Protective Role of a TMPRSS2 Variant on Severe COVID-19 Outcome in Young Males and Elderly Women

Monticelli, Maria; Mele, Bruno Hay; Benetti, Elisa; Fallerini, Chiara; Baldassarri, Margherita; Furini, Simone; Frullanti, Elisa; Mari, Francesca; Andreotti, Giuseppina; Cubellis, Maria Vittoria; Renieri, Alessandra; Study, Gen-Covid Multicenter

doi:10.3390/genes12040596

Cited by 50 publications

(46 citation statements)

References 47 publications

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“…Finally, there is some evidence that genetic polymorphisms may impact the risk for infection by SARS-CoV-2 through viral entry including ACE2 and TMPRSS2 [ 22 , 23 ]. Several studies have utilized a target gene approach to identify functional variants of these proteins associated with COVID-19 disease and severity.…”

Section: Genome-wide Association Studies Of Severe Covid-19mentioning

confidence: 99%

“…Several studies have utilized a target gene approach to identify functional variants of these proteins associated with COVID-19 disease and severity. For example, two independent studies found that the p.Val160Met variant of TMPRSS2 was associated with decreased disease severity [ 23 , 24 ] (Table 1 ). Other studies have found more frequent ACE2 allelic variability in uninfected versus SARS-CoV-2 infected individuals in Italy [ 25 ], and specific SNPs enriched in health-care works highly exposed but never infected with SARS-CoV-2 [ 26 ] (Table 1 ).…”

Section: Genome-wide Association Studies Of Severe Covid-19mentioning

confidence: 99%

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Host genetics of pediatric SARS-CoV-2 COVID-19 and multisystem inflammatory syndrome in children

Schulert

Blum

Cron

2021

Current Opinion in Pediatrics

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Purpose of review This review is meant to describe the genetic associations with pediatric severe COVID-19 pneumonia and the postinfectious complication of the multisystem inflammatory syndrome in children (MIS-C). Multiple genetic approaches have been carried out, primarily in adults with extrapolation to children, including genome-wide association studies (GWAS), whole exome and whole genome sequencing (WES/WGS), and target gene analyses. Recent findings Data from adults with severe COVID-19 have identified genomic regions (human leukocyte antigen locus and 3p21.31) as potential risk factors. Genes related to viral entry into cells (ABO blood group locus, ACE2, TMPRS22 ) have been linked to severe COVID-19 patients by GWAS and target gene approaches. Type I interferon (e.g. IFNAR2 ) and antiviral gene (e.g. TLR7 ) associations have been identified by several genetic approaches in severe COVID-19. WES has noted associations with several immune regulatory genes (e.g. SOCS1 ). Target gene approaches have identified mutations in perforin-mediated cytolytic pathway genes in children and adults with severe COVID-19 and children with MIS-C. Summary Several genetic associations have been identified in individuals with severe COVID-19 and MIS-C via various genetic approaches. Broadly speaking, COVID-19 genetic associations include genes involved with antiviral functions, viral cell entry, immune regulation, chemotaxis of white blood cells, and lymphocyte cytolytic function.

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Section: Genome-wide Association Studies Of Severe Covid-19mentioning

confidence: 99%

Section: Genome-wide Association Studies Of Severe Covid-19mentioning

confidence: 99%

Host genetics of pediatric SARS-CoV-2 COVID-19 and multisystem inflammatory syndrome in children

Schulert

Blum

Cron

2021

Current Opinion in Pediatrics

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“…However, the genetic variant of TMPRSS2, namely, p.V197M (p.Val197Met) (rs12329760), has a protective role in individuals against COVID-19 infection through its destructive effect on TMPRSS2 protease activity. This genetic variant is higher in individuals who have experienced milder clinical symptoms of COVID-19 (45). Therefore, it seems that by determining the polymorphisms in the TMPRSS2 gene, it is possible to identify the individual risk of infection and susceptibility to COVID-19.…”

Section: Tmprss2: Gene Polymorphisms and Their Association To Covid-19mentioning

confidence: 99%

TMPRSS2 As an Influential Human Gene for COVID-19

Abdollahi¹,

Izadi²

2021

J Human Gen Genom

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: In December 2019, the new virus, COVID-19, emerged and led to a pandemic respiratory acute disease. Almost all countries have experienced different rates of morbidity and mortality. These differences can be attributed to factors such as a diagnostic test capacity for COVID-19 and the health system efficiency. Besides the differences between countries related to the COVID-19 management, different patients represent a diverse range of clinical symptoms, from outpatient to patients admitted to the intensive care unit (ICU) due to the severity of symptoms. To gain deeper insights into such disparities in the severity of COVID-19 clinical presentations, epidemiological studies have reported risk factors such as old age, male sex, underlying chronic diseases such as diabetes, inflammatory and cardiovascular diseases, which have a bearing on susceptibility to COVID-19. In addition to these risk factors, the molecular mechanism involved in the virus entry process has been under investigation. Apart from a well-known protein called ACE2 (angiotensin-converting enzyme 2), which plays the receptor role for COVID-19, another essential protein in this pathway is TMPRSS2 (transmembrane protease, serine 2). This protease has a crucial role in effective membrane integration between the virus and the target cell. This process can affect the severity of the infection and the mortality rate of the disease. Thus, it seems that understanding the role of TMPRSS2 in COVID-19 infection can help better management by designing TMPRSS2 inhibitors drugs. Given the variants of the TMPRSS2 gene, which are associated with the severity of symptoms, people exposed to severe forms of this disease can be identified before the deterioration of the disease to adopt appropriate therapeutic approaches. Therefore, this study focused on the different levels of the TMPRSS2 interactions with COVID-19 virus and disease severity.

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“…It consists of a 20 aa cytoplasmic region, a 14 aa transmembrane domain, and a 120 aa extracellular SEA domain, followed by a C-terminal trypsin-like serine proteinase domain, with the characteristic catalytic triad of Ser195, His57, and Asp102 ( Fig. 3 c) [ [21] , [22] , [23] ].…”

Section: Introductionmentioning

confidence: 99%

A multi-targeted approach to identify potential flavonoids against three targets in the SARS-CoV-2 life cycle

Kumar

Paul

Yadav

et al. 2022

Computers in Biology and Medicine

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The advent and persistence of the Severe Acute Respiratory Syndrome Coronavirus – 2 (SARS-CoV-2)-induced Coronavirus Disease (COVID-19) pandemic since December 2019 has created the largest public health emergency in over a century. Despite the administration of multiple vaccines across the globe, there continues to be a lack of approved efficacious non-prophylactic interventions for the disease. Flavonoids are a class of phytochemicals with historically established antiviral, anti-inflammatory and antioxidative properties that are effective against cancers, type 2 diabetes mellitus, and even other human coronaviruses. To identify the most promising bioactive flavonoids against the SARS-CoV-2, this article screened a virtual library of 46 bioactive flavonoids against three promising targets in the SARS-CoV-2 life cycle: human TMPRSS2 protein, 3CLpro, and PLpro. By examining the effects of glycosylation and other structural-activity relationships, the presence of sugar moiety in flavonoids significantly reduces its binding energy. It increases the solubility of flavonoids leading to reduced toxicity and higher bioavailability. Through protein-ligand contact profiling, it was concluded that naringin formed more hydrogen bonds with TMPRSS2 and 3CLpro. In contrast, hesperidin formed a more significant number of hydrogen bonds with PLpro. These observations were complimented by the 100 ns molecular dynamics simulation and binding free energy analysis, which showed a considerable stability of docked bioflavonoids in the active site of SARS-CoV-2 target proteins. Finally, the binding affinity and stability of the selected docked complexes were compared with the reference ligands (camostat for TMPRSS2, GC376 for 3CLpro, and GRL0617 for PLpro) that strongly inhibit their respective SARS-COV-2 targets. Overall analysis revealed that the selected flavonoids could be potential therapeutic agents against SARS-CoV-2. Naringin showed better affinity and stability for TMPRSS2 and 3CLpro, whereas hesperidin showed a better binding relationship and stability for PLpro.

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Protective Role of a TMPRSS2 Variant on Severe COVID-19 Outcome in Young Males and Elderly Women

Cited by 50 publications

References 47 publications

Host genetics of pediatric SARS-CoV-2 COVID-19 and multisystem inflammatory syndrome in children

Host genetics of pediatric SARS-CoV-2 COVID-19 and multisystem inflammatory syndrome in children

TMPRSS2 As an Influential Human Gene for COVID-19

A multi-targeted approach to identify potential flavonoids against three targets in the SARS-CoV-2 life cycle

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