COVID-19 Genetic Risk Variants Significantly Associated With The Expression Of 11 Protein-Coding Genes That Impact Immune Cell Types And Disease Severity

COVID-19 genetic risk variants significantly associated with the expression of 11 protein-coding genes that impact immune cell types and COVID-19 disease severity were identified in a new study by researchers from La Jolla Institute for Immunology-California and the University of California San Diego.


 
In the study abstract, the researchers said that common genetic polymorphisms associated with severity of COVID-19 illness can be utilized for discovering molecular pathways and cell types driving disease pathogenesis.
 
The study team assessed the effects of 679 COVID-19-risk variants on gene expression in a wide-range of immune cell types. Severe COVID-19-risk variants were significantly associated with the expression of 11 protein-coding genes, and overlapped with either target gene promoter or cis-regulatory regions that interact with target promoters in the cell types where their effects are most prominent.
 
For instance, the team identified that the association between variants in the 3p21.31 risk locus and the expression of CCR2 in classical monocytes is likely mediated through an active cis-regulatory region that interacted with CCR2 promoter specifically in monocytes. The expression of several other genes showed prominent genotype-dependent effects in non-classical monocytes, NK cells, B cells, or specific T cell subtypes, highlighting the potential of COVID-19 genetic risk variants to impact the function of diverse immune cell types and influence severe disease manifestations.
 
The study findings were published on a preprint server but are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2020.12.01.407429v1
 
Presently, the clinical manifestations of COVID-19 disease ranges from mild flu-like symptoms in many patients to severe respiratory failure and death in patients with comorbidities. Though studies have shown correlations between hyperactivation of the immune system and the formation of a cytokine storm in patients with severe COVID-19, the host genetic factors that rule these immune events and determine the susceptibility of some patients to severe disease is not well understood till now.
 
To rectify this lack of information, genome-wide association studies (GWAS) have been performed, and they have identified several genetic variants linked to COVID-19 susceptibility and severity.
 
But even then, the genes they target and the immune cell types most affected by these variants were not fully clear till now.
 
Importantly identifying common genetic polymorphisms linked to the severity of COVID-19 disease can help uncover molecular pathways and immune cell types that drive COVID-19 pathogenesis.
 
The DICE database of immune cell gene expression, epigenomics, and expression quantitative trait loci (eQTLs) was created to answer such questions and to help specify the functional variants in dense haploblocks associated with disease susceptibility.
 
The study team used the DICE database and 3D cis-interactome maps to generate a list of target genes and immune cell types that are most affected by the genetic variants associated with COVID-19 severity.
 
The study team systematically assessed the effects of 679 COVID-19-risk variants (as defined by the COVID-19 Host Genetics Initiative) on gene expression in 13 immune cell types and two activation conditions.
 
Importantly the expression of 11 protein-coding genes and one non-coding RNA or eGenes was linked to the genetic variants associated with severe COVID-19 requiring hospitalization. Interestingly, most of the eGenes linked to severe illness showed noticeable effects in specific immune cell types.
 
Also on applying a more liberal GWAS association P value threshold of 1 x 10-5, the researchers identified 41 additional eGenes linked to genetic variants non-significantly associated with severe COVID-19. Some of these variants might reach statistical significance as more donors with severe illness are included in the subsequent phases of the analysis.
 
The study findings show links between genetic variants and gene expression in specific immune cell types.
 
The study findings show that severe COVID-19-risk variants were significantly linked to the expression of 11 protein-coding genes and overlapped with cis-regulatory or target gene promoter regions that interact with target promoters in the immune cell types where their effects are most noticeable.
 
The study team identified that the links between variants in the 3p21.31 risk locus and CCR2 expression in classical monocytes are likely mediated via an active cis-regulatory region that interacted with CCR2 promoter in monocytes.
 
The severe COVID-19-risk variants in the 3p21.31 locus contains 17 known protein-coding genes including SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6, XCR1, CCR1, CCR3, CCR2 and CCR5. Among these genes CCR2 (encoding for C-C type chemokine receptor, also known as monocyte chemoattractant protein 1 receptor) expression showed the strongest association with 3p21.31 severe COVID-19-risk variants identified by GWAS studies. Importantly, the risk variants were associated with expression of CCR2 in certain CD4+ memory T cell subsets (TH17, TH1/17) and classical monocytes. https://pubmed.ncbi.nlm.nih.gov/32404885/
 
Defects in the type 1 interferon pathway have been reported in patients with severe COVID-19 illness. https://pubmed.ncbi.nlm.nih.gov/32972996/
 
https://pubmed.ncbi.nlm.nih.gov/32661059/
 
https://pubmed.ncbi.nlm.nih.gov/32972995/
 
The study team found many severe COVID-19-risk variants in chromosome 21, overlapping the IFNAR2 gene that encodes for interferon receptor 2, were associated with the expression of IFNAR2 in multiple immune cell types. H3K27ac HiChIP-based chromatin interaction maps in this locus showed that the severe COVID-19- risk variants overlapping the IFNAR2 gene promoter and an intronic enhancer interacted with the promoter of a neighboring gene, IL10RB and also influenced its expression levels. The effects of these risk variants were most prominent in NK cells (rs2284551, adj. association P value = 8.99x10-7 ). IL10RB, encodes for IL-10 receptor beta, and given the immunomodulatory role of IL-1016, it is likely that the lower expression on the IL10RB in NK cells may perturb their responsiveness to IL-10.
 
Hence the findings point to a potentially important role for IL-10 signaling and NK cells in influencing susceptibility to severe COVID-19 illness.
 
Also the expression of two interferon-inducible genes (OAS1 and OAS3) was also influenced by severe COVID-19-risk variants in chromosome 12. OAS1 and OAS3, encode for oligoadenylate synthase family of proteins that degrades viral RNA and activate antiviral responses. https://pubmed.ncbi.nlm.nih.gov/18575461/
 
OAS1 showed a peak COVID-19-risk eQTL (rs2057778, adj. association P value = 1.77x10-7 ) specifically in patrolling non-classical monocytes, whereas OAS3 showed prominent eQTLs in T cells, further highlighting cell-type-restricted effects of severe COVID-19-risk variants.
 
Significantly, the study team found that a severe COVID-19-risk variant (rs2010604, adj. association P value = 4.50x10-2 ) in the OAS1/OAS3 locus also influenced the expression of a neighboring gene (DTX1) specifically in naïve B cells.
 
Active chromatin interaction maps in naïve B cells showed that a cisregulatory region near the eQTL (rs2010604) interacts with the promoter of DTX1, located >80kb away, and likely modulates its transcriptional activity. This notion is supported by recent reports showing that promoters can interact with neighboring gene promoters and regulate their expression. https://pubmed.ncbi.nlm.nih.gov/29673772/
 
DTX1, encodes for a ubiquitin ligase Deltex1 that regulates NOTCH activity in B cells. Deltex1 has also been shown to promote anergy, a functionally hypo-responsive state, in T cells; if Deltex1 has a similar function in B cells, then genetic modulation of DTX1 levels may have a profound impact on the function of B cells in COVID-19 illness. https://pubmed.ncbi.nlm.nih.gov/19592273/
 
Several COVID-19 risk variants located in the promoter region of TCF19 were associated with its expression in multiple lymphocyte subsets but not in classical or non-classical monocytes. TCF19 encodes for a transcription factor. TCF19 that has been shown to regulate activation of T cells and also involved in cell proliferation.  A noteworthy example of a highly cell-specific severe COVID-19-risk eGene in regulatory T cells (TREG) was PDE4A. https://pubmed.ncbi.nlm.nih.gov/23396170/
 
https://onlinelibrary.wiley.com/doi/abs/10.1002/cbin.11189
 
https://pubmed.ncbi.nlm.nih.gov/23860123/
 
This gene encodes for phosphodiesterase 4A, which has been shown to reduce the levels of cAMP, and thus influence T cell activity to module immune responses. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4896925/
 
The study findings point to a potentially important role for IL-10 signaling and NK cells in influencing susceptibility to severe COVID-19 illness.
 
Significantly the expression of many other genes suggested the presence of distinct genotype-dependent effects in non-classical monocytes, B cells, NK cells, or specific T cell subtypes. This highlights the possibility of COVID-19 risk variants impacting the function of various immune cell types and influencing severe COVID-19 manifestations.
 
The study shows that genetic polymorphism data can help define pathways and cell types that drive COVID-19 pathogenesis
 
Many genetic risk variants of severe COVID-19 show immune cell-type-restriction of their impact on gene expression and thus may have the potential to affect the function of various immune cell types and genetic pathways.
 
The study tea says that their analysis of eQTLs and cis-interaction maps in diverse immune cell types enabled a definition of the immune cell types and genes that drive susceptibility to severe COVID-19 disease, which possibly contributes to the difference in clinical outcomes.
 
The study team concluded, “The research findings highlights how information about common genetic polymorphisms can be used to define molecular pathways and cell types that play a role in disease pathogenesis.”
 
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