Human genetic factors associated with susceptibility to SARS-CoV-2 infection and COVID-19 disease severity

Abstract

Background The emergence of the novel coronavirus in Wuhan, Hubei Province, China, in December 2019 marked the synchronization of the world to a peculiar clock that is counting infected cases and deaths instead of hours and minutes. The pandemic, highly transmissible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has indeed caused considerable morbidity and mortality and drastically changed our everyday lives. As we continue to become acquainted with the seventh coronavirus known to infect our species, a number of its characteristics keep surprising us. Among those is the wide spectrum of clinical manifestations of the resulting coronavirus disease 2019 (COVID-19), which ranges from asymptomatic or mildly symptomatic infections to severe pneumonia, respiratory failure, and death. Main body Data, now from patient populations, are beginning to accumulate on human genetic factors that may contribute to the observed diversified disease severity. Therefore, we deemed it prudent to review the associations between specific human genetic variants and clinical disease severity or susceptibility to infection that have been reported in the literature to date (at the time of writing this article in early August 2020 with updates in mid-September). With this work, we hope (i) to assist the fast-paced biomedical research efforts to combat the virus by critically summarizing current knowledge on the potential role of host genetics, and (ii) to help guide current genetics and genomics research towards candidate gene variants that warrant further investigation in larger studies. We found that determinants of differing severity of COVID-19 predominantly include components of the immune response to the virus, while determinants of differing susceptibility to SARS-CoV-2 mostly entail genes related to the initial stages of infection (i.e., binding of the cell surface receptor and entry). Conclusion Elucidating the genetic determinants of COVID-19 severity and susceptibility to SARS-CoV-2 infection would allow for the stratification of individuals according to risk so that those at high risk would be prioritized for immunization, for example, if or when safe and effective vaccines are developed. Our enhanced understanding of the underlying biological mechanisms could also guide personalized therapeutics. Such knowledge is already beginning to provide clues that help explain, at least in part, current epidemiologic observations regarding the typically more severe or benign disease course in older males and children, respectively.

Alu retrotransposons and COVID-19 susceptibility and morbidity

“…The Alu polymorphisms that we reviewed here in ACE , PGR , PLAT , and F13B constitute an example of potentially important alleles (or a combination of) that would not be identified by GWAS and non-targeted sequencing techniques. Firstly, GWAS has been mostly unsuccessful in detecting epistatic effects in humans [ 10 , 13 ]. Polymorphisms in genes from the RAAS, KKS, and the fibrinolytic system, including ACE Alu I/D, are known to exert epistatic effects on the development of cardiovascular accidents [ 67 ].…”

“…Currently, a number of single-nucleotide polymorphisms (SNPs) in several genes and chromosome regions, such as ACE2 , TMPRSS2 , HLA alleles, and locus 3p21.31, have been identified to be associated with the susceptibility and outcome of COVID-19 by GWAS and exome sequencing as recently reviewed by Anastassopoulou et al and Brest et al [ 10 , 11 ]. The initial whole-genome sequencing was completed in China and confirmed the association of HLA alleles and TMEM189-UBE2V1 region with the development of severe outcomes of COVID-19 in the Chinese population [ 12 ].…”

Laboratory-Based Resources for COVID-19 Diagnostics: Traditional Tools and Novel Technologies. A Perspective of Personalized Medicine

“…It is necessary to carefully examine the patient’s molecular profile with determination of the state of all links of his immunity, in order to timely identify genetic predisposition to infectious diseases before infection or in the early stages. This will make it possible to identify a risk group with a low or high probability of developing complications of a particular disease, predict an individual response to immunomodulatory therapy, and predict the likelihood of developing side effects to antiviral therapy [ 83 , 90 , 98 , 99 , 100 ].…”

“…With the increased introduction of molecular diagnostic methods, the cost of separate study is decreasing and over time in infectious diseases hospitals it will become possible to use microchips with a panel for detecting genetic polymorphisms associated with hypersensitivity to commonly used antibacterial or antiviral drugs, which will prevent a large number of deaths [ 88 , 90 , 91 , 99 ].…”

A rational approach to COVID-19

“…CCR1 deficiency increases susceptibility to fatal coronavirus infection [ 10 ]. Associations of genes with severe disease were reported for apolipoprotein E, Toll-like receptor 7, and IL-1 signaling pathway [ 11 ]. The most significant marker of poor prognosis and high mortality risk in patients with acute respiratory failure due to COVID-19 is vitamin D deficiency [ 12 ].…”