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

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, <i>IRF1</i>) with ARDS risk and survival and conducted a mediation analysis. Through discovery and validation, we found that the GReX of <i>IRF1</i> was associated with ARDS risk (odds ratio [OR _MEARDS] = 0.84, <i>P</i> = 0.008; OR _MESSI = 0.83, <i>P</i> = 0.034). Furthermore, individual-level measured <i>IRF1</i> expression was associated with reduced ARDS risk (OR = 0.58, <i>P</i> = 8.67 × 10 ^-4), and improved overall survival in ARDS patients (hazard ratio [HR _28-day] = 0.49, <i>P</i> = 0.009) and sepsis patients (HR _28-day = 0.76, <i>P</i> = 0.008). Mediation analysis revealed that <i>IRF1</i> may enhance immune function by regulating the major histocompatibility complex, including <i>HLA-F</i>, which mediated more than 70% of protective effects of <i>IRF1</i> on ARDS. The findings were validated by <i>in vitro</i> biological experiments including time-series infection dynamics, overexpression, knockout, and chromatin immunoprecipitation sequencing. Early prophylactic interventions to activate <i>IRF1</i> in sepsis patients, thereby regulating <i>HLA-F</i>, may reduce the risk of ARDS and mortality, especially in severely ill patients.