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, the cells lining the lungs seem to do less to protect themselves from infection with the coronavirus SARS-CoV-2.
The gene version that increases COVID-19 risk is present in 60 percent of people of South Asian descent, 15 percent of people of European descent, 2.4 percent of people of African descent and 1.8 percent of the people of East Asian descent.
“It’s one of the most common genetic signals, so it’s by far the biggest 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.
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Increase the risk
No gene can explain every aspect of a person’s risk for a disease like COVID-19. Many factors come into play, Davies told Live Science.
These include age, other health problems and socioeconomic status, which can affect both the level of exposure to the virus a person faces and the quality of health care they receive when they are sick.
India, for example, faced congested hospitals during the Delta wave, and the country has a high prevalence of type 2 diabetes and heart disease, which played a major role in the population’s death rate. But the risky version of LZTFL1 seems to have a remarkable impact. By comparison, every decade between the ages of 20 and 60, a person’s risk of severe COVID-19 doubles.
That means carrying the risky version of the LZTFL1 gene “basically roughly equals being 10 years older for your risk of COVID severity,” Davies said.
Researchers first discovered this gene using what’s called a genome-wide association study (GWAS). They compared the genomes of a group of patients with severe COVID-19 — defined as those with 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 set of genes that were more common in the severely affected patients than in the control group.
But figuring out which of those genes actually put you at increased risk wasn’t easy, 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 difficult to untangle which specific variation is responsible for an outcome, Hughes said. And while genetic sequences are present in every cell of 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 make up the blueprint for a protein. Instead, they were so-called enhancer regions — non-coding 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.
Enhancer sequences are very complex, and to make matters worse, they often don’t come close to the genes they regulate.
Imagine that DNA is all coiled up, like a tangled thread, in a cell nucleus: the enhancers just need to be in contact with the genes they control in that muddle, which means that if you stretched the DNA, the gene switch and its target may be a million base pairs of DNA apart.
To unravel the problem, the researchers turned to machine learning, which can make predictions about an enhancer’s function and the cell type in which it functions based on its DNA sequence. This approach to artificial intelligence lit up a particular amplifier “like a Christmas tree,” Hughes said.
The researchers had expected their risky enhancer sequence to be one that acted on nearby immune system genes, but they were surprised to find that their candidate worked in lung cells instead.
The next step was to find out which gene controlled that enhancer. The researchers used a technique called Micro Capture-C, with which the DNA tangle in a cell nucleus can be mapped in great detail. They found that the enhancer only came into contact with one gene: LZTFL1.
This was an exciting finding. Typically, GWAS research usually yields tens or hundreds of genes that influence a particular outcome.
“That double hit [to disease severity] is huge compared to your average GWAS hit for coronary heart disease, diabetes or something else,” Hughes said. “It’s incredibly strong.”
hope for therapy
LZTFL1 hadn’t been well studied before, but previous research had revealed something about the protein it encodes, which is involved in a complex array of signaling and communication surrounding wound healing. In the context of infection and inflammation, low levels of LZTFL1 promote the transition of certain specialized lung cells to 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 from COVID and found that their lungs were lined with large areas of these non-specialized cells. But counterintuitively, the process may be an attempt by the lungs to protect itself.
It’s not certain yet, Davies said, but unspecialized lung cells have fewer ACE2 receptors, the doorknobs SARS-CoV-2 uses to enter cells. It is possible that the despecialized cells are thus better protected against hijacking by the virus.
That means that in people with more LZTFL1 expression, this protective retraction is slowed down, allowing the virus to more effectively destroy the lungs before the cells can arm themselves in a new form. However, more direct research into lung damage from COVID-19 is needed to prove this, Davies said.
The discovery of the importance of LZTFL1, reported Nov. 4 in the journal Natural Genetics, could lead to new research on COVID-19 treatments, Hughes said.
Carrying the risky version of the gene is not a death sentence; although it increases the risk of serious illness, it does not guarantee it. Other genes or non-genetic factors can lower a person’s risk of serious disease, even in the presence of the high-risk 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 respond to COVID-19 vaccination like everyone else.
“We think vaccination will completely negate this effect,” he said.
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This article was originally published by Live Science. Read the original article here.