What genetic factors play a part in the illness?

The pathophysiology (body function disruption) of critical COVID-19 cases is qualitatively different from other cases. Amongst other elements, hyper-inflammation, massive infiltration of macrophage into the lungs and thromboses have been noted, with overall damage to lung functioning. In patients with respiratory distress, corticosteroids (steroidal anti-inflammatory drugs) have substantial therapeutic benefits, while in other patients they tend to cause damage.

Two biological components are linked to risks of mortality: the degree of sensitivity to viral infections and the propensity to develop deregulated lung inflammation. These components can be linked to other hereditary factors as has been shown in studies of other pathologies. Research has been carried out analyzing the numerous genetic variations in the entire genomes of many individuals in order to make correlations with certain physiological or pathological particularities. These studies use complex and specialized statistics (Mendelian randomization…) to limit errors in interpretation, sometimes cross-referencing data from a number of clinical research projects. Their aims are, above all, to improve patient care and enable personalized therapies.

Researchers at the University of Edinburgh carried out the GenOMICC (Genetics Of Mortality In Critical Care) study, using patients who had been the victims of several serious respiratory infections (flu, emerging infections, sepsis) over a 5 year period, in 208 emergency services in the UK (95% of beds). Amongst them, 2636 patients had COVID-19. The genetic data of 2244 critically ill (that is, needing respiratory assistance) patients, taken from blood samples, was studied. The results of these analyses were compared with control groups from other genetic studies on UK residents. The recruitment method ensured a large genetic diversity, and no sexual or ethnic factors were taken into account.

What were the conclusions? Five genes are most frequently mutated in critical COVID-19 cases:

• 3 of these genes are linked to the inflammatory process: DPP9 (chromosome 19), TYK2 (chromosome 19) and CCR2 (chromosome 3).
• 2 of these genes are linked to antiviral processes: IFNAR2 (chromosome 21) and OAS1/2/3 (chromosome 12).

In-depth analysis (WAS Transcriptome) on the TYK2 gene suggests that the more this protein is present, the more the patient is liable to develop severe forms of COVID-19, making it the most interesting therapeutic target of this study.

Similarly, the OAS genes are involved in the overall defence of the organism (breakdown of viral RNA) and may be targeted by phosphodiesterase inhibitors (PDE-12), effective in vitro in other cases of viral infection.

The authors also suggest that increasing the activity of the interferon type I receptor IFNAR2 gene, as well as treating interferon type I patients, could protect them, but only if they are treated early. We already know that when applied late, these treatments are ineffective.

CCR2 is a receptor involved in macrophage mobility at inflammation sites, and anti-CCR2 antibodies, already used to treat rheumatoid arthritis, may limit macrophage infiltration into the lungs.

This study provides important information on the pathophysiology of COVID-19 but also helps to identify genes relevant to treatments. Baricitinib, a TYK2 inhibitor commonly used in the treatment of rheumatoid arthritis, has recently been included in clinical trials for the treatment of COVID-19. The authors suggest that these tests should be extended to other compounds. They intend to extend this research to 35,000 people they are currently recruiting through the website genomicc.org.