Genetic and transcriptomic evidence linking IFNG +874T/A and IFN-γ signaling to COVID-19 severity
4 affiliations
- 1Departments of Internal Medicine, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences
- 2Medical Genetics Center, Shahid Sadoughi Hospital, Shahid Sadoughi University of Medical Sciences
- 3Biotechnology Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences
- 4Hematology and Oncology Research Center, Non-Communicable Diseases Research Institut, e, Shahid Sadoughi University of Medical Sciences
Abstract
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.
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BibTeX
@article{samet2026genetic,
title = {{Genetic and transcriptomic evidence linking IFNG +874T/A and IFN-γ signaling to COVID-19 severity}},
author = {Mohammad Samet and Faezeh Niknam and Masoud Tajamolian and Maryam Karimipanah and Mehran Yazdi and Panteha Abessi and Alireza Nematollahi and Seyed Mehdi Hoseini},
journal = {Scientific Reports},
year = {2026},
month = jul,
doi = {10.1038/s41598-026-63412-3},
url = {https://doi.org/10.1038/s41598-026-63412-3},
note = {CC BY},
}
RIS
TY - JOUR
TI - Genetic and transcriptomic evidence linking IFNG +874T/A and IFN-γ signaling to COVID-19 severity
AU - Mohammad Samet
AU - Faezeh Niknam
AU - Masoud Tajamolian
AU - Maryam Karimipanah
AU - Mehran Yazdi
AU - Panteha Abessi
AU - Alireza Nematollahi
AU - Seyed Mehdi Hoseini
PY - 2026
DA - 2026/07/01
JO - Scientific Reports
DO - 10.1038/s41598-026-63412-3
UR - https://doi.org/10.1038/s41598-026-63412-3
AB - 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.
SN - 2045-2322
ER -