How Much Does Our GENETIC Makeup Influence Severe SARS-CoV-2 Infection (COVID-19)?

Why do some people experience COVID-19, the infection caused by SARS-CoV-2, severely, while others have mild or asymptomatic illness? Certain clinical risk factors for COVID-19 are well established: older age, obesity, male sex, and comorbidities… Yet COVID-19 can also be severe in some people without these risk factors. Recent research shows that, for a small number of people, in addition to clinical factors, genetic factors also influence the different clinical presentations of COVID-19.

The immune system, genetics, and infection risk

Immune system defects' effects on susceptibility to infections were recognized in 1952 with gammaglobulin deficiency being described.

To date, more than 400 inborn immune system disorders have been described. Genetics and immunology have clearly established that congenital immune deficiency determines susceptibility to infections. While science works against COVID-19 to develop new vaccines and treatments, genetic factors affecting the course of the disease are also being investigated.

What are the current studies on SARS-CoV-2 and genetic susceptibility?

1. In July 2020, “JAMA Network” published a study performing genetic analyses in 4 young men with severe COVID-19 infection. The analyses identified, in the TLR7 gene on the X chromosome, function-disrupting variants (changes). These variants were found to cause errors in type 1 and type 2 interferon production. Interferons are important molecules involved in the immune response to viral infections.
2. In July 2020, “Nature” published analyses in 113 COVID-19 patients showing that a “mismatched and excessive” immune response contributed to a poor course of COVID19.
3. In September 2020, the COVID-19 Genetics Study Group published in “NEJM” a study involving 1980 COVID-19 patients, in which a variant in the 3p21.31 region on chromosome 3 was found to confer genetic susceptibility to COVID-19.
4. In September 2020, “Nature” published a study finding that this risk factor identified in the chromosome 3 region was inherited from the Neanderthal genome. This risk factor was found in 50 percent of people in South Asia and 16 in Europe.
5. In October 2020, “Science” published a study in which genomes from 659 patients with severe COVID-19 and asymptomatic (without symptoms) COVID-19 patients, numbering 534, were analyzed. Function-disrupting variants in 13 chromosomal regions were identified in only 3.5% of patients with fatal COVID-19 pneumonia. These variants were found to cause errors in TLR3- and IRF7-dependent type 1 interferon immunity. Defects in type 1 interferon immunity cause COVID19 to follow a severe course. However, these genetic changes explain only a small percentage of severely ill patients.
6. In October 2020, the American Society of Human Genetics Congress featured the largest multi-ancestry exome sequencing study to date, identifying 4 gene regions and 3 specific genes associated with COVID-19 course and susceptibility. The researchers screened data from more than 860 thousand people across six studies and four different ancestries, examining genetic differences in three categories: susceptibility to SARS-CoV-2 infection, need for hospitalization, and severe clinical presentations (intubation and death). As in earlier studies, 3p21.31 variation was associated with severe disease. GPS2, METTL7B, and PLPPR3 genes were also found to confer susceptibility to COVID-19. Chromosomal regions 22q21.1, 16q24.3,1p31.1 were associated with severe disease.
7. Another study presented at the same congress analyzed data from 14,000 positive cases and more than 1 million controls. A variation on chromosome 3 was found potentially to influence the course of COVID-19. However, this variant was not associated with susceptibility to COVID-19.
8. A study by researchers from the United States and Canada identified 6 genes (CCR9, SLC6A20, CXCR6, LZTFL1, FYCO1, and IFNAR2) in 2 chromosomal regions associated with the clinical condition of hospitalized COVID-19 patients.
9. A study published in December 2020 and led by Turkish scientist Ferhat Ay found an association between genetic risk variants and gene expression in immune cells. For example, the 3P21.31 risk variant was found to affect CCR2 gene expression in immune cells.

Do we know enough about genetic susceptibility to COVID-19?

Not all genes determining genetic susceptibility to COVID-19 have been identified yet! As we know, genetic research is conducted according to “scientific methods”. This process requires lengthy clinical research and various analyses.

Studies published in recent months show that some genes and gene variations affect the immune response to SARS-CoV-2. However, these studies require analyses involving more participants, considering sex, age, and other chronic diseases.

The effect of the 3p21.31 genetic variant on disease course has been demonstrated in studies. This variant needs examination and confirmation in different patient groups. Different studies have reported differing results concerning its role in disease course and/or susceptibility.

What proportion of patients with severe COVID-19 is explained by current genetic research?

We need time to obtain clearer results on COVID19 and genetic susceptibility. The role of genetics in whether COVID-19 is severe or mild remains unclear. As the examples above show, genetic changes can explain only a small proportion of patients with severe disease. Older age, obesity, male sex, and other chronic conditions remain the most important risk factors for severe COVID-19. There are also case examples that cannot be explained by genetic status. For example, on December 8, “Annals of Internal Medicine” published a study reporting that, among identical twins, one of the two siblings had severe COVID-19 while the other had mild disease. These genetically identical twins were also entirely similar in weight and absence of comorbidities. They had also contracted SARS-CoV-2 from the same source. This example suggests that COVID-19 can follow different courses even in genetically identical people, prompting us to consider epigenetic factors as a possible influence.

Can a test tell you your genetic risk for COVID-19?

As genetic studies on COVID-19 increase and some data come to light, “COVID-19 Genetic Susceptibility Tests” have started to come onto the agenda. Naturally, this brings many questions and potential problems.

First, to determine who will develop severe COVID-19, “offering immature scientific data as a commercial genetic test kit” raises many ethical issues. Screening society with these tests would particularly cause misunderstandings.

For example, a COVID-19 Genetic Susceptibility Test finds that a person's risk of severe disease is high. How will this person be protected, and how will their psychological wellbeing be protected? Conversely, if a genetic test finds a low risk of severe disease, what happens if that person abandons precautions and develops severe COVID-19? How should genetic susceptibility tests be interpreted in people with clinical risk factors such as older age, obesity, or comorbidities, and what recommendations should be given to those tested in clinical practice?

We do not yet have sufficiently clear information from COVID-19 genetic susceptibility studies. Comprehensive genotype-phenotype analysis of study findings has not been possible. Analyses with more participants are needed, considering individuals' unknown clinical conditions (obesity, heart disease).

In such a significant pandemic, these genetic tests may create a new form of discrimination. Until an effective vaccine or treatment arrives, people with genetic susceptibility may be considered unsuitable for certain jobs. They may face problems with health insurance and similar matters. There are also many legal gaps concerning the confidentiality of genetic information.

In conclusion, genetic differences may play a meaningful role in how we experience COVID-19, but the findings so far explain only a small proportion of severe COVID-19 cases. Regardless of genetic susceptibility, you should follow the basic rules for protection against SARS-CoV-2. Social distancing, mask use, and regular hand disinfection can reduce the risk of COVID-19.

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