Initial Study on TMPRSS2 p.Val160Met Genetic Variant in COVID-19 patients

Wulandari, Laksmi; Hamidah, Berliana; Pakpahan, Cennikon; Damayanti, Nevy Shinta; Kurniati, Neneng Dewi; Adiatmaja, Christophorus Oetama; Wigianita, Monica Rizky; Soedarsono, -; Husada, Dominicus; Tinduh, Damayanti; Prakoeswa, Cita Rosita Sigit; Endaryanto, Anang; Puspaningsih, Ni Nyoman Tri; Mori, Yasuko; Lusida, Maria Inge; Shimizu, Kazufumi; Oceandy, Delvac; orcid,

doi:10.21203/rs.3.rs-292930/v1

Cited by 13 publications

(23 citation statements)

References 25 publications

(35 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To date, various in silico analyses have been made using different bioinformatics tools to identify and predict TMPRSS2 gene host polymorphism against SARS-CoV-2. As our results show, a study by [48] has shown that the TMPRSS2 p. Val160Met polymorphism was associated with SARS-CoV-2 infectivity. A recent investigation by Asselta et al reported the existence of some TMPRSS2 polymorphisms, namely, rs2070788, rs9974589, and rs7364083.…”

Section: Discussionsupporting

confidence: 76%

Computational Analysis of Missense Variants in the Human Transmembrane Protease Serine 2 (TMPRSS2) and SARS-CoV-2

Saih

Bouqdayr

Baba

et al. 2021

BioMed Research International

View full text Add to dashboard Cite

The human transmembrane protease serine 2 (TMPRSS2) protein plays an important role in prostate cancer progression. It also facilitates viral entry into target cells by proteolytically cleaving and activating the S protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In the current study, we used different available tools like SIFT, PolyPhen2.0, PROVEAN, SNAP2, PMut, MutPred2, I-Mutant Suite, MUpro, iStable, ConSurf, ModPred, SwissModel, PROCHECK, Verify3D, and TM-align to identify the most deleterious variants and to explore possible effects on the TMPRSS2 stability, structure, and function. The six missense variants tested were evaluated to have deleterious effects on the protein by SIFT, PolyPhen2.0, PROVEAN, SNAP2, and PMut. Additionally, V160M, G181R, R240C, P335L, G432A, and D435Y variants showed a decrease in stability by at least 2 servers; G181R, G432A, and D435Y are highly conserved and identified posttranslational modifications sites (PTMs) for proteolytic cleavage and ADP-ribosylation using ConSurf and ModPred servers. The 3D structure of TMPRSS2 native and mutants was generated using 7 meq as a template from the SwissModeller group, refined by ModRefiner, and validated using the Ramachandran plot. Hence, this paper can be advantageous to understand the association between these missense variants rs12329760, rs781089181, rs762108701, rs1185182900, rs570454392, and rs867186402 and susceptibility to SARS-CoV-2.

show abstract

Section: Discussionsupporting

confidence: 76%

Computational Analysis of Missense Variants in the Human Transmembrane Protease Serine 2 (TMPRSS2) and SARS-CoV-2

Saih

Bouqdayr

Baba

et al. 2021

BioMed Research International

View full text Add to dashboard Cite

show abstract

“…Of these, eight studies were pooled to explore associations of genetic polymorphisms with COVID-19 severity. 13,14,20,[36][37][38][39][40][41][42][43] After scrutinising all eligible studies, we summarised and classified major events associated with polymorphisms by focussing on host genetic variants: ACE1 rs1799752, ACE1 rs4646994, ACE2 rs2285666, and TMPRSS2 rs12329760. Descriptive data of the included studies are demonstrated in Table 1.…”

Section: Systematic Searchmentioning

confidence: 99%

“…For the disease severity, eight out of 11 studies providing data on genetic distributions of ACE1 rs4646994, 13,14,37,38 ACE2 rs2285666, 13,37,40 and TMPRSS2 rs12329760 [41][42][43] in non-severe and severe COVID-19 patients were selected for meta-analyses. All meta-analyses unveiled that three genetic polymorphisms of ACE1 rs4646994, ACE2 rs2285666, and TMPRSS2 rs12329760 were significantly associated with a higher risk of developing severe Subsequent meta-analysis demonstrated significant associations between ACE2 rs2285666 polymorphism and an increased risk of developing severe COVID-19 in two genetic models (recessive GG vs. GA + AA, OR = 2.14, 95% CI: 1.26, 3.66, p = 0.005, I 2 = 21%; additive GG vs. GA, OR = 2.14, 95% CI: 1.14, 4.01, p = 0.02, I 2 = 0%), as illustrated in Figure 3c,d.…”

Section: Disease Severity Of Sars-cov-2 Infectionmentioning

confidence: 99%

“…Furthermore, Monticelli et al showed a predictive value of TMPRSS2 rs12329760 in identifying individuals at risk of developing severe COVID-19 53. Conversely,Wulandari et al discovered no association between TMPRSS2 rs12329760 polymorphism and COVID-19 severity, while the CC genotype was significant associated with mortality of COVID-19 patients 43. To clarify the above contrasting results, we conducted meta-analysis and also demonstrated that COVID-19 positive patients with CC genotype of TMPRSS2 rs12329760 had a 1.79-fold increased risk of developing infectious symptoms (mild to severe) compared to those with CT and TT genotypes.Despite the fact that this meta-analysis contributes to our current understanding of host genetic susceptibility to SARS-CoV-2 infection, the following caveats should be considered.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Genetic polymorphisms of ACE1, ACE2, and TMPRSS2 associated with COVID‐19 severity: A systematic review with meta‐analysis

Saengsiwaritt

Jittikoon

Chaikledkaew

et al. 2022

Reviews in Medical Virology

View full text Add to dashboard Cite

Novel coronavirus disease 2019 (COVID-19) poses a global threat, due to its fluctuating frequency and lethality. Published data revealed associations of COVID-19 susceptibility and severity with host genetic polymorphisms in renin-angiotensinaldosterone system (RAAS)-related genes including angiotensin-converting enzyme (ACE)1, ACE2, and transmembrane protease (TMPRSS)2. However, the findings remain inconclusive. Accordingly, we aimed to clarify associations of genetic variants in those genes with COVID-19 susceptibility and severity using a systematic review with meta-analysis. From inception through 1 July 2021, a literature search was performed using PubMed, Scopus, Web of Science, and Cochrane Library databases. Allelic distributions for each polymorphism were calculated as pooled odds ratios (OR) with 95% confidence intervals (CI) to assess the strength of association. A total of 3333 COVID-19 patients and 5547 controls from 11 eligible studies were included. From a systematic review, ACE1 rs1799752, ACE1 rs4646994, ACE2 rs2285666, and TMPRSS2 rs12329760 were identified as common polymorphisms of RAAS-related genes. Meta-analysis showed a significant association between TMPRSS2 rs12329760 C-allele and an increased risk of developing severe COVID-19 (OR = 1.32, 95% CI: 1.01, 1.73). Likewise, additional meta-analyses uncovered that both ACE1 rs4646994 DD-genotype and ACE2 rs2285666 GG-genotype carriers had a significantly increased risk of developing severe COVID-19 (OR = 2.06, 95% CI: 1.45, 2.93; OR = 2.14, 95% CI: 1.26, 3.66; respectively). Genetic polymorphisms of ACE1 rs4646994 DD-genotype, ACE2 rs2285666 GG-genotype, and TMPRSS2 rs12329760 CC-genotype and C-allele may serve as predictive models of COVID-19 severity.

show abstract

“…However, exploring the role of the in ammasomes in the SARS-CoV-2 infection is still needed due to the recent onset of this pathogen. Genetic factors contributing to the outcome of SARS-CoV-2 infection are still little known; recently, variants in the speci c sites of the ACE2 and TMPRSS2 genes, as well as the ABO locus and fewer others gene targets were considered as genetic risk factors for COVID-19 outcomes (31)(32)(33).…”

Section: Introductionmentioning

confidence: 99%

Nlrp3 Inflammasome Genetic Variants Are Associated With Risk And/Or Protection To Hospitalization Among Covid-19 Patients From Rio De Janeiro, Brazil

Sá

Neira-Goulart

Ribeiro-Alves

et al. 2021

Preprint

View full text Add to dashboard Cite

Background COVID-19 has a broad spectrum of clinical manifestations, from asymptomatic to mild or moderate symptoms, reaching the most severe forms and death. The mechanisms underlying the SARS-CoV-2 infection and its clinical evolution are still unclear. Once SARS-CoV-2 infects individuals, host factors are activated by the presence of the virus inside the cells, such as the inflammasome system. The search of risk factors for COVID-19 is of relevance for clinical management. In this study, we investigated the impact of 11 single-base polymorphisms (SNPs) in the NLRP3, CARD8, AIM2, CASP-1, IFI16, and IL-1β inflammasome genes in SARS-CoV-2 infected individuals with distinct disease outcomes. Methods Patients were divided into two groups: (1) inpatients, with severe/critical disease (Hospitalized group, n=451), and (2) convalescent volunteers with prior SARS-CoV-2 infection and a history of asymptomatic to mild symptoms (Mild group, n=43). Patients hospitalized were followed up at a Hospital Center for COVID-19 Pandemic – National Institute of Infectology (INI)/FIOCRUZ, Rio de Janeiro, Brazil, from June 2020 to March 2021. The Mild group was recruited at Oswaldo Cruz Institute (IOC)/FIOCRUZ, Rio de Janeiro, Brazil, in 2020. Genotyping of the SNPs was determined by Real-Time PCR. Protection and risk estimations were performed by unconditional logistic regression models. Results Among the genotyped SNPs, significant differences in the NLRP3 rs1539019 and rs10754558 frequencies were observed between the groups. The C/C genotype (ORadj=6.31; Padj=0.026) or allele C (ORadj=1.05; Padj=0.002) in rs1539019 polymorphism were associated with the risk for hospitalization, while the C/G genotype (ORadj=0.16; Padj=0.016) or carrier-G (ORadj=0.2; Padj=0.028) in rs10754558 polymorphism were associated with protection for hospitalization. Regarding the NLRP3 genetic variants, the A-C-G-C-G haplotype (ORadj=0.14; Padj= 0.030) was associated with protection for hospitalization. No significant association was observed for the other polymorphisms. Conclusions As of our knowledge, this is the first study demonstrating the association of inflammasome NLRP3 variants with risk and/or protection for hospitalization in COVID-19. Studies linking the NLRP3 inflammasome and SARS-CoV-2 infection are still scarce due to the recent emergence of this pathogen. Our results contribute to the discussion of the impact of inflammasomes in the clinical evolution of COVID-19.

show abstract

Initial Study on TMPRSS2 p.Val160Met Genetic Variant in COVID-19 patients

Cited by 13 publications

References 25 publications

Computational Analysis of Missense Variants in the Human Transmembrane Protease Serine 2 (TMPRSS2) and SARS-CoV-2

Computational Analysis of Missense Variants in the Human Transmembrane Protease Serine 2 (TMPRSS2) and SARS-CoV-2

Genetic polymorphisms of ACE1, ACE2, and TMPRSS2 associated with COVID‐19 severity: A systematic review with meta‐analysis

Nlrp3 Inflammasome Genetic Variants Are Associated With Risk And/Or Protection To Hospitalization Among Covid-19 Patients From Rio De Janeiro, Brazil

Contact Info

Product

Resources

About