Unknown,Transcriptomics,Genomics,Proteomics

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A Genomic Score Prognostic of Outcome in Trauma Patients

ABSTRACT: Physiological, anatomical, and clinical laboratory analytic scoring systems (APACHE, Injury Severity Score (ISS)) have been utilized, with limited success, to predict outcome following injury. We hypothesized that a peripheral blood leukocyte gene expression score could predict outcome, including multiple organ failure, following severe blunt trauma. Contributor: The Inflammation and the Host Response to Injury Large Scale Collaborative Research Program Keywords: expression profiles cRNA derived from whole blood leukocytes obtained within 12 hours of hospital admission provided gene expression data for the entire genome that were used to create a gene expression score for each patient. Expression profiles from healthy volunteers were averaged to create a reference gene expression profile which was used to compute a difference from reference (DFR) score for each patient. This score described the overall genomic response of patients within the first 12 hours following severe blunt trauma. Regression models were used to compare the association of the DFR, APACHE and ISS scores with outcome.

ORGANISM(S): Homo sapiens

SUBMITTER: IDDC Inflammation & the Host Response to Injury

PROVIDER: E-GEOD-11375 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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A genomic score prognostic of outcome in trauma patients.

Warren H Shaw HS Elson Constance M CM Hayden Douglas L DL Schoenfeld David A DA Cobb J Perren JP Maier Ronald V RV Moldawer Lyle L LL Moore Ernest E EE Harbrecht Brian G BG Pelak Kimberly K Cuschieri Joseph J Herndon David N DN Jeschke Marc G MG Finnerty Celeste C CC Brownstein Bernard H BH Hennessy Laura L Mason Philip H PH Tompkins Ronald G RG

Molecular medicine (Cambridge, Mass.) 20090410 7-8

Traumatic injuries frequently lead to infection, organ failure, and death. Health care providers rely on several injury scoring systems to quantify the extent of injury and to help predict clinical outcome. Physiological, anatomical, and clinical laboratory analytic scoring systems (Acute Physiology and Chronic Health Evaluation [APACHE], Injury Severity Score [ISS]) are utilized, with limited success, to predict outcome following injury. The recent development of techniques for measuring the ex ...[more]

PMID: 19593405

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Project description:The study was aimed to identify mechanisms linked to complicated courses after severe trauma by a systems biology approach. In severe trauma, overwhelming systemic inflammation can result in adverse events and the development of complications, including sepsis. In a prospective study, RNA samples from circulating leukocytes from patients with multiple injury (injury severity score â¥ 17) were analyzed for dynamic changes in gene expression over a period of 21 days by whole genome screening. Based on their clinical presentation, patients were divided into two subgroups: patients with secondary sepsis after trauma (n=5) and patients with systemic inflammation without infection (n=5). Expression cluster were defined by correlating gene expression data with clinical outcome parameters. Using unsupervised clustering, patients with systemic inflammation only and patients with sepsis showed a distinct expression pattern and the discrimination of clinical presentation was reflected by clustering of the samples. Explorative gene set analysis revealed robust upregulation of genes related to âhemoglobin metabolism/oxygen transportâ and âpathogenic E.coli infectionâ. 10 patients with multi-system trauma (ISS â¥ 17 points) admitted to the Division of Trauma Surgery at the University Hospital Zurich were included. Whole blood from trauma patients was collected within the first 6 h after trauma (day 0) and on days 1, 2, 3, 5, 7, 10, 14, and 21. Total cellular RNA from circulating leukocytes was isolated using PaxGene Blood RNA Kit (PreAnalytix) for transcriptome profiling. RNA from blood of trauma patients was extracted and subjected to microarray analysis for comparison of longitudinal transcriptomic responses of patients. RNA samples of circulating leukocytes covering time points directly after admission (D0) and on the consecutive days (D1-D21) were subject to multifactorial microarray data analysis: Differences in dynamics of transcripts were assessed by contrasting time- and individual-resolved changes for sepsis and systemic inflammation without infection.

Project description:BACKGROUND: Patients encountering severe trauma are at risk of developing sepsis syndrome and subsequent multiple organ failure. This is often associated with fatal outcome despite survival of the initial injury. We undertook a prospective cohort study of trauma patients to examine the role of tumor necrosis factor alpha (TNF-alpha) in the pathogenesis of sepsis syndrome and mortality. METHODS: 159 severely traumatized patients from a single centre were included. Serial blood samples were analyzed for serum concentrations of TNF-alpha and lymphotoxin alpha (LT-alpha). We genotyped nine polymorphisms in the TNF gene and tested for an association with sepsis syndrome and outcome. Genetic associations were validated in an external replication sample (n=76). We examined the peripheral blood transcriptome in n=28 patients by whole genome-based profiling and validated the results. RESULTS: Carriage of the TNF rs1800629 A allele was associated with higher TNF-alpha serum concentrations on the first day after trauma and during follow up (two-sided p=5.0x10-5), with development of sepsis syndrome (OR 7.14, two-sided p=1.2x10-6; external validation sample (n=76): OR 3.3, one-sided p=0.03), and with fatal outcome (OR 7.65, two-sided p=1.9x10-6). Carriage of the TNF rs1800629 A allele was associated with differential expression of genes representing stronger pro-inflammatory and apoptotic responses as compared to carriage of the wild type allele. CONCLUSIONS: Common TNF gene variants are associated with sepsis syndrome and death after severe injury. These findings are strongly supported by functional data and may be important for developing preemptive anti-inflammatory interventions in carriers of the risk-associated allele. Keywords: Disease state analysis 159 consecutive traumatized patients were included in the study upon admission to the intensive care unit (ICU), fulfilling all of the following inclusion criteria: severe injuries of at least two body regions or three major fractures, between 18 and 65 years of age, an estimated Injury Severity Score (ISS)21 of ≥12 points after thorough assessment of injuries, <12 hours between the occurrence of the accident and time of admission to the ICU, and at least more than 3 days of survival. None of the patients underwent neuro- or cardiac surgery. We excluded patients with severe intracranial head injuries, coagulation abnormalities known at the day of admission to the ICU, acute renal failure, liver failure, malignant disease, or hemofiltration in the patient`s history. All patients were genotyped for nine polymorphisms in the TNF gene and tested for an association with sepsis syndrome and outcome. The genotyping results revealed significant association for the carriage of a TNF rs1800629 A allele with higher TNF-alpha serum concentrations on the first day after trauma and during follow up, with development of sepsis syndrome (OR 7.14), and with fatal outcome (OR 7.65). To obtain more insight into the biological mechanisms underlying the findings in the genotyping study, we searched for differences in the peripheral blood transcriptome from patients with and without the TNF rs1800629 A variant. From 28 patients, we examined the transcpriptome from peripheral blood using the CodeLink UniSet Human 10 K Bioarrays (GE Healthcare, Freiburg, Germany). Only whole blood samples drawn upon admission to the ICU were used for this investigation. Microarray results were validated by quantification of mRNA by TaqMan® technology. The patients were dichotomized into two groups: group A) 16 patients without the TNF rs1800629 A variant (WT1-16) and group B) 12 patients carrying the TNF rs1800629 A variant (MUT1-12). Each patient sample was hybridized in duplicate on microarrays (label-extract technical replicate). A total of 75 arrays (42 group A, 33 group B) were subjected to microarray quality analysis. Of these, 17 arrays (12 group A, 5 group B) were excluded from the data set due to quality reasons and a final set of 58 arrays (30 group A and 28 group B) was subjected to microarray analysis. The arrays were designated WTx.y or MUTx.y with WT for patients with and MUT for patients without the TNF rs1800629 A variant, with x for the patient-ID (1,2,3,4..) and y for the technical replicate number (1,2 or 3).

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A Genomic Score Prognostic of Outcome in Trauma Patients

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A genomic score prognostic of outcome in trauma patients.

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