New insights into genetic susceptibility of COVID-19: an ACE2 and TMPRSS2 polymorphism analysis

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); COVID-19; Coronavirus; Genetic susceptibility; SARS-CoV-2; TMPRSS2.

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

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