Discovering genetic variants that most expose people to critical COVID-19

Please, could you introduce yourself, and tell us about your background in medical informatics, and what inspired you with your latest research to identify independent variables that significantly predispose to critical COVID-19?

My name is Irola Bairro-Castinera, and I am a postdoctoral researcher specializing in statistical genetics in Professor Bailey’s laboratory at the University of Edinburgh.

I’m interested in the differences in DNA sequences between people and how this affects how sick you are when infected with SARS-CoV-2. Most people are asymptomatic or have mild symptoms when infected, while some people need hospitalization and others need to be admitted to an intensive care unit to receive mechanical ventilation. Although some factors such as age and gender affect your predisposition to critical COVID-19, there are differences even among people of similar age, gender, and other variables that affect the severity of COVID-19.

Our research aims to find genetic factors that may predispose to critical COVID-19 and to learn how COVID-19 affects cells in the body. The main goal of the project is to find the critical biological pathways that affect COVID-19 so that you can find drug-amenable targets that may benefit everyone.

What is meant by the term “Covid-19” and what are the mechanisms that cause it?

People with COVID-19 have been admitted to the intensive care unit. They will have all of the classic symptoms of COVID-19, such as cough and fever, but also have very low blood oxygen. The mechanism causing it is inflammation of the lung, where the virus multiplies.

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Previous studies have found associations between certain genetic variations and critical COVID-19. What did these findings reveal about genetic predisposition to COVID-19?

In our first study, we found five critical COVID-19-associated genetic signals related to host antiviral defense mechanisms and mediators of inflammatory organ damage. Other studies have since found indications of susceptibility to SARS-CoV-2 infection and hospitalization and critical illness with COVID-19.

In your most recent research, you performed whole genome sequencing. What advantages does this provide over microarray genotyping?

Microarray genotyping reads a range of variants in the genome, among which, using information about the genomes of known populations, we infer the rest of the genome. It is very difficult to do this for rare variants, which will have low inference accuracy, and are also affected by the quality of the reference board used. Even in the best cases, not all variables can be retrieved with high accuracy, and some must be filtered. Whole genome sequencing reads every base in our genome, providing high accuracy for all variants.

How was the genome-wide association study conducted, and what new insights did the current study provide?

To perform the analysis, we compared the genomes of people who have contracted the critical COVID-19 virus, focusing on people in intensive care units in UK hospitals, individuals who developed only mild symptoms during SARS-CoV-2 infection, and with the general population. . The comparison highlights genome variants that influence your likelihood of developing critical illness with COVID-19.

In this study, we found 16 new regions associated with critical COVID-19. We were also able to identify some of these variants as variants that affect the function of some proteins (for example, a protein called IFNA10). In other cases, we can show that changes in gene expression will influence the likelihood of severe COVID-19 infection.

Five critical variables associated with COVID-19 have direct roles in interferon signaling. What are interferon signals, and what do these associations suggest about critical COVID-19?

Interferons are a large family of proteins that have a role in antiviral defense. They are produced when a cell recognizes a viral intruder, spreading both defensive and offensive signals to help destroy the virus and protect neighboring cells. Interferons can induce inflammation by activating the transcription of a number of different genes and, if not tightly controlled during the immune reaction, can cause severe inflammation.

There are different types of interferon called Interferon Type-I, Interferon Type-II, and Interferon Type-III. The genes that we found are mainly related to type I interferon signaling. Interestingly, one of these genes (TYK2) contains a protein product that can be inhibited by a widely available drug, baricitinib. It was recently shown in the RECOVERY trial (a large-scale randomized control trial of several potential COVID-19 treatments in the UK) that administration of baricitinib can reduce mortality in COVID-19.

Image Credit: Thanapipat Kulmuangdoan / Shutterstock.com

Image Credit: Thanapipat Kulmuangdoan / Shutterstock.com

Your results provided evidence supporting the causal roles of myeloid cell adhesion molecules and coagulation factor F8, all of which are potentially treatable targets. How do you see the impact of your results on future treatment goals?

In the case of baristinib, it was fortunate that it was already available for rheumatoid arthritis, so it was shown to be safe and effective. Usually, the process is much longer when a potential genetic target is identified. The most important first step is to confirm the associations we see in the DNA data in cells and tissues – in the laboratory Experiments will be required to ensure that the goal is worth pursuing. The appropriate drug must be identified, tested, and proven safe. It can be a long process; However, our analysis can narrow down the most likely drug targets, which is a major step forward.

What are the limitations of your study, and how can it be improved in future studies of this type?

The main limitation of the study is that we recruited cases in the middle of a pandemic, so we did not have genotypes for the mild cases to use as controls. Instead of mild COVID-19 cases, we used controls from different studies of the general population. This was a technical challenge due to the different genotyping tools or whole genome sequencing used, and we had to account for these differences. We now have genotypes of mild COVID-19 cases generated using the same pipelines as critical COVID-19 cases.

Your business was in partnership with Genomics England. How important is cooperation in this area and this work in particular?

Collaboration is vital to this research. People with very different experiences are needed to perform an analysis like this. To perform this analysis, we needed people to work in many different roles. Administrative staff organized the paperwork and established sites, doctors and nurses recruited patients, research technicians sequenced DNA, and then information specialists processed this DNA information into a computer and analyzed it to find DNA regions related to COVID-19. Finally, findings rarely make sense immediately, so there have been a number of groups of researchers working closely together to interpret the biological meaning of the findings.

What’s next for you and your research?

We are still working on a critical COVID-19 solution. We have recruited more individuals and will soon begin a new analysis with 15,000 critical cases and 15,000 mild controls (people with mild or asymptomatic COVID-19). We also have gene expression data from patients in the hospital that we can link to our analysis output and potentially help us address some of the limitations mentioned above.

Where can readers get more information?

About Irola Castenera

My name is Erola Pairo-Castineira I am currently a Postdoctoral Researcher at the Roslin Institute at the University of Edinburgh. For the past two years, I’ve been working on host genetic studies for COVID-19. Several analyzes have been conducted that have led to the discovery of new genetic associations with the serious disease COVID-19. Prior to my current position, I was a postdoctoral researcher at MRC-HGU, working on integrating omics and genotype data to identify causal genes and pathways underlying pigmentation traits.

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