In a recent study published in the Nature Genetics journal, researchers evaluated the probable impact of the chr12q24.13 domain on the outcomes of laboratory-validated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
The interaction between the pathogen and the host variables determines how the body reacts to pathogens like SARS-CoV-2, the Coronavirus disease 2019 (COVID-19) causative agent. The heterogeneity of clinical outcomes of SARS-CoV-2 infection has encouraged researchers to look for host genetic markers to delineate underlying disease processes and direct optimal therapeutic approaches. Latest genome-wide association studies (GWASs), which compare COVID-19 patients with general public controls, have shown several genetic variants in specific loci linked to vulnerability to SARS-CoV-2 infection in general or severe illness.
The sentinel variant at 12q24.13 for one of the found loci is rs10774671. The locus contains three genes encoding antiviral 2′,5′-oligoadenylate synthetase (OAS) enzymes (OAS3, OAS1, and OAS2), antiviral proteins inducing interferon (IFN) stimulating the ribonuclease L (RNase L) latent form. The RNase L pathway is crucial for the immune reaction to SARS-CoV-2, a ribonucleic acid (RNA) virus.
About the study
In the present work, the researchers compared non-hospitalized versus hospitalized SARS-CoV-2 patients drawn from African and European ancestries to determine whether the locus determining COVID-19 susceptibility at 12q24.13, i.e., the chr12q24.13 area, was connected with SARS-CoV-2 severity. The team revealed functional, genomic, and clinical data of this locus associated with SARS-CoV-2 severity.
In a case-by-case analysis, the authors assessed 3,084 COVNET participants and contrasted non-hospitalized and hospitalized COVID-19 patients, comparing patients with European ancestry (1,035 against 1,214) and African heritage (324 versus 511), respectively. They investigated the functional traits of the OAS1 haplotypes connected to the severity of SARS-CoV-2 infection.
The scientists measured the expression of OAS1 isoforms in multiple RNA-sequence (RNA-seq) data to examine whether the observed OAS1 protein deficit was influenced by genetic control of messenger RNA (mRNA) expression. They conducted a long-read Oxford Nanopore RNA-seq in A549 and HT1376 cells at initiation and after IFN-β treatment to investigate the effects of exon 3 splicing on OAS1 transcripts.
Besides, the team exposed Caco2, infection-permissive intestinal cells (heterozygous for OAS1 rs1131454 and rs10774671) to IFN-λ 4 h or IFN-β pre- and post-SARS-CoV-2 infection to evaluate whether IFN therapy may lessen or prevent viral infection in vitro.
Results and conclusions
A shared OAS1 haplotype made up of derived human-specific risk alleles of two OAS1 variants (rs1131454-A and rs10774671-A) was found to be linked to the likelihood of hospitalized disease in the assessment of 2,249 and 835 patients with European and African ancestries, respectively, with non-hospitalized versus hospitalized COVID-19. Indeed, in a clinical experiment using pegylated IFN-λ1 (PEG IFN-λ1), this OAS1 haplotype was linked to decreased SARS-CoV-2 clearance.
In vitro assessments and bioinformatic evaluations uncovered the functional role of two linked OAS1 exonic variants that make up the risk haplotype. OAS1 protein abundance was decreased by the derived human-specific alleles rs1131454-A and rs10774671-A due to allele-specific control of splicing and nonsense-mediated decay (NMD).
The authors hypothesize that the non-risk alleles rs1131454-G and rs10774671-G of two variants shield OAS1 transcripts against NMD. The rs10774671-G allele, which results in the OAS1-p46 isoform, contributes to the main functional effect.
Meanwhile, rs1131454-G makes an independent and additional contribution by generating an exonic splicing enhancer (ESE) that boosts the addition of long exon 3, thereby preventing NMD from removing either OAS1-p42 or OAS1-p46. Both variants' non-risk G alleles produce the most prevalent OAS1 isoform resistant to NMD, i.e., OAS1-p46-long. Contrarily, while the haplotype containing rs10774671-A but rs1131454-G allele forms the OAS1-p42 isoform exhibiting an intermediate expression and NMD resistance levels, the risk A alleles of two variants produced NMD-suspectable and low-expressed OAS1-p42 isoform.
The investigators conclude that lower OAS1 expression brought on by a shared haplotype via its connection with SARS-CoV-2 clearance and risk of COVID-19 hospitalization contribute to the severity of the disease. The exploratory findings imply that early therapy with pegIFN-λ1 may be able to compensate for the lack of OAS1 expression that causes poor viral clearance in people with the OAS1 risk haplotype, which merits further investigation in clinical trials. Moreover, the study findings shed light on the molecular processes by which early IFN therapy could hasten SARS-CoV-2 clearance and lessen the severity of COVID-19.