Genetic and transcriptomic evidence linking IFNG +874T/A and IFN-γ signaling to COVID-19 severity

Host genetic variation influencing interferon-γ (IFN-γ) regulation is a critical determinant of immune heterogeneity in COVID-19. We investigated the functional IFNG +874T/A polymorphism (rs2430561), a key regulator of IFN-γ transcription, in 255 PCR-confirmed COVID-19 patients stratified as Outpatient ( n = 103), Severe ( n = 84), and Critical ( n = 68). In parallel, systems-level transcriptomic analyses were conducted using publicly available GEO datasets, including pseudobulk RNA-sequencing of 406 peripheral blood mononuclear cell (PBMC) samples from GSE196198, GSE221066, and GSE300696, categorized into Outpatient ( n = 162), Mild–Moderate ( n = 140), and Severe–Critical ( n = 104) groups, as well as single-nucleus RNA-sequencing of lung tissue from 20 COVID-19 decedents and 7 controls (GSE171524). Genotype-based analyses revealed no significant differences across clinical severity groups under multiple inheritance models. However, the IFNG +874T/A polymorphism showed significant associations with erythrocyte sedimentation rate under the co-dominant model ( p = 0.03) and with hematological parameters, including an increased risk of leukopenia associated with the A allele ( p = 0.006) and the AA genotype ( p = 0.015). At the systemic level, PBMC-derived transcriptomes from Severe–Critical patients demonstrated coordinated upregulation of IFNG , its regulatory antisense transcript IFNG-AS1 , and both IFN-γ receptor subunits ( IFNGR1 and IFNGR2 ), indicating preserved transcriptional competence of the IFN-γ signaling axis as disease severity increased. In contrast, lung tissue transcriptomes from COVID-19 decedents did not exhibit parallel activation of the IFN-γ pathway and instead showed modest downregulation of IFNGR1 , suggesting impaired tissue-level responsiveness to IFN-γ in advanced disease.