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

Overview

Journal Ann Surg

Specialty General Surgery

Date 2014 Sep 10

PMID 25203887

Citations 16

Authors

Jason L Sperry

Samuel Zolin

Brian S Zuckerbraun

Yoram Vodovotz

Rami Namas

Matthew D Neal

Robert E Ferrell

Matthew R Rosengart

Andrew B Peitzman

Timothy R Billiar

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

A putative "chemokine switch" that regulates systemic acute inflammation in humans.

Azhar N, Namas R, Almahmoud K, Zaaqoq A, Malak O, Barclay D Sci Rep. 2021; 11(1):9703.

PMID: 33958628 PMC: 8102583. DOI: 10.1038/s41598-021-88936-8.

Perspectives and Challenges in the Fight Against COVID-19: The Role of Genetic Variability.

Guilger-Casagrande M, de Barros C, Antunes V, de Araujo D, Lima R Front Cell Infect Microbiol. 2021; 11:598875.

PMID: 33791232 PMC: 8005637. DOI: 10.3389/fcimb.2021.598875.

Metabolic Profiling of a Porcine Combat Trauma-Injury Model Using NMR and Multi-Mode LC-MS Metabolomics-A Preliminary Study.

Laserna A, Lai Y, Fang G, Ganapathy R, Atan M, Lu J Metabolites. 2020; 10(9).

PMID: 32948079 PMC: 7570375. DOI: 10.3390/metabo10090373.

Polymorphism Is Associated With Altered Systemic Inflammation and Adverse Trauma Outcomes.

Schimunek L, Namas R, Yin J, Barclay D, Liu D, El-Dehaibi F Front Genet. 2019; 10:1115.

PMID: 31781170 PMC: 6857553. DOI: 10.3389/fgene.2019.01115.

Directional X Chromosome Skewing of White Blood Cells from Subjects with Heterozygous Mosaicism for the Variant IRAK1 Haplotype.

Morcillo P, Qin Y, Pena G, Mosenthal A, Livingston D, Spolarics Z Inflammation. 2019; 43(1):370-381.

PMID: 31748848 DOI: 10.1007/s10753-019-01127-6.

References

Mollen K, Levy R, Prince J, Hoffman R, Scott M, Kaczorowski D . Systemic inflammation and end organ damage following trauma involves functional TLR4 signaling in both bone marrow-derived cells and parenchymal cells. J Leukoc Biol. 2007; 83(1):80-8. DOI: 10.1189/jlb.0407201. View

Yokoyama Y, Schwacha M, Samy T, Bland K, Chaudry I . Gender dimorphism in immune responses following trauma and hemorrhage. Immunol Res. 2002; 26(1-3):63-76. DOI: 10.1385/ir:26:1-3:063. View

Holcomb J, Minei K, Scerbo M, Radwan Z, Wade C, Kozar R . Admission rapid thrombelastography can replace conventional coagulation tests in the emergency department: experience with 1974 consecutive trauma patients. Ann Surg. 2012; 256(3):476-86. DOI: 10.1097/SLA.0b013e3182658180. View

MIGEON B . X chromosome inactivation: theme and variations. Cytogenet Genome Res. 2003; 99(1-4):8-16. DOI: 10.1159/000071568. View

MIGEON B . X-chromosome inactivation: molecular mechanisms and genetic consequences. Trends Genet. 1994; 10(7):230-5. DOI: 10.1016/0168-9525(94)90169-4. View

Brohi K, Cohen M, Ganter M, Matthay M, Mackersie R, Pittet J . Acute traumatic coagulopathy: initiated by hypoperfusion: modulated through the protein C pathway?. Ann Surg. 2007; 245(5):812-8. PMC: 1877079. DOI: 10.1097/01.sla.0000256862.79374.31. View

Cohen M, Call M, Nelson M, Calfee C, Esmon C, Brohi K . Critical role of activated protein C in early coagulopathy and later organ failure, infection and death in trauma patients. Ann Surg. 2011; 255(2):379-85. PMC: 3549308. DOI: 10.1097/SLA.0b013e318235d9e6. View

Medzhitov R, Preston-Hurlburt P, Janeway Jr C . A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature. 1997; 388(6640):394-7. DOI: 10.1038/41131. View

Okamura Y, Watari M, Jerud E, Young D, Ishizaka S, Rose J . The extra domain A of fibronectin activates Toll-like receptor 4. J Biol Chem. 2001; 276(13):10229-33. DOI: 10.1074/jbc.M100099200. View

10.

Wohltmann C, Franklin G, Boaz P, Luchette F, Kearney P, Richardson J . A multicenter evaluation of whether gender dimorphism affects survival after trauma. Am J Surg. 2001; 181(4):297-300. DOI: 10.1016/s0002-9610(01)00582-7. View

11.

Liu G, Park Y, Abraham E . Interleukin-1 receptor-associated kinase (IRAK) -1-mediated NF-kappaB activation requires cytosolic and nuclear activity. FASEB J. 2008; 22(7):2285-96. DOI: 10.1096/fj.07-101816. View

12.

Sauaia A, Moore F, Moore E, Moser K, Brennan R, Read R . Epidemiology of trauma deaths: a reassessment. J Trauma. 1995; 38(2):185-93. DOI: 10.1097/00005373-199502000-00006. View

13.

Sperry J, Nathens A, Frankel H, Vanek S, Moore E, Maier R . Characterization of the gender dimorphism after injury and hemorrhagic shock: are hormonal differences responsible?. Crit Care Med. 2008; 36(6):1838-45. DOI: 10.1097/CCM.0b013e3181760c14. View

14.

CARRICO C, Meakins J, Marshall J, Fry D, Maier R . Multiple-organ-failure syndrome. Arch Surg. 1986; 121(2):196-208. DOI: 10.1001/archsurg.1986.01400020082010. View

15.

Roumen R, Redl H, Schlag G, Zilow G, Sandtner W, Koller W . Inflammatory mediators in relation to the development of multiple organ failure in patients after severe blunt trauma. Crit Care Med. 1995; 23(3):474-80. DOI: 10.1097/00003246-199503000-00010. View

16.

Yang S, Hu S, Chen J, Choudhry M, Rue 3rd L, Bland K . Mechanism of hepatoprotection in proestrus female rats following trauma-hemorrhage: heme oxygenase-1-derived normalization of hepatic inflammatory responses. J Leukoc Biol. 2009; 85(6):1015-26. PMC: 2698585. DOI: 10.1189/jlb.0508288. View

17.

Kashuk J, Moore E, Sawyer M, Le T, Johnson J, Biffl W . Postinjury coagulopathy management: goal directed resuscitation via POC thrombelastography. Ann Surg. 2010; 251(4):604-14. DOI: 10.1097/SLA.0b013e3181d3599c. View

18.

Niles S, McLaughlin D, Perkins J, Wade C, Li Y, Spinella P . Increased mortality associated with the early coagulopathy of trauma in combat casualties. J Trauma. 2008; 64(6):1459-63. DOI: 10.1097/TA.0b013e318174e8bc. View

19.

Kashuk J, Moore E, Wohlauer M, Johnson J, Pezold M, Lawrence J . Initial experiences with point-of-care rapid thrombelastography for management of life-threatening postinjury coagulopathy. Transfusion. 2011; 52(1):23-33. DOI: 10.1111/j.1537-2995.2011.03264.x. View

20.

Sperry J, Friese R, Frankel H, West M, Cuschieri J, Moore E . Male gender is associated with excessive IL-6 expression following severe injury. J Trauma. 2008; 64(3):572-8. DOI: 10.1097/TA.0b013e3181650fdf. View