X Chromosome-Linked IRAK-1 Polymorphism Is a Strong Predictor of Multiple Organ Failure and Mortality Postinjury

Objective(s):Clinical research characterizing the mechanisms responsible for sex-based outcome differences postinjury remain conflicting. We sought to characterize an X chromosome-linked IRAK-1 (IL-1 receptor-associated kinase) polymorphism as an alternative mechanism responsible for sex differences postinjury. IRAK-1 is key intermediate in the toll-like receptor (TLR) pathway thought to drive inflammation postinjury. Methods:A prospective cohort study was performed over a 24-month period. Bluntly injured patients requiring intensive care unit admission were enrolled, whereas patients with isolated brain and spinal cord injuries were excluded. Outcomes of interest included multiple organ failure (MOF, Marshall MOD score > 5) and mortality. Logistic regression was utilized to determine the independent risk of poor outcome associated with the IRAK-1 variant after controlling for important differences. Results:In an enrolled cohort of 321 patients, the IRAK-1 variant was common (12.5%). Patients with and without the variant were similar in age, injury severity, and 24hr blood transfusion. After controlling for important confounders, the IRAK1 variant was independently associated with more than eightfold (OR = 8.4, P = 0.005, 95% CI: 1.9–37.1) and 11-fold (OR = 11.8, P = 0.037, 95% CI: 1.1–121) greater risk of MOF and mortality, respectively. These differences were most prominent in men, whereas women heterozygous for the variant demonstrated worse outcome in a dose-dependent fashion. Conclusions:The IRAK1 polymorphism is a strong independent predictor of MOF and mortality postinjury and represents a common variant with prognostic potential. These data demonstrate the importance of TLR signaling postinjury and supports that a genetic mechanism may drive sex outcome differences postinjury.

[1]  A. Peitzman,et al.  Characterization of acute coagulopathy and sexual dimorphism after injury: Females and coagulopathy just do not mix , 2012, The journal of trauma and acute care surgery.

[2]  C. Wade,et al.  Admission Rapid Thrombelastography Can Replace Conventional Coagulation Tests in the Emergency Department: Experience With 1974 Consecutive Trauma Patients , 2012, Annals of surgery.

[3]  A. Peitzman,et al.  Racial disparities and sex-based outcomes differences after severe injury. , 2012, Journal of the American College of Surgeons.

[4]  K. Brohi,et al.  Acute traumatic coagulopathy , 2012, Current opinion in anaesthesiology.

[5]  M. Cohen,et al.  Critical Role of Activated Protein C in Early Coagulopathy and Later Organ Failure, Infection and Death in Trauma Patients , 2012, Annals of surgery.

[6]  A. Sauaia,et al.  Initial experiences with point‐of‐care rapid thrombelastography for management of life‐threatening postinjury coagulopathy , 2012, Transfusion.

[7]  John D. Storey,et al.  A genomic storm in critically injured humans , 2011, The Journal of experimental medicine.

[8]  C. Wade,et al.  Rapid thrombelastography delivers real-time results that predict transfusion within 1 hour of admission. , 2011, The Journal of trauma.

[9]  V. Viallon,et al.  IRAK1 functional genetic variant affects severity of septic shock* , 2010, Critical care medicine.

[10]  Vafa Ghaemmaghami,et al.  Changing Epidemiology of Trauma Deaths Leads to a Bimodal Distribution , 2010, Proceedings.

[11]  R. Tompkins,et al.  EARLY ELEVATION IN RANDOM PLASMA IL-6 AFTER SEVERE INJURY IS ASSOCIATED WITH DEVELOPMENT OF ORGAN FAILURE , 2010, Shock.

[12]  A. Sauaia,et al.  Postinjury coagulopathy management: goal directed resuscitation via POC thrombelastography. , 2010, Annals of surgery.

[13]  E. Moore,et al.  Noncitrated whole blood is optimal for evaluation of postinjury coagulopathy with point-of-care rapid thrombelastography. , 2009, The Journal of surgical research.

[14]  I. Chaudry,et al.  Mechanism of hepatoprotection in proestrus female rats following trauma‐hemorrhage: heme oxygenase‐1‐derived normalization of hepatic inflammatory responses , 2009, Journal of leukocyte biology.

[15]  B. Migeon.  X inactivation, female mosaicism, and sex differences in renal diseases. , 2008, Journal of the American Society of Nephrology : JASN.

[16]  Young-Jun Park,et al.  Interleukin‐1 receptor‐associated kinase (IRAK) ‐1‐ mediated NF‐κ activation requires cytosolic and nuclear activity , 2008, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[17]  C. Wade,et al.  Increased mortality associated with the early coagulopathy of trauma in combat casualties. , 2008, The Journal of trauma.

[18]  J. Minei,et al.  Characterization of the gender dimorphism after injury and hemorrhagic shock: Are hormonal differences responsible?* , 2008, Critical care medicine.

[19]  Lesly A. Dossett,et al.  High levels of endogenous estrogens are associated with death in the critically injured adult. , 2008, The Journal of trauma.

[20]  J. Minei,et al.  Gender dimorphism following injury: making the connection from bench to bedside , 2008, Journal of leukocyte biology.

[21]  T. Billiar,et al.  Early events in the recognition of danger signals after tissue injury , 2008, Journal of leukocyte biology.

[22]  A. Peitzman,et al.  Male gender is associated with excessive IL-6 expression following severe injury. , 2008, The Journal of trauma.

[23]  Lesly A. Dossett,et al.  Serum estradiol concentration as a predictor of death in critically ill and injured adults. , 2008, Surgical infections.

[24]  Timothy R Billiar,et al.  Systemic inflammation and end organ damage following trauma involves functional TLR4 signaling in both bone marrow‐derived cells and parenchymal cells , 2008, Journal of leukocyte biology.

[25]  K. Tracey,et al.  Hemorrhagic Shock Induces NAD(P)H Oxidase Activation in Neutrophils: Role of HMGB1-TLR4 Signaling1 , 2007, The Journal of Immunology.

[26]  M. Cohen,et al.  Acute Traumatic Coagulopathy: Initiated by Hypoperfusion: Modulated Through the Protein C Pathway? , 2007, Annals of surgery.

[27]  R. Lefering,et al.  Early coagulopathy in multiple injury: an analysis from the German Trauma Registry on 8724 patients. , 2007, Injury.

[28]  T. Billiar,et al.  EMERGING PARADIGM: TOLL-LIKE RECEPTOR 4-SENTINEL FOR THE DETECTION OF TISSUE DAMAGE , 2006, Shock.

[29]  J. Minei,et al.  Inflammation and the Host Response to Injury, a large-scale collaborative project: patient-oriented research core--standard operating procedures for clinical care. III. Guidelines for shock resuscitation. , 2006, The Journal of trauma.

[30]  E. Abraham,et al.  Variant IRAK-1 haplotype is associated with increased nuclear factor-kappaB activation and worse outcomes in sepsis. , 2006, American journal of respiratory and critical care medicine.

[31]  I. Chaudry,et al.  Gender and susceptibility to sepsis following trauma. , 2006, Endocrine, metabolic & immune disorders drug targets.

[32]  Timothy R Billiar,et al.  Systemic inflammation and remote organ damage following bilateral femur fracture requires Toll-like receptor 4. , 2006, American journal of physiology. Regulatory, integrative and comparative physiology.

[33]  J. Minei,et al.  Inflammation and the Host Response to Injury, a Large-Scale Collaborative Project: patient-oriented research core--standard operating procedures for clinical care. II. Guidelines for prevention, diagnosis and treatment of ventilator-associated pneumonia (VAP) in the trauma patient. , 2006, The Journal of trauma.

[34]  B. Migeon.  The role of X inactivation and cellular mosaicism in women's health and sex-specific diseases. , 2006, JAMA.

[35]  Y. Vodovotz,et al.  Toll-like receptor-4 signaling mediates hepatic injury and systemic inflammation in hemorrhagic shock. , 2006, Journal of the American College of Surgeons.

[36]  I. Chaudry,et al.  GENDER DIFFERENCES IN ACUTE RESPONSE TO TRAUMA-HEMORRHAGE , 2005, Shock.

[37]  Stephen M Cohn,et al.  Predictors of Mortality in Trauma Patients , 2004, The American surgeon.

[38]  J. Platt,et al.  Cutting Edge: An Endogenous Pathway to Systemic Inflammatory Response Syndrome (SIRS)-Like Reactions through Toll-Like Receptor 41 , 2004, The Journal of Immunology.

[39]  B. Migeon.  X chromosome inactivation: theme and variations , 2003, Cytogenetic and Genome Research.

[40]  Mauricio Lynn,et al.  Early coagulopathy predicts mortality in trauma. , 2003, The Journal of trauma.

[41]  David B Hoyt,et al.  Does sexual dimorphism influence outcome of traumatic brain injury patients? The answer is no! , 2003, The Journal of trauma.

[42]  Richard L. George,et al.  The association between gender and mortality among trauma patients as modified by age. , 2003, The Journal of trauma.

[43]  Richard L. George,et al.  Age-Related Gender Differential in Outcome After Blunt or Penetrating Trauma , 2003, Shock.

[44]  T. Fabian,et al.  Does gender difference influence outcome? , 2002, The Journal of trauma.

[45]  D. Hoyt,et al.  Female gender does not protect blunt trauma patients from complications and mortality. , 2002, The Journal of trauma.

[46]  M. Fenton,et al.  Toll-like receptors: a family of pattern-recognition receptors in mammals , 2002, Genome Biology.

[47]  Amer A. Beg,et al.  An Essential Role of the NF-κB/Toll-Like Receptor Pathway in Induction of Inflammatory and Tissue-Repair Gene Expression by Necrotic Cells1 , 2001, The Journal of Immunology.

[48]  D. Spain,et al.  A multicenter evaluation of whether gender dimorphism affects survival after trauma. , 2001, American journal of surgery.

[49]  B. Beutler,et al.  The evolution and genetics of innate immunity , 2001, Nature Reviews Genetics.

[50]  Jerome F. Strauss,et al.  The Extra Domain A of Fibronectin Activates Toll-like Receptor 4* , 2001, The Journal of Biological Chemistry.

[51]  I. Chaudry,et al.  EFFECT OF GENDER AND SEX HORMONES ON IMMUNE RESPONSES FOLLOWING SHOCK , 2000, Shock.

[52]  U. Steckholzer,et al.  Incidence of septic complications and multiple organ failure in severely injured patients is sex specific. , 2000, The Journal of trauma.

[53]  H. Kolb,et al.  Cutting Edge: Heat Shock Protein 60 Is a Putative Endogenous Ligand of the Toll-Like Receptor-4 Complex1 , 2000, The Journal of Immunology.

[54]  J. Marshall.  Organ dysfunction as an outcome measure in clinical trials. , 1999, The European journal of surgery. Supplement. : = Acta chirurgica. Supplement.

[55]  E. Moore,et al.  Male gender is a risk factor for major infections after surgery. , 1999, Archives of surgery.

[56]  E. Faist,et al.  SYSTEMIC INFLAMMATORY RESPONSE SYNDROME (SIRS), MULTIPLE ORGAN DYSFUNCTION SYNDROME (MODS), MULTIPLE ORGAN FAILURE (MOF): ARE WE WINNING THE BATTLE? , 1998, Shock.

[57]  C. Janeway,et al.  A human homologue of the Drosophila Toll protein signals activation of adaptive immunity , 1997, Nature.

[58]  J. Marshall,et al.  Sepsis, SIRS, and MODS: What’s in a Name? , 1996, World Journal of Surgery.

[59]  C. Sprung,et al.  Multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome. , 1995, Critical care medicine.

[60]  R. Goris,et al.  Inflammatory mediators in relation to the development of multiple organ failure in patients after severe blunt trauma. , 1995, Critical care medicine.

[61]  B. Migeon.  X-chromosome inactivation: molecular mechanisms and genetic consequences. , 1994, Trends in genetics : TIG.

[62]  F. Cerra,et al.  Multiple organ failure syndrome. , 1990, Disease-a-month : DM.

[63]  L. Manship,et al.  The influence of sepsis and multisystem and organ failure on mortality in the surgical intensive care unit. , 1984, The American surgeon.

[64]  D. Demetriades,et al.  Sexual dimorphism in trauma? A retrospective evaluation of outcome. , 2003, Injury.

[65]  I. Chaudry,et al.  Gender dimorphism in immune responses following trauma and hemorrhage , 2002, Immunologic research.

[66]  A. Sauaia,et al.  Epidemiology of trauma deaths: a reassessment. , 1993, The Journal of trauma.