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April 28, 2020 – Coronavirus disease 2019 (Covid-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease was first identified in December 2019 in Wuhan, the capital of China’s Hubei province, and has since spread globally, resulting in the ongoing 2019–20 coronavirus pandemic. Common symptoms of Covid-19 include fever, cough, fatigue, shortness of breath and loss of smell. While the majority of cases result in mild symptoms, some progress to viral pneumonia, multi-organ failure, or cytokine storm. These more concerning symptoms include difficulty breathing, persistent chest pain, confusion, difficulty waking, and bluish skin. The time from exposure to onset of symptoms is typically around five days but may range from two to fourteen days.
Strikingly, it seems that male individuals are much more affected by Covid-19 than female individuals and that the course of the disease is often much much serious, if not fatal in males. This observation is independent from the seeming bias towards the elderly for very serious disease. In this context, the question has arisen whether, besides different physiological. live style (e.g., fuming), and environmental risk factors that may predispose male to Covid-19, underlying genetic factors might play a role. This was the key hypothesis put forth in preliminary research published this month in bioRxiv that highlights the potential benefits of testing Covid-19 patients for genetic variants of the ACE2 gene, that codes for the ACE2 protein (i.e., the angiotensin converting enzyme 2). ACE2 is already known to be the key point of entry for SARS-CoV-2 into human cells.
What makes the ACE2 gene very interesting in the observation of the startling differences in the Covid-19 death rates between men and women such as noted In the United Kingdom and the United States where men with Covid-19 are dying at twice the rate as women is the that the gene for ACE2 lies on the X chromosome, meaning men and boys only have a single version of the gene, while women and girls have two copies of this gene since they carry two copies of the X-chromosome in contrast to men and boys who carry only one copy of the X-chromosome. Thus, males who carry a rare ACE2 coding variants will express those variants (i.e., ACE2 allelic variants) in all ACE2-expressing cells, whereas females will typically express those variants in a mosaic distribution determined by early X-inactivation events. Recently, rare structural variants of the ACE2 gene have been described in the literature whose expressed proteins show some variations in their binding properties towards the SARS-CoV-2 spike protein. It is possible that in some individuals, if not all, the positive prognosis of the Covid‐19 may be due to the existence of ACE2 variants such as these described variants rs73635825 (S19P) and rs143936283 (E329G). Therefore, the findings of this investigation provide clues to screen frequencies of the candidate alleles in different populations to predict the prognosis of Covid‐19.
Of course, much more research needs still to be done in order to establish the genetics behind Covid-19. Typically, human geneticists would prefer to study the whole genomes of huge number of people infected with SARS-CoV-2 without choosing a preferred (i.e., a candidate gene such as the ACE2 gene in the present case) gene at the beginning of their studies. That’s the best genetic way to identify factors that might influence why and how sick a patient might get. But during the present Covid-19 pandemic, there may not be enough time or resources to do this. In this situation, relaying on a candidate gene such as the ACE2 gene appears justified and might yield valuable information soon enough to help clinicians and patients alike in prospective disease risk evaluation and in taking treatment decisions. Around the world physicians are already making difficult decisions about who to treat and how; a genetic test around a candidate gene such as ACE2 could arm clinicians with the knowledge they need to intervene earlier in certain cases and thereby save more lives.
The quickest way to find these variants would be to examine the ACE2 gene in unusual cases of Covid-19, taking the so called “extreme phenotypes” approach. For example, children are less likely to come down with severe disease after being exposed to Covid-19, so any child with unusually severe Covid-19 (requiring ICU care, for example), could, in principle, have this gene sequenced where resources allow. Adding up the data from many, many children and adults would then reveal how these rare ACE2 variants truly affect disease severity.
Follow here this short illustrative sequence on SARS-CoV-2: