Introduction
Coronaviruses are a large family of single-stranded RNA viruses, which
cause illnesses ranging from mild cold to more severe diseases such as
Severe Acute Respiratory Syndrome (SARS)-CoV and Middle East Respiratory
Syndrome (MERS-CoV) [1]. COVID-19 was first reported in Wuhan,
China, and subsequently spread worldwide. As of February 2021, there
have been more than a hundred million cases of COVID-19 worldwide and
nearly two and a half million deaths [2].
The entry of SARS-CoV-2, the agent that causes COVID-19, into the cell
occurs by binding viral spike proteins to Angiotensin-Converting Enzyme
2 (ACE2) receptors of the host membrane. It was suggested that increase
susceptibility to Covid-19 infection is associated with the expression
of the target ACE2 receptor in the epithelium exposed to the virus
[3]. The low infection and complication level is a fact among
children. Serum ACE levels in children are higher than in adults and
ACE2 receptor gene expression in the nasal epithelium that is the first
point of contact for SARS-CoV-2, was age-dependent, lowest in younger
children and increasing with age into adulthood [4]. It was also
suggested that the lower risk among children is due to the lower
expression of the ACE2 receptor [5]. Epidemiological data show that
a majority of pediatric COVID-19 cases showed mild to moderate clinical
features, and only a few developed severe or critical diseases (0.6%
and 0.3%, respectively) [6]. Total 44 672 cases, only 1% is under
10 years old and in China [7]. Also lower ACE2 receptor expression
in children, highlighting the importance of ACE and ACE2 receptor
expression level in Covid19 severity.
A counter-regulatory relationship between ACE2 and ACE located on
opposite axes in the Renin-Angiotensin System (RAS) was reported. ACE
plays important role in converting angiotensin I to angiotensin II and
ACE2 is a negative regulator of the RAS and counterbalances the function
of ACE. The lungs are primary organs for ACE receptor expression and
generating circulating angiotensin II. RAS plays a role in the
pathogenesis of pulmonary hypertension and fibrosis, which are common
chronic lung diseases. Recent studies show that RAS also plays important
role in acute lung diseases, particularly acute respiratory distress
syndrome (ARDS) [8].
A common 287 base pair insertion/deletion (I/D) polymorphism has been
reported in intron 16 of the ACE gene and is known to be
associated with serum levels of circulating ACE. Serum ACE
concentrations were reported to be significantly higher in subjects with
the D/D genotype compared to the I/D and I/I genotypes [9].
Considering the opposite effect between ACE and ACE2, decreased ACE2
receptor gene expression is strongly related to an increase in ACE
expression. So it could be hypothesized that having a D allele for ACE
I/D polymorphism affects the clinical course of the Covid-19 by
decreasing the ACE2 receptor level.
Besides, it has been shown that patients with chronic obstructive
pulmonary disease (COPD) have increased gene expression of ACE2 receptor
in bronchial epithelial cells in the lower respiratory tract, and also
smoking has been shown to increase both the expression and activity of
ACE-2 in the airways. While up-regulation of ACE-2 is beneficial in
protecting the host against acute lung injury, this makes individuals
more susceptible to coronavirus infections that use this receptor to
enter epithelial cells [10,11].
In the changes in ACE2 receptor gene expression level, genetic
variations play a very important role as well as environmental factors.
Of the many polymorphisms identified in the ACE2 receptor gene,
rs2106809 and rs2285666 are particularly remarkable. A bioinformatics
tool called Human Splicing Finder (HSF) (v.3.0) predicts that rs2106809
polymorphism, intronic SNP found in the ACE2 receptor gene, might create
an intronic-exonic splicing enhancer site (ESE). It was suggested that
the splicing efficiency of the ACE2 receptor gene may be influenced by
the creation of these enhancer motifs [12]. It was also found that
ACE2 rs2106809 CC or CT genotype carriers had higher circulating ACE2
receptor levels compared to TT genotype carriers [13].
G8790A (rs2285666) polymorphism is at the fourth base of the third
intron and situated in the intron adjoined to the exon, suggesting, this
locus could alter mRNA alternate splicing and
affect ACE2 receptor gene expression. It has also been reported
that this polymorphism shows a strong linkage disequilibrium with the
other SNPs (rs1978124 intron 1 and rs714205 intron 16) in the ACE2
receptor gene [14].
The relationship between ACE2 gene expression and Covid-19 has been
shown in the literature, however, most of the studies conducted to
investigate the role of ACE receptor gene polymorphisms are in-silico
analyzes or epidemiological studies. Also, to the best of our knowledge,
there is no study investigating the relationship between ACE I/D and
ACE2 receptor gene rs2106809 and rs2285666 polymorphism and Covid-19
severity. In this study, it is aimed to investigate whether the course
of the disease (mild, moderate, and severe) is predictable by
determining the genotypes of ACE I/D and ACE2 receptor gene
polymorphism.