Five genes have been identified which increase the likelihood of a Covid-19 patient being admitted to intensive care and dying.
A landmark study from the University of Edinburgh gathered DNA from 2,700 Covid-19 patients in 208 intensive care units across the UK.
These are the most severe cases of Covid, and 22 per cent of patients studied died, with 74 per cent unable to breathe on their own and needing mechanical ventilation.
The genetic information of these patients was compared to 100,000 anonymous Britons, and five genes emerged as being extremely common in severe Covid cases.
Researchers say the discovery of five genes that appear so clearly to be linked to the disease is unprecedented in the field.
Knowing which genes are involved in severe cases of coronavirus infection can help scientists identify pre-existing drugs that could help treat Covid, the researchers say.
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Identifying genes which are involved in severe cases of coronavirus infection can help identify which preexisting drugs could be repurposed to fight Covid, the researchers say (file photo)
Revealed: the five genes
Creates an enzyme that can lead to inflammation
Is targeted with JAK inhibitors and one already approved for use in humans is baricitinib which treats rheumatoid arthritis
Targetable by drugs that are in trials but are not widely used, for psoriasis
Evidence for this gene is not as strong as for other genes in the study, but Dr Baillie says it is still ‘compelling’
Is a gene that initiates a signal that activates an enzyme which degrades RNA derived from viruses.
Several other coronavirus have a way of preventing this mechanism. No evidence yet for SARS-CoV-2, but it might be a specific feature that does this.
Targettable by a class of drugs called phosphodiesterase 12 inhibitors.
These are not currently in clinical trials but theoretically would enhance antiviral effect of this system.
This is a core part of signalling that is responsible to the host antiviral response.
Signalling in this pathway is important in the chance of getting sick.
Relevant in fighting the virus directly, much like OAS1. This is more important early in the disease as later in the disease, virus levels drops and the issue comes from the body’s immune system attacking itself.
Known to play several roles in inflammation but the researchers do not yet know exactly where it fits in to the Covid-19 disease progression.
They are therefore unable to make a direct therapeutic prediction.
It is associated with pulmonary fibrosis and might be associated with ‘long covid’.
The genes were identified across the genome, with two on chromosome 19 called TYK2 and DPP9. One, called IFNAR2, is found on chromosome 21.
CCR2 is a gene found on chromosome four and OAS1 is located on the twelfth chromosome.
The high prevalence of these genes can partially explain why some people become desperately sick with Covid-19, while others are not affected.
The importance of this study is that it identifies specific genes which play a role in coronavirus disease, and therefore exposes them as targets for potential treatments.
All five of the genes fell into one of two groups: modulators of inflammation or antivirals. The latter stops the virus from replicating in the body.
But in severe cases of Covid the virus levels have often already dwindled, and the vast majority of the damage is being caused by a malfunction in the body’s own immune system, causing it to attack the lungs and trigger severe inflammation.
There is no current cure for this. A similar phenomenon occurs in sepsis, and it can be fatal in both cases.
The closest thing to a cure is dexamethasone, a steroid which can save the lives of up to 35 per cent of patients relying on ventilators
One of the inflammatory genes is TYK2, which was singled out by the researchers as being a prime target for future clinical trials.
As part of the study the researchers ran a process called Mendelian randomisation, which allowed them to simulate a clinical trial.
The researchers used this to compare people with differing levels of expression of TYK2 and found ‘people who produce more TYK2 are more at risk of Covid’, said study lead author Dr Kenneth Baillie.
TYK2 creates an enzyme and, if production of this enzyme goes awry, it can lead to excessive inflammation – a potentially fatal outcome following infection.
But the discovery of TYK2’s involvement in Covid-19 is key as there is already a drug that targets it, called baricitinib.
It is known as a JAK inhibitor and is already approved for human use in the treatment of rheumatoid arthritis.
‘We predict that JAK inhibitors should confer benefit on [Covid-19] patients that should decrease the probability of them developing life-threatening lung inflammation,’ said Dr Baillie.
A landmark study from the University of Edinburgh gathered DNA from 2,700 Covid-19 patients in 208 intensive care units across the UK. These are the most severe cases of Covid and 22 per cent of patients studied died (file photo)
Making these associations and predictions based on genetic clues found in ICU patients is imperative in informing decisions about which pre-approved drugs are next tested as part of clinical trials.
‘Our results immediately highlight which drugs should be at the top of the list for clinical testing. We can only test a few drugs at a time, so making the right choices will save thousands of lives,’ Dr Baillie says.
‘It’s absolutely startling that we have seen this result so quickly after the start of the outbreak,’ he adds.
‘This result took six months to find it but we don’t have this level of biological insight into sepsis or influenza or other forms of critical illness that we see every year.
‘It’s a really important kind of evidence, it’s very strong causal evidence.
‘It’s a kind of evidence we have been crying out for in critical care medicine for decades and it is completely astonishing we have got it already for Covid.’
Professor Sir Mark Caulfield, chief scientist for Genomics England, a partner in the project, said: ‘I’ve been in complex trait genetics for 30 years trying to understand the biology of these diseases and the effects you see here, and the number of them, is extremely unusual.
‘This is telling us that our genetic makeup really does play a part in severity.’
Minister for Innovation, Lord Bethell, said: ‘Research like this is a big step forward in going further to advance our understanding of COVID-19 to help us protect the most vulnerable – ultimately saving lives across the world.’
The paper is published today in Nature.