E-GEOD-5760 - Gene Expression Profiling of Patients with a Variation in the TNF-alpha gene and suffering from Multiple Trauma
Released on 22 August 2007, last updated on 27 March 2012
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).
transcription profiling by array
Felix Johannes Thierer <firstname.lastname@example.org>, Gregor Bein, Hamid Hossain, Inke Koenig, Simon Little, Svetlin Tchatalbachev, Thilo Menges, Trinad Chakraborty
Sepsis syndrome and death in trauma patients are associated with variation in the gene encoding tumor necrosis factor. Menges T, König IR, Hossain H, Little S, Tchatalbachev S, Thierer F, Hackstein H, Franjkovic I, Colaris T, Martens F, Weismüller K, Langefeld T, Stricker J, Hempelmann G, Vos PE, Ziegler A, Jacobs B, Chakraborty T, Bein G. , Europe PMC 18434886