Early Leukocyte Gene Expression Associated with Age, Burn Size, and Inhalation Injury in Severely Burned Adults Journal Article

Authors: Sood, R. F.; Gibran, N. S.; Arnoldo, B. D.; Gamelli, R. L.; Herndon, D. N.; Tompkins, R. G.; Inflammation, T.; Investigators, T. H.
Article Title: Early Leukocyte Gene Expression Associated with Age, Burn Size, and Inhalation Injury in Severely Burned Adults
Abstract: BACKGROUND: In the burn-injured patient, older age, larger percent total body surface area (%TBSA) 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 these three risk factors. METHODS: We performed a retrospective analysis of the Glue Grant database. From 2003-2010, 324 adults with >/=20% TBSA burned were prospectively enrolled at five US burn centers, and 112 provided blood samples within one week post-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 >60 (RR 4.53; 95% CI: 2.93-6.99), burn size >40% TBSA (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 >60 or inhalation injury. Fifty-one probe sets representing thirty-nine unique genes were differentially expressed in leukocytes from patients with burn size >40% TBSA; these genes were associated with platelet activation and degranulation/exocytosis, and gene-set enrichment analysis suggested increased cellular proliferation and down-regulation of pro-inflammatory cytokines. CONCLUSIONS: 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% TBSA burn. The 39-gene signature we identified may provide novel targets for the development of therapies to reduce morbidity and mortality associated with burns >40% TBSA. LEVEL OF EVIDENCE: Epidemiologic study, level III.
Journal Title: The journal of trauma and acute care surgery
Volume: 80
Issue: 2
ISSN: 2163-0763; 2163-0755
Publisher: Unknown  
Date Published: 2016
Start Page: 250
End Page: 257
Language: ENG
Notes: LR: 20151117; GR: U54 GM062119/GM/NIGMS NIH HHS/United States; JID: 101570622; aheadofprint