Hidden protein linked to severe COVID-19 and lung disease risk

Researchers found that the genetic variant alters a newly discovered enzyme found in lung tissue, revealing a hidden biological pathway that could help explain why some people are more susceptible to serious lung disease.

The findings add to growing evidence that the human genome contains many previously overlooked proteins that may have important roles in health and disease, experts say. 

Researchers add that understanding where these proteins are found in the body, how they change during disease and how genetic variation affects their function could help explain the causes of disease, improve diagnosis and reveal new targets for treatment.

The human genome contains around 20,000 genes, many of which can produce more than one protein. Some of these proteins are specific to particular tissues or diseases, but many have remained unknown until recently.

As a result, genetic differences affecting these proteins have often been overlooked, limiting scientists' understanding of how inherited genetic variation contributes to disease.

Researchers from the Institute of Genetics and Cancer, with partners at the University of Syndey, investigated how genetic differences associated with both rare diseases and common conditions affect these newly identified proteins.

They found that many genetic variants previously thought not to affect proteins can, in fact, alter the structure and function of these newly discovered molecules. These variants had remained hidden within poorly understood regions of the genome, limiting understanding of how they contribute to disease.

To better understand the role of these proteins, the team developed a new method to measure their abundance within cells. The new method allows researchers to make measurements even at very low quantities in cells.

The researchers focused on a newly identified enzyme found in lung tissue. This enzyme is linked to infections, inflammation and lung cancer. They found that the variant changes the function of the enzyme and alters its response to a drug, providing new insight into how genetic differences may influence both disease risk and treatment response.

The team also identified similar genetic changes affecting newly discovered proteins that may influence vitamin D levels and contribute to kidney or heart disease. Some of these variants are common, affecting nearly 50 per cent of the population, but are likely to have only modest effects on disease risk. Others are extremely rare – affecting as few as one in a million people – but are thought to cause more severe forms of disease.

The findings suggest that many disease-associated genetic variants may act through proteins that have only recently been recognised, opening new opportunities to improve diagnosis and identify therapeutic targets.

The study was funded by the Medical Research Council, the Scottish Government’s Chief Scientist Office, EU Horizons and the Intensive Care Society.