<i>ACE2</i>gene variants may underlie interindividual variability and susceptibility to COVID-19 in the Italian population

Benetti, Elisa; Tita, Rossella; Spiga, Ottavia; Ciolfi, Andrea; Birolo, Giovanni; Bruselles, Alessandro; Doddato, Gabriella; Giliberti, Annarita; Marconi, Cterina; Musacchia, Francesco; Pippucci, Tommaso; Torella, Annalaura; Trezza, Alfonso; Valentino, Floriana; Baldassarri, Mrgherita; Brusco, Alfredo; Asselta, Rosanna; Bruttini, Mirella; Furini, Simone; Seri, Marco; Nigro, Vincenzo; Matullo, Giuseppe; Tartaglia, Marco; Mari, Francesca; Renieri, Alessandra; Pinto, Annamaria

doi:10.1101/2020.04.03.20047977

Cited by 32 publications

(30 citation statements)

References 32 publications

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“…Structural analysis of variation in human ACE2 . We applied the same approach used to compare species, sequence identity and protein structural analysis, to examine the variation in ACE binding residues within humans, some of which have been proposed to alter binding affinity (18,(27)(28)(29)(30) . We integrated data from six different sources: dbSNP (31) , 1KGP (32) , Topmed (33) , UK10K (34) and CHINAMAP (28) , and identified a total of 11 variants in ten of the 25 ACE2 binding residues (Dataset S2).…”

Section: Resultsmentioning

confidence: 99%

Broad Host Range of SARS-CoV-2 Predicted by Comparative and Structural Analysis of ACE2 in Vertebrates

Damas¹,

Hughes

Keough³

et al. 2020

Preprint

162

241

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The novel coronavirus SARS-CoV-2 is the cause of Coronavirus Disease-2019 (COVID-19). The main receptor of SARS-CoV-2, angiotensin I converting enzyme 2 (ACE2), is now undergoing extensive scrutiny to understand the routes of transmission and sensitivity in different species. Here, we utilized a unique dataset of 410 vertebrates, including 252 mammals, to study cross-species conservation of ACE2 and its likelihood to function as a SARS-CoV-2 receptor. We designed a five-category ranking score based on the conservation properties of 25 amino acids important for the binding between receptor and virus, classifying all species from very high to very low . Only mammals fell into the medium to very high categories, and only catarrhine primates in the very high category, suggesting that they are at high risk for SARS-CoV-2 infection. We employed a protein structural analysis to qualitatively assess whether amino acid changes at variable residues would be likely to disrupt ACE2/SARS-CoV-2 binding, and found the number of predicted unfavorable changes significantly correlated with the binding score. Extending this analysis to human population data, we found only rare (<0.1%) variants in 10/25 binding sites. In addition, we observed evidence of positive selection in ACE2 in multiple species, including bats. Utilized appropriately, our results may lead to the identification of intermediate host species for SARS-CoV-2, justify the selection of animal models of COVID-19, and assist the conservation of animals both in native habitats and in human care.

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Section: Resultsmentioning

confidence: 99%

Broad Host Range of SARS-CoV-2 Predicted by Comparative and Structural Analysis of ACE2 in Vertebrates

Damas¹,

Hughes

Keough³

et al. 2020

Preprint

162

241

View full text Add to dashboard Cite

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“…Genetics may also play a role through polymorphisms of genes which encode for 1) proteins that are exploited by SARS-CoV-2, such as the highly conserved Angiotensin Converting Enzyme 2 (ACE2), which, as was also the case for SARS-CoV, it uses for docking and cellular entry in respiratory cells, or 2) proteins which provide protection against the effects of the virus (such as surfactant proteins, but also ACE2 itself) 22 . Genetic association studies are currently ongoing to unravel such hypotheses, and have found correlations between ACE2 variants and COVID-19 susceptibility 23,24 . Interestingly, as an X-linked phenotype, the effectiveness of interaction-booster and interaction-inhibitor variants of ACE2 can be more definite in males than females, and could contribute towards a higher mortality rate in males, accounting for up to ∼70% of death caused by SARS-CoV2, SARS-CoV or MERS-CoV 25 , in addition to a likely higher rate of risk factors (e.g.…”

Section: Genetics In Covid-19mentioning

confidence: 99%

Histopathology and genetic susceptibility in COVID‐19 pneumonia

Thüsen

Eerden

2020

Eur J Clin Investigation

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Background The clinical features of COVID‐19 pneumonia range from a mild illness to patients with a very severe illness with acute hypoxemic respiratory failure requiring ventilation and Intensive Care Unit admission. Aims To provide a brief overview of the existing evidence for such differences in host response and outcome, and generate hypotheses for divergent patterns and avenues for future research, by highlighting similarities and differences in histopathological appearance between COVID‐19 and influenza as well as previous coronavirus outbreaks, and by discussing predisposition through genetics and underlying disease. Materials and Method We assessed the available early literature for histopathological patterns of COVID‐19 pneumonia and underlying risk factors. Result The histopathological spectrum of COVID‐19 pneumonia includes variable patterns of epithelial damage, vascular complications, fibrosis and inflammation. Risk factors for a fatal disease include older age, respiratory disease, diabetes mellitus, obesity and hypertension. Discussion While some risk factors and their potential role in COVID‐19 pneumonia are increasingly recognized, little is known about the mechanisms behind episodes of sudden deterioration or the infrequent idiosyncratic clinical demise in otherwise healthy and young subjects. Conclusion The answer to many of the remaining questions regarding COVID‐19 pneumonia pathogenesis may in time be provided by genotyping as well careful clinical, serological, radiological and histopathological phenotyping.

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“…No reuse allowed without permission. SARS-CoV-2 virus is a single stranded (+) sense RNA virus with a genome length of about 30 Kb. It encodes 29 structural and non-structural proteins, including ORF1a/b polyprotein, spike (S) glycoprotein, envelope (E), membrane (M) and the nucleocapsid (N) protein (8,17).…”

Section: Introductionmentioning

confidence: 99%

“…In ACE2, the majority of observed variants occur at low frequencies (non-polymorphic) in most human populations. Even though some recent studies (29,30) have attempted to implicate these variants with susceptibility to infection by SARS-CoV-2, there is no convincing evidence yet that the lowfrequency, non-polymorphic variants in ACE2 can modulate susceptibility to SARS-Cov-2 infection.…”

Section: Introductionmentioning

confidence: 99%

Global Spread of SARS-CoV-2 Subtype with Spike Protein Mutation D614G is Shaped by Human Genomic Variations that Regulate Expression ofTMPRSS2andMX1Genes

Bhattacharyya

Das

Ghosh

et al. 2020

Preprint

114

112

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COVID-19 pandemic is a major human tragedy. Worldwide, SARS-CoV-2 has already infected over 3 million and has killed about 230,000 people. SARS-CoV-2 originated in China and, within three months, has evolved to an additional 10 subtypes. One particular subtype with a non-silent (Aspartate to Glycine) mutation at 614 th position of the Spike protein (D614G) rapidly outcompeted other preexisting subtypes, including the ancestral. We assessed that D614G mutation generates an additional serine protease (Elastase) cleavage site near the S1-S2 junction of the Spike protein. We also identified that a single nucleotide deletion (delC) at a known variant site (rs35074065) in a cis-eQTL of TMPRSS2, is extremely rare in East Asians but is common in Europeans and North Americans. The delC allele facilitates entry of the 614G subtype into host cells, thus accelerating the spread of 614G subtype in Europe and North America where the delC allele is common. The delC allele at the cis-eQTL locus rs35074065 of TMPRSS2 leads to overexpression of both TMPRSS2 and a nearby gene MX1. The cis-eQTL site, rs35074065 overlaps with a transcription factor binding site of an activator (IRF1) and a repressor (IRF2). IRF1 activator can bind to variant delC allele, but IRF2 repressor fails to bind. Thus, in an individual carrying the delC allele, there is only activation, but no repression. On viral entry, IRF1 mediated upregulation of MX1 leads to neutrophil infiltration and processing of 614G mutated Spike protein by neutrophil Elastase. The simultaneous processing of 614G spike protein by TMPRSS2 and Elastase serine proteases facilitates the entry of the 614G subtype into host cells. Thus, SARS-CoV-2, particularly the 614G subtype, has spread more easily and with higher frequency to Europe and North America where the delC allele regulating expression of TMPRSS2 and MX1 host proteins is common, but not to East Asia where this allele is rare.

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ACE2gene variants may underlie interindividual variability and susceptibility to COVID-19 in the Italian population

Cited by 32 publications

References 32 publications

Broad Host Range of SARS-CoV-2 Predicted by Comparative and Structural Analysis of ACE2 in Vertebrates

Broad Host Range of SARS-CoV-2 Predicted by Comparative and Structural Analysis of ACE2 in Vertebrates

Histopathology and genetic susceptibility in COVID‐19 pneumonia

Global Spread of SARS-CoV-2 Subtype with Spike Protein Mutation D614G is Shaped by Human Genomic Variations that Regulate Expression ofTMPRSS2andMX1Genes

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