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An artist's impression of a DNA molecule. A version of the gene LZTFL1, involved in the regulation of lung cells in response to infection, increases the risk of severe infection and death from COVID-19.
(Image credit: KATERYNA KON/SCIENCE PHOTO LIBRARY via Getty Images)
Researchers have identified a version of a gene that doubles a person's risk of severe COVID-19 and doubles the risk of death from the disease for people under 60.
The gene, LZTFL1, is involved in the regulation of lung cells in response to infection. When the risky version of the gene is present, cells lining the lungs seem to do less to protect themselves from infection with the coronavirus SARS-CoV-2. The gene version that raises COVID-19 risk is present in 60% of people of South Asian ancestry, 15% of people of European ancestry, 2.4% of people with African ancestry and 1.8% of people with East Asian ancestry.
"It's one of the more prevalent genetic signals, so it's by far the most important genetic hit in COVID," said James Davies, a professor of genomics at the University of Oxford and one of the leaders of the new research.
No single gene can explain every aspect of someone's risk from a disease like COVID-19. Many factors play a role, Davies told Live Science. These include age, other health conditions and socioeconomic status, which can influence both how much exposure to the virus a person faces and the quality of health care they receive if ill. India, for example, experienced overwhelmed hospitals during its delta surge, and the country has a high prevalence of type 2 diabetes and heart disease, which played a huge role in the mortality rate in its population. But the risky version of LZTFL1 does seem to have a notable impact. For comparison, each decade of age between 20 and 60 doubles a person's risk of severe COVID-19.
That means that carrying the risky version of the LZTFL1 gene "is roughly equivalent to being 10 years older, in effect, for your risk of severity of COVID," Davies said.
Researchers first homed in on this gene using what’s called a genome-wide association study (GWAS). They compared the genomes of a group of patients who had severe COVID-19 — defined as those who had respiratory failure — with the genomes of a control group of participants who had either no evidence of infection or a history of infection with mild symptoms. This study revealed a suite of genes that were more prevalent in the severely impacted patients than in the control group.
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But figuring out which of those genes actually conferred increased risk was not straightforward, said Jim Hughes, a professor of gene regulation at the University of Oxford who co-led the study. Variations in genes are often inherited as a block, making it hard to untangle which particular variation is responsible for an outcome, Hughes said. And while genetic sequences are present in every cell in the body, they affect only a few cell types.
Finally, the genetic sequences the researchers were trying to understand were not the simple, straightforward genes that provide the blueprint for a protein. Instead, they were so-called enhancer regions — noncoding sequences that regulate how other genes are expressed. An enhancer is a bit like a switch, turning target genes on and off and up and down at different times in different tissues, Hughes said.
Genetic detective
Enhancer sequences are very complex, and to make matters worse, they are often nowhere near the genes they regulate. Imagine DNA all balled up, like tangled yarn, inside a cell nucleus: The enhancers just have to be in contact with the genes they control in that jumbled ball, meaning that if you were to stretch out the DNA, the gene switch and its target might be a million DNA base pairs away from each other.
To unravel the problem, the researchers turned to machine learning, which can make predictions about an enhancer's function and the cell type it functions in based on the DNA sequence. This artificial intelligence approach lit up one particular enhancer "like a Christmas tree," Hughes said. The researchers had expected their risky enhancer sequence to be one that acted on nearby genes of the immune system, but they were surprised to find that their candidate acted, instead, in lung cells.
The next step was to figure out which gene that enhancer was controlling. The researchers used a technique called Micro Capture-C, which allows for extremely detailed mapping of the tangle of DNA inside a cell nucleus. They found that the enhancer contacted just one gene: LZTFL1.
This was an exciting finding. Typically, GWAS research usually returns dozens or hundreds of genes that affect any given outcome.
"That twofold hit [to disease severity] is massive compared to your average GWAS hit for coronary heart disease, diabetes or anything else," Hughes said. "It's incredibly strong."
Hope for therapeutics
LZTFL1 hadn't been well-studied before, but previous research had revealed a bit about the protein it codes for, which is involved in a complex series of signalling and communication around wound healing. In the context of an infection and inflammation, low levels of LZTFL1 promote the transition of certain specialized lung cells into a less specialized state. Higher levels of LZTFL1 slow this transition.
The transition certainly occurs in patients with severe COVID-19. The research team examined lung biopsies from people who had died of COVID and found that their lungs were lined with large areas of these despecialized cells. But counterintuitively, the process may be an attempt by the lungs to protect themselves.
It's not yet certain, Davies said, but despecialized lung cells have fewer ACE2 receptors, the doorknobs that SARS-CoV-2 uses to enter cells. It's possible that the despecialized cells are thus more protected from being hijacked by the virus.
That means that in people with more LZTFL1 expression, this protective retreat is slowed, allowing the virus to ravage the lungs more effectively before the cells can armor themselves in a new form. More direct research on COVID-19 lung damage is needed to prove this, however, Davies said.
The discovery of LZTFL1's importance, reported Nov. 4 in the journal Nature Genetics, may lead to new research into COVID-19 treatments, Hughes said.
Carrying the risky version of the gene is not a death sentence; while it raises the risk of severe disease, it does not guarantee it. Other genes or non-genetic factors may lower a person's risk of severe disease even in the presence of the risky sequence. And because the gene isn't involved in the immune system, Davies said, people who carry the high-risk version of the gene are likely to be just as responsive to COVID-19 vaccination as everyone else.
"We think that vaccination will completely cancel out this effect," he said.
Stephanie Pappas is a contributing writer for Live Science, covering topics ranging from geoscience to archaeology to the human brain and behavior. She was previously a senior writer for Live Science but is now a freelancer based in Denver, Colorado, and regularly contributes to Scientific American and The Monitor, the monthly magazine of the American Psychological Association. Stephanie received a bachelor's degree in psychology from the University of South Carolina and a graduate certificate in science communication from the University of California, Santa Cruz.
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