Neutrophils cause critical illness in COVID-19 and reveal CDK6 inhibitors as potential treatment
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Abstract
Background
Despite recent development of vaccines and monoclonal antibodies to prevent SARS-CoV-2 infection, treatment of critically ill COVID-19 patients remains an important goal. In principle, genome-wide association studies (GWAS) could shortcut the clinical evidence needed to repurpose drugs - the use of an existing drug for a new indication. However, it has been shown that the genes found in GWA studies usually do not encode an established drug target and the causal role for disease, a key requirement for drug efficacy, is unclear. We report here an alternative method for finding and testing causal target candidates for drug repurposing.
Methods
Rather than focusing on the genetics of the disease, we looked for disease-causing traits by searching for significant differences in 33 blood cell types, 30 blood biochemistries, and body mass index between an infectious disease phenotype and healthy controls. We then matched critically ill COVID-19 cases with controls that exhibited mild or no symptoms after SARS-CoV-2 infection in order to identify disease-causing traits by applying causal inference methods.
Results
We found high neutrophil cell count as a causal trait for the immune overreaction in critical illness due to COVID-19. Based on these findings, we identified the enzyme CDK6 as a potential drug target to prevent the immune overreaction in critical illness due to COVID-19.
Conclusions
The genetics of disease-causing traits turns out to be a rich reservoir for the identification of known drug targets. This is due to the usually larger datasets of traits, as they also cover healthy ones. A clinical trial testing CDK6 inhibitor palbociclib in critically ill COVID-19 patients is currently ongoing ( ClinicalTrials.gov Identifier: NCT05371275 ).
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SciScore rigor report
Sciscore is an AI platform that assesses the rigor of the methods used in the manuscript. SciScore assists expert referees by finding and presenting information scattered throughout a manuscript in a simple format.
Not required = Field is not applicable to this study
Not detected = Field is applicable to this study, but not included.
Ethics
IRB: I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Field Sample Permit: The research has been conducted using the UK Biobank Resource and has been approved by the UK Biobank under Application no. 36226.
Consent: I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample …
SciScore rigor report
Sciscore is an AI platform that assesses the rigor of the methods used in the manuscript. SciScore assists expert referees by finding and presenting information scattered throughout a manuscript in a simple format.
Not required = Field is not applicable to this study
Not detected = Field is applicable to this study, but not included.
Ethics
IRB: I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Field Sample Permit: The research has been conducted using the UK Biobank Resource and has been approved by the UK Biobank under Application no. 36226.
Consent: I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.
Inclusion and Exclusion Criteria
Similarly , individuals where a large proportion of SNPs could not be measured were excluded.
Attrition
not detected.
Sex as a biological variable
not detected.
Subject Demographics
Age: not detected.
Weight: not detected.
Randomization
Mendelian randomization ( MR ) is a robust and accessible tool to examine the causal relationship between an exposure variable and an outcome from GWAS summary statistics. [ 19 ] We employed two-sample summary data Mendelian randomization to further validate causal effects of neutrophil cell count genes on the outcome of critical illness due to COVID-19
Blinding
not detected.
Power Analysis
not detected.
Replication
not required.
Data Information
Identifiers: medRxiv preprint doi: https:// doi.org/10.1101/2021.05.18.21256584; this version posted February 14 , 2022 . https://doi.org/10.1101/2021.05.18.21256584
Identifiers: Manhattan plot of neutrophil cell count showing that we reproduce the reported CDK6 signal ( rs445 ) on chromosome 7 . rs445
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SciScore for 10.1101/2021.05.18.21256584: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Software and Algorithms Sentences Resources Variants reported by Pairo-Castineira et al.8 and Ellinghaus et al.7 as well as variants reported by the ClinVar database35 for the genes reported by the papers were included in the dataset. ClinVarsuggested: (ClinVar, RRID:SCR_006169)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from Tr…
SciScore for 10.1101/2021.05.18.21256584: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Software and Algorithms Sentences Resources Variants reported by Pairo-Castineira et al.8 and Ellinghaus et al.7 as well as variants reported by the ClinVar database35 for the genes reported by the papers were included in the dataset. ClinVarsuggested: (ClinVar, RRID:SCR_006169)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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