The world’s largest genetic study of critically-ill Covid patients, involving more than 200 treated at Addenbrooke's, reveals extensive insights into the disease.
The study found 16 new genetic variants associated with severe Covid, including some related to blood clotting, immune response and intensity of inflammation.
These findings will act as a roadmap for future efforts, opening new fields of research focused on potential new therapies and diagnostics with pinpoint accuracy, experts say.
Researchers from the GenOMICC consortium – a global collaboration to study genetics in critical illness – led by University of Edinburgh in partnership with Genomics England, made these discoveries by sequencing the genomes of 7,491 patients from 224 intensive care units in the UK.
More than 200 patients who were treated in critical care at Cambridge University Hospitals (CUH) were included in the analysis.
Their DNA was compared with 48,400 other people who had not had Covid, participants in Genomics England's 100,000 Genomes Project and that of a further 1,630 people who had experienced mild Covid.
Determining the whole genome sequence for all participants in the study allowed the team to create a precise map and identify genetic variation linked to severity of Covid.
Understanding these differences is critical to being able to develop treatments that work for patientsProf Charlotte Summers, intensive care specialist CUH
Professor Charlotte Summers, a co-author and intensive care specialist at CUH said:
“We are delighted to have recruited more than 200 participants into this important study that aims to understand why some people become critically unwell from Covid and others do not. Understanding these differences is critical to being able to develop treatments that work for patients”.
The team found key differences in 16 genes in intensive care unit (ICU) patients when compared with the DNA of the other groups.
They also confirmed the involvement of seven other genetic variations already associated with severe Covid discovered in earlier studies from the same team.
The findings included how a single gene variant that disrupts a key messenger molecule in immune system signaling – called interferon alpha-10 – was enough to increase a patient’s risk of severe disease.
This highlights the gene’s key role in the immune system and suggests that treating patients with interferon – proteins released by immune cells to defend against viruses – may help manage disease in the early stages.
The study also found that variations in genes that control the levels of a central component of blood clotting – known as Factor 8 – were associated with critical illness in Covid.
This may explain some of the clotting abnormalities that are seen in severe cases of Covid. Factor 8 is the gene underlying the most common type of haemophilia.
This study using whole genome sequencing has paved the way for major advances in our understanding of why some people have very severe illness with Covid.Prof Sharon Peacock
Professor Sharon Peacock, director of the COVID-19 Genomics UK (COG-UK) Consortium and non-executive director of CUH said:
"The study strongly compliments COG-UK’s viral sequencing programme by providing the human genomic architecture of critical illness. In the future, combining the clinical and human and viral genomic environment will offer the chance to highlight novel interventions that minimise the impact on humanity from Covid.”
It is now true to say that we understand the mechanisms of Covid better than the other syndromes we treat in intensive care.Professor Kenneth Baillie
Professor Kenneth Baillie, the project’s chief investigator and a Consultant in Critical Care Medicine at University of Edinburgh, said:
“Our latest findings point to specific molecular targets in critical Covid.
"It is now true to say that we understand the mechanisms of Covid better than the other syndromes we treat in intensive care in normal times – sepsis, flu, and other forms of critical illness. Covid is showing us the way to tackle those problems in the future.”
Dr Rich Scott, Chief Medical Officer at Genomics England, said:
"This study illustrates the value of whole genome sequencing to detect rare and common variants that influence critical illness requiring intensive care. It represents a major leap forward in our understanding of how our genetic makeup influences severe illness with Covid.
“All those involved in the study went to great efforts to engage with all communities within the UK – including groups that have historically been under-represented in medical studies. The inclusive element of our work has generated meaningful results for everyone in the country.”
The findings have been published in Nature: https://www.nature.com/articles/s41586-022-04576-6