Over 200 molecules and genes linked to COVID-19 severity

A team has identified 219 molecules and genes that influence the severity of COVID-19 in patients, providing information that could aid the development of therapeutics.


Researchers who investigated COVID-19 in patients have identified over 200 molecular factors that strongly correlate with its severity. They say their findings could offer insight into treatment options for those with advanced disease.

The team were from the Morgridge Institute for Research, the University of Wisconsin-Madison and Albany Medical College, all US. The team analysed 102 blood samples from patients diagnosed with COVID-19 and 26 samples from patients with acute respiratory distress syndrome (ARDS) – but negative for COVID-19 – as controls.

Using mass spectrometry, RNA sequencing and machine learning, the researchers explored a database of more than 17,000 different proteins, metabolites, lipids and RNA transcripts associated with clinical outcomes. They identified 219 molecules and genes that influence blood coagulation, vessel damage, inflammation and other biological process reported to play a role in severe disease.

“In most of the research done in proteomics, the blood samples use the serum fraction that does not have the clotting factors,” said one of the lead researchers Dr Ariel Jaitovich. “This is very important because patients with COVID-19 have accelerated clotting activity.”

According to the researchers, a metabolite called citrate is used as a therapeutic anticoagulant to decrease the likelihood of developing clotting. However, the study revealed that the presence of metabolic citrate decreased as patients presented with more severe illness.

“The fact that citrate is reduced in these patients will potentially indicate that the reduction facilitates the hypercoagulation phenotype that we found in these patients,” said Jaitovich.

Another molecule possibly contributing to hypercoagulation in severe COVID-19 is a protein called gelsolin, which is normally released as a response to inflammation due to cellular injury or infection. Gelsolin was also reduced in the plasma samples from people with severe disease. In addition to biomarkers associated with hypercoagulation, the team also identified a cluster of proteins involved with blood vessel damage, with higher abundance in severe COVID-19 samples.

“There are all these factors upstream of the process that are actually being changed that you need to address as much as just the process of clotting in order to manage this phenotype,” said Evgenia Shishkova, one of the researchers. 

The analysis also revealed increased levels of proteins and upregulated genes involved in neutrophil degranulation, which has been associated inflammation, thrombosis and the development of ARDS.

“So it seems like there is this really strong interplay between the inflammatory response and probably these thrombotic events, which are also being seen in the COVID patients,” said Katie Overmyer, associate director of the Laboratory for Biomolecular Mass Spectrometry at UW-Madison.

Finally, the multi-omic analysis revealed that a network of high-density lipoproteins – the proteins APOA1 and APOA2, and a group of lipids known as plasmalogens that act as antioxidants – were all lower in the severe COVID-19 cases.

“These aspects were not on our radar,” said Jaitovich. “The ability to merge these dimensions in one single unifying narrative allowed us to make sense of stuff that was completely obscured to us.”

By identifying these various molecules, the team say it opens up the potential for developing targeted therapeutics that may help alleviate disease.

The study was published in Cell Systems