Oxford Scientists Identify Gene That Could Be Responsible For Increasing Severity Of Covid-19 In People Of Southern Asia; Vaccine More Effective In Such Cases

Researchers at the University of Oxford have discovered a gene that could increase the risk of lung failure and mortality from Covid-19, explaining why the people of South Asian heritage had a higher risk of severe disease compared to others.

The team of experts discovered that a higher-risk form of the gene hinders the cells lining the airways and lungs from effectively responding to the virus.

According to the study published on 4 November in Nature Genetics, 60 per cent of people with South Asian ancestry had this variant of the gene, compared to 15 per cent of persons with European ancestry.

In the study, the team noted: “Genome-wide association studies identified the 3p21.31 region as conferring a twofold increased risk of respiratory failure.”

“Selective spatial transcriptomic analysis of lung biopsies from patients with Covid-19 shows the presence of signals associated with epithelial–mesenchymal transition (EMT), a viral response pathway that is regulated by LZTFL1,” the study added.

The team also said: “We conclude that pulmonary epithelial cells undergoing EMT, rather than immune cells, are likely responsible for the 3p21.31-associated risk. Since the 3p21.31 effect is conferred by a gain-of-function, LZTFL1 may represent a therapeutic target.”

In simple terms, the scientists said that the LZTFL1 gene affects how the lungs respond to viral infection and is the most important genetic risk factor discovered thus far.

According to the researchers, vaccination, which remains the greatest form of protection for people with the LZTFL1 gene, would be especially beneficial. However, this finding highlight the prospect of research into medicines targeted to patients with this gene.

The New Gene

James Davies, co-lead author of the study and associate professor of genomics at Oxford, who also worked in intensive care during the peak of the pandemic said that the genetic element the team of researchers discovered explains why some people become critically ill after being infected with the novel virus.

“It shows that the way in which the lung responds to the infection is critical. This is important because most treatments have focussed on changing the way in which the immune system reacts to the virus” he added.

The researchers utilised a new way to focus on the DNA behind this specific genetic signal after training an algorithm to scan enormous amounts of genetic data from hundreds of different types of cells all across the body.

Davies explained that “if you have the higher-risk genotype and you get very unwell with Covid, there’s a 50 per cent chance that that wouldn’t have happened to you had you had the lower-risk genotype”.

The findings may explain why particular groups across the Indian subcontinent have witnessed greater rates of illness and death. Even many other factors, such as socioeconomic conditions, play a role, according to the scientists, therefore the gene cannot be used as a sole explanation.

According to the study, it was also discovered that 2 per cent of people with Afro-Caribbean ancestry had the higher risk genotype, implying that this genetic factor does not fully explain why black and minority ethnic communities had higher death rates.

In this case, Davies said: “The higher risk DNA code is found more commonly in some black and minority ethnic communities but not in others. Socioeconomic factors are also likely to be important in explaining why some communities have been particularly badly affected by the Covid-19 pandemic.”

He said that despite the fact that we can't modify our genes, these findings demonstrate that persons with the higher risk gene are more likely to benefit from immunisation.

“Since the genetic signal affects the lung rather than the immune system it means that the increased risk should be cancelled out by the vaccine,” he added.

This is not the first time when scientists found a link between genetics and Covid-19 severity. According to a separate study published in 2020, two German scientists found “a gene cluster on chromosome 3 as a risk locus for respiratory failure” after infection with SARS-CoV-2.

At that time scientists noted that “the risk is conferred by a genomic segment of around 50 kilobases in size that is inherited from Neanderthals and is carried by around 50 per cent of people in south Asia and around 16 per cent of people in Europe”.

When scientists in Sweden and Germany matched the DNA of very sick Covid-19 patients to that of Neanderthals and their enigmatic sibling group, the Denisovans, they discovered the origins of the risk genes. A segment of DNA found in a Neanderthal in Croatia closely matched the DNA found in people who are more prone to become very ill.