IRF9 – COVID‑19 Susceptibility

IRF9 (HGNC:6131) is a key mediator of interferon‐stimulated gene expression and plays a critical role in the antiviral immune response. Large‐scale exome-wide analyses in 586,157 individuals, which included 20,952 COVID‑19 cases (PMID:34115965), did not identify any significant association between rare protein‑coding variants in IRF9 and COVID‑19 susceptibility. Additionally, a targeted case‑control study in Moroccan patients encompassing key genes in the JAK/STAT pathway similarly failed to provide robust genetic evidence supporting the involvement of IRF9 in COVID‑19 (PMID:39647533). No familial segregation data were reported, and the absence of clear genetic signals suggests a limited role for IRF9 in directly predisposing individuals to severe COVID‑19 outcomes.

In contrast, functional studies offer moderate experimental support for the biological relevance of IRF9 in immune modulation. Notably, a study in swine demonstrated that a synonymous variant, c.459A>G (p.Thr153=), was associated with altered serum cytokine levels (PMID:26518782), indicating that even subtle changes in IRF9 may impact interferon signaling dynamics. Although these functional findings provide a plausible mechanistic link, they have not translated into clear genetic associations in human cohorts. Key take‑home: Despite its essential role in antiviral signaling, current genetic evidence does not support IRF9 as a strong predictor of COVID‑19 risk, limiting its immediate clinical utility in diagnostic decision‑making.

References

• American journal of human genetics • 2021 • Pan-ancestry exome-wide association analyses of COVID‑19 outcomes PMID:34115965
• Virus research • 2024 • Association study of the JAK/STAT signaling pathway with susceptibility to COVID‑19 in Moroccan patient and in-silico analysis of rare variants PMID:39647533
• Immunogenetics • 2016 • A genomic variant in IRF9 is associated with serum cytokine levels in pig PMID:26518782

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