Case study: Harnessing genetics to treat serious illness from COVID-19 - GenOMICC
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Can genes affect how sick you get from infections?
Some young, healthy people experience life-threatening illness when they get COVID-19, despite not having risk factors that may predispose them to serious infection.
Susceptibility to infections, such as sepsis and influenza, is known to be very strongly determined by a person's genetics. It is harder to tell if there are specific genetic factors that alter a patient's chance of survival once they are already desperately sick. Researchers anticipate that the same genetic links apply to infection with coronavirus.
The Genetics of Susceptibility and Mortality in Critical Care (GenOMICC) study is researching which specific genes mean that some people are more likely to get particular infections and which genes mean some people become severely ill.
The international study, which is the largest of its kind anywhere in the world, was initially set up in 2016 to investigate sepsis and other forms of critical illness resulting from infection. Crucially, it was also set up to study emerging infections, with SARS and MERS being the relevant diseases at the time.
“I have a long-standing interest in outbreaks of respiratory virus, and like many infectious diseases specialists knew that a big pandemic would appear sooner or later,” says Dr Kenneth Baillie, Chief Investigator of the GenOMICC study at the University of Edinburgh. “We designed this study with a catch-all inclusion criterion for emerging infections, to prepare for this upcoming unknown outbreak.”
The study takes blood samples from critically ill patients in intensive care units (ICUs), from which the patient’s DNA is extracted and analysed. This DNA is compared with DNA from healthy people, using information from the UK BioBank, and with DNA from people with other types of critical illness.
Turning the focus to COVID-19
Once the scale of the COVID-19 pandemic became clear, Dr Baillie and his colleagues rapidly set up the emerging infections element of GenOMICC to recruit patients with coronavirus infection. “Without changing anything about the study, people could start recruiting COVID-19 patients,” he says. “The study was ready for it.”
A critical milestone in the set up and recruitment of COVID-19 patients to GenOMICC was the help of the NIHR. “We applied for and were granted Urgent Public Health Research status, which meant that with the help of the NIHR Clinical Research Network we could rapidly double recruitment to more than 200 ICUs, almost all units in the country,” says Dr Baillie.
The study also received a boost in May with the award of £28 million of funding from Genomics England, UK Research and Innovation, the Department of Health and Social Care, and the NIHR.
This funding has facilitated a collaboration with life sciences company Illumina that has allowed the researchers to expand from analysing sets of specific genes to sequencing patients' entire genetic code. In addition, the extra funding means that the researchers can recruit a whole new comparison group for the study of patients with mild COVID-19.
The GenOMICC study has already recruited more than 11,600 participants with COVID-19 in over 200 ICUs across the UK (as of 3 March 2021), with researchers aiming to recruit around 20,000 COVID-19 patients in total.
“In the UK we have the extraordinary capability to recruit across the UK using the NIHR Clinical Research Network, which means we have an ability to recruit on a scale not possible in other countries. The NIHR is the envy of researchers around the world.
Dr Kenneth Baillie, Chief Investigator of the GenOMICC study
One of these study sites is the ICU at Maidstone and Tunbridge Wells NHS Trust, which has been recruiting to GenOMICC since last year, before the COVID-19 pandemic took hold.
“It is interesting looking at the unknowns and why some people fall particularly ill with an infection when other people don't, and the answer may be in DNA,” says Ciaran Hart, Critical Care Research Nurse at the trust. “We aim to recruit anyone who has tested COVID-19 positive, whereas before we were only recruiting people aged over 70 with particular illnesses. People have been keen to participate in this study and donate blood samples.”
New centres that hadn’t previously engaged with the study have started engaging in large numbers, adds Dr Baillie. “The response from the UK medical and nursing community has been tremendous,” he says. “The Urgent Public Health Research badging acts as independent confirmation that the study is really important and gives people the confidence that it will make a difference.”
From genes to treatments
In December 2020, the study reported its first findings, identifying five genes associated with whether someone is susceptible to severe COVID-19. These genes - IFNAR2, TYK2, OAS1, DPP9 and CCR2 – are involved in antiviral immunity and lung inflammation.
Importantly, GenOMICC is not just a study of susceptibility to infection. By determining the genes linked to COVID-19 outcomes and the biological pathways they use, researchers can identify drugs that target these pathways and test whether they are effective at treating patients with COVID-19.
“The research is less about why people get sick and more about finding treatments,” says Dr Baillie. “We can use the information we gather from GenOMICC to make very well informed predictions about what drugs to test next in patients with COVID-19.”
He and his colleagues are in constant communication with the teams behind the big platform trials that are testing existing drugs for COVID-19, such as REMAP-CAP, to share data about drugs that they predict could be effective and could feed into the trials.
The GenOMICC team continues to recruit as many patients as possible so that their genetic data show reliable signals. “And with the extraordinary capability to recruit across the UK using the NIHR Clinical Research Network, we can recruit on a scale not possible in other countries,” says Dr Baillie.