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<p>Host genetic variation influencing interferon-γ (IFN-γ) regulation is a critical determinant of immune heterogeneity in COVID-19. We investigated the functional <i>IFNG</i> +874T/A polymorphism (rs2430561), a key regulator of IFN-γ transcription, in 255 PCR-confirmed COVID-19 patients stratified as <i>Outpatient</i> (<i>n</i> = 103), <i>Severe</i> (<i>n</i> = 84), and <i>Critical</i> (<i>n</i> = 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 <i>Outpatient</i> (<i>n</i> = 162), <i>Mild–Moderate</i> (<i>n</i> = 140), and <i>Severe–Critical</i> (<i>n</i> = 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 <i>IFNG</i> +874T/A polymorphism showed significant associations with erythrocyte sedimentation rate under the co-dominant model (<i>p</i> = 0.03) and with hematological parameters, including an increased risk of leukopenia associated with the A allele (<i>p</i> = 0.006) and the AA genotype (<i>p</i> = 0.015). At the systemic level, PBMC-derived transcriptomes from <i>Severe–Critical</i> patients demonstrated coordinated upregulation of <i>IFNG</i>, its regulatory antisense transcript <i>IFNG-AS1</i>, and both IFN-γ receptor subunits (<i>IFNGR1</i> and <i>IFNGR2</i>), 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 <i>IFNGR1</i>, suggesting impaired tissue-level responsiveness to IFN-γ in advanced disease.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月24日

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  • Mohammad Samet,
  • Faezeh Niknam,
  • Masoud Tajamolian,
  • Maryam Karimipanah,
  • Mehran Yazdi,
  • Panteha Abessi,
  • Alireza Nematollahi,
  • Seyed Mehdi Hoseini

摘要

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.