Genetic study gives extensive insights into severe COVID-19

Date:
March 7, 2022
Source:
University of Edinburgh
Summary:
The world's largest study of the genetics of critical COVID-19,
involving more than 57,000 people, has revealed fresh details
about some of the biological mechanisms behind the severe form of
the disease.



FULL STORY ==========================================================================
The world's largest study of the genetics of critical Covid-19, involving
more than 57,000 people, has revealed fresh 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 related to blood clotting, immune response and intensity of
inflammation, have been identified.

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.

Their DNA was compared with 48,400 other people who had not had Covid-19, 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-19. The team found key differences in 16
genes in the 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-19 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-19.

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



========================================================================== 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-19. These results explain why some people develop life-threatening Covid-19, while others get no symptoms at all. But more importantly,
this gives us a deep understanding of the process of disease and is a
big step forward in finding 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, flu, and other forms of critical illness. Covid-19 is showing
us the way to tackle those problems in the future." Professor Sir Mark Caulfield from Queen Mary University of London, formerly Chief Scientist
at Genomics England and co-author on this study, said: "As Covid-19
evolves, we need to focus on reducing the number of people getting
seriously ill and being hospitalised. Through our whole genome sequencing research, we've discovered novel gene variants that predispose people to
severe illness -- which now offer a route to new tests and treatments,
to help protect the public and the NHS from this virus." Dr Rich Scott,
Chief Medical Officer at Genomics England, said: "Strategically, we're
at a point where genomic science is becoming an integral part of the
national infrastructure in routine healthcare. 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-19." "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." 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 the
UK's innovation is enabling us to transform our health service and ensure
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
action to protect the most vulnerable and save lives." The findings
have been published in Nature.

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

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

The ground-breaking 100,000 Genomes Project was established 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 bringing advanced diagnosis and personalised treatments.

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

========================================================================== Story Source: Materials provided by University_of_Edinburgh. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Athanasios Kousathanas, Erola Pairo-Castineira, Konrad Rawlik, Alex
Stuckey, Christopher A. Odhams, Susan Walker, Clark D. Russell,
Tomas Malinauskas, Yang Wu, Jonathan Millar, Xia Shen, Katherine
S. Elliott, Fiona Griffiths, Wilna Oosthuyzen, Kirstie Morrice,
Sean Keating, Bo Wang, Daniel Rhodes, Lucija Klaric, Marie Zechner,
Nick Parkinson, Afshan Siddiq, Peter Goddard, Sally Donovan,
David Maslove, Alistair Nichol, Malcolm G. Semple, Tala Zainy,
Fiona Maleady-Crowe, Linda Todd, Shahla Salehi, Julian Knight,
Greg Elgar, Georgia Chan, Prabhu Arumugam, Christine Patch,
Augusto Rendon, David Bentley, Clare Kingsley, Jack A.

Kosmicki, Julie E. Horowitz, Aris Baras, Goncalo R. Abecasis,
Manuel A.

R. Ferreira, Anne Justice, Tooraj Mirshahi, Matthew Oetjens,
Daniel J.

Rader, Marylyn D. Ritchie, Anurag Verma, Tom A. Fowler, Manu
Shankar- Hari, Charlotte Summers, Charles Hinds, Peter Horby, Lowell
Ling, Danny McAuley, Hugh Montgomery, Peter J. M. Openshaw, Paul
Elliott, Timothy Walsh, Albert Tenesa, Angie Fawkes, Lee Murphy,
Kathy Rowan, Chris P.

Ponting, Veronique Vitart, James F. Wilson, Jian Yang, Andrew D.

Bretherick, Richard H. Scott, Sara Clohisey Hendry, Loukas
Moutsianas, Andy Law, Mark J. Caulfield, J. Kenneth Baillie. Whole
genome sequencing reveals host factors underlying critical
Covid-19. Nature, 2022; DOI: 10.1038/s41586-022-04576-6 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220307113002.htm

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