Genetic variants in extremely ill COVID patients explain how fatally sick people may get

Last Updated on February 6, 2022 by Joseph Gut – thasso

February 02, 2022 – The search to better understand the tremendous range of responses to infection with the SARS-CoV-2 virus, from symptom free to critically or even fatally ill has uncovered in some of the sickest patients a handful of rare structural gene variants involved in bodily processes such as inflammation, which the virus needs to be successful.

In apparently the first study of its kind, investigators used optical genome mapping, to get a thorough, three-dimensional assessment of the genome of 52 severally ill patients with COVID-19 disease. In nine of the sickest patients, they identified seven rare structural variants affecting a total of 31 genes involved in key pathways mediating the response between a person, or host, and a virus. These include innate immunity, our frontline immune defense against invaders like viruses; the inflammatory response, a key response to an infection that, gone awry, can also destroy the lungs of some of the sickest patients; and the ability of a virus to replicate and spread. As an example, one genetic variant they identified can lead to over-expression of keratin genes. Keratins are proteins that are the structural components of things like our hair and nails, but that also have been identified as key to the transmission of both flu viruses and the SARS-CoV-2 virus between cells and are known to be up-regulated in the respiratory tract during an infection. This reflects a hyper-activation of the normal cellular systems /pathways.

Millions of people get infected, and fortunately only a very small percentage become symptomatic, and a very small percentage of the symptomatic individuals require oxygen and a small percentage of those individuals are hospitalized and die. But even a small percentage amounts to millions of people and that is too many. As identified by optical genome mapping,  large structural variants might further explain the inter-individual clinical variability and phenotypical discrepancies of individuals in response to SARS-CoV-2.

Previously, clinical studies have identified factors like older age, being male, hypertension, diabetes and other chronic conditions as risk factors associated with the degree / severity of illness from SARS-CoV-2. The nine sickest patients in the present study shared common comorbid conditions, 32 of the patients required mechanical ventilation to support their breathing and a total of 13 of the 52 patients died while in intensive care. But in their studies, which also included individuals who were negative for the SARS-CoV-2 virus and those who were positive but asymptomatic, there were again outliers, including individuals with comorbid conditions who remained asymptomatic when infected with SARS-CoV-2 and those who were perfectly healthy but became extremely ill when infected, another indicator of a role for genetics in determining the degree of response, Large structural variants account for much of the genetic diversity among us, including changes that are just unique to the individual and those that can increase their risk of problems like cancer. In the present study, optical genome mapping was used to detect these larger variants with multiple changes, like deletion or insertion of genetic material and/or when a section of chromosome is reversed. The researchers also note that the large structural variants they found in the sickest patients were not caused by the virus but rather used by the virus and may not increase susceptibility to other, even similar, conditions.

Overall, this means that the structural genetic variants are preexisting in individuals severely affected by SARS-CoV-2. Overall, the individuals in the present study had about 40 rare structural variants, which other studies have indicated is about average. Earlier, some studies have found that blood type might be a factor in predicting risk, specifically type A, and there have been some specific gene findings as well that predispose to immune deficiencies that may make people more susceptible to COVID-19 disease. Under these circumstances, even the amount of virus (virus load) in an individual seeemed to not directly correlate with how sick the individual was getting in that individuals with very high viral loads did not even know they were positive.  This definitively points to something in the host genome that is different, i.e., to genetic predisposition.

The present work was embedded in the  COVID-19 Host Genome Research Consortium which currently has a membership of 34 institutions throughout the world and is concerned with different aspects of how structural variants impact the divergent individual responses to infection with the COVID-19 virus. It was formed mainly because more commonplace gene sequencing studies, which essentially lay out the DNA in a straight line to look for problematic and smaller variations in the usual order of its four base pairs, adenine, thymine, guanine and cytosine, on thousands of patients have yielded little information to help explain, and ideally predict, the wide variations in how sick people will get. Better than 30% of the known disease-causing variants are larger than the single base pair changes sequencing can identify, according to the Human Gene Mutation Database.

See here a short sequence on genetic variants in severe COVID-19 disease:

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