Genetic insights unveil promising therapeutic targets for critical COVID-19

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 (SARS-CoV-2), the agent responsible for the coronavirus disease 2019 (COVID-19). The lack of reliable predictive markers has made it difficult to triage cases requiring more intensive care before they become critically ill.

Study: GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19. Image Credit: Yurchanka Siarhei / Shutterstock.com

About the study

A new study recently published in Nature describes the results of genomic research coupled with meta-analyses of other studies of patients with severe-to-critical COVID-19.

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 (WGS) data. The remaining samples were from various the ISARIC4C and SCOURGE studies on hospitalized patients with severe or critical COVID-19.

To fit the study criteria, patients had to have COVID-19 critical enough to require continuous cardiorespiratory monitoring or organ support.

What did the study show?

About 50 genome-wide associations were associated with critical COVID-19, 16 of which were not previously identified. No sex-specific differences were observed.

Genome-wide association study (GWAS) results were coupled with transcriptome-wide association study (TWAS) 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.

Only common gene variants that can be identified on genotyping arrays and imputation panels were used. The effect of the expressed genes was estimated using three types of cells or tissue.

Critical COVID-19 was significantly associated with the expression of predicted genes in the lungs, blood, and monocytes, as well as those identified in the meta-analysis of all tissues.

Generalized summary-level data Mendelian randomization (GSMR) 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.

The five newly identified proteins include biomarkers of sepsis, such as the mannose-binding lectin-2 (MBL2), which is an innate immune pattern recognition receptor, and myeloperoxidase (MPO), which is a neutrophil effector enzyme.

Others include the ADAMTS13 protein, which is involved in regulating platelet clot formation initiated by the von Willebrand factor. This provides a potential mechanism responsible for the hypercoagulability observed in critical COVID-19.

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 (TMPRSS2). 

Previously, the scientists found an association between the expression of TYK2 and critical illness. This led to the testing of a new biologic, baricitinib, in a clinical trial that yielded results supporting its benefit.

The first proof-of-concept for drug target identification using genetics in critical illness and infectious disease.”

Similar therapeutic implications were found with respect to these lead gene variants, baricitinib, and other drugs that inhibit the tumor necrosis factor (TNF) signaling pathway to modify the clinical profile in severe COVID-19.

TMPRSS2 and the angiotensin-converting enzyme 2 (ACE2) receptor are essential for viral entry into target cells. In addition to TMPRSS2, RAB2A was also found to show genome-wide associations with worsening disease.

What are the implications?

The lead variants identified as being significantly associated with critical COVID-19 in this study are not direct causes of critical illness. Nevertheless, certain molecular mechanisms responsible for COVID-19 may also have an impact on disease outcomes. Host genetics may also provide important information regarding the mechanisms associated with severe COVID-19 and, as a result, assist in the identification of druggable targets.

However, despite the increased power to discover genes associated with critical illness, the study suffers from the combination of genetic signals originating at several stages of illness. Further research should be more diverse to represent the spectrum of humanity.

Together, these results deepen our understanding of the pathogenesis of critical COVID-19 and highlight new biological mechanisms of disease, several of which have immediate potential for therapeutic targeting.”