Analysis of ACE2 Genetic Variability among Populations Highlights a Possible Link with COVID-19-Related Neurological Complications

Strafella, Claudia; Caputo, Valerio; Termine, Andrea; Barati, Shila; Gambardella, Stefano; Borgiani, Paola; Caltagirone, Carlo; Novelli, Giuseppe; Giardina, Emiliano; Cascella, Raffaella

doi:10.3390/genes11070741

Cited by 60 publications

(64 citation statements)

References 29 publications

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“…However, this variant deserves further investigation in a larger COVID-19 cohorts as well as functional studies. Concerning the other two variants, the recurrent c.439+4A>G (rs2285666) intronic variant has been previously reported by Strafella et al [14] and by Asselta et al [15] in two different Italian cohorts representative of the country's population. The variant is located in the intron 3 in a splice site region of the gene.…”

Section: Resultsmentioning

confidence: 70%

Analysis of ACE2 genetic variants in 131 Italian SARS-CoV-2-positive patients

et al. 2020

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Background Coronaviruses (CoV) are a large family of viruses that are common in humans and many animal species. Animal coronaviruses rarely infect humans with the exceptions of the Middle East respiratory syndrome (MERS-CoV), the severe acute respiratory syndrome corona virus (SARS-CoV), and now SARS-CoV-2, which is the cause of the ongoing pandemic of coronavirus disease 2019 (COVID-19). Several studies suggested that genetic variants in the ACE2 gene may influence the host susceptibility or resistance to SARS-CoV-2 infection according to the functional role of ACE2 in human pathophysiology. However, many of these studies have been conducted in silico based on epidemiological and population data. We therefore investigated the occurrence of ACE2 variants in a cohort of 131 Italian unrelated individuals clinically diagnosed with COVID-19 and in an Italian control population, to evaluate a possible allelic association with COVID-19, by direct DNA analysis. Methods As a pilot study, we analyzed, by whole-exome sequencing, genetic variants of ACE2 gene in 131 DNA samples of COVID-19 patients hospitalized at Tor Vergata University Hospital and at Bambino Gesù Children’s Hospital, Rome. We used a large control group consisting of 1000 individuals (500 males and 500 females). Results We identified three different germline variants: one intronic c.439+4G>A and two missense c.1888G>C p.(Asp630His) and c.2158A>G p.(Asn720Asp) in a total of 131 patients with a similar frequency in male and female. Thus far, only the c.1888G>C p.(Asp630His) variant shows a statistically different frequency compared to the ethnically matched populations. Therefore, further studies are needed in larger cohorts, since it was found only in one heterozygous COVID-19 patient. Conclusions Our results suggest that there is no strong evidence, in our cohort, of consistent association of ACE2 variants with COVID-19 severity. We might speculate that rare susceptibility/resistant alleles could be located in the non-coding regions of the ACE2 gene, known to play a role in regulation of the gene activity.

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Section: Resultsmentioning

confidence: 70%

Analysis of ACE2 genetic variants in 131 Italian SARS-CoV-2-positive patients

et al. 2020

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“…Among all the common exonic variants, some very recent studies done on ACE2 variants reported population-based frequency differences for a single nucleotide variant (SNV) rs2285666 (also called G8790A) (Asselta et al, 2020;Cao et al, 2020;Strafella et al, 2020). This variant of ACE2 was significantly different for Europeans (0.2), than the East Asians (0.55) (Asselta et al, 2020;Cao et al, 2020).…”

Section: Resultsmentioning

confidence: 99%

Genetic Association of ACE2 rs2285666 Polymorphism With COVID-19 Spatial Distribution in India

et al. 2020

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Studies on host-pathogen interaction have identified human ACE2 as a host cell receptor responsible for mediating infection by coronavirus (COVID-19). Subsequent studies have shown striking difference of allele frequency among Europeans and Asians for a polymorphism rs2285666, present in ACE2. It has been revealed that the alternate allele (TT-plus strand or AA-minus strand) of rs2285666 elevate the expression level of this gene upto 50%, hence may play a significant role in SARS-CoV-2 susceptibility. Therefore, we have first looked the phylogenetic structure of rs2285666 derived haplotypes in worldwide populations and compared the spatial frequency of this particular allele with respect to the COVID-19 infection as well as case-fatality rate in India. For the first time, we ascertained a significant positive correlation for alternate allele (T or A) of rs2285666, with the lower infection as well as case-fatality rate among Indian populations. We trust that this information will be useful to understand the role of ACE2 in COVID-19 susceptibility.

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“…Several differences in clinical manifestations and complications of COVID-19 patients have been observed suggesting variability in the disease process [ 19 ]. Genetic variants in the host human genome, can in part explain the broad inter-individual variation of disease susceptibility and/or severity [ 6 , 19 , 20 , 21 ]. Moreover, the expression levels of human genes encoding the main proteins involved in this mechanism could be critical for the susceptibility, symptoms and outcome of SARS-CoV-2 infection.…”

Section: Discussionmentioning

confidence: 99%

Expression profiles of the SARS-CoV-2 host invasion genes in nasopharyngeal and oropharyngeal swabs of COVID-19 patients

Amati¹,

Vancheri²,

Latini³

et al. 2020

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We collect the nasopharyngeal and oropharyngeal swabs of 63 subjects with severe symptoms or contacts with COVID-19 confirmed cases to perform a pilot-study aimed to verify the “in situ” expression of SARS-CoV-2 host invasion genes ( ACE2 , TMPRSS2 , PCSK3 , EMILIN1 , EMILIN2 , MMRN1 , MMRN2 , DPP4 ). ACE2 (FC = +1.88, p ≤ 0.05) and DPP4 (FC = +3, p < 0.01) genes showed a significant overexpression in COVID-19 patients. ACE2 and DPP4 expression levels had a good performance (AUC = 0.75; p < 0.001) in distinguishing COVID-19 patients from negative subjects. Interestingly, we found a significant positive association of ACE2 mRNA and PCSK3 , EMILIN1 , MMRN1 and MMRN2 expression and of DPP4 mRNA and EMILIN2 expression only in COVID-19 patients. Noteworthy, a subgroup of severe COVID-19 (n = 7) patients, showed significant high level of ACE2 mRNA and another subgroup of less severe COVID-19 patients (n = 6) significant raised DPP4 levels. These results indicate that a group of SARS-CoV-2 host invasion genes are functionally related in COVID-19 patients and suggests that ACE2 and DPP4 expression level could act as genomic biomarkers. Moreover, at the best of our knowledge, this is the first study that shows an elevated DPP4 expression in naso- and oropharyngeal swabs of COVID-19 patient thus suggesting a functional role of DPP4 in SARS-CoV-2 infections.

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Analysis of ACE2 Genetic Variability among Populations Highlights a Possible Link with COVID-19-Related Neurological Complications

Cited by 60 publications

References 29 publications

Analysis of ACE2 genetic variants in 131 Italian SARS-CoV-2-positive patients

Analysis of ACE2 genetic variants in 131 Italian SARS-CoV-2-positive patients

Genetic Association of ACE2 rs2285666 Polymorphism With COVID-19 Spatial Distribution in India

Expression profiles of the SARS-CoV-2 host invasion genes in nasopharyngeal and oropharyngeal swabs of COVID-19 patients

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