Small group of genetic variants found in extremely ill patients with
COVID may help explain big differences in how sick people get

Date:
January 31, 2022
Source:
Medical College of Georgia at Augusta University
Summary:
The search to better understand the tremendous range of responses
to infection with the COVID-19 virus -- from symptom free to
critically ill -- has uncovered in some of the sickest patients a
handful of rare structural gene variants involved in body processes,
like inflammation, which the virus needs to be successful.



FULL STORY ==========================================================================
The search to better understand the tremendous range of responses to
infection with the COVID-19 virus -- from symptom free to critically
ill -- has uncovered in some of the sickest patients a handful of rare structural gene variants involved in body processes, like inflammation,
which the virus needs to be successful.


==========================================================================
"The virus has to attach to our cells, it has to get inside our cells and
it has to multiply inside our cells. It also has to attract inflammation,"
says Dr. Ravindra Kolhe, director of the Georgia Esoteric and Molecular Laboratory at the Medical College of Georgia at Augusta University. "We
have identified genes with structural changes in very sick individuals
that are part of all four of these essential processes." In apparently
the first study of its kind, investigators used optical genome mapping,
to get a thorough, three-dimensional assessment of the genome of 52
severally ill patients with COVID-19.

In nine of the sickest patients, they identified seven rare structural
variants affecting a total of 31 genes involved in key pathways mediating
the response between a person, or host, and a virus. These include innate immunity, our frontline immune defense against invaders like viruses;
the inflammatory response, a key response to an infection that, gone
awry, can also destroy the lungs of some of the sickest patients; and the ability of a virus to replicate and spread. As an example, one variant
they identified can lead to overexpression of keratin genes. Keratins
are proteins that are the structural components of things like our hair
and nails, but that also have been identified as key to the transmission
of both flu viruses and the COVID-19 virus between cells and are known
to be upregulated in the respiratory tract during an infection.

"It's a hyperactivation of the normal systems," says Kolhe, corresponding author of the study, published by the international collaborative COVID-19
Host Genome Research consortium in the journal iScience.

"Millions of people get infected, and fortunately only a very small
percentage become symptomatic, and a very small percentage of the
symptomatic individuals require oxygen and a small percentage of
those individuals are hospitalized and die," Kolhe says. "But even a
small percentage amounts to millions of people and that is too many."
"Our data show that large (structural variants) identified using optical
genome mapping might further explain the inter-individual clinical
variability in response to COVID-19," the investigators write.



========================================================================== Large structural variants account for much of the genetic diversity among
us, including changes that are just unique to the individual and those
that can increase their risk of problems like cancer. Optical genome
mapping is an emerging technology that can detect these larger variants
with multiple changes, like deletion or insertion of genetic material
and/or when a section of chromosome is reversed.

The investigators say that while more work needs to be done, their
findings about the potential role of structural variants in the host-virus interaction point toward the need to look for genetic variations, ideally
with a simple- to-use blood assay. Once identified, the goal would be to initiate proactive moves for these individuals like ensuring vaccination
and boosting and potentially more aggressive treatment early on, like monoclonal antibody therapy, to help these individuals better combat
COVID, Kolhe says.

Clinical studies have identified factors like older age, being male, hypertension, diabetes and other chronic conditions as risk factors
associated with the degree of illness from COVID-19. The nine sickest
patients in this study shared common comorbid conditions, 32 of the
patients required mechanical ventilation to support their breathing and
a total of 13 of the 52 patients died while in intensive care.

But in their studies, which also included individuals who were negative
for the COVID-19 virus and those who were positive but asymptomatic,
there were again outliers, including individuals with comorbid conditions
who remained asymptomatic when infected with SARS-CoV-2 and those who
were perfectly healthy but became extremely ill when infected, another indicator of a role for genetics in determining the degree of response,
Kolhe says.

Kolhe notes that the large structural variants they found in the sickest patients were not caused by the virus rather used by the virus and may
not increase susceptibility to other, even similar, conditions.



========================================================================== Overall, the individuals in this study had about 40 rare structural
variants, which other studies have indicated is about average.

The COVID-19 Host Genome Research consortium currently has a membership of
34 institutions, including Duke and Columbia universities, the National
Cancer Institute and the New York Genome Center, exploring different
aspects of how structural variants impact the divergent individual
responses to infection with the COVID-19 virus.

The group began to emerge after more commonplace gene sequencing
studies, which essentially lay out the DNA in a straight line to look
for problematic and smaller variations in the usual order of its four
base pairs -- adenine, thymine, guanine and cytosine -- on thousands of patients have yielded little information to help explain -- and ideally
predict -- the wide variations in how sick people will get. Better than
30% of the known disease-causing variants are larger than the single
base pair changes sequencing can identify, according to the Human Gene
Mutation Database.

Even the amount of virus in an individual does not directly correlate with
how sick the individual gets, Kolhe says. "We had individuals with very
high viral loads who did not even know they were positive," he says. "It
is something in the host genome that is different." Some studies have
found that blood type might be a factor in predicting risk, specifically
type A, and there have been some specific gene findings as well that
predispose to immune deficiencies that may make people more susceptible.

Kolhe, who is also associate director for genomics at the Georgia Cancer Center, has been using optical genome mapping to look for patient-specific cancer-causing variations.

========================================================================== Story Source: Materials provided by Medical_College_of_Georgia_at_Augusta_University.

Original written by Toni Baker. Note: Content may be edited for style
and length.


========================================================================== Journal Reference:
1. Nikhil Shri Sahajpal, Chi-Yu Jill Lai, Alex Hastie, Ashis K. Mondal,
Siavash Raeisi Dehkordi, Caspar I. van der Made, Olivier Fedrigo,
Farooq Al-Ajli, Sawan Jalnapurkar, Marta Byrska-Bishop, Rashmi
Kanagal-Shamanna, Brynn Levy, Maximilian Schieck, Thomas Illig,
Silviu-Alin Bacanu, Janet S. Chou, Adrienne G. Randolph, Amyn
M. Rojiani, Michael C. Zody, Catherine A. Brownstein, Alan H. Beggs,
Vineet Bafna, Erich D. Jarvis, Alexander Hoischen, Alka Chaubey,
Ravindra Kolhe. Optical genome mapping identifies rare structural
variations as predisposition factors associated with severe
COVID-19.. iScience, 2022; 103760 DOI: 10.1016/ j.isci.2022.103760 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220131083836.htm

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