Early leukocyte gene expression associated with age, burn size, and inhalation injury in severely burned adults

Ravi F. Sood, Nicole S. Gibran, Brett D. Arnoldo, Richard L. Gamelli, David Herndon, Ronald G. Tompkins

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Background In the patient with burn injury, older age, larger percentage of total body surface area (TBS) burned, and inhalation injury are established risk factors for death, which typically Results from multisystem organ failure and sepsis, implicating burn-induced immune dysregulation as a contributory mechanism. We sought to identify early transcriptomic changes in circulating leukocytes underlying increased mortality associated with these three risk factors. Methods We performed a retrospective analysis of the Glue Grant database. From 2003 to 2010, 324 adults with 20% or greater TBS burned were prospectively enrolled at five US burn centers, and 112 provided blood samples within 1 week after burn. RNA was extracted from pooled leukocytes for hybridization onto Affymetrix HU133 Plus 2.0 GeneChips. A multivariate regression model was constructed to determine risk factors for mortality. Testing for differential gene association associated with age, burn size, and inhalation injury was based on linear models using a fold change threshold of 1.5 and false discovery rate of 0.05. Results After adjusting for potential confounders, age greater than 60 years (relative risk [RR], 4.53; 95% confidence interval [CI], 2.93-6.99), burn size greater than 40% TBS (RR, 4.24; 95% CI, 2.61-6.91), and inhalation injury (RR, 2.08; 95% CI, 1.35-3.21) were independently associated with mortality. No genes were differentially expressed in association with age greater than 60 years or inhalation injury. Fifty-one probe sets representing 39 unique genes were differentially expressed in leukocytes from patients with burn size greater than 40% TBS; these genes were associated with platelet activation and degranulation/exocytosis, and gene-set enrichment analysis suggested increased cellular proliferation and down-regulation of proinflammatory cytokines. Conclusion Among adults with large burns, older age, increasing burn size, and inhalation injury have a modest effect on the leukocyte transcriptome in the context of the "genomic storm" induced by a 20% or greater than TBS burned. The 39-gene signature we identified may provide novel targets for the development of therapies to reduce morbidity and mortality associated with burns greater than 40% TBS. Level of Evidence Epidemiologic study, level III.

Original languageEnglish (US)
Pages (from-to)250-257
Number of pages8
JournalJournal of Trauma and Acute Care Surgery
Volume80
Issue number2
DOIs
StatePublished - Feb 1 2016
Externally publishedYes

Fingerprint

Inhalation Burns
Body Surface Area
Leukocytes
Gene Expression
Wounds and Injuries
Burns
Inhalation
Genes
Mortality
Confidence Intervals
Burn Units
Platelet Activation
Exocytosis
Transcriptome
Adhesives
Epidemiologic Studies
Linear Models
Sepsis
Down-Regulation
Cell Proliferation

Keywords

  • Burn mortality
  • genomic storm
  • inflammatory response to injury
  • transcriptome profiling

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine
  • Surgery

Cite this

Early leukocyte gene expression associated with age, burn size, and inhalation injury in severely burned adults. / Sood, Ravi F.; Gibran, Nicole S.; Arnoldo, Brett D.; Gamelli, Richard L.; Herndon, David; Tompkins, Ronald G.

In: Journal of Trauma and Acute Care Surgery, Vol. 80, No. 2, 01.02.2016, p. 250-257.

Research output: Contribution to journalArticle

Sood, Ravi F. ; Gibran, Nicole S. ; Arnoldo, Brett D. ; Gamelli, Richard L. ; Herndon, David ; Tompkins, Ronald G. / Early leukocyte gene expression associated with age, burn size, and inhalation injury in severely burned adults. In: Journal of Trauma and Acute Care Surgery. 2016 ; Vol. 80, No. 2. pp. 250-257.
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abstract = "Background In the patient with burn injury, older age, larger percentage of total body surface area (TBS) burned, and inhalation injury are established risk factors for death, which typically Results from multisystem organ failure and sepsis, implicating burn-induced immune dysregulation as a contributory mechanism. We sought to identify early transcriptomic changes in circulating leukocytes underlying increased mortality associated with these three risk factors. Methods We performed a retrospective analysis of the Glue Grant database. From 2003 to 2010, 324 adults with 20{\%} or greater TBS burned were prospectively enrolled at five US burn centers, and 112 provided blood samples within 1 week after burn. RNA was extracted from pooled leukocytes for hybridization onto Affymetrix HU133 Plus 2.0 GeneChips. A multivariate regression model was constructed to determine risk factors for mortality. Testing for differential gene association associated with age, burn size, and inhalation injury was based on linear models using a fold change threshold of 1.5 and false discovery rate of 0.05. Results After adjusting for potential confounders, age greater than 60 years (relative risk [RR], 4.53; 95{\%} confidence interval [CI], 2.93-6.99), burn size greater than 40{\%} TBS (RR, 4.24; 95{\%} CI, 2.61-6.91), and inhalation injury (RR, 2.08; 95{\%} CI, 1.35-3.21) were independently associated with mortality. No genes were differentially expressed in association with age greater than 60 years or inhalation injury. Fifty-one probe sets representing 39 unique genes were differentially expressed in leukocytes from patients with burn size greater than 40{\%} TBS; these genes were associated with platelet activation and degranulation/exocytosis, and gene-set enrichment analysis suggested increased cellular proliferation and down-regulation of proinflammatory cytokines. Conclusion Among adults with large burns, older age, increasing burn size, and inhalation injury have a modest effect on the leukocyte transcriptome in the context of the {"}genomic storm{"} induced by a 20{\%} or greater than TBS burned. The 39-gene signature we identified may provide novel targets for the development of therapies to reduce morbidity and mortality associated with burns greater than 40{\%} TBS. Level of Evidence Epidemiologic study, level III.",
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T1 - Early leukocyte gene expression associated with age, burn size, and inhalation injury in severely burned adults

AU - Sood, Ravi F.

AU - Gibran, Nicole S.

AU - Arnoldo, Brett D.

AU - Gamelli, Richard L.

AU - Herndon, David

AU - Tompkins, Ronald G.

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N2 - Background In the patient with burn injury, older age, larger percentage of total body surface area (TBS) burned, and inhalation injury are established risk factors for death, which typically Results from multisystem organ failure and sepsis, implicating burn-induced immune dysregulation as a contributory mechanism. We sought to identify early transcriptomic changes in circulating leukocytes underlying increased mortality associated with these three risk factors. Methods We performed a retrospective analysis of the Glue Grant database. From 2003 to 2010, 324 adults with 20% or greater TBS burned were prospectively enrolled at five US burn centers, and 112 provided blood samples within 1 week after burn. RNA was extracted from pooled leukocytes for hybridization onto Affymetrix HU133 Plus 2.0 GeneChips. A multivariate regression model was constructed to determine risk factors for mortality. Testing for differential gene association associated with age, burn size, and inhalation injury was based on linear models using a fold change threshold of 1.5 and false discovery rate of 0.05. Results After adjusting for potential confounders, age greater than 60 years (relative risk [RR], 4.53; 95% confidence interval [CI], 2.93-6.99), burn size greater than 40% TBS (RR, 4.24; 95% CI, 2.61-6.91), and inhalation injury (RR, 2.08; 95% CI, 1.35-3.21) were independently associated with mortality. No genes were differentially expressed in association with age greater than 60 years or inhalation injury. Fifty-one probe sets representing 39 unique genes were differentially expressed in leukocytes from patients with burn size greater than 40% TBS; these genes were associated with platelet activation and degranulation/exocytosis, and gene-set enrichment analysis suggested increased cellular proliferation and down-regulation of proinflammatory cytokines. Conclusion Among adults with large burns, older age, increasing burn size, and inhalation injury have a modest effect on the leukocyte transcriptome in the context of the "genomic storm" induced by a 20% or greater than TBS burned. The 39-gene signature we identified may provide novel targets for the development of therapies to reduce morbidity and mortality associated with burns greater than 40% TBS. Level of Evidence Epidemiologic study, level III.

AB - Background In the patient with burn injury, older age, larger percentage of total body surface area (TBS) burned, and inhalation injury are established risk factors for death, which typically Results from multisystem organ failure and sepsis, implicating burn-induced immune dysregulation as a contributory mechanism. We sought to identify early transcriptomic changes in circulating leukocytes underlying increased mortality associated with these three risk factors. Methods We performed a retrospective analysis of the Glue Grant database. From 2003 to 2010, 324 adults with 20% or greater TBS burned were prospectively enrolled at five US burn centers, and 112 provided blood samples within 1 week after burn. RNA was extracted from pooled leukocytes for hybridization onto Affymetrix HU133 Plus 2.0 GeneChips. A multivariate regression model was constructed to determine risk factors for mortality. Testing for differential gene association associated with age, burn size, and inhalation injury was based on linear models using a fold change threshold of 1.5 and false discovery rate of 0.05. Results After adjusting for potential confounders, age greater than 60 years (relative risk [RR], 4.53; 95% confidence interval [CI], 2.93-6.99), burn size greater than 40% TBS (RR, 4.24; 95% CI, 2.61-6.91), and inhalation injury (RR, 2.08; 95% CI, 1.35-3.21) were independently associated with mortality. No genes were differentially expressed in association with age greater than 60 years or inhalation injury. Fifty-one probe sets representing 39 unique genes were differentially expressed in leukocytes from patients with burn size greater than 40% TBS; these genes were associated with platelet activation and degranulation/exocytosis, and gene-set enrichment analysis suggested increased cellular proliferation and down-regulation of proinflammatory cytokines. Conclusion Among adults with large burns, older age, increasing burn size, and inhalation injury have a modest effect on the leukocyte transcriptome in the context of the "genomic storm" induced by a 20% or greater than TBS burned. The 39-gene signature we identified may provide novel targets for the development of therapies to reduce morbidity and mortality associated with burns greater than 40% TBS. Level of Evidence Epidemiologic study, level III.

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