Researchers discover specific genetic signals in people who develop severe COVID-19

Researchers from the University of Sheffield and Stanford University in the US have discovered that there are specific genetic signals in people who get a severe coronavirus infection.

Age, body mass index, and pre-existing health conditions are known to account for some of the differences, but genetics also play an important role. This groundbreaking research aimed to address why some people with COVID-19 become seriously ill or die, while others have few or no symptoms.

Using machine learning, researchers from the University of Sheffield and Stanford Medicine have identified more than 1,000 genes linked to the development of severe COVID-19 cases that required respiratory support or were fatal. The team was also able to identify specific types of cells in which those genes act. It is one of the first studies to link coronavirus-associated genes to specific biological functions.

During the research, we uncovered the genetic architecture underlying the coronavirus infection and found that these 1,000 genes make up three quarters of the genetic factors for severe COVID-19. This is important to understand why some people have had more severe symptoms of Covid-19 than others.”

dr. Johnathan Cooper-Knock, NIHR Clinical Lecturer, Department of Neuroscience, University of Sheffield and study co-author

The study, published today (June 14, 2022) in the journal cell systems, was led by senior author Professor Michael P Snyder of Stanford University in collaboration with genetics instructor Dr. Sai Zhang and neuroscientist Dr. Cooper-Knock, who is currently a visiting researcher at Stanford.

The research process

The research team used several large data sets to unravel the genetics behind severe COVID-19. The first dataset contained genetic information from healthy human lung tissue. The data helped identify gene expression in 19 different types of lung cells, including epithelial cells that line the airways and are the first line of defense against infection.

Other data came from the COVID-19 Host Genetics Initiative, one of the largest genetic studies of critically ill coronavirus patients. The researchers looked for genetic clues in the data — DNA mutations, called single nucleotide polymorphisms — that could indicate whether someone is at higher risk for severe COVID-19. They tracked whether some mutations were more or less common in COVID-19 patients with severe disease.

Mutations that continued to appear, or were notably absent, in the patients who developed severe COVID-19 suggested that those variations may be behind the severity of the infection.

But genetic mutations on their own can be difficult to interpret. To better understand their findings, the team used other data describing which regions of the genome are important for different cell types in lung tissue. By overlapping the mutations on the cell-specific genomes, the researchers were able to identify which genes were malfunctioning and within which cell types.

risk genes

The researchers also wanted to know which types of cells harbored defective gene expression. Through their machine learning tool, they determined that severe COVID-19 is largely associated with a weakened response of two known immune cells: natural killer (NK) cells and T cells† NK cells and a subtype called ‘CD56 bright’ are considered the most important.

dr. Cooper-Knock added: “NK cells, which are what humans are born with and which form the body’s first line of defense against infection, are known for their ability to destroy viruses and cancer cells. NK cells also help produce a series of proteins of the immune system called cytokines One cytokine, interferon-gamma, is an important activator of immune cells.In conjunction with interferon-gamma, NK cells form an immediate and coordinated defense against viral infections.

“NK cells are like the generals leading the war. They mobilize other immune cells and tell them where to go and what to do. We found that in people with severe coronavirus infection, crucial genes in NK cells are less expressed “So there’s less robust immune response. The cell isn’t doing what it’s supposed to do.”

Professor Snyder compared COVID-19 risk genes to harmful variants of the BRCA genes that predispose some people to breast and ovarian cancer.

Professor Snyder said: “Our findings lay the foundation for a genetic test that can predict who will be born at increased risk of severe COVID-19.

“Imagine there are 1,000 changes in DNA associated with severe COVID-19. Having 585 of these changes can make you quite susceptible, and you would want to take all the necessary precautions.”

dr. Cooper-Knock also noted that drugs that slow down NK cells have already been suggested to treat some types of cancer. “The drugs bind to receptors on the NK cells and make them have a stronger response,” he said. Trials of NK cell infusions for severe COVID-19 are underway.”

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