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X-Chromosome Linked IRAK1 Polymorphism Is Strong Predictor Of Multiple Organ Failure And Mortality Post-Injury
Jason Sperry*, Brian Zuckerbraun*, Samuel Zolin*, Yorum Vodovotz*, Rami Namas*, Andrew Peitzman, Robert Ferrell*, Timothy Billiar
University of Pittsburgh, Pittsburgh, PA
OBJECTIVE(S): Clinical research characterizing the mechanisms responsible for gender based outcome differences post-injury remain conflicting. We sought characterize an x-chromosome linked IRAK1 polymorphism as an alternative mechanism responsible for gender differences post-injury. IRAK1 is key intermediate in the Toll Like Receptor (TLR) pathway thought to drive inflammation post-injury.
METHODS: A prospective cohort study was performed over an 18 month period. Blunt injured patients requiring ICU admission were enrolled while patients with isolated brain and spinal cord injuries were excluded. Outcomes of interest included Multiple Organ Failure (MOF, Mashall MODscore > 5) and mortality. Logistic regression was utilized to determine the independent risk of poor outcome associated with the IRAK1 variant after controlling for differences in injury and shock severity.
RESULTS: In an cohort of 272 patients, the prevalence of the IRAK1 variant was 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 over a 6-fold (OR 6.4; 95% CI1.8-23) and 5-fold (OR 5.8; 95% CI1.4-24) greater risk of MOF and mortality, respectively. These differences were most prominent in males, while females 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 post-injury and represents a common variant with prognostic potential. These data demonstrate the importance of TLR signaling post-injury and supports that a genetic mechanism may drive gender outcome differences post-injury.
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