In a recent study posted to the medRxiv* pre-print server, researchers reported the association of a single nucleotide polymorphism (SNP) rs9984273 in the interferon-alpha/beta receptor (IFNAR2) gene with outcomes of acute respiratory distress syndrome (ARDS) and coronavirus disease 2019 (COVID-19).
They also analyzed the effect of simultaneous steroid and interferon-beta (IFNβ) administration on disease severity.
The SNP rs9984273 is located in the 3’ untranslated region (3’-UTR) of the IFNAR2 gene. It lies in a region that corresponds to a binding site of the glucocorticoid receptor (GR).
Therefore, the presence of this SNP and glucocorticoid use could probably alter IFNAR gene expression. Moreover, previous study reports on glucocorticoid use in managing pulmonary disorders such as ARDS are contradictory.
About the study
In the present study, researchers evaluated the impact of SNP rs9984273 in the outcomes of COVID-19 and ARDS patients managed with intravenous IFNβ-1a. They based their findings on clinical trials and published literature.
The first open-label Phase I/II trial comprised 37 patients diagnosed with ARDS and managed with intravenous IFNβ-1a.
Based on the trial findings, a large-scale international study known as The INTEREST trial was performed comprising 296 patients with moderate to severe ARDS from 74 intensive care units (ICU) between December 2015 and December 2017. These patients were divided into two groups comprising patients who received 10 μg of IFNβ-1a intravenously (n=144) or a placebo (n=152) for six consecutive days. Among these 144 patients, 78 received glucocorticoids concomitantly whereas 66 patients were not administered glucocorticoids.
Serum samples were obtained from the participants for estimating cytokine interleukin-6 (IL-6), and IFN-gamma levels. Additionally, pulmonary specimens were obtained and frozen. The lung tissues were used to extract deoxyribonucleic acid (DNA) for SNP genotyping assays for the detection of the SNPs rs2236757 and rs9984273. The AmpliSeq® panel was used for genomic sequencing of NT5E(CD73), IFNAR (IFNAR2 and IFNAR1 subunits), Minichromosome Maintenance Complex Component 2 (MCM2), Ras Association Domain Family Member 3 (RASSF3), and Angiopoietin 2 (ANGPT2) genes of 232 participants.
Logistic regression modeling inclusive of sex, age, Acute Physiology and Chronic Health Evaluation (APACHE) II score, ARDS severity, concomitant glucocorticoid use with IFNβ-1a, and SNP rs9984273 prevalence was used to assess independent variables contributing to mortality.
Position weight matrices of individual gene regions from the Transfac database and Encode ChIP-seq data were used to detect the probable binding sites of GR and alterations in the rs9984273 polymorphism, respectively.
Moreover, the lung specimens from 14 subjects were subjected to immunohistochemistry (IHC) analysis for investigating the association of the SNP rs9984273 to IFNAR expression. Next, the phosphorylated STAT1 (PSTAT1), STAT1, and STAT2 levels were determined in patients with homozygous CC or TT or heterozygous CT phenotypes, based on the presence of minor C and major T alleles. This analysis was performed using the lung samples cultured with or without hydrocortisone (HC). Two sample donors were excluded from the IHC analysis as they were on corticosteroids at the time of the analysis.
The COVID-19 Host Genetics Initiative genome-wide association study (COVID-19-hg GWAS) meta-analyses round 4 and 6 summary results were used to determine the association of the SNP rs9984273 with COVID-19 severity. In addition, they assessed whether the presence of the minor alleles of rs2236757 A and rs9984273 C correlated with ARDS mortality.
The results showed that the 28-day mortality was 10.6% and 39.7% in patients managed without and with concomitant glucocorticoid administration with IFNβ-1a, respectively. Also, the glucocorticoids inhibited CD73 upregulation and IFN signaling in the pulmonary endothelium.
Based on the Transfac and ChIP-seq analysis findings, SNP rs9984273 was detected in a predicted binding region of GR and altered the binding site, respectively. Patients with CC/CT genotype had lower IL-6, IFNAR2, IFNAR1, STAT2, and IFN-gamma and higher IFNAR, STAT1, pSTAT1 levels compared to those with TT genotype. This indicates that the concomitant administration of glucocorticoids with IFNβ-1a was not injurious if the patients possessed a copy of the C or minor allele.
For all genotypes, the minor allele carriers had significantly decreased disease mortality than non-carriers or those with homozygous major alleles.
To conclude, although both cortisol and IFNβ-1a are important anti-inflammatory agents to mitigate COVID-19, IFNs must be administered earlier than glucocorticoids. The concomitant use of these agents could lead to increased mortality in patients who do not possess the minor alleles of the SNP rs9984273 in IFNAR2 genes. Thus, SNP rs9984273 could be used as a genetic marker of disease severity among ARDS and COVID-19 patients.
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.
Juho Jalkanen, Sofia Khan, Kati Elima, Teppo Huttunen, Ning Wang, Maija Hollmén, Laura L. Elo, Sirpa Jalkanen. (2022). Polymorphism in IFNAR contributes to glucocorticoid response and outcome in ARDS and COVID-19. medRxiv. doi: https://doi.org/10.1101/2022.03.10.22272123 https://www.medrxiv.org/content/10.1101/2022.03.10.22272123v1
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