Researchers from the Genetics of Susceptibility and Mortality in Critical Care (GenOMICC) consortium compared the genetic information of COVID-19 patients in intensive care units (ICUs) with samples provided by healthy volunteers from other studies, such as:
- UK Biobank
- Generation Scotland
- 100,000 Genomes.
A global collaboration
The GenOMICC consortium is a global collaboration to study genetics in critical illness backed by £28 million from:
- Genomics England
- UK Research and Innovation (UKRI)
- Department of Health and Social Care (DHSC)
- National Institute for Health Research (NIHR).
The study, published in Nature, pinpointed genes involved in two molecular processes – anti-viral immunity and lung inflammation as being associated with the most severe form of the disease.
The findings will help doctors understand how COVID-19 damages lungs at a molecular level and help to identify existing drugs that target the actions of these genes and which therefore have the potential to be repurposed to treat COVID-19.
Immune system
Researchers made the discovery by studying the DNA of 2,700 patients in 208 ICUs in the UK. The team found key differences in five genes of the ICU patients compared with samples provided by healthy volunteers.
The genes – IFNAR2, TYK2, OAS1, DPP9 and CCR2 – partially explain why some people become desperately sick with COVID-19, while others are not affected.
Having highlighted the genes, the team were then able to predict the effect of drug treatments on patients, because some genetic variants respond in a similar way to particular drugs. For example, they showed that a reduction in the activity of the TYK2 gene protects against COVID-19.
Anti-inflammatory drugs
A class of existing anti-inflammatory drugs called JAK inhibitors, which includes the drug baricitinib, are known to also reduce activity of the TYK2 gene, and hence may have potential in managing patient with COVID-19.
Indeed, the Food and Drug Administration has recently issued an emergency use authorisation for baricitinib, in combination with remdesivir, for the treatment of COVID-19 in hospitalised patients.
They also discovered that a boost in the activity of the gene INFAR2 is also likely to create protection, because it is likely to mimic the effect of treatment with interferon – proteins released by cells of the immune system to defend against viruses. However, experts caution that to be effective, patients might need the treatment early in disease.
Key drug targets
Based on the findings published in Nature, the researchers say that clinical trials should focus on drugs that target these specific anti-viral and anti-inflammatory pathways.
Dr Kenneth Baillie, the project’s chief investigator and Academic Consultant in Critical Care Medicine and Senior Research Fellow at The University of Edinburgh’s Roslin Institute, said: "This is a stunning realisation of the promise of human genetics to help understand critical illness. Just like in sepsis and influenza, in COVID-19, damage to the lungs is caused by our own immune system, rather than the virus itself. Our genetic results provide a roadmap through the complexity of immune signals, showing the route to key drug targets.
"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.
"This work is only possible because of the generous contribution of the patients themselves and their families, research teams in NHS hospitals across the country, and the generous funding we’ve received from the public and organisations."
UK’s leading genomics capabilities
Dr Jonathan Pearce, Interim Director for the COVID-19 response at the Medical Research Council, which provided £3 million in funding to the project, said: "Identifying genes associated with severe COVID-19, including in young patients without known underlying health issues, will allow us to better target and accelerate research into new diagnostic and therapeutic approaches. This study builds on the UK’s leading capabilities in the genetic analysis of disease."
GenOMICC started in 2015 as an open, global consortium of intensive care clinicians dedicated to understanding genetic factors that influence outcomes in intensive care from diseases such as SARS, influenza and sepsis. Throughout 2020 it has been focused on COVID-19 research in partnership with Genomics England.
GenOMICC is funded by:
- Sepsis Research (Fiona Elizabeth Agnew Trust)
- Intensive Care Society
- Wellcome
- UKRI
- NIHR
- Scotland’s Chief Scientist Office
- DHSC.
Image by Pete Linforth from Pixabay