Genetic variants linked to severe COVID-19 identified

Five genes associated with the development of critical illness in patients with COVID-19 have been identified.

Researchers led by Dr Kenneth Baillie, academic consultant in critical care medicine, Roslin Institute, University of Edinburgh, performed a genome-wide association study on 2244 critically ill patients with COVID-19 from 208 UK intensive care units, which represents more than 95 percent of all intensive care beds. They compared the genetic make-up of these patients to a control group, and identified five genetic sequences that were more common in those patients who became critically ill with COVID-19. These genetic sequences all relate to genes that are involved in inflammatory processes and the body's response to viruses.

Dr Kenneth Baillie explained 'The really exciting thing about this study is that we have found genes that are directly therapeutically relevant, so they lead us directly to treatments.'

The global collaborative study was intended to understand the genetics underlying susceptibility to life-threatening illness, but also to understand new infections like COVID-19.

Scientists have known for many years that variation in susceptibility to infection is strongly genetic. Hence, looking into the genome is a good place to investigate the complexity of the immune system.

COVID-19 is an inflammatory condition, and for the purpose of this study, only patients were included who had severe inflammatory lung disease, caused by COVID-19, and who were in the ICU with a ventilator breathing for them.

Published recently in Nature, the scientists found crucial differences in the genes IFNAR2, TYK2, OAS1, DPP9 and CCR2.

Of the gene mutations the researchers discovered, the most clinically relevant is TYK2 (tyrosine kinase 2), which is a signalling molecule associated with multiple different pathways that promote inflammation. The scientists performed computational analysis on the genetic variant that changes the amount of TYK2 that your body produces and discovered that people who produce more TYK2 are more susceptible to severe COVID-19. Dr Baillie suggests inhibiting the TYK2 enzyme as a treatment for severe COVID-19.

Importantly, a class of drugs, called JAK inhibitors, inhibit TYK2 and are already approved for medical use. Baricitinib is one such drug that is used in the treatment of rheumatoid arthritis, and now baricitinib is undergoing clinical trials for use in the treatment of COVID-19.

Similarly, a drug called phosphoesterase 12 inhibitor targets the OAS1 (oligoisoadenylate synthetase 1) gene, which promotes the signalling through the anti-viral pathways that these genes initiate and creates an enzyme that degrade viral RNAs.

Furthermore, the scientists propose that increasing the activity of the gene INFAR2 (interferon-α/β receptor 2) could create protection to COVID-19 in the early stages of disease, which they believe may mimic the effect of interferon treatment, which triggers the immune system to defend against viruses.

Overall, the findings suggest that severe COVID-19 is the result of at least two biological mechanisms: innate antiviral defences, which are known to be important early in the disease, and host-driven inflammatory processes, which are a key feature of late, life-threatening COVID-19. The evidence strongly supports the urgent need for large-scale clinical trials to assess the use of drugs targeting the genes involved in the treatment of COVID-19.

Dr Baillie said: 'What our study does is find a much stronger signal, it is by far the strongest genetic signal of any of the studies that have been seen and by far the largest study of its type that is looking at patients with critical illness'.

The team are continuing their efforts with the aim to whole genome sequence 35,000 people. For every patient, they need to find a match who had COVID-19 but did not require hospital treatment. To register for this trial please visit here.