Event Review: Human Genetic Determinants of COVID-19 Susceptibility and Severity

While the world is gradually heading towards a new form of normality, the biomedical research communities continue to work hard and fast in order to improve our understanding of SARS-CoV-2 and our ability to protect humanity from coronavirus disease 2019 (COVID-19).

The online event 'Human genetic determinants of COVID-19 susceptibility and severity', organised by the Royal Society of Medicine (RSM), was co-chaired by Dr Melita Irving, a consultant in clinical genetics at Guy's and St Thomas' NHS Trust, and Dr Idriss Bennani-Baiti, president of the Cancer Epigenetics Society, Austria.

The main webinar included three expert presentations, the first by Dr Christian Devaux, director of research at the French National Centre for Scientific Research. Dr Devaux began with a reminder that bats, which are important contributors to a variety of ecosystems, are natural reservoirs of coronaviruses and explained that deforestation activities, in part triggered by the fast growth of the South Asian population, are believed to have contributed to the transmission of SARS-CoV-2 to the human species.

This was a sobering and thought-provoking synopsis, highlighting the importance and urgency of the wider environmental sustainability aspects, and indirectly reminding us that we have inflicted this pandemic upon humanity ourselves.

Dr Devaux then focused on the role of SARS-CoV-2 in cardiovascular pathophysiology and explained the molecular mechanisms underlying the cardiovascular symptoms observed in a proportion of patients. He presented a very clear and elegant explanation of how the described molecular and cellular events affect disease severity. However, I was hoping to also learn about genetic variants that may determine susceptibility to the disease, for instance: at this stage do we know anything about genetic variants modulating expression of angiotensin-converting enzyme 2 (ACE2), which acts as receptor for SARS-CoV-2, on cellular surfaces, or in specific tissue types?

In the next part of the event Professor William Hildebrand from University of Oklahoma Health Sciences Centre,  provided a perspective on the role of human leukocyte antigen (HLA) molecules in COVID-19 pathology. He outlined the work of the newly formed HLA-COVID-19 Consortium, which brings together clinicians, bioinformaticians and research scientists from academia and industry.

This project is currently in Phase I, perhaps reflecting the fact that the US started feeling the effects of COVID-19 substantially later than other parts of the world, and involves ten laboratories associated with the American Society for Histocompatibility and Immunogenetics (ASHI) and a number of industry partners. The researchers hypothesise that HLA molecules will contribute to susceptibility and/or resistance to SARS-CoV-19, and they aim to determine which viral proteins are presented by which HLA molecules on the surface of infected host cells to cytotoxic T-lymphocytes for recognition.

This presentation explained very well the significance of HLA variability leading to the requirement for HLA typing. However, due to the early stage of this project and possibly also due to the commercial interest of the industry partners of the HLA-COVID-19 Consortium, very little data and no concrete results were presented. Consequently, this part of the webinar was filled predominantly with hypotheses and speculation and did not offer definite answers to why some people are more susceptible to COVID-19 than others.

The final speaker, Dr Mark Daly from the Finnish Institute for Molecular Medicine (FIMM), Helsinki, Finlandtalked about the global effort to identify host genetics contributions for susceptibility and severity. He re-emphasised the unprecedented epidemiology of the SARS-CoV-2 pathogen, with symptoms ranging from none to life-threatening, and explained that this has never been observed before and hence is so remarkable.

The main focus in this part of the webinar was on the importance of collaborative scientific effort, as opposed to the traditional race to be the first researcher or laboratory to arrive at a scientific discovery in order to gain academic recognition. The study began in March 2020, relying on a collaboration launched by Dr Andrea Ganna, group leader at FIMM, with a network of organisations in Lombardy, Italy, the first and one of the most severely hit European regions affected by COVID-19. However, Dr Daly emphasised that so far the number of study participants is insufficient to uncover definite genetic associations, for instance with co-morbidities like obesity.

The impact of this multi-centre international initiative has already been beautifully illustrated by findings based on data contributions from European countries and also Qatar, Brazil and South Korea, which revealed that one locus, located on chromosome three, is linked to a greater risk of developing severe COVID-19. More detailed analyses from Iceland additionally demonstrated that this variant affects COVID-19 severity and not susceptibility, which was also confirmed by AncestryDNA study results, another contributing laboratory.

This event comprehensively addressed the aspect of genetic determinants affecting COVID-19 severity by elegantly depicting, the underlying molecular mechanism of SARS-CoV-2 binding to ACE2 and then the impact of a strong genetic determinant located on chromosome three. The hypothetical roles of the HLA molecules were also discussed, yet, their definite significance in context to SARS-CoV-2 susceptibility remains to be determined. Overall, although I very much enjoyed attending this event, I was hoping to learn more about factors that would explain whether certain groups of people are more susceptible to COVID-19 than others and why. Or are we all just as susceptible as each other, and genetic variants affect only disease severity? Dr Daly explained during the Q&A session, that so far the number of study participants is insufficient to uncover definite genetic associations, including co-morbidities and other genetically determined traits. Therefore, I will look forward to a future event, which will hopefully shed more light on this aspect.

The event 'Human genetic determinants of COVID-19 susceptibility and severity' was the third in a series of COVID-19-related genetics webinars hosted by the RSM online.