TY - JOUR
T1 - Sex-based differences in the genomic response, innate immunity, organ dysfunction, and clinical outcomes after severe blunt traumatic injury and hemorrhagic shock
AU - Lopez, Maria Cecelia
AU - Efron, Phillip A.
AU - Ozrazgat-Baslanti, Tezcan
AU - Zhang, Jianyi
AU - Cuschieri, Joseph
AU - Maier, Ronald V.
AU - Minei, Joseph P.
AU - Baker, Henry V.
AU - Moore, Frederick A.
AU - Moldawer, Lyle L.
AU - Brakenridge, Scott C.
N1 - Funding Information:
This project was supported by funding from the National Institutes of Health, National Institute for General Medical Sciences, including the Inflammation and Host Response to Injury Large-Scale Collaborative Research Program (NIH/NIGMS, U54 GM062119), awarded to Dr Ronald G Tompkins. SCB, TB, JZ, HVB, FA, LLM, and PAE were additionally supported by funding awarded to the University of Florida Sepsis and Critical Illness Research Center (NIH/NIGMS, P50 GM111152-01), awarded to Dr Frederick A Moore. This work was also supported by NIH grants T32 GM-08431, R01 GM-40586-24, R01 GM-081923-06, and ci GM-113945 awarded by the NIGMS. Additionally, SCB was funded with support from the University of Florida Claude D. Pepper Older Americans Independence Center (2P30AG028740).
Publisher Copyright:
© 2016 Wolters Kluwer Health, Inc.
PY - 2016/9/1
Y1 - 2016/9/1
N2 - INTRODUCTION The effect of sex on posttraumatic pathophysiology and outcomes after severe traumatic injury remains debated. We sought to determine the relationship of sex to the genomic and inflammatory responses, and clinical outcomes after hemorrhagic shock. METHODS We analyzed blunt trauma patients in hemorrhagic shock from a prospective multi-institutional cohort study to assess for sex-based differences in the genomic response and clinical outcomes. Serially drawn blood samples were analyzed to evaluate peripheral leukocyte genomewide expression and circulating inflammatory mediators at intervals between 0.5 and 28 days after injury. Multivariate logistic regression models were developed to assess the effect of sex on outcomes after controlling for age, injury and shock severity, blood transfusion, and comorbidities. RESULTS The cohort consisted of 1,285 (67%) male and 643 (33%) female blunt trauma patients. Injury and shock severity were similar between the two groups. There were small but statistically significant differences between males and females regarding their age, body mass index, and 12-hour blood and crystalloid administration. Organ failure was more severe in males, with slower recovery (9.0 vs. 6.5 days) in males compared to females (p < 0.01). However, there were no differences between males and females in plasma levels of IL-6, IL-8, IL-10, IL-1β, tumor necrosis factor alpha, and monocyte chemoattractant protein 1. Multivariate analysis revealed that sex was not a significant independent risk factor for complicated recovery or 28-day mortality. Transcriptomic analysis revealed 333 genes with significant differential expression patterns between males and females (FDR, <0.001), including genes associated with general inflammation, innate immunity, cell adhesion, and cell signaling. None of the former genes were directly associated with sex hormones or X/Y chromosomes. CONCLUSION There are sex-specific differences in the leukocyte genomic response to severe injury that are associated with more robust and longer-duration organ dysfunction. However, these expression patterns do not seem to be associated with sex-linked genes or circulating cytokine level differences, and do not translate to worsened sex-specific organ failure outcomes or inpatient mortality.
AB - INTRODUCTION The effect of sex on posttraumatic pathophysiology and outcomes after severe traumatic injury remains debated. We sought to determine the relationship of sex to the genomic and inflammatory responses, and clinical outcomes after hemorrhagic shock. METHODS We analyzed blunt trauma patients in hemorrhagic shock from a prospective multi-institutional cohort study to assess for sex-based differences in the genomic response and clinical outcomes. Serially drawn blood samples were analyzed to evaluate peripheral leukocyte genomewide expression and circulating inflammatory mediators at intervals between 0.5 and 28 days after injury. Multivariate logistic regression models were developed to assess the effect of sex on outcomes after controlling for age, injury and shock severity, blood transfusion, and comorbidities. RESULTS The cohort consisted of 1,285 (67%) male and 643 (33%) female blunt trauma patients. Injury and shock severity were similar between the two groups. There were small but statistically significant differences between males and females regarding their age, body mass index, and 12-hour blood and crystalloid administration. Organ failure was more severe in males, with slower recovery (9.0 vs. 6.5 days) in males compared to females (p < 0.01). However, there were no differences between males and females in plasma levels of IL-6, IL-8, IL-10, IL-1β, tumor necrosis factor alpha, and monocyte chemoattractant protein 1. Multivariate analysis revealed that sex was not a significant independent risk factor for complicated recovery or 28-day mortality. Transcriptomic analysis revealed 333 genes with significant differential expression patterns between males and females (FDR, <0.001), including genes associated with general inflammation, innate immunity, cell adhesion, and cell signaling. None of the former genes were directly associated with sex hormones or X/Y chromosomes. CONCLUSION There are sex-specific differences in the leukocyte genomic response to severe injury that are associated with more robust and longer-duration organ dysfunction. However, these expression patterns do not seem to be associated with sex-linked genes or circulating cytokine level differences, and do not translate to worsened sex-specific organ failure outcomes or inpatient mortality.
KW - Sex
KW - genomics
KW - hemorrhagic shock
KW - leukocyte
KW - trauma
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U2 - 10.1097/TA.0000000000001113
DO - 10.1097/TA.0000000000001113
M3 - Article
C2 - 27306446
AN - SCOPUS:84974853807
SN - 2163-0755
VL - 81
SP - 478
EP - 485
JO - Journal of Trauma and Acute Care Surgery
JF - Journal of Trauma and Acute Care Surgery
IS - 3
ER -