Hou et al.

BMC Medicine (2020) 18:216

https://doi.org/10.1186/s12916-020-01673-z

CORRESPONDENCE Open Access

New insights into genetic susceptibility of

COVID-19: an ACE2 and TMPRSS2
polymorphism analysis
Yuan Hou1, Junfei Zhao2, William Martin1, Asha Kallianpur1,3, Mina K. Chung3,4,5, Lara Jehi5, Nima Sharifi3,5,
Serpil Erzurum3,5, Charis Eng1,3,6,7 and Feixiong Cheng1,3,7*

Abstract
Background: Coronavirus Disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2), has now been confirmed worldwide. Yet, COVID-19 is strangely and tragically selective. Morbidity and
mortality due to COVID19 rise dramatically with age and co-existing health conditions, including cancer and
cardiovascular diseases. Human genetic factors may contribute to the extremely high transmissibility of SARS-CoV-2
and to the relentlessly progressive disease observed in a small but significant proportion of infected individuals, but
these factors are largely unknown.
Main body: In this study, we investigated genetic susceptibility to COVID-19 by examining DNA polymorphisms in
ACE2 and TMPRSS2 (two key host factors of SARS-CoV-2) from ~ 81,000 human genomes. We found unique genetic
susceptibility across different populations in ACE2 and TMPRSS2. Specifically, ACE2 polymorphisms were found to be
associated with cardiovascular and pulmonary conditions by altering the angiotensinogen-ACE2 interactions, such
as p.Arg514Gly in the African/African-American population. Unique but prevalent polymorphisms (including
p.Val160Met (rs12329760), an expression quantitative trait locus (eQTL)) in TMPRSS2, offer potential explanations for
differential genetic susceptibility to COVID-19 as well as for risk factors, including those with cancer and the high-
risk group of male patients. We further discussed that polymorphisms in ACE2 or TMPRSS2 could guide effective
treatments (i.e., hydroxychloroquine and camostat) for COVID-19.
Conclusion: This study suggested that ACE2 or TMPRSS2 DNA polymorphisms were likely associated with genetic
susceptibility of COVID-19, which calls for a human genetics initiative for fighting the COVID-19 pandemic.
Keywords: Angiotensin-converting enzyme 2 (ACE2), Coronavirus, COVID-19, Genetic susceptibility, SARS-CoV-2,
TMPRSS2

* Correspondence: [email protected]
1
Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic,
Cleveland, OH 44195, USA
3
Department of Molecular Medicine, Cleveland Clinic Lerner College of
Medicine, Case Western Reserve University, Cleveland, OH 44195, USA
Full list of author information is available at the end of the article

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Hou et al. BMC Medicine (2020) 18:216 Page 2 of 8

Background investigated by single-cell RNA sequencing, and the ex-

Coronaviruses (CoVs), so named for their “crown-like” pression of both ACE2 and TMPRSS2 are likely to dic-
appearance by electron microscopy, are a large family of tate SARS-CoV-2 tissue tropism [7]. Clinical studies
viruses that spread from animal hosts (e.g., bats, civet, have reported that incidence and mortality rates are sig-
cats) to humans, causing life-threatening respiratory dis- nificantly different between male and female COVID-19
eases like Middle East respiratory syndrome (MERS) and patients, and the disease is associated with pre-existing
severe acute respiratory syndrome (SARS) [1]. As of June conditions, such as cancer and cardiovascular disorders,
18, 2020, over 8.4 million cases and 450,000 deaths in particular individuals with hypertension receiving
resulting from infection by a novel SARS coronavirus, anti-hypertensive medications [8]. Therefore, a system-
SARS-CoV-2 (also termed Coronavirus Disease 2019 or atic investigation of the functional polymorphisms in
COVID-19), have now been confirmed worldwide; fur- ACE2 and TMPRSS2 among different populations could
thermore, there have been more than 2.2 million con- pave the way for precision medicine and personalized
firmed cases and over 110,000 deaths due to the treatment strategies for COVID-19.
COVID-19 pandemic in the USA alone [2]. Unlike other
CoVs, SARS-CoV-2 has had much larger global spread ACE2 polymorphism analysis across different
and has impacted more people than SARS-CoV-1 and populations
MERS-CoV combined [1]. Morbidity and mortality due Here, we investigated genetic susceptibility to COVID-
to COVID-19 rise dramatically with age and co-existing 19 by examining DNA polymorphisms in ACE2 (OMIM
health conditions, including cancer and cardiovascular 300335) and TMPRSS2 (OMIM 602060) genes. We as-
diseases, and while most infected individuals recover, sembled a total of 437 non-synonymous single-
even very young and otherwise healthy patients may un- nucleotide variants (SNVs) in the protein-coding regions
predictably succumb to this disease [3]. These observa- of ACE2 and TMPRSS2 (Fig. 1a) from three databases:
tions beg the question of how much of the variation in (i) Genome Aggregation Database (gnomAD v3: gno-
COVID-19 disease severity may be explained by genetic mad.broadinstitute.org, covering 9 geographical areas),
susceptibility. Human genetic factors may contribute to (ii) Exome Sequencing Project (ESP: evs.gs.washington.
the extremely high transmissibility of SARS-CoV-2 and edu/EVS/), and (iii) 1000 Genomes Project (1KGP, www.
to the relentlessly progressive disease observed in a small internationalgenome.org). We used ANNOVAR [9] to
but significant proportion of infected individuals; yet, annotate all non-synonymous variants. By applying Poly-
these factors are largely unknown. Development of new phen2 and CADD (Combined Annotation Dependent
preventive and/or therapeutic strategies for COVID-19 Depletion) scores, we identified 63 potentially deleteri-
will be greatly facilitated by systematic identification of ous variants in ACE2 (61 in gnomAD) and 68 deleteri-
host genetic pathways and DNA polymorphisms (vari- ous variants in TMPRSS2 (63 in gnomAD).
ants) which modulate the risk of infection and severe ill- We found that the distribution of deleterious variants
ness, including the overexuberant immune response to in ACE2 differs among 9 populations in gnomAD (v3).
the virus that often portends a poor outcome. Specifically, 39% (24/61) and 54% (33/61) of deleterious
Not only has the COVID-19 pandemic had huge variants in ACE2 occur in African/African-American
health and economic impacts in 188 countries/regions (AFR) and Non-Finnish European (EUR) populations,
across the world, but the disease has also struck in dif- respectively (Fig. 1b). Prevalence of deleterious variants
ferent racial/ethnic subpopulations. Large genetic studies among Latino/Admixed American (AMR), East Asian
in populations of geographically diverse ancestry have (EAS), Finnish (FIN), and South Asian (SAS) populations
demonstrated substantial genetic variation in protein- is 2–10%, while Amish (AMI) and Ashkenazi Jewish
coding regions, with widely varying allele frequencies (ASJ) populations do not appear to carry such variants
[4]. SARS-CoV-2 infection depends on the host cell fac- in ACE2 coding regions (Fig. 1b). Specifically, several
tors angiotensin-converting enzyme 2 (ACE2) for entry variants, including p.Met383Thr, p.Pro389His, and
into cells and the host transmembrane serine protease p.Asp427Tyr, have been reported to slightly inhibit the
TMPRSS2 for SARS-CoV-2 spike (S) protein priming [5] interaction between ACE2 and the spike protein of
(Fig. 1a). ACE2, encoded on the X-chromosome, cata- SARS-CoV-1 [10], which caused the first global SARS-
lyzes the conversion of angiotensin II to angiotensin-(1– CoV-1 outbreak. Only AFR populations carry
7), which acts as a vasodilator and exerts important p.Met383Thr and p.Asp427Tyr variants, with allele fre-
modulatory effects on the cardiovascular system. quencies of 0.003% and 0.01%, respectively (Fig. 1b). The
TMPRSS2 is a key gene in prostate cancer, as an associ- p.Pro389His only occurs in the AMR populations, with
ated translocation drives ETS-family oncogene expres- an allele frequency of 0.015%. The p.Arg514Gly is a low
sion in a large proportion of tumors [6]. The allele frequency (0.003%) variant in AFR populations and
distribution of ACE2 expression has recently been is also somatically mutated in colon cancers and
Hou et al. BMC Medicine (2020) 18:216 Page 3 of 8

Fig. 1 (See legend on next page.)

Hou et al. BMC Medicine (2020) 18:216 Page 4 of 8

(See figure on previous page.)

Fig. 1 The coding-region variants in ACE2 and TMPRSS2 from ~ 81,000 human genomes across 8 populations. a Coding-region variants in the
genes encoding angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) across three human genome
databases: (i) Genome Aggregation Database (gnomAD v3), (ii) Exome Sequencing Project (ESP), and (iii) 1000 Genomes Project (1KGP). SARS-
CoV-2 utilizes the host cell factors angiotensin-converting enzyme 2 (ACE2) for entry into cells and the host transmembrane serine protease
TMPRSS2 for SARS-CoV-2 spike (S) protein priming, offering potential pathway for therapeutic development in treatment of COVID-19. b
Distribution of 61 deleterious variants in the ACE2 coding region identified in gnomAD (v3). Polyphen2 > 0.96 and CADD scores > 20 as cutoff
identify putative deleterious variants. The upper panel using 3 colors shows the functional domains of ACE2, and the height of the vertical line
represents the number of populations that carry this variant. The lower heatmap shows the allele frequencies (color key) of a variant across
different populations. c Distributions of 63 putative deleterious variants in the TMPRSS2 coding region using the same approach of b. AFR,
African/African-American; AMI, Amish; AMR, Latino/Admixed American; ASJ, Ashkenazi Jewish; EAS, East Asian; FIN, Finnish; EUR, Non-Finnish
European; SAS, South Asian; PNA, population not assigned

melanomas from The Cancer Genome Atlas (TCGA: analysis indicates 4% (11/274) of non-synonymous vari-
https://portal.gdc.cancer.gov). This ACE2 variant is lo- ants of TMPRSS2 are stop-gained mutations and carried
cated in the angiotensinogen (AGT)-ACE2 interaction by AFR and EUR with low allele frequency (7.0 ×
surface, which is anticipated to influence the renin- 10−6~1.4 × 10−5). Meanwhile, 35% (22/63) and 59% (37/
angiotensin system (RAS) function. The RAS is critical 63) of deleterious variants in TMPRSS2 coding regions
for regulation of blood pressure, sodium, and fluid bal- are carried by the AFR and EUR populations from gno-
ance, and its dysfunction is associated with cardiovascu- mAD (v3), respectively (Fig. 1c). Each of the EAS, SAS,
lar and kidney disorders [11]. Residues Arg708/710/716 and FIN populations only carries 4 deleterious variants.
are located in the dimeric interface of ACE2 (Fig. 2a), We found 6 germline deleterious variants (p.Val160Met,
and they are essential for its cleavage by TMPRSS2; this p.Gly181Arg, p.Arg240Cys, p.Gly259Ser, p.Pro335Leu,
processing is required for augmentation of SARS-S- and p.Gly432Ala) in the TMPRSS2 coding region, which
driven entry into host cells [12]. The EUR population are also identified as somatic mutations occurring in dif-
carries the p.Arg708Trp, p.Arg710Cys, p. Arg710His, ferent cancer types from TCGA and COSMIC databases
and p.Arg716Cys variants with allele frequency of (https://cancer.sanger.ac.uk/cosmic).
0.01~0.006% (Fig. 1a), while the EAS and the AMR pop- We further evaluated the eQTL profile of TMPRSS2
ulations only carry p.Arg708Trp and p.Arg710His with using the GTEx [13] and QTLbase databases [14] as
allele frequency of 0.04% and 0.01% respectively. In well. We found two eQTLs associated with TMPRSS2
addition to these four variants, p.Leu731Phe has the non-synonymous SNPs (rs12329760 (encoding p.Val160-
highest allele frequency in the AFR and EUR popula- Met), p = 4.54 × 10−5; rs75603675, p = 0.009) in the kid-
tions. We further inspected the expression quantitative ney and bone, respectively, using the QTLbase database
trait loci (eQTL) for ACE2 using the GTEx [13] and [14], while there are no known eQTLs associated with
QTLbase [14] databases. We did not find any eQTLs for TMPRSS2 non-synonymous SNPs from GTEx [13]. Not-
ACE2 from the GTEx, while we found one weak eQTL ably, all populations carry p.Val160Met variants with the
associated with ACE2 non-synonymous SNP highest allele frequency (~ 25%), especially for the EAS
(rs41303171) in the kidney from the QTLbase [14]. population at a 40% allele frequency. Asp435 is a key
Altogether, these comparative genetic analyses suggest residue for catalytic substrate binding of TMPRSS2
that ACE2 genomic variants may play important roles in (Fig. 2b). We found that the p.Asp435Tyr, which has
susceptibilities to COVID-19 and its associated cardio- low allele frequency, is carried by the EUR population
vascular conditions by altering AGT-ACE2 pathway (i.e., only (Fig. 1c). These unique but prevalent polymor-
p.Arg514Gly). In addition to differential polymorphisms phisms in TMPRSS2 offer potential explanations for dif-
which may explain susceptibility and even outcome in ferential genetic susceptibility to COVID-19 as well as
different ethnic populations, the fact that ACE2 is local- for risk factors, including those with cancer and the
ized to Xp22.2 may help explain the observed male- high-risk group of male patients. Because TMPRSS2 is
associated risk. As such, even in the absence of variation located on 21q22.3, we could speculate that individuals
in this gene, the monoallelic versus biallelic presence of with Down syndrome would be at high risk for COVID-
this gene may impact the natural history and prognosis 19 infection. In addition, oncogenic roles of TMPRSS2
of COVID-19 in males. may be linked to poor outcomes with COVID-19 as well
[16], which should be studied in the future. Using
TMPRSS2 polymorphism analysis across different single-cell RNA-sequencing analysis, Schuler et al.
populations showed that TMPRSS2 expression was highest in ciliated
TMPRSS2 enzyme activity is important for coronavirus cells and type I alveolar epithelial cells (AT1) and in-
spread and pathogenesis in the infected host [15]. Our creased with aging in humans and mice [17]. This
Hou et al. BMC Medicine (2020) 18:216 Page 5 of 8

Fig. 2 (See legend on next page.)

Hou et al. BMC Medicine (2020) 18:216 Page 6 of 8

(See figure on previous page.)

Fig. 2 Structural view of the coding-region variants in ACE2 and TMPRSS2 and a proposed pharmacogenomics model of effective combination
therapies for COVID-19. a Full-length structures of the sodium-dependent neutral amino acid transporter B(0)AT1 (SLC6A19, red)–ACE2 (blue)
heterodimer in its homodimeric form complexed with the receptor binding domain (RBD, mint) of SARS-CoV-2 (PDB ID: 6M17). Highly deleterious
variants are labeled as yellow spheres on ACE2. Insets depict mutations in residues 383 through 427 (top) and residues 708 through 731
(bottom). b Homology model of the catalytic chain (256–492) of TMPRSS2. Highly deleterious mutations are labeled as yellow spheres. c A
proposed model of effective combination therapies (i.e., hydroxychloroquine, E-64D (a protease inhibitor), and camostat mesylate (an approved
TMPRSS2 for treatment of chronic pancreatitis in Japan)) for COVID-19 by blocking ACE2 and TMPRSS2 across different populations with three
genotypes. Relationship among spike (S) protein of SARS-CoV-2, ACE2, and TMPRSS2 were shown as a triangle, with each pair connecting by
physical binding (double-headed arrow) or cleavage (single-headed arrow). We propose three hypotheses for COVID-19 therapeutic options: (i)
for patients with wild-type or naïve expression of ACE2 and TMPRSS2, hydroxychloroquine (or chloroquine, or E-64D) combined with camostat
may offer more clinical benefit; (ii) for patients with polymorphisms or dysregulation on TMPRSS2, hydroxychloroquine or chloroquine
monotherapy may offer more clinical benefit; and (iii) for patients with polymorphisms or dysregulation on ACE2, the patients who might have
mild symptoms can recover in a short period. All three pharmacogenomics models for COVID-19 must be validated both experimentally and
clinically before being used in patients

observation suggests that developmental regulation of entry into the host cell [23]. This process can be blocked
TMPRSS2 may link the relative protection of infants and by a TMPRSS2 inhibitor (camostat mesylate, a drug ap-
children from COVID-19. Thus, it should be of great proved in Japan) [5]. The mechanisms whereby
interest to investigate the age-related polymorphisms for TMPRSS2 promotes cellular entry of SARS-CoV-2 can
TMPRSS2, such as using the Genetic Epidemiology Re- be summarized by two aspects based on its proteolytic
search on Adult Health and Aging (GERA) cohort [18], function (Fig. 2). The first is S protein cleavage at S1/S2
in the future. and S2’ sites, which might be the reason why SARS-
CoV-2 entry into cells depends on TMPRSS2. The infec-
Host genetic factors guide personalized treatment tion and pathogenesis of SARS-CoV-2 depends on the
of COVID-19 presence of TMPRSS2, in the face of the cellular ele-
There are currently no approved effective medications vated pH environment [5, 24, 25]. The inhibitors of
against COVID-19. Several national and international re- endosomal acidification such as CatB/L inhibitor E-64D
search groups are working on the development of vac- and hydroxychloroquine/chloroquine may only work for
cines to prevent COVID-19, but effective vaccines not TMPRSS2-absence patients who are infected by SARS-
likely to be available for many months. Several poten- CoV-2, and may have less effect or no effect for the pa-
tially repurposable drugs (Fig. 2c), including melatonin tients with wild-type of TMPRSS2 [5, 24]. Therefore, the
[19], hydroxychloroquine, and chloroquine, are under in- EUR and AFR populations might be more sensitive to
vestigation for treatment of COVID-19 [20]. A primary hydroxychloroquine or chloroquine by carrying missense
mechanism-of-action of hydroxychloroquine and chloro- variants and stop-gained variants on TMPRSS2 (Figs. 1c
quine is to inhibit virus entry by targeting the endosomal and 2c). Yet, for patients who have wild-type of ACE2
pathway [20]. Hydroxychloroquine and chloroquine is and TMPRSS2, a combination of camostat with hydroxy-
known to increase the pH of endosomes, which inhibits chloroquine or chloroquine may have better clinical
membrane fusion, a required mechanism for viral entry benefit. However, all discussed treatment strategies must
into the cell [21]. Additionally, inhibition of SARS-CoV- be validated by randomized controlled trials before clin-
2 could be due to differential glycosylation of both ical use. The second mechanism is cleavage of ACE2 by
ACE2 and the spike protein [21]. As shown in Fig. 1b, TMPRSS2 at Arginine 697 to 716 [12], which enhances
several variants identified in the AFR and AMR popula- viral uptake. Thus, the EUR population with
tions, including p.Met383Thr, p.Pro389His, and p.Arg708Trp, p.Arg710Cys, p.Arg710His, and
p.Asp427Tyr (the pathogenic variants in ACE2 slightly p.Arg716Cys variants in ACE2 may have mild symptoms
inhibit interaction with the S protein), may influence the after SARS-CoV-2 infection as ACE2 loses the cleavage
clinical efficacy of hydroxychloroquine or chloroquine. site by TMPRSS2 and changes the ACE2 dimer forma-
This may help explain why treatment of hydroxychloro- tion [26] (Fig. 2c).
quine was not significantly associated with difference in
in-hospital mortality [22]. However, further pharmaco- Discussion and future directions: call for host
genomic studies that integrate drug response and genetic genetics initiative for COVID-19
data from patients with COVID-19 are urgently needed. A few limitations merit consideration. Current analysis
In addition to the endosomal pathway, fusion of viral examined massive genomic data from general popula-
and host cellular membranes through S protein con- tion, not COVID-19 patient-specific populations. All
formational changes is another way for coronavirus genetic associations identified in current study are
Hou et al. BMC Medicine (2020) 18:216 Page 7 of 8

urgently needed to be tested in COVID-19 patients in Abbreviations

the near future. As the high-resolution protein structure 1KGP: 1000 Genomes Project; ACE2: Angiotensin-converting enzyme 2;
CoV: Coronavirus; COVID-19: Coronavirus Disease 2019; eQTL: Expression
of TMPRSS2 is not yet available, further functional ob- quantitative trait loci; gnomAD: Genome Aggregation Database;
servations and clinical validation are warranted for all MERS: Middle East respiratory syndrome; SARS: Severe acute respiratory
abovementioned genetic and pharmacogenomics find- syndrome; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2;
ESP: Exome Sequencing Project; S: Spike; TMPRSS2: Transmembrane serine
ings. We anticipate that large-scale genome-wide associ- protease 2
ation studies (GWAS) are urgently needed to identify
likely causal host genetic risk factors for severe COVID- Acknowledgements
We thank all helpful discussions and critical comments regarding this
19 outcomes using genetic data from patients with manuscript from the COVID-19 Research Intervention Advisory Committee
COVID-19; such knowledge will improve risk stratifica- members at the Cleveland Clinic. SCE is the Alfred Lerner Memorial Chair of
tion of individuals exposed to or testing positive for Innovative Research and CE is the Sondra J. and Stephen R. Hardis Endowed
Chair of Cancer Genomic Medicine at the Cleveland Clinic.
SARS-CoV-2 and allow for precision medicine interven-
tions for COVID-19. A COVID-19 host genetics initia- Authors’ contributions
tive is already underway to bring together the human F.C. conceived the study. Y.H., J.Z., and W.M. performed all experiments and
genetics research community to generate, share, and data analysis. A.K., M.K.C, N.S., L.J., C.E., and S.E. discussed and interpreted all
results. F.C., Y.H., C.E., and S.E. wrote and critically revised the manuscript with
analyze data in a search for the genetic determinants of contributions from other co-authors. All authors read and approved the final
COVID-19 susceptibility, severity, and outcomes [27]. manuscript.
The first COVID-19 GWAS identified the 3p21.31 gene
cluster (including SLC6A20, LZTFL1, CCR9, FYCO1, Funding
This work was supported by the National Heart, Lung, and Blood Institute of
CXCR6, and XCR1) as a genetic susceptibility locus in the National Institutes of Health (NIH) under Award Number R00HL138272
severe patients with COVID-19 and respiratory failure and the National Institute of Aging under Award Number R01AG066707 to
[28]. Yet, our study aims to look for SNPs associated F.C. This work was supported, in part, by the VeloSano Pilot Program
(Cleveland Clinic Taussig Cancer Institute).
with disease severity of COVID-19, but not disease sus-
ceptibility. In summary, systematic identification of the Availability of data and materials
genetic determinants of COVID-19 susceptibility, sever- All population genetic data used in this study are free and available at three
databases: (i) Genome Aggregation Database (gnomAD v3: gnomad.
ity, and clinical outcome, including both virus and host broadinstitute.org, covering 9 geographical areas), (ii) Exome Sequencing
factors (e.g., ACE2 and TMPRSS2 polymorphisms), could Project (ESP: evs.gs.washington.edu/EVS/), and (iii) 1000 Genomes Project
guide personalized treatment in the emerging COVID- (1KGP, www.internationalgenome.org).
19 pandemic and even explain current epidemiologic ob-
Ethics approval and consent to participate
servations (i.e., males, elderly at high risk, and clinical Not applicable.
comorbidities) and natural history.
Consent for publication
Conclusions Not applicable.

This comprehensive comparative genetic analysis of ap- Competing interests

proximately 81,000 human genomes suggested possible The content of this publication does not necessarily reflect the views of the
associations of ACE2 and TMPRSS2 DNA polymor- Cleveland Clinic. The authors declare no competing interests.
phisms with COVID-19 susceptibility, severity, and clin- Author details
ical outcomes. We found that ACE2 polymorphisms 1
Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic,
were more likely to be associated with cardiovascular Cleveland, OH 44195, USA. 2Department of Systems Biology and Department
of Biomedical Informatics, Herbert Irving Comprehensive Center, Columbia
and pulmonary conditions by altering the University, New York, NY 10032, USA. 3Department of Molecular Medicine,
angiotensinogen-ACE2 interactions, such as p.Arg514- Cleveland Clinic Lerner College of Medicine, Case Western Reserve University,
Gly in the African/African-American population. Unique Cleveland, OH 44195, USA. 4Department of Cardiovascular Medicine, Heart,
Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
but prevalent polymorphisms in TMPRSS2, including 5
Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
p.Val160Met (rs12329760), may provide potential expla- 6
Department of Genetics and Genome Sciences, School of Medicine, Case
nations for differential genetic susceptibility to COVID- Western Reserve University, Cleveland, OH 44106, USA. 7Case Comprehensive
Cancer Center, School of Medicine, Case Western Reserve University,
19 as well as for risk factors, including cancer and the Cleveland, OH 44106, USA.
high-risk group of male patients. We highlighted that
polymorphisms in ACE2 or TMPRSS2 could guide per- Received: 25 April 2020 Accepted: 22 June 2020
sonalized treatments (i.e., hydroxychloroquine and
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