Integrative omics and multi-cohort identify IRF1 and biological targets related to sepsis-associated acute respiratory distress syndrome
Jiajin Chen1
Ruili Hou2
Xiaowen Xu2
Ning Xie2
Jiaqi Tang2
Yi Li3
Xiaoqing Nie4
Nuala J.Meyer5
Li Su6
David C.Christiani7
Feng Chen2
Ruyang Zhang8
1.Institute of Cardiovascular Diseases,Xiamen Cardiovascular Hospital of Xiamen University,Xiamen University School of Medicine,Xiamen,Fujian 361006,China;Department of Biostatistics,Center for Global Health,School of Public Health,Nanjing Medical University,Nanjing,Jiangsu 211166,China;China International Cooperation Center for Environment and Human Health,Nanjing Medical University,Nanjing,Jiangsu 211166,China2.Department of Biostatistics,Center for Global Health,School of Public Health,Nanjing Medical University,Nanjing,Jiangsu 211166,China;China International Cooperation Center for Environment and Human Health,Nanjing Medical University,Nanjing,Jiangsu 211166,China3.Department of Biostatistics,University of Michigan,Ann Arbor,MI 48109,USA4.Institute of Cardiovascular Diseases,Xiamen Cardiovascular Hospital of Xiamen University,Xiamen University School of Medicine,Xiamen,Fujian 361006,China5.Pulmonary,Allergy,and Critical Care Medicine Division,University of Pennsylvania Perelman School of Medicine,Philadelphia,PA 19104,USA6.Department of Environmental Health,Harvard T.H.Chan School of Public Health,Boston,MA 02115,USA7.Department of Environmental Health,Harvard T.H.Chan School of Public Health,Boston,MA 02115,USA;Pulmonary and Critical Care Division,Department of Medicine,Massachusetts General Hospital and Harvard Medical School,Boston,MA 02114,USA8.Department of Biostatistics,Center for Global Health,School of Public Health,Nanjing Medical University,Nanjing,Jiangsu 211166,China;China International Cooperation Center for Environment and Human Health,Nanjing Medical University,Nanjing,Jiangsu 211166,China;Changzhou Medical Center,Nanjing Medical University,Changzhou,Jiangsu 213164,China
摘要：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 1 972 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[ORMEARDS]=0.84,P=0.008;ORMESSI=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[HR28-day]=0.49,P=0.009)and sepsis patients(HR28-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.
机标关键词：acuteassociatedbiologicaldistressidentifyintegrativemulti-cohortomics
分类号：R563.8(呼吸系及胸部疾病)
论文发表日期：2026-01-30
在线出版日期：2026-01-29（本平台首次上网日期，不代表文献的发表时间）
页数：12( 11-22 )
英文信息