Genetic predisposition models to COVID-19 infection.

A wide range of disease severity among patients with coronavirus disease (COVID-19) has attracted scientists’ attention worldwide. Development of severe symptoms in some adults without any underlying diseases is a challenge. Herein, we explain the potential “genetic predisposition models” to COVID-19 infection with particular emphasis on hypothesizing the possibility of moderately rare dominant variants in severe cases without any underlying medical conditions.

Three genetic-related models for predisposition to COVID-19 could be described: 1-Common variants in multiple loci that have weak effect through single contribution. However, they might manifest significant effect through additive contribution in specific individuals to increase infection risk and severity. 2-Moderately rare variants in limited genes are expected to have strong effects, and thus be highly penetrant and even dominant trait as long as COVID-19 infection is considered. These variants could underlie severe forms in young patients without any other medical conditions. 3-Gene-environment interactions define host predisposition. The concept of susceptibility to COVID-19 is getting more and more complex when gene interactions with environment factors, such as smoking, are considered (see Fig. 1 ).

Fig. 1

Schematic visualization of genetic predisposition of COVID-19 infection. Risk of sex difference is not considered. The number of individuals is not to scale.

In order to reach more specific and sensitive results of indecisive variants, the assessment of targeted genes could be preferred. The receptor-binding domain (RBD) of the COVID-19 spike-protein shows strong interaction with human angiotensin-converting enzyme 2 (ACE2) receptor. It is assumed that the virus binds to ACE2 to enter cells. Consequently, ACE2 genetic variants that could affect its gene expression, protein conformation, and protein stability are the one of most questionable underlying factors involving in genetic predisposition to COVID-19 infection [1]. ACE2 is an X-linked gene that harbours a strong variant with tendency to X-linked dominant inheritance pattern in severely affected patients. It might be a clue to the higher prevalence and severity of COVID-19 in men than in women [2].

The immune-related genetic variants involving the prior strain of coronavirus, namely SARS-CoV, are suspected to have roles in genetic predisposition of COVID-19 infection [3], [4], since COVID-19 has 80% genetic identity to SARS-CoV [5]. Notably, Mannose-Biding Lectin, CD147, CCL2, Interleukin-12, and HLA genes should be considered [6], [7], [8], [9].

COVID-19 appears to be less severe in children [10]. However, severe illness is seldom developed in children. Being detected DNA-driven interplay points and prospective rare dominant variants could shed light on this mystery.

Definitely, the outcome of genetic variants inspection will be a pivotal step to help personalized and predictive medicine in high-risk individuals for severe COVID-19 infection.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.