Human-SARS-CoV-2 interactome and human genetic diversity: TMPRSS2-rs2070788, associated with severe influenza, and its population genetics caveats in Native Americans

Kehdy, Fernanda S. G.; Pita-Oliveira, Murilo; Scudeler, Mariana M; Torres-Loureiro, Sabrina; Zolini, Camila; Moreira, Rennan G.; Michelin, Lucas; Alvim, Isabela; Silva-Carvalho, Carolina; Furlan, Vinícius; Mendes, Marla; Santolalla, Meddly L.; Borda, Víctor; Souza, Soares; Jaramillo‐Valverde, Luis; Vasquez-Dominguez, Andres; Neira, Cesar; Aguiar, Renato Santana; Verdugo, Ricardo A.; Td, O'Connor; Tarazona‐Santos, Eduardo; Leal, Thiago P.; Rodrigues‐Soares, Fernanda

doi:10.1590/1678-4685-gmb-2020-0484

Cited by 7 publications

(9 citation statements)

References 11 publications

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“…In males, rs8134378 (A>T), rs383510 (T>C), and rs2070788 (G>A) have been shown to increase the expression of TMPRSS2, favoring the fusion of H1N1 and H7N9 viral membranes [40]. In summary, TMPRSS2 expression is influenced by the G-allele of rs2070788 and the T-allele of rs383510, which are collectively associated with elevated TMPRSS2 expression in lung tissue [132]. Rs2070788 and rs383510 have been further identified as causal SNPs of COVID-19 disease severity [133].…”

Section: Tmprss2mentioning

confidence: 99%

Genetic Variants within SARS-CoV-2 Human Receptor Genes May Contribute to Variable Disease Outcomes in Different Ethnicities

Adimulam

Arumugam

Gokul

et al. 2023

IJMS

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The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved into a global pandemic, with an alarming infectivity and mortality rate. Studies have examined genetic effects on SARS-CoV-2 disease susceptibility and severity within Eurasian populations. These studies identified contrasting effects on the severity of disease between African populations. Genetic factors can explain some of the diversity observed within SARS-CoV-2 disease susceptibility and severity. Single nucleotide polymorphisms (SNPs) within the SARS-CoV-2 receptor genes have demonstrated detrimental and protective effects across ethnic groups. For example, the TT genotype of rs2285666 (Angiotensin-converting enzyme 2 (ACE2)) is associated with the severity of SARS-CoV-2 disease, which is found at higher frequency within Asian individuals compared to African and European individuals. In this study, we examined four SARS-CoV-2 receptors, ACE2, Transmembrane serine protease 2 (TMPRSS2), Neuropilin-1 (NRP1), and Basigin (CD147). A total of 42 SNPs located within the four receptors were reviewed: ACE2 (12), TMPRSS2 (10), BSG (CD147) (5), and NRP1 (15). These SNPs may be determining factors for the decreased disease severity observed within African individuals. Furthermore, we highlight the absence of genetic studies within the African population and emphasize the importance of further research. This review provides a comprehensive summary of specific variants within the SARS-CoV-2 receptor genes, which can offer a better understanding of the pathology of the SARS-CoV-2 pandemic and identify novel potential therapeutic targets.

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Section: Tmprss2mentioning

confidence: 99%

Genetic Variants within SARS-CoV-2 Human Receptor Genes May Contribute to Variable Disease Outcomes in Different Ethnicities

Adimulam

Arumugam

Gokul

et al. 2023

IJMS

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Section: Discussionmentioning

confidence: 99%

“…In this sense, the variants p.Gly8Val/c.23G>T (rs75603675) and p.Val197Met/c.589G>A (rs12329760) have been reported to influence its interaction with ACE2 and the S protein (29, 31, 32). rs2070788 has been reported to be highly expressed in the lungs of patients at risk of developing severe COVID-19 (33), suggesting that these variants could play an important role in the severity of SARS-CoV-2 infection (34)(35)(36).…”

Section: Discussionmentioning

confidence: 99%

“…In some studies, TMPRSS2 expression of the G allele of rs2070788 was associated with increased protein expression in lung tissue, which could lead to an association with increased susceptibility to COVID-19 (35,41). Recently, a bioinformatics analysis performed by Mujalli et al (2022) revealed the overexpression of genes implicated in the ACE2-TMPRSS2 signaling pathway in COVID-19 patients with severe and fatal phenotypes.…”

Section: Discussionmentioning

confidence: 99%

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The fatal contribution of serine protease-related genetic variants to COVID-19 outcomes

Martínez-Gómez,

Martinez-Armenta,

Tusie-Luna

et al. 2024

Front. Immunol.

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IntroductionSerine proteases play a critical role during SARS-CoV-2 infection. Therefore, polymorphisms of transmembrane protease serine 2 (TMPRSS2) and serpine family E member 1 (SERPINE1) could help to elucidate the contribution of variability to COVID-19 outcomes.MethodsTo evaluate the genetic variants of the genes previously associated with COVID-19 outcomes, we performed a cross-sectional study in which 1536 SARS-CoV-2-positive participants were enrolled. TMPRSS2 (rs2070788, rs75603675, rs12329760) and SERPINE1 (rs2227631, rs2227667, rs2070682, rs2227692) were genotyped using the Open Array Platform. The association of polymorphisms with disease outcomes was determined by logistic regression analysis adjusted for covariates (age, sex, hypertension, type 2 diabetes, and obesity).ResultsAccording to our codominant model, the GA genotype of rs2227667 (OR=0.55; 95% CI = 0.36-0.84; p=0.006) and the AG genotype of rs2227667 (OR=0.59; 95% CI = 0.38-0.91; p=0.02) of SERPINE1 played a protective role against disease. However, the rs2227692 T allele and TT genotype SERPINE1 (OR=1.45; 95% CI = 1.11-1.91; p=0.006; OR=2.08; 95% CI = 1.22-3.57; p=0.007; respectively) were associated with a decreased risk of death. Similarly, the rs75603675 AA genotype TMPRSS2 had an OR of 1.97 (95% CI = 1.07-3.6; p=0.03) for deceased patients. Finally, the rs2227692 T allele SERPINE1 was associated with increased D-dimer levels (OR=1.24; 95% CI = 1.03-1.48; p=0.02).DiscussionOur data suggest that the rs75603675 TMPRSS2 and rs2227692 SERPINE1 polymorphisms are associated with a poor outcome. Additionally, rs2227692 SERPINE1 could participate in hypercoagulable conditions in critical COVID-19 patients, and this genetic variant could contribute to the identification of new pharmacological targets and treatment strategies to block the inhibition of TMPRSS2 entry into SARS-CoV-2.

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“…Such findings further underscore the importance of understanding organ-specific mechanisms—such as lung and liver—that may be responsible for the observed difference. Interestingly, certain single nucleotide polymorphisms (SNPs; rs2070788 and rs383510) that were associated with severe pulmonary damage caused by influenza A(H7N9) in 2014 and influenza A(H1N1) in 2009 are surprisingly the highest in Native American individuals in a worldwide study ( 35 ).…”

Section: Discussionmentioning

confidence: 99%

Disparities in outcomes of COVID-19 hospitalizations in native American individuals

Bime,

Wang,

Carr

et al. 2023

Front. Public Health

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ObjectivesThis study aimed to investigate COVID-19-related disparities in clinical presentation and patient outcomes in hospitalized Native American individuals.MethodsThe study was performed within 30 hospitals of the Banner Health system in the Southwest United States and included 8,083 adult patients who tested positive for SARS-CoV-2 infection and were hospitalized between 1 March 2020 and 4 September 2020. Bivariate and multivariate analyses were used to assess racial and ethnic differences in clinical presentation and patient outcomes.ResultsCOVID-19-related hospitalizations in Native American individuals were over-represented compared with non-Hispanic white individuals. Native American individuals had fewer symptoms at admission; greater prevalence of chronic lung disease in the older adult; two times greater risk for ICU admission despite being younger; and 20 times more rapid clinical deterioration warranting ICU admission. Compared with non-Hispanic white individuals, Native American individuals had a greater prevalence of sepsis, were more likely to require invasive mechanical ventilation, had a longer length of stay, and had higher in-hospital mortality.ConclusionNative American individuals manifested greater case-fatality rates following hospitalization than other races/ethnicities. Atypical symptom presentation of COVID-19 included a greater prevalence of chronic lung disease and a more rapid clinical deterioration, which may be responsible for the observed higher hospital mortality, thereby underscoring the role of pulmonologists in addressing such disparities.

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Human-SARS-CoV-2 interactome and human genetic diversity: TMPRSS2-rs2070788, associated with severe influenza, and its population genetics caveats in Native Americans

Cited by 7 publications

References 11 publications

Genetic Variants within SARS-CoV-2 Human Receptor Genes May Contribute to Variable Disease Outcomes in Different Ethnicities

Genetic Variants within SARS-CoV-2 Human Receptor Genes May Contribute to Variable Disease Outcomes in Different Ethnicities

The fatal contribution of serine protease-related genetic variants to COVID-19 outcomes

Disparities in outcomes of COVID-19 hospitalizations in native American individuals

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