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

A genetic variant carried by nearly one in three people worldwide has been linked to an increased risk of severe COVID-19, lung fibrosis and other serious lung diseases, as well as altered responses to treatment, in a new international study from the University of Edinburgh and the University of Sydney¹.

The research, conducted in the UK and Australia, reveals that this common genetic difference disrupts the function of a previously unknown lung enzyme, uncovering a hidden biological pathway that may explain why some individuals are more vulnerable to life-threatening respiratory disease.

Newly discovered lung enzyme reveals hidden disease pathway

Researchers identified a newly discovered enzyme present in lung tissue that is associated with infections, inflammation and lung cancer. By analysing genetic data, the team found that a specific variant alters the structure and function of this enzyme, changing how it behaves in the lung and how it responds to a drug.

This discovery highlights a previously unrecognized biological pathway that may contribute to severe COVID-19 and lung fibrosis. It also suggests that inherited genetic differences can influence both disease susceptibility and how patients respond to certain treatments.

Overlooked proteins in the human genome

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

Because these proteins were not known, genetic differences that affect them have often been overlooked. This has limited scientists’ understanding of how inherited genetic variation contributes to conditions such as severe respiratory disease, kidney disease, heart disease and rare genetic disorders.

The new study adds to growing evidence that the human genome contains many previously overlooked proteins that may have important roles in health and disease. Understanding where these proteins are found in the body, how they change during illness and how genetic variation affects their function could improve diagnosis and reveal new therapeutic targets.

New method to measure hidden proteins in cells

To investigate these newly identified proteins, researchers from the University of Edinburgh’s Institute of Genetics and Cancer, working with partners at the University of Sydney’s Centenary Institute, developed a new method to measure their abundance within cells.

This approach allows scientists to detect and quantify these proteins even when they are present at very low levels. Using this method, the team showed 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 risk and severity.

Genetic variants linked to COVID-19, lung, kidney and heart disease

Focusing on the newly identified lung enzyme, the researchers demonstrated that a common genetic variant changes the enzyme’s function and modifies its response to a drug. This provides new insight into how genetic differences may influence the risk of severe COVID-19, lung fibrosis and other lung diseases, as well as how patients may respond to specific therapies.

The team also identified similar genetic changes affecting other 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.

Experts say the findings suggest that many disease-associated genetic variants may act through proteins that have only recently been recognized, opening new opportunities to improve diagnosis and identify therapeutic targets across a range of conditions, from severe COVID-19 and lung fibrosis to kidney and heart disease.

Dr Simon Biddie, of the University of Edinburgh’s Institute of Genetics and Cancer, said, “For decades, we have interpreted genetic variation through the lens of the proteins we knew existed. Our findings show that many genetic changes linked to disease may actually act through previously hidden proteins that have only recently come to light. Understanding these proteins could transform how we diagnose genetic diseases and identify new targets for treatment.”

Professor Mark Gorrell, of the Centenary Institute and the University of Sydney, who first discovered the enzyme and was part of the team for this study, added: “This new research both explains the association of the enzyme with lung diseases and opens up new avenues to understand this enzyme in disease and help us devise potential therapies.”

References

1. Weykopf G, Badonyi M, Friman ET, et al. Disease-associated genetic variants can cause missense effects in tissue-specific protein isoforms. Nat Commun (2026). https://doi.org/10.1038/s41467-026-74280-w

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