Life-threatening COVID-19 associated with specific genetic variants

Results of a genome-wide association study on 2,244 critically-ill patients due to coronavirus disease (COVID-19) from 208 intensive care units across the United Kingdom revealed significant host-specific genetic determinants that can predispose people to the severe form of the disease. The report is currently available on the medRxiv* preprint server.

Critical forms of COVID-19, a disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), arise due to an inflammatory injury that affects the lungs and lung blood vessels. Consequently, at least two specific biological components: susceptibility to viral infection and predisposition to deleterious pulmonary inflammation.

Such propensity for developing life-threatening infections and immune-mediated diseases are strongly heritable. More specifically, sensitivity to respiratory viruses (such as influenza) is heritable and can be linked to specific genetic variants.

This transmission electron microscope image shows SARS-CoV-2, the virus that causes COVID-19, isolated from a patient in the U.S. Virus particles are shown emerging from the surface of cells cultured in the lab. The spikes on the outer edge of the virus particles give coronaviruses their name, crown-like. Image captured and colorized at NIAID
This transmission electron microscope image shows SARS-CoV-2, the virus that causes COVID-19, isolated from a patient in the U.S. Virus particles are shown emerging from the surface of cells cultured in the lab. The spikes on the outer edge of the virus particles give coronaviruses their name, crown-like. Image captured and colorized at NIAID's Rocky Mountain Laboratories (RML) in Hamilton, Montana. Credit: NIAID

Genetic conundrum of COVID-19

In COVID-19, one particular genetic locus on chromosome 3 (3p21.31) has been frequently associated with increased hospitalization risk. Akin to other viral diseases, there are examples of loss-of-function variants that affect essential immune processes and lead to severe disease in young people (one known example are TLR7 defects among individuals with severe disease).

Since these traits are highly individual, we can arguably use a modified quote from Shakespeare's Julius Caesar for severe COVID-19: "The fault, dear Brutus, is not in our stars, but in ourselves." In other words, genes can be responsible for developing severe and life-threatening COVID-19.

And this is something that definitely warrants further appraisal while the pandemic is still rampant around the world. Understanding the molecular mechanisms underlying critical cases of COVID-19 may reveal novel therapeutic targets to modulate host immune response and, in turn, promote survival.

With this in mind, a large research group (led by Dr. Erola Pairo-Castineira from the University of Edinburgh in the United Kingdom) conducted a genome-wide association study that compared severe cases to controls from population genetic studies across the United Kingdom.

Appraising casual effects of gene expression

In this paper, critically-ill cases were enrolled through the GenOMICC study in 208 UK Intensive Care Units and hospitalized cases through the International Severe Acute Respiratory Infection Consortium (ISARIC) Coronavirus Clinical Characterisation Consortium (4C) study.

Standard protocols were used as a guidance to extract deoxyribonucleic acid (DNA) from whole blood samples, as well as for genome-wide genotyping and all necessary quality controls. Ancestry-matched controls without COVID-19 PCR tests were included from the large population-based cohort UK Biobank, following a ratio of five controls to one case.

The researchers employed Mendelian randomization (i.e., a popular method for appraising and estimating the causal effects of various risk factors) to evaluate the evidence that supports the causal effects of ribonucleic acid (RNA) expression of various genes on the odds of developing critical COVID-19.

New significant, genome-wide associations

In this study, researchers identified and replicated three new significant, genome-wide associations: at chromosome 19 within the gene encoding dipeptidyl peptidase 9 (DPP9), at chromosome 12 in a gene cluster encoding antiviral restriction enzyme activators, and at chromosome 21 in the interferon receptor gene known as IFNAR2.

In line with their focus on extreme COVID-19 in younger patients with a lower burden of comorbidities, these scientists detected a stronger signal at the aforementioned 3p21.31 locus than previous research endeavors. All of the above means that we have new potential targets for repurposing already licensed medications.

"Using Mendelian randomization, we found evidence in support of a causal link from low expression of IFNAR2, and high expression of Tyrosine Kinase 2 (TYK2), to life-threatening disease", study authors further explain in this paper.

Finally, a transcriptome-wide association study of lung tissue demonstrated that high expression of the monocyte/macrophage chemotactic receptor CCR2 is indeed associated with the occurrence of severe COVID-19 - which is another novel genetic association.

Targeted treatment

"Our results identify robust genetic signals relating to key host antiviral defense mechanisms and mediators of inflammatory organ damage in COVID-19", concludes study authors in their medRxiv paper.

Both of these mechanisms may be compliant to targeted treatment with drugs that we already have available. What we have to target is augmenting interferon signaling, antagonize monocyte activation and lung infiltration, or specifically aiming harmful inflammatory pathways.

However, while these findings contribute substantially to the biological rationale that guides specific treatment approaches, each therapeutic option must be tested in well-designed, large-scale clinical trials before it can enter clinical practice.

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Dr. Tomislav Meštrović

Written by

Dr. Tomislav Meštrović

Dr. Tomislav Meštrović is a medical doctor (MD) with a Ph.D. in biomedical and health sciences, specialist in the field of clinical microbiology, and an Assistant Professor at Croatia's youngest university - University North. In addition to his interest in clinical, research and lecturing activities, his immense passion for medical writing and scientific communication goes back to his student days. He enjoys contributing back to the community. In his spare time, Tomislav is a movie buff and an avid traveler.

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