COVID-19 research

Gene: ACE2

Preprint: Wooster et al 2020 - https://doi.org/10.1101/2020.06.18.20135152
Analysed association between ACE2 polymorphisms and COVID-19 severity in 62 patients. 10 SNPs were significantly associated with tissue expression of ACE2. Of these, 6 SNPs were also significantly associated with hospitalisation, after adjusting for sex and age (5 SNPs associated with higher tissue expression and increased need for hospitalisation due to COVID-19; and 1 SNP with lower tissue expression and reduced COVID-19 severity not requiring hospitalisation).

Created: 28 Jul 2020, 3:16 p.m. | Last Modified: 28 Jul 2020, 3:16 p.m.

Panel Version: 1.62

Green List (high evidence)

Co-receptor for coronaviruses including SARS-CoV-1 and SARS-CoV-2. PMID:32228252: Used as co-receptor to gain intracellular entry into the lungs and brain. No variants have been demonstated as yet to modulate susceptiblity to SARS-CoV-2 infection.

Created: 11 Jun 2020, 5:58 p.m. | Last Modified: 11 Jun 2020, 5:58 p.m.

Panel Version: 1.9

Mode of inheritance
Unknown

Publications

• 32228252

I don't know

Novelli et al https://doi.org/10.1101/2020.05.23.20111310 No evidence for allelic association between Covid-19 and ACE2 genetic variants by direct exome sequencing in 99 SARS-CoV-2 positive patients.

Created: 27 May 2020, 2:37 p.m. | Last Modified: 27 May 2020, 2:37 p.m.

Panel Version: 0.332

ACE2 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 2 grouping (experimental and/or genetic evidence, suggesting a biological role linking to corona viruses, may not be a GDA)

Created: 11 Jun 2020, 6:10 p.m. | Last Modified: 11 Jun 2020, 6:10 p.m.

Panel Version: 1.10

Preprint: https://doi.org/10.1101/2020.04.30.20081257 reports increased expression of ACE2 and natriuretic peptides during heart failure, which predisposes to SARS-CoV-2 infection. Modulating the levels of ACE2, NPs therefore may potentially be a novel therapeutic target to prevent the SARS-CoV-2 infection. The authors speculated that modulation levels of ACE2 and natriuretic peptides may potentially be a novel therapeutic target to prevent the SARS-CoV-2 infection.

Preprint: https://doi.org/10.1101/2020.05.03.074781 uses mCSM-PPI212 mutation effect predictor for protein-protein complex affinity, primarily validated against published experimental ACE2 variant SARS-CoV S-protein affinities to analysis variants from gnomAD. p.Gly326Glu, predicted to enhances ACE2 binding affinity for SARS-CoV-2 S, therefore a potential risk factor for COVID-19. p.Glu37Lys, p.Gly352Val and p.Asp355Asn predicted to reduce ACE2 affinity for SARS-CoV-2 S, therefore potentially protective against COVID-19.

Created: 11 May 2020, 3:50 p.m. | Last Modified: 12 May 2020, 7:32 a.m.

Panel Version: 0.206

I don't know

Receptor for SARS-CoV 1 and 2. Could anticipate that variants might modulate COVID susceptibility but no such effect yet demonstrated. Size of any such effect not predictable (few complete LOF variants on GNOMAD but NB X-linked, not always well-covered)

Created: 27 Apr 2020, 11:45 a.m. | Last Modified: 27 Apr 2020, 11:45 a.m.

Panel Version: 0.163

Mode of inheritance
Unknown

Mode of pathogenicity
Other

Preprint: Gupta et al https://doi.org/10.1101/2020.05.15.098616 Using the Viral Integrated Structural Evolution Dynamic Database and population genomic databases they identified 47 potential functional missense variants within ACE2/SLC6A19/TMPRSS2, warranting genomic enrichment analyses in SARS-CoV-2 patients. Two noncoding variants (rs4646118 and rs143185769) found in ~9% of African descent individuals for ACE2 may regulate expression and be related to increased susceptibility of African Americans to SARS-CoV-2.

Created: 22 May 2020, 10:58 a.m. | Last Modified: 22 May 2020, 10:59 a.m.

Panel Version: 0.303

Preprint: Pach et al https://doi.org/10.1101/2020.05.14.092767 - by looking at species that are susceptible and non-susceptible to SARS-COV-2, they have developed dynamic computational models for ACE2-RBD complexes of different species allowing us to anticipate the effects of amino acid sequence variation of ACE2 on viral entry

Created: 22 May 2020, 10:02 a.m. | Last Modified: 22 May 2020, 10:02 a.m.

Panel Version: 0.299

Preprint: https://doi.org/10.1101/2020.05.12.20098160 - Shovlin and Vizcaychip - variants in 213,158 exomes/genomes were integrated for ACE2 . ACMG/AMP-based pathogenicity criteria were applied. Modelling the ″COVID-resistant ″ state where pathogenic alleles would be beneficial, nine null alleles met PVS1. Thirty-seven variants met PM1 based on critical location +/-PP3 based on computational modelling. Modelling a ″COVID-susceptible ″ state, 31 variants in four upstream open reading frames and 5′ untranslated regions could meet PM1, and may have differential effects if aminoglycoside antibiotics were prescribed for pneumonia and sepsis.

Created: 21 May 2020, 11:35 p.m. | Last Modified: 21 May 2020, 11:35 p.m.

Panel Version: 0.298

PMID: 32133153 Cao et al 2020 - Analyzed coding-region variants in ACE2 and the eQTL variants, which may affect the expression of ACE2 using the GTEx database to compare the genomic characteristics of ACE2 among different populations. Their findings indicated that no direct evidence was identified genetically supporting the existence of coronavirus S-protein binding-resistant ACE2 mutants in different populations. East Asian populations have much higher AFs in the eQTL variants associated with higher ACE2 expression in tissues.

Created: 13 May 2020, 6:41 p.m. | Last Modified: 13 May 2020, 6:43 p.m.

Panel Version: 0.232

PMID: 32249956 Hussain et al 2020 - show through molecular modelling that ACE2 alleles, rs73635825 (S19P) and rs143936283 (E329G) showed noticeable variations in their intermolecular interactions with the viral spike protein of SARS-CoV-2

Created: 13 May 2020, 5:56 p.m. | Last Modified: 13 May 2020, 5:56 p.m.

Panel Version: 0.230

PMID: 32015507 - Zhou et al 2020 - Nature article. Confirmed that 2019-nCoV uses the same cell entry receptor-angiotensin converting enzyme II (ACE2)-as SARS-CoV.

PMID: 32142651 - Hoffman et al 2020 - demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry

Created: 26 Apr 2020, 2:19 p.m. | Last Modified: 26 Apr 2020, 2:29 p.m.

Panel Version: 0.161

Preprint - https://www.biorxiv.org/content/10.1101/2020.04.14.041434v1 - Li et al
Total death rate is higher in Spain compared to China, so looked differences between the Asian and Caucasian populations for ACE2 polymorphisms using gnomAD v2.1 exomes and compare the variability of hACE2 expression in peripheral blood among eight different populations. Four genetic variants reached statistical significance for differences in MAF between the two populations N720D, K26R, N638S, I468V. Found small differences in expression of hACE2 among various populations.

Preprint - https://www.biorxiv.org/content/10.1101/2020.04.05.026633v1 - Gibson et al
Analyse ACE2 variants in the gnomAD database and identify 15 missense variants likely to affect the affinity of the human ACE2 protein for the viral spike protein and estimated the change in binding energy of the 15 missense variants.

Preprint - https://www.biorxiv.org/content/10.1101/2020.04.07.024752v1 - Stawiski et al
Aassessed ACE2 protein-altering variations from a number of databases including the gnomAD, RotterdamStudy, ALSPAC, GenomeAsia100k, HGDP, TOMMO-3.5kjpnv2, IndiGen, and HGDP. Identified variants that are likely to either increase or decrease the binding affinity of ACE2 to the S-protein and thereby alter the ability of the
virus to infect the host cell.

Preprint - https://www.biorxiv.org/content/10.1101/2020.03.16.994236v1 Procko
Made a library of coding sequence of ACE2 containing all possible single amino acid substitutions at 117 sites spanning the interface with S and lining the substrate cavity. The ACE2 library was transiently expressed in human Expi293F cells and cells were then incubated in medium containing the receptor binding domain of SARS-CoV-2 fused C-terminallyto superfolder GFP. Sorted cells with high and low binding and the transcripts sequenced to identify the variants.

Preprint - https://www.medrxiv.org/content/10.1101/2020.04.03.20047977v1 - Renieri et al
Using the Network of Italian Genomes (NIG), they mined around 7000 exomes from 5 different Centers looking for ACE2 variants. Identified variants with a potential impact on protein stability. 3 missense changed identified that have never been reported in the Eastern Asia population, were predicted to interfere with protein cleavage and stabilization. Rare truncating variants that are likely to interfere with the internalization process and one missense variant, p.Trp69Cys, predicted to interfere with 2019-nCov spike protein binding were also observed.

Preprint - https://www.biorxiv.org/content/10.1101/2020.04.12.037580v1 - Asselta et al
ACE2 SNP rs2285666 (also called G8790A), more common in Italians and Europeans that East Asians. This variant was extensively studied as a potential risk factor for hypertension, type 2 diabetes, and coronary artery disease hence possibly constituting a predisposing factor also for the comorbidities observed in COVID-19 patients.

Created: 23 Apr 2020, 2:52 a.m. | Last Modified: 23 Apr 2020, 4:40 a.m.

Panel Version: 0.140

Publications

• 32015507
• https://doi.org/10.1101/2020.05.15.098616

I don't know

Added 'treatable' tag based on preprint http://biorxiv.org/cgi/content/short/2020.05.07.082230 which suggests that a modified ACE2 peptide could act as a treatment to block the viral receptor forming a complex with ACE2.

Created: 11 May 2020, 11:18 a.m. | Last Modified: 11 May 2020, 11:18 a.m.

Panel Version: 0.204

Preprint https://www.biorxiv.org/content/10.1101/2020.04.22.056127v1 show that ACE2 levels in the respiratory tract did not increase in association with risk factors for severe COVID-19 (e.g. age and underlying chronic comorbidities).

Created: 28 Apr 2020, 3:36 p.m. | Last Modified: 28 Apr 2020, 3:36 p.m.

Panel Version: 0.165

Preprint https://www.biorxiv.org/content/10.1101/2020.04.24.050534v1 conclude that higher expression of ACE2 facilitated by natural variations (with different frequencies in different populations) results in ACE2 homo-dimerization which is disadvantageous for TMPRSS2 mediated cleavage of ACE2. They propose that monomeric ACE2 has higher preferential binding with SARS-CoV-2 S-Protein.

Created: 28 Apr 2020, 3:22 p.m. | Last Modified: 28 Apr 2020, 3:22 p.m.

Panel Version: 0.165

Preprint https://www.biorxiv.org/content/10.1101/2020.04.24.056259v2 suggests that ACE2 and TMPRSS2 co-expression in the prostate may explain sex differences in the observed COVID-19 disaparities.

Created: 28 Apr 2020, 2:30 p.m. | Last Modified: 28 Apr 2020, 2:30 p.m.

Panel Version: 0.165

Preprint https://www.medrxiv.org/content/10.1101/2020.04.22.20074963v1 Lopera et al shows a LACK of association between genetic variants at ACE2 and TMPRSS2 and human quantitative phenotypes. The authors recognise that the SARS-CoV-2 virus uses ACE2 for cell invasion, and the serine protease TMPRSS2 for S protein priming and therefore they investigated whether genetic variation in these two genes modulates an individual's genetic predisposition to infection and virus clearance. They examined 178 quantitative phenotypes in relation to 1,273 genetic variants located in or near ACE2 and TMPRSS2: none reached the threshold for significance though these variants may play a role in diseases such as hypertension and chronic inflammation that are often observed in the more severe COVID-19 cases.

Created: 27 Apr 2020, 12:53 p.m. | Last Modified: 27 Apr 2020, 12:53 p.m.

Panel Version: 0.163

Comment on list classification: Updated rating from Amber to Green. Multiple functional data demonstrates a role for ACE2 as a receptor for Coronaviruses. Plus a vast amount of preprint data that suggests SNPs in ACE2 should be explored for regional differences.

Created: 23 Apr 2020, 4:21 p.m. | Last Modified: 23 Apr 2020, 4:21 p.m.

Panel Version: 0.149

ACE2 gene present in the UniProt COVID portal (https://covid-19.uniprot.org/ 6-April-2020) which provides the latest available pre-release UniProtKB data for the SARS-CoV-2 coronavirus and other entries relating to the COVID-19 outbreak.

Created: 23 Apr 2020, 4:07 p.m. | Last Modified: 23 Apr 2020, 4:07 p.m.

Panel Version: 0.145

Added ACE2 to the panel as an Amber gene: many papers demonstrate that ACE2 acts as a cell receptor for Coronaviruses (e.g. PMIDs 32142651, 15897467, 14647384).

Created: 14 Apr 2020, 4:36 p.m. | Last Modified: 14 Apr 2020, 4:36 p.m.

Panel Version: 0.101

Sources: Other

Created: 14 Apr 2020, 4:33 p.m.

Mode of inheritance
Unknown

Publications

• 14647384
• 15897467
• 16007097
• 32142651