IL10RB as a key regulator of COVID-19 host susceptibility and severity
Abstract
Background
Recent efforts have identified genetic loci that are associated with coronavirus disease 2019 (COVID-19) infection rates and disease outcome severity. Translating these genetic findings into druggable genes and readily available compounds that reduce COVID-19 host susceptibility is a critical next step.
Methods
We integrate COVID-19 genetic susceptibility variants, multi-tissue genetically regulated gene expression (GReX) and perturbargen signatures to identify candidate genes and compounds that reverse the predicted gene expression dysregulation associated with COVID-19 susceptibility. The top candidate gene is validated by testing both its GReX and observed blood transcriptome association with COVID-19 severity, as well as byin vitroperturbation to quantify effects on viral load and molecular pathway dysregulation. We validate thein silicodrug repositioning analysis by examining whether the top candidate compounds decrease COVID-19 incidence based on epidemiological evidence.
Results
We identifyIL10RBas the top key regulator of COVID-19 host susceptibility. Predicted GReX up-regulation ofIL10RBand higherIL10RBexpression in COVID-19 patient blood is associated with worse COVID-19 outcomes.In vitroIL10RB overexpression is associated with increased viral load and activation of immune-related molecular pathways. Azathioprine and retinol are prioritized as candidate compounds to reduce the likelihood of testing positive for COVID-19.
Conclusions
We establish an integrative data-driven approach for gene target prioritization. We identify and validateIL10RBas a suitable molecular target for modulation of COVID-19 host susceptibility. Finally, we provide evidence for a few readily available medications that would warrant further investigation as drug repositioning candidates.
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