In a recent study posted to the medRxiv* preprint server, researchers discovered multiple novel genetic processes underpinning severe coronavirus disease 2019 (COVID-19). For this, they used genome-wide association studies (GWAS) and meta-analyses.
In COVID-19, pulmonary inflammation causes severe disease, resulting in a clinically homogenous extreme phenotype. The current study's authors previously demonstrated that this phenotype was immensely beneficial in the identification of genetic associations in severe COVID-19.
The authors have also identified that immunomodulatory medications have considerable therapeutic benefits in this population, despite the advanced state of COVID-19. Additional genetic findings might lead to the discovery of new therapeutic targets for severe disease modulation.
About the study
In the present study, the scientists depict an updated evaluation of the international Genetics of Mortality in Critical Care (GenOMICC) research. In this new GenOMICC data release study, the researchers incorporated fresh microarray genotyping datasets from 11,325 critically sick COVID-19 patients in Brazil and the United Kingdom (UK).
Further, data from severe COVID-19 cohorts from the SCOURGE and ISARIC4C (Coronavirus Clinical Characterisation Consortium) investigations were also integrated into the study. There were 5,934 and 655 COVID cases from SCOURGE and ISARIC4C, respectively.
Further, confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients needing continuous organ support or cardiorespiratory monitoring were enrolled for the study during 2020 and 2021. Combining the recruited COVID-19 patients and genotyped in the ISARIC4C and GenOMICC after the initial reported GenOMICC GWAS, the scientist performed ancestry-specific GWAS. Integrating these GWAS results, prior GenOMICC GWAS results, and GenOMICC Brazil's data trans-platform and -ancestry meta-analyses within the GenOMICC research was conducted.
Lastly, the team performed detailed meta-analyses to place these novel findings in the context of current information.
Findings and discussions
The results revealed a strong link between Janus kinase 1 (JAK1), a crucial intracellular signaling kinase, and critical COVID-19. JAK1 was activated by various cytokines, including interleukin 6 (IL-6) and type I interferons (IFNs). Like tyrosine kinase 2 (TYK2), which the authors previously documented to be linked with severe SARS-CoV-2, JAK1 was recently found to be an effective therapy in COVID-19. This inference was mainly because JAK inhibitors targeted JAK1. Although the study's genetic data for either gene did not reveal the direction of impact, the therapeutic signal was constant throughout numerous trials, demonstrating the feasibility of utilizing genetics to identify targets in critical illness.
A novel lead variant was identified inside the gene encoding granulocyte-macrophage colony-stimulating factor (GM-CSF), CSF2. GM-CSF was a crucial cytokine in the synthesis and differentiation of myeloid cells such as neutrophils, macrophages, and monocytes.
The authors previously demonstrated that the circulating GM-CSF levels were linked to the severity of COVID-19, indicating its role as a pharmacological target in severe illness. Furthermore, in the current study, the team demonstrated that the low phosphodiesterase 4A (PDE4A) gene expression was linked to critical COVID-19. PDE4A controlled the generation of a variety of inflammatory cytokines from myeloid cells and was a target for many of the current medicines for the treatment of inflammatory illnesses.
In addition to angiotensin-converting enzyme 2 (ACE2), a substantial GWAS relationship in transmembrane serine protease 2 (TMPRSS2) with critical COVID-19 was detected. TMPRSS2 is a crucial host protease that aids viral entry, which the authors previously investigated as a potential gene. This association might be lineage-specific. Further, the RAB2A gene had a substantial GWAS relationship with severe COVID-19, and The World Academy of Sciences (TWAS) data suggests that higher RAB2A expression was linked to worse illness. This gene had high ratings in the authors’ earlier MAIC27 meta-analysis of host genes involved in the SARS-CoV-2 interaction based on clinical and in vitro data. Further, clustered regularly interspaced short palindromic repeats (CRISPR) screen findings showed that RAB2A was necessary for SARS-CoV-2’s replication.
TWAS results suggested fascinating and conflicting effect estimates for anticipated expression of several chemokine receptors such as C-C chemokine receptor type 9 (CCR9), CCR2, CCR1 versus CCR5 and CCR3; IFN-α subtypes such as IFNA8 versus IFNA10; and intercellular adhesion molecules (ICAM) such as ICAM1 versus ICAM5, ICAM3. However, these results must be interpreted cautiously as the molecular process behind the connection is unknown.
The study findings discovered 45 genomic associations with severe SARS-CoV-2, of which 14 were novel genetic relationships. The majority of them were druggable targets in monocyte-macrophage differentiation (CSF2), immunometabolism (SLC2A5, AK5), inflammatory signaling (JAK1, PDE4A), and host factors essential for the entrance of virus and its replication (RAB2A, TMPRSS2). Future investigations should integrate the complete range of human populations as European ancestry contributed to the vast majority of the participants in the current study.
Although focusing on severe COVID-19 improved discovery potential, it has the drawback of merging genetic signals for many phases of disease progression, such as the development of inflammatory lung disease, viral replication, infection, and exposure to the virus. Hence, it was not possible to determine when the causative effect occurs in the disease progression or where it occurs in the body based on these results.
A meta-analysis of numerous research with slightly varying effect sizes and phenotypic definitions was conducted in the study. This, along with ancestry-specific impacts, might account for variation in strong GWAS signals like the LZTFL1 signal. The probability (p)-values among variants in high linkage disequilibrium (LD) appeared more diverse than predicted since various studies contain collections of variants that did not overlap completely.
Overall, similar to the authors' earlier research, the present study provides in-depth knowledge on COVID-19 pathogenesis and sheds light on novel biological processes of the SARS-CoV-2 infection. Thereby, it points to tractable treatment targets for reducing detrimental host-mediated inflammation in SARS-CoV-2.
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.