is more common in patients who are hospitalized or admitted to an intensive care unit due to COVID-19 infection. However, it can also occur in patients who have mild symptoms of COVID-19.

The COVID-19 Host Genetics Initiative (HGI) has identified 51 distinct genome-wide significant loci linked to COVID-19 pathophysiology ranging from infection to hospitalization.

To understand the underlying causes of long COVID, it is imperative to evaluate these variants to elucidate viral pathways and mechanisms of entry.

About the study

In this collaborative study, researchers performed the first GWAS focusing on long COVID. They conducted 24 independent GWAS conducted in 16 countries representing populations of 6 ancestry, 6,450 people with long-term COVID diagnoses, and 1,093,995 controls.

They conducted four GWAS meta-analyses based on a test-verified infection, which was listed as a strict case definition (including 11 studies, N=3,018), and a self-reported or self-reported SARS-CoV-2 infection. physician listed as broad definition control (all contributed 994,582 studies).

Individuals who survived SARS-CoV-2 infection without long COVID were classified as strict controls, while samples who were genetically ancestry-matched and did not have long COVID were classified as population controls.

In addition, a questionnaire-based approach to symptom assessment was followed.

Results

The analysis uncovered a strong genome-wide relationship in the FOXP4 gene. The C allele in rs9367106 was also identified to be linked to a higher risk of long COVID. Concordant results (although not genome-wide) were observed in all three meta-analyses. rs9367106-C at the FOXP4 locus has also been shown to have high epidemiological variability.

The genomic area surrounding the primary variation linked to long COVID (+/-100 kilobases) comprises four genes (FOXP4-AS1, FOXP4, MIR4641, LINC01276).

Because all variants in linkage disequilibrium (LD) with the parent variant were noncoding, the authors scanned for variants linked to neighboring genes with differential expression spanning a 100 kb window.

They identified that rs12660421-A (a proxy allele related to rs9367106-C, the long COVID risk allele) is linked to increased expression of FOXP4 in the lung.

Since FOXP4 has robust expression in nearly all tissues, including lung cells and immune cells, a colocalization analysis confirmed the same differential expression of long COVID.

Additionally, the COVID and Biobank Japan meta-analyses labeled variants in this region as risk factors for COVID-19-related hospitalization. The colocation analysis conducted by the authors correlated the COVID-19 severity haplotype to the FOXP4 risk haplotype.

Furthermore, single cell sequencing analysis suggested that FOXP4 is abundantly expressed in alveolar type 2 cells, which mount robust innate immune responses, secrete surfactant, keep alveoli dry, and act as progenitor cells in replenishing damaged epithelium. .

Furthermore, granulocytes that regulate innate immunity also share the same expression level of FOXP4.

The authors mined data from the VannoPortal, Regulome and ENCODE databases and discovered four variants of interest through chip sequencing. POLR2A and EP300 bound rs2894439 at the start of risk haplotypes, and EP300 and FOXA1 bound rs7741164 and rs55889968, among others.

Finally, one variant (rs9381074) was shown to be directly associated with DNA methylation signatures in immune and lung cells (H3K27me3 and H3K4me1, H3K27ac, H3K4me3, H3K4me2, H3K4me3), indicating that they are located in euchromatin.

A phenomenal level association study between all phenotypes from Biobank Japan and rs9367106 identified that the long COVID risk allele was linked to lung cancer.

Furthermore, known risk mutations for lung cancer in non-smoking Asian women and non-small cell lung cancer in European and Chinese populations are in LD with the long COVID risk allele.

Colocalization analyzes showed that lung cancer and long COVID shared the same genetic signal within 500 kb of rs9367106. Interestingly, the authors also found significant genetic associations between long COVID and symptoms of depression, asthma and diabetes.

They also suggested that the FOXP4 signal demonstrated an unusually strong association with long-term COVID, which cannot be caused by COVID-19 severity alone.

Conclusion

The present research offers direct genetic evidence that lung pathology could substantially contribute to the emergence of long-term COVID.

Like other post-viral conditions, long-term COVID is a heterogeneous disease entity in which both genetic and epigenetic factors decide the fate of the patient in terms of disease risk, severity and hospitalisation.

Since FOXP4 is expressed in various tissues, including the lungs and intestines, its polymorphisms can influence lung diseases such as long-term COVID, cancer and other diseases.

Thus, this study paves the way for future research and provides more insight into the biological processes that underlie long-term COVID.

*Important Notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be considered conclusive, guide clinical practice/health-related behavior, or treated as established information.