Integrative omics and multi-cohort identify IRF1 and biological targets related to sepsis-associated acute respiratory distress syndrome

Abstract

Interferon-related genes are involved in antiviral responses, inflammation, and immunity, which are closely related to sepsis-associated acute respiratory distress syndrome (ARDS). We analyzed 1972 participants with genotype data and 681 participants with gene expression data from the Molecular Epidemiology of ARDS (MEARDS), the Molecular Epidemiology of Sepsis in the ICU (MESSI), and the Molecular Diagnosis and Risk Stratification of Sepsis (MARS) cohorts in a three-step study focusing on sepsis-associated ARDS and sepsis-only controls. First, we identified and validated interferon-related genes associated with sepsis-associated ARDS risk using genetically regulated gene expression (GReX). Second, we examined the association of the confirmed gene (interferon regulatory factor 1, IRF1) with ARDS risk and survival and conducted a mediation analysis. Through discovery and validation, we found that the GReX of IRF1 was associated with ARDS risk (odds ratio [OR_MEARDS] = 0.84, P = 0.008; OR_MESSI = 0.83, P = 0.034). Furthermore, individual-level measured IRF1 expression was associated with reduced ARDS risk (OR = 0.58, P = 8.67 × 10⁻⁴), and improved overall survival in ARDS patients (hazard ratio [HR_28-day] = 0.49, P = 0.009) and sepsis patients (HR_28-day = 0.76, P = 0.008). Mediation analysis revealed that IRF1 may enhance immune function by regulating the major histocompatibility complex, including HLA-F, which mediated more than 70% of protective effects of IRF1 on ARDS. The findings were validated by in vitro biological experiments including time-series infection dynamics, overexpression, knockout, and chromatin immunoprecipitation sequencing. Early prophylactic interventions to activate IRF1 in sepsis patients, thereby regulating HLA-F, may reduce the risk of ARDS and mortality, especially in severely ill patients.

Keywords

acute respiratory distress syndrome / sepsis / interferon regulatory factor 1 / causal inference / immunity

Funding

This study was supported by the National Natural Science Foundation of China (Grant No. 82220108002 to F.C. and Grant No. 82273737 to R.Z.), the U.S. National Institutes of Health (Grant Nos. CA209414, HL060710, and ES000002 to D.C.C.; Grant Nos. CA209414 and CA249096 to Y.L.), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD). R.Z. was partially supported by the Qing Lan Project of the Higher Education Institutions of Jiangsu Province and the Outstanding Young Level Academic Leadership Training Program of Nanjing Medical University.

Acknowledgments

The authors thank the patients and investigators who participated in MEARDS, MESSI, and MARS for providing the data, and the researchers who provided original experimental data.

Additional information

The online version contains supplementary material available at http://www.jbr-pub.org.cn/article/doi/10.7555/JBR.39.20250066.

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