Integrative omics and multi-cohort identify IRF1 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 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 (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 (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 activate immune functions by regulating the major histocompatibility complex, including HLA-F, which mediated over 70% of the protective effects of IRF1 on ARDS. The findings were validated by in vitro biological experiments involving time-series infection dynamics, overexpression, knockout, and chromatin immunoprecipitation sequencing. Early prophylactic interventions to activate IRF1 in sepsis patients, thereby regulating HLA-F, might reduce the risk of ARDS development and mortality, especially in severely illness patients.