Genetic polymorphisms of ACE1, ACE2, IFTM3, TMPRSS2 and TNFα genes associated with susceptibility and severity of SARS-CoV-2 infection: a systematic review and meta-analysis

Pecoraro, Valentina; Cuccorese, Michela; Trenti, Tommaso

doi:10.1007/s10238-023-01038-9

Cited by 15 publications

(11 citation statements)

References 57 publications

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“…Accompanying the spread of COVID-19 disease all over the world, recognizing factors connected to the susceptibility and outcome of the disease is at the top of medical and pharmacological concerns [ 23 ]. This work was performed to identify possible COVID-19 prognostic markers with special concern for ACE-2 and IFITM-3 genetic variations and IL-6 level assays.…”

Section: Discussionmentioning

confidence: 99%

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Angiotensin-Converting Enzyme-2 (ACE-2) with Interferon-Induced Transmembrane Protein-3 (IFITM-3) Genetic Variants and Interleukin-6 as Severity and Risk Predictors among COVID-19 Egyptian Population

Makled,

Ali,

Eldahdouh

et al. 2023

International Journal of Microbiology

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Introduction. The host genetic background is a crucial factor that underlies the interindividual variability of COVID-19 fatality and outcomes. Angiotensin-converting enzyme-2 (ACE-2) and interferon-induced transmembrane protein-3 (IFITM-3) have a key role in viral cell entrance and priming. The evoked immune response will also provide a predictive prognosis for COVID-19 infection. This study aimed to explore the association between ACE-2 and IFITM-3 genotypes and their corresponding allele frequencies with disease severity indices in the Egyptian COVID-19 population. The serum level of interleukin-6, as a biomarker of hyperinflammatory response, and cytokine storm, was correlated with disease progression, single nucleotide polymorphisms (SNPs) of the selected receptors, and treatment response. Methodology. We enrolled 900 COVID-19-confirmed cases and 100 healthy controls. Genomic DNA was extracted from 200 subjects (160 patients selected based on clinical and laboratory data and 40 healthy controls). The ACE-2 rs2285666 and IFITM-3 rs12252 SNPs were genotyped using the TaqMan probe allelic discrimination assay, and the serum IL-6 level was determined by ELISA. Logistic regression analysis was applied to analyze the association between ACE-2 and IFITM-3 genetic variants, IL-6 profile, and COVID-19 severity. Results. The identified genotypes and their alleles were significantly correlated with COVID-19 clinical deterioration as follows: ACE2 rs2285666 CT + TT, odds ratio (95% confidence interval): 12.136 (2.784–52.896) and IFITM-3 rs12252 AG + GG: 17.276 (3.673–81.249), both p<0.001. Compared to the controls, the heterozygous and mutant genotypes for both SNPs were considerable risk factors for increased susceptibility to COVID-19. IL-6 levels were significantly correlated with disease progression (p<0.001). Conclusion. ACE-2 and IFITM-3 genetic variants are potential predictors of COVID-19 severity, critical outcomes, and post-COVID-19 complications. Together, these SNPs and serum IL-6 levels explain a large proportion of the variability in the severity of COVID-19 infection and its consequences among Egyptian subjects.

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Section: Discussionmentioning

confidence: 99%

“…A meta-analytic study involving more than four studies from England, Italy, and Spain showed a significant association of the IFITM-3 rs12252/ ACE-2 rs2285666 polymorphism with COVID-19 susceptibility [ 43 ]. However, neither rs2285666 nor rs12252 were shown to be substantially related to illness severity [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

Angiotensin-Converting Enzyme-2 (ACE-2) with Interferon-Induced Transmembrane Protein-3 (IFITM-3) Genetic Variants and Interleukin-6 as Severity and Risk Predictors among COVID-19 Egyptian Population

Makled,

Ali,

Eldahdouh

et al. 2023

International Journal of Microbiology

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“…ACE2 acts as a receptor and serves as a possible route by which the coronavirus can enter cells, while TMPRSS2 is a membrane proteinase that can aid the virus in entering cells. The ACE2 protein is the cause of the lung infection triggered by SARS-CoV-2; it is mainly expressed on the surfaces of the human respiratory tract and lung cells [ 3 ]. When the virus enters the host cells, TMPRSS2 cuts the virus membrane protein, promoting its replication and infection, and it is mainly located on the surfaces of human respiratory tract cells [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Anti-SARS-CoV-2 Viral Activity of Sweet Potato Trypsin Inhibitor via Downregulation of TMPRSS2 Activity and ACE2 Expression In Vitro and In Vivo

Jiang,

Deng,

et al. 2024

IJMS

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. Known as COVID-19, it has affected billions of people worldwide, claiming millions of lives and posing a continuing threat to humanity. This is considered one of the most extensive pandemics ever recorded in human history, causing significant losses to both life and economies globally. However, the available evidence is currently insufficient to establish the effectiveness and safety of antiviral drugs or vaccines. The entry of the virus into host cells involves binding to angiotensin-converting enzyme 2 (ACE2), a cell surface receptor, via its spike protein. Meanwhile, transmembrane protease serine 2 (TMPRSS2), a host surface protease, cleaves and activates the virus’s S protein, thus promoting viral infection. Plant protease inhibitors play a crucial role in protecting plants against insects and/or microorganisms. The major storage proteins in sweet potato roots include sweet potato trypsin inhibitor (SWTI), which accounts for approximately 60% of the total water-soluble protein and has been found to possess a variety of health-promoting properties, including antioxidant, anti-inflammatory, ACE-inhibitory, and anticancer functions. Our study found that SWTI caused a significant reduction in the expression of the ACE2 and TMPRSS2 proteins, without any adverse effects on cells. Therefore, our findings suggest that the ACE2 and TMPRSS2 axis can be targeted via SWTI to potentially inhibit SARS-CoV-2 infection.

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“…Another systematic review and meta-analysis revealed that genetic variants within the angiotensin-converting enzyme 1 and 2 genes (ACE and ACE2, respectively) and the transmembrane serine protease 2 (TMPRSS2) gene were associated with COVID-19 severity [28]. Moreover, a systematic review found that ACE and the interferon-induced transmembrane protein 3 (IFTM3) gene polymorphisms may lead to a genetic predisposition for severe lung injury in COVID-19 patients [29]. Also, genome-wide association study (GWAS) metaanalyses of the COVID-19 Host Genetics Initiative identified 14 loci associated with COVID-19 disease severity or hospitalization [30].…”

Section: Introductionmentioning

confidence: 99%

Uncovering associations between pre-existing conditions and COVID-19 Severity: A polygenic risk score approach across three large biobanks

Fritsche,

Nam,

et al. 2023

PLoS Genet

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Objective To overcome the limitations associated with the collection and curation of COVID-19 outcome data in biobanks, this study proposes the use of polygenic risk scores (PRS) as reliable proxies of COVID-19 severity across three large biobanks: the Michigan Genomics Initiative (MGI), UK Biobank (UKB), and NIH All of Us. The goal is to identify associations between pre-existing conditions and COVID-19 severity. Methods Drawing on a sample of more than 500,000 individuals from the three biobanks, we conducted a phenome-wide association study (PheWAS) to identify associations between a PRS for COVID-19 severity, derived from a genome-wide association study on COVID-19 hospitalization, and clinical pre-existing, pre-pandemic phenotypes. We performed cohort-specific PRS PheWAS and a subsequent fixed-effects meta-analysis. Results The current study uncovered 23 pre-existing conditions significantly associated with the COVID-19 severity PRS in cohort-specific analyses, of which 21 were observed in the UKB cohort and two in the MGI cohort. The meta-analysis yielded 27 significant phenotypes predominantly related to obesity, metabolic disorders, and cardiovascular conditions. After adjusting for body mass index, several clinical phenotypes, such as hypercholesterolemia and gastrointestinal disorders, remained associated with an increased risk of hospitalization following COVID-19 infection. Conclusion By employing PRS as a proxy for COVID-19 severity, we corroborated known risk factors and identified novel associations between pre-existing clinical phenotypes and COVID-19 severity. Our study highlights the potential value of using PRS when actual outcome data may be limited or inadequate for robust analyses.

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Genetic polymorphisms of ACE1, ACE2, IFTM3, TMPRSS2 and TNFα genes associated with susceptibility and severity of SARS-CoV-2 infection: a systematic review and meta-analysis

Cited by 15 publications

References 57 publications

Angiotensin-Converting Enzyme-2 (ACE-2) with Interferon-Induced Transmembrane Protein-3 (IFITM-3) Genetic Variants and Interleukin-6 as Severity and Risk Predictors among COVID-19 Egyptian Population

Angiotensin-Converting Enzyme-2 (ACE-2) with Interferon-Induced Transmembrane Protein-3 (IFITM-3) Genetic Variants and Interleukin-6 as Severity and Risk Predictors among COVID-19 Egyptian Population

Anti-SARS-CoV-2 Viral Activity of Sweet Potato Trypsin Inhibitor via Downregulation of TMPRSS2 Activity and ACE2 Expression In Vitro and In Vivo

Uncovering associations between pre-existing conditions and COVID-19 Severity: A polygenic risk score approach across three large biobanks

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