LONDON – The U.K. is launching a £28 million (US$34.5 million) project to sequence the whole genome of every COVID-19 patient in the country treated in intensive care, with the aim of uncovering host genetic factors that lead some people to be more severely affected by the infection.

The study will involve up to 20,000 people currently or previously treated in one of 170 intensive care units (ICUs), whose genomes will be compared to 15,000 people with a confirmed infection who had mild or moderate symptoms.

It was evident from the first cases in China that people with co-morbidities experience more severe illness, but patients with the same underlying conditions have been found to respond very differently. While co-morbidities and factors such as age and obesity are important, it is thought this high variability in the severity of COVID-19 infections is linked to underlying genetic factors that influence response to the virus.

Backed by detailed medical records, the study will explore the spectrum of symptoms and attempt to pinpoint their genetic roots. The findings will provide biomarkers for assessing in advance which patients will react badly, help inform treatment with existing drugs and provide de novo targets.

This large-scale whole genome sequencing project is not beginning from a standing start, but builds on Genomicc (Genetics Of Mortality In Critical Care), launched in 2016, to sequence the genomes of patients with any condition who were so ill they required critical care.

To date, DNA samples have been collected from patients who were critically ill with influenza, SARS-CoV-1, MERS, sepsis and other causes.

“With over 2,000 patients recruited, it is by far the largest study of critical care genetics in the world,” said Kenneth Baillie, academic consultant in critical care at Edinburgh University and principal investigator. “In total, we have 2,133 cases in Genomicc, but no results yet for COVID-19,” he told BioWorld.

To date, Genomicc has been funded by a sepsis charity; the U.K. government funding and the urgency behind all COVID-19 research will accelerate the study.

Genomicc also will have the backing of Genomics England, the not-for-profit government funded company which has been working on translating advances in genomics into clinical practice.

So far, that work has focused on delivering genetic diagnoses for rare disease patients and selecting gene-targeted therapies in cancer, but Mark Caulfield, chief scientific officer, said Genomics England’s expertise can be applied to understanding why the virus is life-threatening for some, while others have a mild infection. “By reading the whole genome, we may be able to identify variation that affects response to COVID-19 and discover new therapies,” he said.

Genomics England is now recruiting volunteers who have been ill with COVID-19 to take part in the study. All of 35,000 COVID-19 genomes will be sequenced by Illumina Inc., which will share some of the costs via an in-kind contribution.

Focus on susceptibility

Baillie’s research into the genomes of critically ill patient builds on the observation that the cause of death following a serious infection is often not attributable to the direct impact of the pathogen or any toxin it produces, but a consequence of a systemic immune response.

Exploring the genetic underpinnings of that is one source of drug targets. A second source will be in identifying host factors the virus depends on for replication. In research published in January, Baillie and colleagues reported the results of a wide-scale screen in which they identified 121 host genes that are required for influenza A replication.

In a hugely heterogeneous disease, the large-scale sequencing of whole genome sequences is the best way to track down the factors underlying the spectrum of response to COVID-19 infection, Baillie said. “I think this is one of the best ways to tackle this question. By focusing on extreme susceptibility, that is, patients with critical illness caused by COVID-19, we can increase the size of effect that we see for any genetic signals, making them easier to find,” he said.

One very striking characteristic of people who suffer the worst effects of COVID-19 is that far more of them are men than women. Baillie said, “It may well be that [Genomicc] gives us clues to explain the difference in susceptibility between the sexes.”

Part of the overall study will focus on children and young adults with no known underlying health problems who have been severely affected by COVID-19. There have been reports that a very small number of children in the U.K., U.S. and Italy developed a significant multisystem inflammatory response associated with COVID-19.

The power of the COVID-19 whole genome sequence data will be amplified by linking it to virus genome data. Worldwide, the repository of viral sequences from patients now numbers tens of thousands. In the U.K., the COVID-19 Genomics UK (COG-UK) consortium has sequenced more than 10,000 virus genomes, meaning it will be possible to put together matched pairs of viral/patient genomes.

“Linking [viral sequence] data to the patient’s own genome data in the Genomicc study may provide unique insights into how patient and virus genomes act together to influence the patient’s response to the infection,” said Sharon Peacock, director of COG-UK.

“The program is significant for many reasons – not only to provide insights into the cause of the potential role of human genome in the severity of COVID-19, but also to provide a real opportunity to link other similar datasets globally,” Naveed Aziz, chief administrative and scientific officer at CGEN, Canada’s national genome sequencing and analysis platform, told BioWorld.

For example, the Canadian HostSeq program aims to sequence genomes of 10,000 COVID-19 positive people. “The ability to query a larger dataset from across the globe will allow researchers to increase the power of COVID-19-related studies when it comes to investigating human gene variations associated with the immune response against infection by SARS-CoV-2,” Aziz said.

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