AGTR2 absence or antagonism prevents cystic fibrosis pulmonary manifestations

Darrah, Rebecca J.; Jacono, Frank J.; Joshi, Nitin; Mitchell, Anna L.; Sattar, Abdus; Campanaro, Cara K.; Litman, Paul; Frey, J. A.; Nethery, David; Barbato, Eric; Hodges, Craig A.; Corvol, Harriet; Cutting, Garry R.; Knowles, Michael R.; Strug, Lisa J.; Drumm, Mitchell L.

doi:10.1016/j.jcf.2018.05.013

Cited by 19 publications

(15 citation statements)

References 42 publications

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“…Their severity probabilities calculated on sex-age (0.9 and 0.94) do not mirror the relatively mild clinical outcome, which is instead better represented by the severity probability calculated in IPGS only (0.23 and 0.41). Those two patients presented ultra-rare variants in ACE2 gene, likely responsible for reduced viral load [35], and in AGTR2 gene, which reduced activity is known to prevent cystic fibrosis pulmonary manifestation [36].…”

Section: Resultsmentioning

confidence: 99%

Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

Fallerini

Picchiotti

Baldassarri

et al. 2021

Preprint

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The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole exome sequencing data of about 4,000 SARS-CoV-2-positive individuals were used to define an interpretable machine learning model for predicting COVID-19 severity. Firstly, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthly, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management.

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Section: Resultsmentioning

confidence: 99%

Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

Fallerini

Picchiotti

Baldassarri

et al. 2021

Preprint

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“…Gene modifier studies in CF have identified some therapeutic targets. 101 To date no clinical interventions have resulted, however, early trials are underway, which will hopefully result in efficacious new treatments. 101 Another potential application of identifying gene modifiers, that has not been the primary aim, but perhaps represents a missed opportunity, is using them to stratify patients into different risk categories (i.e mild lung disease, severe lung disease).…”

Section: Discussionmentioning

confidence: 99%

Gene modifiers of cystic fibrosis lung disease: A systematic review

Shanthikumar

Neeland

Saffery

et al. 2019

Pediatric Pulmonology

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Background Lung disease is the major source of morbidity and mortality in cystic fibrosis (CF), with large variability in severity between patients. Although accurate prediction of lung disease severity would be extremely useful, no robust methods exist. Twin and sibling studies have highlighted the importance of non‐cystic fibrosis transmembrane conductance regulator (CFTR) genes in determining lung disease severity but how these impact on the severity in CF remains unclear. Methods A systematic review was undertaken to answer the question “In patients with CF which non‐CFTR genes modify the severity of lung disease?” The method for this systematic review was based upon the “Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA)” statement, with a narrative synthesis of results planned. Results A total of 1168 articles were screened for inclusion, with 275 articles undergoing detailed assessment for inclusion. One hundred and forty articles were included. Early studies focused on candidate genes, whereas more recent studies utilized genome‐wide approaches and also examined epigenetic mechanisms, gene expression, and therapeutic response. Discussion A large body of evidence regarding non‐CFTR gene modifiers of lung disease severity has been generated, examining a wide array of genes. Limitations to existing studies include heterogeneity in outcome measures used, limited replication, and relative lack of clinical impact. Future work examining non‐CFTR gene modifiers will have to overcome these limitations if gene modifiers are to have a meaningful role in the care of patients with CF.

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“…Our study revealed that the expression of AGTR2mRNA is less in kidney tissue and the highest in lung tissue, which is tissue-specific. And in 2015 the GWAS study confirmed that the variation of the locus containing AGTR2 on the X chromosome was significantly associated with lung function in patients with cystic fibrosis [28] .In vitro, studies have demonstrated that the deficiency of the AGTR2 gene can normalize the pulmonary function index of mice with cystic pulmonary fibrosis [29] . Overexpression of the AGTR2 receptor can increase pulmonary vascular permeability and worsen pulmonary inflammation in mice with LPS-induced acute lung injury [30] .…”

Section: Fig 6 Schematic Diagram Of Lung Injury Model Mediated By Comentioning

confidence: 98%

Potential Pathogenesis of Multiple Organ Injury in COVID-19

Guo¹,

Yu²,

Li³

et al. 2020

Preprint

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Novel coronavirus (COVID-19) can lead to multiple organ injuries such as acute respiratory distress syndrome (ARDS), acute renal injury (AKI) and so on. ACE2 is an important part of the renin-angiotensin system (RAS) and a key protein needed for COVID-19 to invade cells. First of all, we searched the HPA, GTEx and FANTOM5 Databases and found that the expression of ACE2 in kidney tissue was significantly higher than that in lung tissue. Then, by searching the Nephroseq Database, it is further verified that ACE2 is highly expressed in renal tissue and plays a protective role in renal tissue. However, current studies have found that the incidence of AKI caused by COVID-19 is much lower than that of ARDS. Because of this, we further searched the proteins interacting with ACE2 protein through the STING Database and analyzed the expression of tissue protein mRNA in the HPA Database. It was noted that AGTR2 mRNA was highly expressed in lung tissue, but low in kidney tissue, and hard tissue specificity in lung tissue. Through further research, it is found that AGTR2 plays a major role in the development of pulmonary fibrosis. Therefore, AGTR2 may be a key protein in COVID-19 pneumonia, and AGTR2 may be a potential new therapeutic target for the treatment of COVID-19 patients.

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AGTR2 absence or antagonism prevents cystic fibrosis pulmonary manifestations

Cited by 19 publications

References 42 publications

Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

Gene modifiers of cystic fibrosis lung disease: A systematic review

Potential Pathogenesis of Multiple Organ Injury in COVID-19

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