title: X chromosome-linked IRAK-1 polymorphism is a strong predictor of multiple organ failure and mortality postinjury.
abstract: OBJECTIVE
  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.
authors.affiliation: From the Division of Trauma and General Surgery, Department of Surgery, University of Pittsburgh, PA.
authors.forename: Jason L
authors.initials: JL
authors.lastname: Sperry
authors.forename: Samuel
authors.initials: S
authors.lastname: Zolin
authors.forename: Brian S
authors.initials: BS
authors.lastname: Zuckerbraun
authors.forename: Yoram
authors.initials: Y
authors.lastname: Vodovotz
authors.forename: Rami
authors.initials: R
authors.lastname: Namas
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Neal
authors.forename: Robert E
authors.initials: RE
authors.lastname: Ferrell
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Rosengart
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Peitzman
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
mesh_terms: D000328:Adult; D000368:Aged; D041321:Chromosomes, Human, X; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009102:Multiple Organ Failure / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011446:Prospective Studies; D012307:Risk Factors; D018805:Sepsis / Q000235:genetics; D012737:Sex Factors; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism; D014949:Wounds, Nonpenetrating / Q000235:genetics* / Q000276:immunology / Q000401:mortality*
chemical_list: D051193:Toll-Like Receptors; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases