Genetic study gives detailed information on severe COVID-19

The world’s largest study on the genetics of critical Covid-19, involving more than 57,000 people, has revealed new details about some of the biological mechanisms behind the severe form of the disease.

Some 16 new genetic variants associated with severe Covid-19, including some linked to blood clotting, immune response and intensity of inflammation, have been identified.

These findings will serve as a roadmap for future efforts, opening up new areas 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 serious diseases – led by the University of Edinburgh in partnership with Genomics England, made the discoveries by sequencing the genomes of 7,491 patients from 224 intensive care units UK.

Their DNA was compared to 48,400 other people who had not had Covid-19, to participants in Genomics England’s 100,000 Genomes project and to that of 1,630 other people who had experienced mild Covid.

Determining the complete genome sequence for all study participants allowed the team to create an accurate map and identify genetic variation related to the severity of Covid-19. The team found key differences in 16 genes in intensive care patients compared to DNA from other groups.

They also confirmed the involvement of seven other genetic variations already associated with severe Covid-19 discovered in previous studies by the same team.

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 the disease in the early stages. .

The study also found that variations in genes that control levels of a central component of blood clotting – known as factor 8 – were associated with severe disease in Covid-19.

This may explain some of the clotting abnormalities seen in severe cases of Covid-19. Factor 8 is the gene underlying the most common type of hemophilia.

Professor Kenneth Baillie, the project’s lead researcher and consultant in critical care medicine at the University of Edinburgh, said: “Our latest findings point to specific molecular targets in critical Covid-19. These findings explain why some people develop life-threatening Covid-19, while others show no symptoms. But more importantly, it gives us a deep understanding of the disease process and is a big step forward in the search for more effective treatments.

“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, influenza and other forms of serious illness. Covid-19 shows us the way to combat these problems in the future.”

Professor Sir Mark Caulfield of Queen Mary University of London, former chief scientist at Genomics England and co-author of this study, said: “As Covid-19 evolves, we need to focus on reducing the number of people becoming seriously ill and hospitalized.Through all of our genome sequencing research, we have discovered new gene variants that predispose people to serious diseases – which now offer a pathway to new tests and treatments, to help protect the public and the NHS from this virus.

Dr Rich Scott, Chief Medical Officer of Genomics England, said: “Strategically, we are at a point where genomic science is becoming an integral part of the national infrastructure for routine healthcare. This study illustrates the value of sequencing of the whole genome to detect rare diseases and common variants that influence serious illnesses requiring intensive care.This represents a big step forward in our understanding of how our genetic makeup influences serious illnesses with Covid-19.

“Everyone who took part in the study made great efforts to engage with all communities across the UK, including groups that have historically been under-represented in medical education. The inclusive element of our work has generated meaningful results for everyone in the country.”

Lord Kamall, Minister for Innovation at the Department of Health and Social Care (DHSC), said: “Clinical research has been vital in our fight against Covid-19 and innovation from the UK is enabling us to transform our health service and to ensure that the NHS is able to deliver world-class care.

“This research is an important step forward in better understanding how Covid-19 impacts certain people, allowing us to take the necessary measures to protect the most vulnerable and save lives.”

The results were published in Nature.

GenOMICC (Genetics of Susceptibility and Mortality in Critical Care) began in 2015 as an open global consortium of critical care clinicians dedicated to understanding the genetic factors influencing critical care outcomes of diseases such as SARS, influenza and sepsis.

The consortium is led by the University of Edinburgh and since 2020 has focused on Covid-19 research in partnership with Genomics England and in collaboration with NHS Lothian, the National Center for Audit and Care Research (ICNARC) and Queen Mary University. from London.

The groundbreaking 100,000 Genomes Project was created in 2014 to sequence 100,000 genomes from people with a rare disease or cancer. The project was completed in 2018 and paved the way for the creation of a new genomic medicine service for NHS England, transforming patient care by providing advanced diagnosis and personalized treatments.

GenOMICC is funded by DHSC, LifeArc, the charity Sepsis Research FEAT, Intensive Care Society, Wellcome, UK Research and Innovation, Scotland’s Chief Scientific Office, Department of Health and Social Care and the National Institute for Health Research (NIHR), and supported by Illumina.

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