Genetic insights unveil promising therapeutic targets for critical COVID-19 COVID19 Genetics ImmunomodulatoryTherapies TherapeuticTargets Immunometabolism PrecisionMedicine Nature
By Dr. Liji Thomas, MDMay 21 2023Reviewed by Benedette Cuffari, M.Sc. Over 6.93 million deaths have occurred due to critical illness following infection with the severe acute respiratory syndrome coronavirus 2 , the agent responsible for the coronavirus disease 2019 . The lack of reliable predictive markers has made it difficult to triage cases requiring more intensive care before they become critically ill.
More specifically, researchers explored over 24,000 cases of critical COVID-19. Approximately half of these cases belonged to the GenOMICC study, all of which were accompanied by microarray genotypes and whole-genome sequencing data. The remaining samples were from various the ISARIC4C and SCOURGE studies on hospitalized patients with severe or critical COVID-19.
Genome-wide association study results were coupled with transcriptome-wide association study results from a monocyte study of gene expression. This data elucidated whether non-synonymous variants of these genes might affect the structure of the encoded protein. To this end, many of these genes were expressed at high levels in the monocyte-macrophage system.
Generalized summary-level data Mendelian randomization was also used to study both gene and protein expression. To this end, 15 proteins were uniquely linked to critical illness, which is five more than were found in a previous GSMR analysis. Three other genes, all of which could be potential drug targets, were also mutated in association with severe disease. Some of these include the inflammatory signaling JAK1 pathway, PDE4A genes that deal with endothelial permeability, and host factors that encode genes essential for viral entry and replication, such as transmembrane serine protease S2 .
Similar therapeutic implications were found with respect to these lead gene variants, baricitinib, and other drugs that inhibit the tumor necrosis factor signaling pathway to modify the clinical profile in severe COVID-19.
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