REVIEW PAPER

Genetic Susceptibility to Coronavirus Disease 19
(COVID-19): A Review

Tajudeen O. Yahaya a Esther O. Oladele b Aliyu A. Turaki c Kelechi Nnochiril a Haliru Abdullahi a Josephine Nathaniel a

Coresponding author(s): yahaya.tajudeen@fubk.edu.ng

aDepartment of Biology, Federal University Birnin Kebbi, PMB 1157, Birnin Kebbi, Nigeria,bBiology Unit, Distance Learning Institute, University of Lagos, Nigeria, and
cDepartment of Biochemistry and Molecular Biology, Federal University Birnin Kebbi, Nigeria

Certain gene polymorphisms are suspected to contribute to the
geographic-specific susceptibility of people to coronavirus dis-
ease 19 (COVID-19), which may be used as therapeutic targets.
Accordingly, this review articulates suspected COVID-19 suscep-
tibility genes to assist researchers and medical practitioners to
formulate effective drug and treatment procedures. Reputable
electronic academic databases, including PubMed, Springer-
Link, and Scopus were searched for relevant information on the
subject. The search identified seven COVID-19 susceptibility
genes, which are TICAM2, TLRs, ACE, ABO blood group gene,
HLA, and TMPRSS2. Polymorphisms in ACE and TMPRSS2 may
increase or decrease the binding of the virus to the human cell,
while polymorphisms in TICAM2, TLRs, and HLA may enhance
or compromise the immune system. Type O blood group seems
to be the most protective ABO blood group because of its abun-
dant antibodies and blood clothing inhibition, while type A blood
group is the least protective. The distribution of the polymor-
phisms is influenced by geographical locations, which could
contribute to the worldwide differential vulnerability of people
to the disease. Most protective polymorphisms are prevalent
among Africans and Asians, which could be the reason for their
less susceptibility to the disease compared to Europeans and
Americans. Most of these genes are X-linked, which could partly
explain the dominance of the severe form of the disease among
men than women. Overall, these show that polymorphisms in
certain genes may modulate COVID-19 infectivity and severity.
Thus, a thorough understanding of the biological mechanisms
of these genes may help design a cure.

| COVID-19 | Gene | Immune system | Susceptibility |
| X-chromosome |

The causative agent of coronavirus disease 19 (COVID-19)known as the severe acute respiratory syndrome coronavirus
2 (SARS-COV-2) was first reported in Wuhan, China in Decem-
ber 2019 (1). Shortly after, the International Committee on Tax-
onomy of Viruses classified the virus as a member of the species

of severe acute respiratory syndrome-related coronavirus (2). Phy-
logenetic analyses further indicated that SARS-CoV-2 belongs to
the subgenus Sarbecovirus and genus Betacoronavirus as was se-
vere acute respiratory syndrome (SARS-CoV) (3). These classifi-
cations bring to three the number of human coronaviruses (HCoV)
that had emerged and spread in human populations in recent times.
Aside from SARS-CoV mentioned above, the other HCoV that has
emerged previously is the Middle East respiratory syndrome coro-
navirus (MERS-CoV). Being in the same genus, SARS-CoV and
SARS-CoV-2 are more related (about 80% genetically compatible)
than MERS-CoV, which belongs to the subgenus Merbecovirus (4,
5).

Coronaviruses are highly pathogenic with symptoms ranging
from mild to moderate and severe respiratory illness, but SARS-
CoV-2 could be asymptomatic in some cases. Coronaviruses spread
primarily through saliva droplets and nasal discharges when cough-
ing and sneezing, respectively (6). SARS-CoV-2 is particularly very
pathogenic as evident in its transition to a global pandemic within
a few months of the outbreak, affecting around 210 countries (7).
The disease has caused a global lockdown of activities and unprece-
dented health burdens in recent times. As of June 14, 2020, cases
and mortality of COVID-19 worldwide had reached 7,896,400 mil-
lion and 432,887, respectively (8). In Nigeria, as of 13th June 2020,
15, 682 cases and 407 deaths have been recorded (9). The high inci-
dence and mortality of COVID-19 have resulted in huge economic
losses and gradually drifting the world into a recession. As of April
2020, the United States unemployment rate has risen to a record
14.7%, with over 20 million jobs lost in March (7). The European

Submitted: 04/08/2020, published: 23/06/2021.

Freely available online through the UTJMS open access option

6–11 UTJMS 2021 Vol. 9 translation@utoledo.edu

mailto:yahaya.tajudeen@fubk.edu.ng 


Union gross domestic product is predicted to drop by 7.5% during
2020 (7).

According to United Nations Economic Commission for Africa,
around half of jobs in Africa could be lost to the COVID-19 out-
break (7). As of this date, the incidence and mortality of the disease
are still increasing, indicating that its burden could be worse. Con-
cerns are rife worldwide because up till this moment, no drug or
treatment procedure has been certified safe and effective for the dis-
ease. This has put scientists in a frantic search for a cure and one
area which some scientists opined can be leveraged on is the virus’s
selective infectivity and pathogenicity. Some people appear to be
immune to the virus, while others are susceptible, suggestive of cer-
tain genetic and environmental predisposing factors. It is believed
that these factors may be employed as therapeutic targets to develop
drugs and vaccines. Understanding the selective infectivity of the
virus may also help identify individuals that are at risk, which may
be used as a preventive measure. It may also be used to prevent or
manage the future occurrences of the disease. To this end, some
researchers have identified certain genes whose polymorphisms or
mutations may protect or predispose to the disease. This review was
initiated to articulate the identified genes to guide researchers and
medical practitioners in the search for a COVID-19 cure.

Material and Methods

Databases Searched and Search Terms

Academic databases searched for relevant information on the
topic include Scopus, PubMed, SpringerLink. Search terms used to
retrieve articles are ‘coronavirus’, ‘COVID-19’, ‘severe acute res-
piratory syndrome’, ‘SARS-COV-2’, ‘genes predisposing to coro-
navirus diseases’, and ‘coronavirus susceptibility genes’. Other
search terms used include ‘coronavirus overview’, ‘incidence of
COVID-19’, ‘prevalence of COVID-19’, ‘mortality of COVID-19’,
and ‘economic burden of COVID-19’. The articles retrieved were
pooled together and double citations removed using EndNote soft-
ware.

Article Inclusion Criteria
• Research published in the English language.
• Research that focused on COVID-19.
• Studies that focused on the genetic basis of COVID-19.
• Studies that centered on the prevalence and mortality of COVID-
19.

Article Exclusion Criteria
• Studies that are not available in the English language.
• Studies with only abstract available.
• Research that described COVID-19, but with no clear genetic
mechanisms.

Genetic susceptibility to COVID-19

To infect a person, a virus invades the cell, hijacks the cel-
lular mechanisms, and reconfigures the cell to produce copies of
the virus, thus infecting more cells, and so on. Normally, when a
virus infects human cells, the immune mechanism becomes acti-
vated, identifies the virus, and sends a subtype of white blood cells
called cytotoxic T cells to destroy the infected cells and slow the
infection (10). However, some individuals have different alleles of
the genes that make up the immune system, some of which predis-
pose to microbial infection (11), while some protect. Based on the
foregoing, Darbeheshti and Rezaei (12) proposed three models of
genetic variations among humans, which may produce differential
susceptibility to COVID-19. These include common genetic vari-

ants in multiple loci with weak effects individually, but additively
increase the infection risk and severity of individuals. Moderately
rare variants in few genes may also combine to increase susceptibil-
ity to COVID-19. Some of these rare variants may be dominant and
could be responsible for the severe infection noticed in some young
patients expressing no underlying medical condition. Moreover, ge-
netic and environmental factors such as smoking and pollution ex-
posure increase an individual’s susceptibility to COVID-19. This
review identified seven genes whose polymorphisms or mutations
may employ one or more of the above models to protect or predis-
pose to COVID-19.

TICAM2 and TLRs

Toll-Like Receptor Adaptor Molecule 2 (TICAM2) codes for
a protein that helps activate a family of receptors called toll-like
receptors (TLRs) (13). Toll-Like Receptors (TLR) are important
components of the innate immune system (14). They constitute
a multigenic family of receptors, which collectively bind several
types of exogenous and endogenous ligands (14). Studies show that
TLRs functionally fight against infections and autoimmunity and
thus can be viewed as a structurally distinct counterpart of major
histocompatibility complex (MHC) (14). To date, 10 TLRs termed
TLR1 to TLR10 have been described in human genomes (14). The
TLRs recognize microbes by pairing with each other. The pairing
of TLR1 and 2 or TLR2 and 6 recognizes bacteria, such as those
that cause tuberculosis (15). The TLR3 recognizes certain viruses,
while TLR4 recognizes certain molecules on bacteria found in the
gastrointestinal tract such as E. coli (15). The TLR5 recognizes
whip-like structures on bacteria called flagella, and TLR 7, 8, and
9 recognize certain viruses such as influenza and human immun-
odeficiency virus I (HIV-I) (15). After sensing a viral or microbial
molecule, TLRs begin a series of chemical reactions that signal the
innate immune cells to produce type I interferons (IFNs), other cy-
tokines, and chemokines, killing the microbes (15,16). However,
TLRs are highly polymorphic, some may hinder the recruitment of
immune cells and predispose humans to microbial infection (14,
15), including coronaviruses.

Several instances in which mutations in TLRs predispose to in-
fections have been reported. In a cross-mouse multi-parent popu-
lation, strains with TICAM2 deletion, causing loss of function of
TLRs, were highly susceptible to SARS-CoV infection (17). The
mice exhibited increased weight loss and pulmonary hemorrhage
than control mice (17). These results suggest an important role for
TICAM2 in SARS-CoV disease (17). Given the genetic compati-
bility of SARS-CoV and SARS-CoV-2, it is expected that the gene
will also contribute to the genetic susceptibility of individuals to
SARS-CoV-2. Beyond this, the gene may help explain the observed
high proportion of men who suffer from severe COVID-19 com-
pared to women (13). Though behavioral and hormonal differences
may be partly responsible for the differences, genetic factors, partic-
ularly mutation in the TLR7 gene, may also be involved (13). The
gene is X-linked, thus making men more predisposed because men
have one copy of the X chromosome, unlike women who carry two
copies. It then follows that if one TLR7 gene is mutated in a female,
the other will make up for it and prevent the infection.

ABO Blood Gene

Polymorphisms in the ABO blood gene are suspected to con-
tribute to the differential susceptibility of humans to microbial in-
fections, including SARS-CoV-2. The ABO gene contains three
alleles, two of which encode different enzymes that coat the surface
of red blood cells (RBC) with certain sugar molecules (glycopro-
tein). The sugar molecules are often referred to as antigens and
tagged type A and B, respectively. The third allele is inactive and

Yahaya et al. UTJMS 2021 Vol. 9 7



thus lacks enzyme and sugar molecule on the surface of RBC and
is referred to as type O. Based on the Mendelian principle, an indi-
vidual can only inherit two alleles for a trait, so the possible ABO
blood group genotype (allelic combination) of an individual are AA,
AO, AB, BB, BO, or OO. Being inactive, type O is recessive, thus
giving rise to four ABO blood group phenotypes, namely; type A
(AA or AO), type B (BB or BO), type AB and type O. So, individ-
uals expressing A antigen are type A, B antigen are type B, both A
and B are type AB, and type O has neither antigen (16). Accord-
ingly, the immune systems of type A blood develops antibodies for
B antigen, type B has antibodies for A antigen, type O has antibod-
ies for both, and AB type has none (18, 13). This shows that, in the
ABO blood group system, type O blood is the richest in antibodies,
possessing both antibodies A and B, whereas type AB blood has
neither of them (13). This could explain, in part, the reason type
O blood is protective against certain microbial infections, including
SARS-CoV-2.

Furthermore, the spikes of SARS-CoV-2, which are important
molecules the virus uses to infect cells, contain numerous sugars,
which are bound using the host cell enzymes (18). As a result, the
spike protein of coronavirus particles often carries the blood group
sugar antigen of the infected host cells (18). So, when an infected
person coughs or sneezes, viral particles coated in the blood type
antigens of the person are released. If an individual with type A
blood transmits the virus to a person with type O blood, the type O
individual may resist it because it has numerous antibodies to fight
the virus. However, if the person who inhaled the particles is also
type A, he/she may not have antibody to resist it (18). This find-
ing is corroborated by a study that monitored the transmission of
SARS-CoV among 45 exposed healthcare workers in a Hong Kong
hospital, China. Of the 19 people with type O blood, 8 became
infected, but of the 26 people with other blood types, 23 became in-
fected (19). The ABO blood group antibodies also react differently
to the angiotensin-converting enzyme 2 (ACE2) receptor, which is
necessary for SARS-CoV-2 to bind to the body cells. Guillon et al.
(20) demonstrated that SARS-CoV spike protein’s binding to ACE2
is inhibited by the anti-A antibody. Anti-A antibody is secreted by
type B blood, which may point to the protective advantage of type B
blood over type A if the latter lacks the property. However, the reac-
tion of anti-B antibody could not be ascertained in the studies due to
a lack of data. Aside from the effect of blood type antibodies, blood
types also influence blood clotting, which is an important pathology
of COVID-19. Studies show that COVID-19 often involves over-
active blood clotting, which is suppressed by type O blood. People
with type O blood have lower levels of proteins that promote blood
clotting, which may lead to reduced severity of COVID-19 in the
affected (18).

Most studies conducted on the association of ABO blood types
with COVID-19 proved that type A blood is more susceptible,
while type O is protective. In one study, researchers sequenced
the genomes of 1,610 COVID-19 patients in Spain and Italy and
compared their DNA to those of 2,245 healthy subjects (19). In all,
the scientists analyzed 8,582,968 single-nucleotide polymorphisms
(SNPs) and found two regions of DNA in which sequence varia-
tions were related to the severity of the disease. One of the regions
is 9q34 which encodes ABO blood group genes, while the other is
the 3p21.31 region that encodes the ACE2 gene. When the patients
were grouped according to blood types, individuals with type A had
a higher chance of developing severe respiratory failure compared
with type O (21). In another study, a retrospective cohort study of
SARS-CoV-2 patients in three hospitals in China also associated
the prevalence and severity of the virus with blood types. In the
study, the proportions of type A and O blood in SARS-CoV-2 pa-
tients were significantly higher and lower, respectively, than that in

healthy controls (22). This shows that blood group A patients were
at higher risk of hospitalization following SARS-CoV-2 infection,
while blood group O patients had a lower risk (22). This further sug-
gests that ABO blood types could be used as a biomarker to predict
the risk of SARS-CoV-2 infection (22). However, no relationship
was found between the ABO blood types and differential suscep-
tibility to COVID-19 in the United States (18). Type O blood is
more prevalent among African Americans in the United States, yet
African Americans exhibited high incident rates (23). This suggests
that blood types might contribute a minor effect to the variability ob-
served in SARV-CoV-2 infectivity and severity (18) and that other
factors might be involved. Most studies did not report an association
between blood type B and AB, probably due to a lack of sufficient
data (18). This may reflect the low prevalence of the blood types in
human populations, particularly where some of these studies were
carried out.

ACE

The ACE genes code for the angiotensin-converting enzymes
(24). They are part of the renin-angiotensin system, which reg-
ulates blood pressure as well as body fluids and salts (24). The
ACE enzymes can cleave proteins and, by cutting a protein called
angiotensin I, the angiotensin-converting enzyme converts this pro-
tein to angiotensin II (24). Angiotensin II causes blood vessels to
constrict, resulting in increased blood pressure (24). This protein
also stimulates the production of the hormone aldosterone, which
triggers the absorption of salt and water by the kidneys (24). The
increased concentrations of fluid in the body also increase blood
pressure (24). Proper blood pressure during fetal growth, which de-
livers oxygen to the developing tissues, is required for the normal
development of the kidneys (24). Among the ACE gene family, in
order of importance, angiotensin-converting enzyme 2 (ACE2) and
angiotensin-converting enzyme 1 (ACE1) are associated with coro-
navirus infection and severity (13).

The receptor-binding domain of the COVID-19 spike-protein
shows a strong interaction with the ACE2 receptor (25). It has been
shown that similar to SARS-CoV, the SARS-CoV-2 spike protein
binds to ACE2 to enter cells (26, 27). Spike glycoproteins comprise
two major functional domains, which are the N-terminal domain
(S1) for binding to the host cell receptor, and a C-terminal domain
(S2) that is responsible for the fusion of the viral and cellular mem-
branes (28). SARS-CoV-2 and SARS-CoV spike proteins share
very high phylogenetic similarities, about 99% (29, 30). However,
SARS-CoV-2’s S-protein has accumulated mutations that increase
its binding to ACE2 by about 10-15-fold compared to SARS-CoV’s
S-protein, making it more infectious (31). Considering the impor-
tance of ACE2 receptor to viral infection, genetic variants that affect
its expression, conformation, and stability can alter genetic predis-
position to COVID-19 (25). ACE2 is expressed on the surface of
type II lung alveolar epithelial cells and its mRNAs are expressed
in almost all organs, including the heart, blood vessels, kidney, and
testis (27, 32). This indicates that loss of function of ACE2 gene
due to massive binding of coronavirus can cause multi-organ dam-
age as evidenced in COVID-19 [32, 36). Mouse experiments with
ACE2 gene knockout expressed pulmonary vascular congestion, in-
creased lung weight, congestive heart failure, and death (33). ACE2
differential cellular expression and polymorphisms have also been
reported in humans, which could partly explain varied susceptibility
to SARS-CoV-2 (26). Calcagnile et al. (27) identified two single-
nucleotide polymorphisms (SNPs) of the ACE2 gene, which are
S19P (common among Africans) and K26R (common among Eu-
ropeans). The S19P decreases, while K26R increases the ACE2
binding to SARS-CoV-2 spike, suggesting that the S19P genetically
protects, while K26R predisposes to more severe SARS-CoV-2 dis-
ease (27). This can partly explain varied ethnic and geographical

8 translation@utoledo.edu Yahaya et al.



susceptibility to the disease. In a study that examines the binding of
ACE2 allelic proteins with SARS-CoV-2 spike protein, again, S19P
(rs73635825) allele and E329G (rs143936283) allele were found
protective (34). However, in a study by Stawiski et al. (31), S19P
was included among ACE2 variants that increase susceptibility to
SARS-CoV-2; along with others such as I21V, E23K, K26R, T27A,
N64K, T92I, Q102P, and H378R. Other ACE2 variants detected
were protective, which include T92I K31R, N33I, H34R, E35K,
E37K, D38V, Y50F, N51S, M62V, K68E, F72V, Y83H, G326E,
G352V, D355N, Q388L, and D509Y (31).

Varied expression of ACE2 may also explain the COVID-
19 differential susceptibility and severity of men versus women.
Estrogen-induced overexpression of ACE2 may increase the sus-
ceptibility of some women to COVID-19, but less severe and of-
ten asymptomatic (27). Furthermore, the ACE2 gene is located
on Xp22, in an area where genes may escape from X-inactivation,
which further explains the increased susceptibility of some females
(27). Generally, men showed higher incidences and mortality of
COVID-19, probably due to underlying conditions such as cardiac,
respiratory, and metabolic co-morbidities (27). The X-linked inher-
itance pattern of the ACE2 gene might also be another reason for the
high prevalence and severity of COVID-19 in men than in women
(35). However, regardless of sex, antihypertensive drugs, such as
ACE inhibitors and sartans, which can increase ACE2 expression,
may increase susceptibility and severity of COVID-19 (36). En-
vironmental factors such as nitrogen dioxide exposure may over-
express ACE2 and increase susceptibility and severity of infection
(36). In brief, ACE2 plays a dual role in infection mounting and
pathogenesis. First, its overexpression promotes the entry of the
virus into the cell as well as its replication. Second, its loss of func-
tion due to viral load causes accumulation of angiotensin II that
further aggravates the acute lung injury observed in infected indi-
viduals (27). However, certain polymorphisms in the ACE2 gene
such as the S19P mentioned earlier could reduce the spike affinity,
subsequently lowering susceptibility to infection (27).

A close relative of ACE2 in blood pressure control is
angiotensin-converting enzyme 1 (ACE1) (13). The ACE1D, one
of the several genetic variants of the enzyme involving a deletion
or insertion, reduces the expression of the ACE2 gene and thus pre-
vents SARS-CoV infection (13). The frequency of ACE1D differs
from one country to another, particularly in Europe, and reflects the
global epidemiological incidence of the disease (13). Data from 25
countries, mainly Europe and Asia, showed that some variability in
disease prevalence and mortality is explained by the frequency of
the ACE1D variant (37). The study also noted that the ACE1D vari-
ant is less frequent in China and South Korea, which were severely
hit by SARS-CoV-2 (37). However, an earlier study by Chan et al.
(38) found no association between the ACE1D variant and the fre-
quency and severity of SARS-CoV infection.

HLA

Some genetic susceptibility to COVID-19 may reside in the
genes that encode human leukocyte antigens (HLAs), which is a
set of proteins that prevent the immune system from attacking self-
cells (13). Each individual has several alleles of the HLA genes and
each allele codes for a different HLA protein (11). These proteins
constitute the major histocompatibility complex (MHC), which dis-
tinguishes self from foreign antigens (13). The proteins bind to
the peptides of foreign antigens and carry them to the cell surface,
where they are killed by the immune system (11). The higher the
number of virus peptides or other microbes a person’s HLA genes
can detect, the stronger the immune response (11). Given the role
of HLA genes in immune maintenance, it is very likely a link ex-
ists between HLA genes and COVID-19 infectivity and pathogenic-

ity. Indeed, some scientists, including Nguyen et al (8) have estab-
lished a link between certain HLA gene variants and susceptibility
to COVID-19. The scientists observed that, among other alleles,
individuals expressing the HLA-B*46:01 variant were most at risk
of SARS-CoV-2 infection, as was observed during the SARS-CoV
epidemic (8). Whereas, individuals expressing the HLA-B*15:03
variant were the most protected. In a computer modeling experi-
ment by Nguyen et al (10), some HLA alleles bind to numerous
SARS-CoV-2 peptides while others bind to very few. This again
suggests that the HLA genes of some individuals are genetically
programmed to resist SARS-CoV-2 infections, while others may be
genetically predisposed. When SARS-CoV-2 was compared with
SARS-CoV retrospectively, the HLA gene alleles react the same
way, which could be due to the genetic compatibility of the two
viruses. The study again observed that the B46:01 allele increases
susceptibility to both SARS-CoV-2 and SARS-CoV (11).

Though there is no scientific evidence yet linking HLA al-
lele geographical distribution with the differential vulnerability of
COVID-19 (39, 40), there are some evidence pointing along the di-
rection. The predisposing allele, HLA-B*46:01 is prevalent among
the Southeast Asian descent, and the Southeast Asia continent, a re-
gion that experienced a high incidence of COVID-19 (41). On the
contrary, the predisposing allele is absent in regions with a low inci-
dence of the disease such as India and Africa, and rarely present
in Europe (40, 42). The protective allele, HLA-B*15:03 is ab-
sent among East Asians while it is the most dominant allele among
African descent (40, 42). Another protective allele, HLA-A*02, is
common among Indian and African populations, while a suscepti-
bility allele, HLA-C*12:03, is the most frequent allele among Eu-
ropean descent (40, 42). These show that HLA alleles might, in
part, be responsible for the differential susceptibility of SARS-CoV-
2 worldwide. According to Zahn (43), most people carry between
three and six different HLA alleles that show geographically spe-
cific distributions.

TMPRSS2

The Transmembrane Serine Protease 2 (TMPRSS2) is an
androgen-responsive serine protease that cleaves SARS-CoV-2
spike protein, facilitating viral entry and activation (44). TMPRSS2
is highly expressed in the lung (45) as well as cardiac endothelium,
kidney, and digestive tract, suggesting that these organs may be tar-
geted by SARS-CoV-2 (46). TMPRSS2 works synergistically with
ACE2 to initiate and maintain infection. After the spike (S) pro-
tein on SARS-CoV-2 binds ACE2, transmembrane protease serine
2 primes the S protein to allow cellular uptake of the virus (45).
Therefore, individual expression of TMPRSS2 may be an impor-
tant determinant of SARS-CoV-2 susceptibility (45, 47). In a co-
hort study that investigated TMPRSS2 expression in the lungs of
people from different continents, four variants, namely rs464397,
rs469390, rs2070788, and rs383510 significantly affect TMPRSS2
expression (45). The results showed that TMPRSS2 upregulating
variants (rs464397, rs383510, and rs469390) are present at higher
frequencies among Europeans and Americans than in Asians, which
implies that the former might be at increased risk of SARS-CoV-2
infection (45). Similar findings were observed in another study that
compared the TMPRSS2 pulmonary expression between European
and East Asia subjects. The European populations had higher lev-
els of pulmonary expression of the TMPRSS2 gene, suggesting that
the gene increased their vulnerability to SARS-CoV-2 (48). The
findings of these studies suggest that the TMPRSS2 gene may be
responsible for the higher prevalence and mortality of COVID-19
among European populations than eastern Asians. TMPRSS2 has
also been observed to be modulated by sex steroids, which could
have contributed to the worldwide reported increased vulnerability

Yahaya et al. UTJMS 2021 Vol. 9 9



of men to SARS-CoV-2 compared with women (49).

TMPRSS2 protein has no known indispensable function, thus,
it could be considered a good therapeutic target for COVID-19 and
related diseases (49). The therapeutic target of the gene is appeal-
ing because its inhibitors are available (49). In an in vitro study, an
inhibitor of the protease activity of TMPRSS2, camostat mesylate,
partially inhibited the entry of SARS-CoV-2 into the lung epithe-
lial cells (44). Moreover, in a TMPRSS2 knockout model, mice in-
fected with the H1N1 influenza virus showed a small viral load, mild
symptoms, and no death compared with control (50). These make
it tempting to speculate that androgen receptor{inhibitory therapies
might reduce susceptibility to COVID-19 pulmonary symptoms and
mortality (49).

Conclusion

The review discovered that polymorphisms in TICAM2, TLRs,
ACE, ABO blood group gene, HLA, and TMPRSS2 may mod-
ify an individual’s susceptibility to COVID-19. ACE and TM-
PRSS2 variants may affect the attachment of the virus’s spike pro-
tein to the membrane of the human cell, increasing or reducing viral
loads. Polymorphisms in TICAM2, TLRs, and HLA may disrupt or
boost the innate immunity, increasing or decreasing susceptibility
to COVID-19. Type O blood contains numerous antibodies, mak-

ing it the most protective ABO blood type, while type A is the least
protective blood type. Type O blood also inhibits blood clotting,
reducing the severity of the disease. The frequency of the polymor-
phisms of each gene varies worldwide, which could, in part, explain
the differential vulnerability of people to the disease. Africa and
Asia have higher frequencies of the beneficial variants than Europe
and the United States, which revealed why Africans and Asians are
less susceptible. Some of the genes are X-linked, which could partly
explain the dominance of the severe form of the disease among men
than women. A proper understanding of the biological functions of
these genes may provide information for designing effective drugs
and treatment procedures.

Conflict of interest

Authors declare no conflict of interest.

Authors’ contributions

TY conceptualized, did literature search, wrote the article, and
did corresponding. EO and AT did literature search and proofread-
ing. KN, HA, and JN did article sorting and referencing. All authors
have read and approved the final document.

1. Zhu N, Zhang D, Wang W, et al. (2020). A novel coronavirus from patients with
pneumonia in China, 2019. N Engl J Med 382 (8):727{733.

2. Coronaviridae Study Group of the ICTV (2020). The species severe acute res-
piratory syndrome-related coronavirus: classifying 2019-nCoV and naming it
SARS-CoV-2. Nat Microbiol 5:236{544.

3. Peng Z, Xing-Lou Y, Xian-Guang W, et al. (2020). A pneumonia outbreak associ-
ated with a new coronavirus of probable bat Origin. Nature 579(7798):270{273.

4. Lu R, Zhao X, Li J, Niu P, Yang B, Wu H. (2020). Genomic characterisation and epi-
demiology of 2019 novel coronavirus: implications for virus origins and receptor
binding. The Lancet 395(10224):565{574.

5. Sironi M, Hasnain SE, Rosenthal B, et al. (2020). SARS-CoV-2 and COVID-19:
A genetic, epidemiological, and evolutionary perspective. Infect Genet Evol
84:104384.

6. World Health Organization (2020). Coronavirus disease (COVID-19) outbreak.
Available at https://www.who.int/health-topics/coronavirus tab=tab 1.

7. World Economic Forum (2020). The economic effects of COVID-19 around
the world. Available at https://www.weforum.org/agenda/2020/02/coronavirus-
economic-effects-global-economy-trade-travel/.

8. Worldometer (2020). Covid-19 Coronavirus Pandemic. Avail-
able at https://www.worldometers.info/coronavirus/?utm cam-
paign=homeAdvegas1?%22%20%5Cl%20%22.

9. Nairametrics (2020). COVID-19 Update in Nigeria.Available at
https://nairametrics.com/2020/06/14/covid-19-update-in-nigeria/.

10. Nguyen A, David JK, Maden SK, et al. (2020). Human leukocyte antigen sus-
ceptibility map for severe acute respiratory syndrome coronavirus 2. J Virol
94:e00510-20.

11. Nguyen A, Nello A, Thompson R. (2020). Your genes could determine whether
the coronavirus puts you in the hospital { and we’re starting to unravel which
ones matter. The Conversation-Academic rigour journalistic fair. Available
at https://theconversation.com/your-genes-could-determine-whether-the-
coronavirus-puts-you-in-the-hospital-and-were-starting-to-unravel-which-ones-
matter-137145.

12. Darbeheshti F, Rezaei N. (2020). Genetic predisposition models to COVID-19 in-
fection. Med Hypotheses 6:142.

13. Mangin L (2020). Do Your Genes Predispose You to COVID-19? Scientific
America. Available at https://www.scientificamerican.com/article/do-your-genes-
predispose-you-to-covid-19/ (Accessed June 11, 2020).

14. Georgel P, Macquin C, Bahram S. (2009). The Heterogeneous Allelic Repertoire
of Human Toll-Like Receptor (TLR) Genes. PLoS ONE 4(11): e7803.

15. Immune Deficiency Foundation (2020). Innate Immune Defects. Avail-
able at https://primaryimmune.org/about-primary-immunodeficiencies/specific-
disease-types/innate-immune-defects.

16. Mazaleuskaya L, Veltrop R, Ikpeze N, Martin-Garcia J, Navas-Martin S. (2012).
Protective role of Toll-like Receptor 3-induced type I interferon in murine coron-
avirus infection of macrophages. Viruses 4(5):901-23.

17. Gralinski LE, Menachery VD, Morgan AP, et al. (2017). Allelic Variation in the
Toll-Like Receptor Adaptor Protein Ticam2 Contributes to SARS-Coronavirus
Pathogenesis in Mice. G3 7: 1653-1663.

18. Katsnelson A. (2020). Genetic study suggests that people’s blood type may af-
fect their COVID-19 risk. c en 98 (23). Available at https://cen.acs.org/biological-
chemistry/infectious-disease/Genetic-study-suggests-peoples-blood/98/i23.

19. Cheng Y, Cheng G, Chui C, et al. (2005). ABO Blood Group and Susceptibility to
Severe Acute Respiratory Syndrome. JAMA 293(12):1447-1451.

20. Guillon P, Clément M, Sebille V, et al. (2008). Inhibition of the interaction between
the SARS-CoV Spike protein and its cellular receptor by anti-histo-blood group
antibodies. Glycobiology 18 (12): 1085{1093.

21. Ellinghaus D, Degenhardt F, Bujanda L, et al. (2020). The ABO blood group locus
and a chromosome 3 gene cluster associate with SARS-CoV-2 respiratory failure
in an Italian-Spanish genome-wide association analysis. medRxiv (preprint).

22. Li J, Wang X, Chen J, Cai Y, Deng A, Yang M. (2020). Association between ABO
blood groups and risk of SARS-CoV-2 pneumonia. British J Haematol 1-4.

23. Yancy CW. (2020). COVID-19 and African Americans. JAMA 323 (19):1891{1892.
24. Genetics Home Reference (2020). ACE gene. Available at

https://ghr.nlm.nih.gov/gene/ACE.
25. Cao Y, Li L, Feng Z, Wan S, Huang P, Sun X. (2020). Comparative genetic analy-

sis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different
populations. Cell Discov 6(1):1{4.

26. Devaux CA, Rolain J-M, Raoult D. (2020). ACE2 receptor polymorphism: Suscep-
tibility to SARS-CoV-2, hypertension, multi-organ failure, and COVID-19 disease
outcome. J Microbiol Immunol Infect 53 (3): 425-435.

27. Calcagnile M, Forgez P, Iannelli A, Bucci C, Alifano M, Alifano P. (2020). ACE2
polymorphisms and individual susceptibility to SARS-CoV-2 infection: insights
from an in silico study. bioRxiv (preprint)

28. Belouzard S, Millet JK, Licitra BN, Whittaker GR. (2012). Mechanisms of coron-
avirus cell entry mediated by the viral spike protein. Viruses 4: 1011-1033.

29. Walls AC, Park Y-J, Tortorici MA, Wall A, McGuire AT, Veesler D. (2020). Structure,
Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell 181 (2):
281-292.e6.

30. Wrapp D, Wang N, Corbett KS, et al. (2020). Cryo-EM structure of the 2019-nCoV
spike in the prefusion conformation. Science 367: 1260-1263.

31. Stawiski EW, Diwanji D, Suryamohan K, et al. (2020). Human ACE2 receptor poly-
morphisms predict SARS-CoV-2 susceptibility. bioRxiv (preprint).

32. Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G, Turner AJ. (2000). A human
homolog of angiotensin-converting enzyme. Cloning and functional expression
as a captopril-insensitive carboxypeptidase. J BiolChem 275:33238-33243.

33. Cirulli ET, Riffle S, Bolze A, Washington NL. (2020). Revealing variants in SARS-
CoV-2 interaction domain of ACE2 and loss of function intolerance through anal-
ysis of >200,000 exomes. bioRxiv (preprint).

34. Hussain M, Jabeen N, Raza F, et al. (2020). Structural variations in human ACE2
may influence its binding with SARS-CoV-2 spike protein. J Med Virol 92(9):1580-
1586.

35. Cai H. (2020). Sex difference and smoking predisposition in patients with COVID-
19. Lancet Respir Med 8(4):e20

36. Alifano M, Alifano P, Forgez P, Iannelli A. (2020). Renin-angiotensin system at the
heart of COVID-19 pandemic. Biochimie 174:30-33.

10 translation@utoledo.edu Yahaya et al.



37. Delanghe JR, Speeckaert MM, De Buyzere ML. (2020). The host’s angiotensin-
converting enzyme polymorphism may explain epidemiological findings in
COVID-19 infections. Clin Chim Acta 505:192-193.

38. Chan KA, Tang NL, Hui, DS, et al. (2005). Absence of association between an-
giotensin converting enzyme polymorphism and development of adult respira-
tory distress syndrome in patients with severe acute respiratory syndrome: a
case control study. BMC Infect Dis 5:26.

39. Sanchez-Mazas A. (2020). HLA studies in the context of coronavirus outbreaks.
Swiss Med Wkly 150: w20248.

40. Debnath M, Banerjee M, Berk M. (2020). Genetic gateways to COVID-19 infection:
Implications for risk, severity, and outcomes. FASEB J 34 (7): 8787-8795.

41. González-Galarza F, Takeshita L, Santos E, et al. (2015). Allele frequency net 2015
update: new features for HLA epitopes, KIR and disease and HLA adverse drug
reaction associations. Nucleic Acids Res 43: D784-D788.

42. Allele Frequency Databases (AFND) (2020). Allele Frequency in Worldwide Pop-
ulation. http://www.allelefrequencies.net/hla6006a.asp. (Accessed on June 20,
2020).

43. Zahn LM. (2020). HLA genetics and COVID-19. Science 368 (6493): 841.

44. Hoffmann M, Kleine-Weber H, Schroeder S, et al. (2020). SARS-CoV-2 cell entry
depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease
inhibitor. Cell 181(2):271-280.

45. Irham LM, Chou W-H, Calkins MJ, Adikusuma W, Shie-LiangHsieh S-L, Chang
W-C. (2020). Genetic variants that influence SARS-CoV-2 receptor TMPRSS2 ex-
pression among population cohorts from multiple continents. Biochem Biophys
Res Commun 529 (2): 263-269.

46. Bertram S, Heurich A, Lavender H, et al. (2012). Influenza and SARS coronavirus
activating proteases TMPRSS2 and HAT are expressed at multiple sites in human
respiratory and gastrointestinal tracts. PLoS One 7 (4):e35876.

47. Maya EAL, van der Graaf A, Lanting P, et al. (2020). Lack of Association Between
Genetic Variants at ACE2 and TMPRSS2 Genes Involved in SARS-CoV-2 Infection
and Human Quantitative Phenotypes. Front Genet 11:613.

48. dos Santos NPC, Khayat AS, Rodrigues JCG, et al. (2020). TMPRSS2 variants and
their susceptibility to COVID-19: focus in East Asian and European populations.
medRxiv (preprint).

49. Stopsack KH, Mucci LA, Antonarakis ES, Nelson PS, Kantoff PW. (2020). TM-
PRSS2 and COVID-19: Serendipity or Opportunity for Intervention? Cancer
Discov 10 (6):779{82.

50. Hatesuer B, Bertram S, Mehnert N, et al. (2013). Tmprss2 is essential for influenza
H1N1 virus pathogenesis in mice. PLoS Pathog 9:e1003774.

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