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Further genetic clues to severe COVID-19

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New research published in Nature has revealed important genetic causes of the most severe forms of COVID-19 disease.

Researchers studied over 2,000 severely ill patients with COVID-19, and compared their genomes to those of healthy people from existing population studies in the UK. They found that patients were much more likely to possess variations in a small number of genes that affect anti-viral immune responses and inflammation – information that suggests existing drugs could be useful treatments for severe disease.

An unpredictable picture

COVID-19 has been known for almost a year now, but the variation in effects on different people remains baffling: some experience no discernible symptoms at all, others a mild or moderate illness, and some a very distinct, severe and life-threatening illness. Although certain clear risk factors have emerged for the most dangerous forms of the disease, notably older age and certain conditions such as heart disease, diabetes and severe obesity, both within and outside these groups, SARS-CoV-2 infection causes a bewildering and unpredictable range of responses.

Understanding precisely who is and is not at greater risk of dangerous forms of the disease would play a very important role in ongoing efforts to control the disease and prevent the worst effects. It would allow preventative efforts – including new vaccines – to be directed first towards those at greatest risk. It also offers important clues to the underlying mechanisms that drive the most severe forms of disease, and hence to potential treatments.

Why genetics matters

It has seemed likely from the beginning that genetic variation between different people accounts for some of the otherwise inexplicable variation in disease severity. It may also account for differing disease susceptibility – how likely someone is to become infected; this is the case for many other infectious diseases, though it is less obvious to see and hence to study. Doctors and scientists around the world have thrown themselves into efforts to uncover the genomic factors driving severe disease.

This new paper used DNA samples from over 2,200 patients with severe COVID-19 treated in over 200 intensive care units were obtained from to major research initiatives, the GenOMICC (Genetics Of Mortality In Critical Care) and the ISARIC Coronavirus Clinical Characterisation Consortium 4C studies. Genome sequences were compared with healthy control subject genomes from the UK Biobank to identify areas of the genome where there were significant differences. Findings were checked against samples from a similar number of hospitalised cases from the COVID-19 Host Genetics Initiative.

Genetic handles on severe disease

A handful of important genes involved in severe COVID-19 were identified, of two main types. The first group were genes involved in antiviral defences; the OAS gene helps block replication and spread of the virus, whilst IFNAR2 is involved in the production of an important immune mediator, interferon, which helps to trigger immune responses to viral infections. Weak early responses to infection could help the SARS-CoV-2 virus to spread and grow in the patient.

These discoveries are in line with earlier findings that pinpointed genetic changes that impaired interferon function among severe COVID-19 patients. Whilst giving interferon to critically ill patients has not proved very effective, there is hope that early administration to people with genetic predisposition to poor interferon responses who are infected by the virus might prevent severe disease.

The second group of genes implicated in severe COVID-19 were likely to play a role in the dangerous inflammatory lung damage seen in patients in critical care. These included rare variants in the TYK2, DPP9 and CCR2 genes. TYK2 is involved in controlling immune response; a rare variant that causes excessive inflammation was common among patients. This is a positive finding, since there are already anti-inflammatory drugs that target this particular biological pathway, and could prove to be valuable new treatments. Both DPP9 and CCR2 are also involved in different aspects of inflammatory responses to infection.

Genome-powered progress

The researchers expect that there are other genes that affect the risk of severe disease, and hope to uncover more of these in due course as they analyse genomes additional patients; rarer genetic changes are harder to find and require larger numbers of people in studies. They are particularly interested in additional genetic factors that might account for the increased risk of severe disease seen in certain ethnic groups.

Meanwhile, other researchers continue to employ genome sequencing of the virus itself, rather than human hosts, to aid the battle against COVID-19. The UK government recently announced an additional £12.2 million funding for the COVID-19 Genomics UK (COG-UK) Consortium to continue and expand viral genome sequencing. Combining this information with patient data helps to identify whether the virus is becoming more or less infectious, or dangerous, or amenable to new vaccines – all vital information.

Tackling COVID-19 without the insights provided by genomics would be infinitely more difficult – like trying to understand the virus and the disease blindfolded – and would undoubtedly have hugely slowed the development of vaccines, treatments and other responses to limit the harm caused by the pandemic.

Take a look at our short animation on pandemic in the genomic era

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