Does Genetic Predisposition Contribute to the Exacerbation of COVID-19 Symptoms in Individuals with Comorbidities and Explain the Huge Mortality Disparity between the East and the West?

Abstract

The elderly and patients with several comorbidities experience more severe cases of coronavirus disease 2019 (COVID-19) than healthy patients without underlying medical conditions. However, it is unclear why these people are prone to developing alveolar pneumonia, rapid exacerbations, and death. Therefore, we hypothesized that people with comorbidities may have a genetic predisposition that makes them more vulnerable to various factors; for example, they are likely to become more severely ill when infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To test this hypothesis, we searched the literature extensively. Polymorphisms of genes, such as those that encode angiotensin-converting enzyme 1 (ACE1), have been associated with numerous comorbidities, such as cardiovascular disease, hypertension, diabetes, chronic kidney disease, and obesity, and there are potential mechanisms to explain these associations (e.g., DD-type carriers have greater ACE1 activity, and patients with a genetic alpha-1 anti-trypsin (AAT) deficiency lack control over inflammatory mediators). Since comorbidities are associated with chronic inflammation and are closely related to the renin-angiotensin-aldosterone system (RAAS), these individuals may already have a mild ACE1/ACE2 imbalance before viral infection, which increases their risk for developing severe cases of COVID-19. However, there is still much debate about the association between ACE1 D/I polymorphism and comorbidities. The best explanation for this discrepancy could be that the D allele and DD subtypes are associated with comorbidities, but the DD genotype alone does not have an exceptionally large effect. This is also expected since the ACE1 D/I polymorphism is only an intron marker. We also discuss how polymorphisms of AAT and other genes are involved in comorbidities and the severity of SARS-CoV-2 infection. Presumably, a combination of multiple genes and non-genetic factors is involved in the establishment of comorbidities and aggravation of COVID-19.

Keywords: AAT deficiency; ACE1 DD genotype; ACE2; ADAM17; Ang II; COVID-19; RAAS; SARS-CoV-2; aggravation; comorbidities; inflammation.

Figure 1

Comorbidities possibly established by interplay among variable genetic and non-genetic factors. Various underlying medical conditions and comorbidities, aging, obesity, and smoking have been reported as risk factors for contracting the new coronavirus infection. Most illnesses are thought to begin with a condition called Mibyo (pre-illness) or Suboptimal Health Status (SHS) [14,15,16], and as it progresses, some physical conditions occur. Comorbidities seem to be established by a complex intertwining of many genetic and environmental factors. Regarding genetic factors, the relationship between comorbidities and ACE1 genotypes, especially the DD type and AAT deficiency, has been studied extensively (see text). A common feature of patients with underlying medical conditions and comorbidities is mild inflammation (low-grade inflammation, LGI) presenting with dysregulation of the immune system. In the ACE1 DD genotype, renin–angiotensin–aldosterone system (RAAS) activation and oxidative stress, which lead to immune activation, are considered to be important. The effect of individual gene mutations is mild, but these gene mutations might have a great effect when combined with surrounding genes, or variants of completely different genes, and other non-genetic factors, such as lifestyle-related factors (e.g., a diet high in sugars and fats). Comorbidities are thought to make patients vulnerable to a variety of stimuli because of the many intrinsic problems they have [17,18,19,20]. Especially in the case of SARS-CoV-2 infection, it may be due to their increased susceptibility to such infection.

Figure 2

Possible steps leading to severe cases of COVID-19 among individuals with comorbidities after SARS-CoV-2 infection. Upon binding to receptors on target cells, such as epithelial cells and endothelial cells, SARS-CoV-2 induces ACE2 downregulation (endocytosis) along with the endocytosis of viral particles. As a result, Ang II is not subjected to ACE2-mediated degradation, and the ACE1/AT1R axis becomes more dominant. Additionally, it is well recognized that people with the ACE DD type show higher ACE1 activity in serum [21]. Thus, when ACE2 deficiency due to SARS-CoV-2 infection occurs, excessive Ang II stimulation will further amplify the RAAS imbalance. Stimulation by Ang II induces the activation of PKC and causes the production of reactive oxygen species and the activation of ADAM17, a pleiotropic enzyme. When ADAM17 is activated, many membrane proteins, such as TNF-α, HB-EGF, IL-6Rα, ACE2, and amphiregulin (AREG), are cleaved. As a result, the activation of proinflammatory substances (IL-6, STAT3, EGFR, TNF-α, and neutrophil elastase) leads to a cytokine storm [22,23,24]. These data support the hypothesis that the RAAS is a major mediator of inflammation. On the other hand, several SARS-CoV proteins have been shown to inhibit multiple arms of type I IFN responses and significantly suppress IFN-β production during infection. Utilizing these strategies, SARS-CoV-2 may replicate more efficiently in infected individuals. AAT suppresses SARS-CoV-2 infection through the inhibition of TMPRSS2 and ADAM17 protease. AAT-mediated ADAM17 inhibition can also regulate ACE2 cleavage and protect lung and heart tissue from the harmful effects of RAAS imbalance. In addition, AAT inhibits ADAM17, resulting in the inhibition of TNF-α and IL6-R cleavage, which can exert anti-inflammatory effects. In addition, AAT is involved in the control of neutrophil chemotaxis and the suppression of neutrophil elastase (NE). An upward and a downwards black arrows indicate an increase and a decrease in protein, respectively.