The recent GenOMICC study led by Dr Kenneth Baillie, an Academic Consultant in Critical Care Medicine from the Roslin Institute, University of Edinburgh, has revealed novel genetic associations with critical illness in COVID-19.

As a new student at the IGMM, starting my PhD during a world-wide pandemic has been a strange and challenging experience. Nevertheless, it is clear that scientific research is now more important than ever, and COVID-19 has served to highlight to me the relevance of genetic studies in understanding how patients’ immune systems respond to novel viruses. Exemplifying this is the recent GenOMICC (Genetics of Mortality in Critical Care) study “Genetic mechanisms of critical illness in COVID-19” led by critical care specialist Kenneth Baillie from the Roslin Institute, University of Edinburgh.

GenOMICC is an open-source, global consortium of clinicians and scientists trying to understand how our DNA determines our susceptibility to emerging infections, sepsis, and other forms of critical illness. Launched by Dr Baillie in 2016, the project aims to analyse the genomes of 100,000 critically ill patients, in order to identify specific genes that influence outcome in critical illness. Ultimately, this research can help identify new drug targets and therapeutic avenues¹. Recently, the group collaborated with Genomics England and COG-UK to sequence the whole genomes of patients with severe COVID-19. They have now reported the results of a genome-wide association study (GWAS) that identified and replicated four significant genetic associations with critical illness in COVID-19². As the name suggests, GWAS is an approach used to identify associations between specific genetic variants and traits, such as disease³. The study also identified potential targets for repurposing licenced medication, which could help save the lives of patients with COVID-19⁴. I found this work fascinating and reached out to Dr Baillie, who kindly agreed to discuss his research with me.

What motivated you to establish the GenOMICC community?

“I started the project because I think the problems that we have in understanding disease biology and critical care medicine have been very difficult to solve. I think genomics represents a new opportunity and a new tool that could offer tremendous insights into the biological processes that we are trying to modify with treatment.”

Which result from the study was most interesting to you?

“They are all interesting! There are four new genetic associations with critical illness in COVID-19 which are robust and were replicated by external studies. We have just discovered them, and we are trying to work out what they mean – so, I think my answer to that question will change every week, as I learn more about each of them.”

“However, the one that I think is most thrilling is the TYK2 association. We showed by Mendelian randomisation that expressing more of the RNA encoding that enzyme [TKY2] is associated with worse disease. This suggests that inhibiting TYK2 might make people less likely to get severe COVID-19.”

“If that is the case, it would be great news, because there is a drug [baricitinib] that does this already, and it is already in consideration for treatment of COVID-19.” Baricitinib has previously been approved for the treatment of rheumatoid arthritis, meaning it could relatively easily be repurposed. “In fact, there are a whole class of drugs called JAK inhibitors that inhibit TYK2 and are very plausible for use in the treatment of COVID-19. If that bears out of clinical trials it will be a really great step forward.” JAK inhibitors act as anti-inflammatory drugs – these findings suggest that limiting the host inflammatory response could be key for improving the outcome of severe COVID-19.

What is the timeframe for repurposing medication?

“Straightaway – we have done it for COVID-19 faster than any other disease. I am very fortunate to be on the steering committee for the RECOVERY [Randomised Evaluation of COVID-19 Therapy] trial, led by Peter Horby and Martin Landray at the University of Oxford. We set the trial up in March, and the first results were available at the end of June. This was an astonishingly rapid turn-around.“

“The treatment that we repurposed there is called dexamethasone, a synthetic corticosteroid, and it is an effective treatment for severe COVID-19. In fact, in critically ill patients it reduced the chance of dying by more than 30%, which is an absolutely extraordinary effect size. If the same is true for other drugs, then we could potentially detect it quite quickly.”

“Another factor that determines how quickly you can get an answer is the event rate for the outcome of interest, which for the RECOVERY trail is mortality at 28 days. Sadly, that is still a very large portion of patients. For these reasons, we have been able to answer questions relating to treatment of COVID-19 very quickly.”

We might be able to save tens of thousands of lives by getting effective treatments sooner

– Dr Kenneth Baillie, Rosilin Institute

Can this work still be helpful now that we have a vaccine for COVID-19?

“It can! We now know more about COVID-19 than we do about any of the other diseases that I treat year in, year out. The most common disease process in critical care is sepsis – it kills tens of millions of people around the world each year. There are two things that we do not know about sepsis that we do know about COVID-19. One: we have got a treatment for COVID-19 while we don’t have any at all for sepsis, despite 40 years of clinical trials. We know that we need to modify the host response, and we have never managed to do it [for sepsis], whereas, for COVID-19 we did it within three months. Two: we now also know genetic variants that alter the propensity to develop critical illness.”

“It is quite possible that some of those genetic variants will also be relevant to your chance of developing lung injury in flu, or other disease processes. Therefore, having that knowledge itself could directly impact our understanding of other forms of critical illness. Furthermore, demonstrating that genetics can lead to treatments that modify the host response in critical illness – we have never done that before. Now that we have shown that we can, I think that really does open up a huge opportunity to make an impact in disease processes that we have never touched on before.”

How will your work with GenOMICC help inform our response to future novel viruses?

“Our response has been very fast, this time around. I think we could do it even faster next time around. At the start of the outbreak we were already recruiting to GenOMICC in around half of the ICUs in the UK. We are now recruiting in almost all of them, and we are recruiting in 6 countries internationally, as well. The aim of the GenOMICC project has always been to get to 100,000 critical illness genomes and really tackle these complicated problems that we have never understood in sepsis, flu, and other forms of critical illness. The very first inclusion criteria, from the beginning of study, was SARS, MERS, or other emerging infections. Therefore, the fact that we are already recruiting makes it possible to do these things quickly.”

“The probability of another novel outbreak occurring is always there, and it is something we need to be ready for. New diseases require new treatments, so we need the ability to try new treatments and to identify new disease mechanisms. Large-scale genetic studies, like this one, are now part of that process.“

As the largest study of its kind anywhere in the world, the GenOMICC project has the potential to make a substantial impact on the way we treat critical illness. The exciting results obtained by Kenneth Baillie and his team have identified specific gene variants that increase risk of severe COVID-19, in addition to demonstrating that these findings can be translated into clinical practice³. It will be very interesting to see what future insights can be obtained from this type of genetic analysis.

Read the paper: https://doi.org/10.1038/s41586-020-03065-y

The GenOMICC study is supported by Sepsis Research (FEAT), the Intensive Care Society, the Wellcome Trust, and the Medical Research Council.

It is because of their support that this study could be established, and it has been tremendously valuable to work with them

– Dr Kenneth Baillie, Rosilin Institute

References and further reading

1. Cano-Gamez, E., Trynka, G. (2020) From GWAS to Function: Using Functional Genomics to Identify the Mechanisms Underlying Complex Diseases. Front Genet. 11:424
2. Castineira, E.P., et al. (2020) Genetic mechanisms of critical illness in Covid-19. Nature. 762
3. Visscher, P.M. et al. (2017) 10 Years of GWAS Discovery: Biology, Function, and Translation. Am. J. Hum. Genet. 101(1):5-22
4. Pushpakom, S. et al. (2018) Drug repurposing: progress, challenges, and recommendations. Nat. Rev. Drug Discov. 18:41-58

Using our genetic code to understand critical illness in COVID-19 / Institute of Genetics and Cancer by blogadmin is licensed under a Creative Commons Attribution CC BY 3.0

Share