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Gene Expression Profiling of Patients with a Variation in the TNF-alpha gene and suffering from Multiple Trauma

ABSTRACT: 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

ORGANISM(S): Homo sapiens

PROVIDER: GSE5760 | GEO | 2007/08/22

SECONDARY ACCESSION(S): PRJNA97093

REPOSITORIES: GEO

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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).

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:While the paradigm that genetic predisposition and environmental exposures interact to shape development and function of the human brain and ultimately the risk of psychiatric disorders has drawn wide interest, the corresponding molecular mechanisms have not been elucidated yet. Here we show that a functional polymorphism altering chromatin interaction between the transcription start site and long range enhancers in the FK506 binding protein 5 (FKBP5) gene, an important regulator of the stress hormone system, increases the risk of developing stress-related psychiatric disorders in adulthood by allele-specific, childhood trauma-dependent DNA demethylation in functional glucocorticoid response elements (GREs) of FKBP5. This demethylation is linked to increased stress-dependent gene transcription followed by a long-term dysregulation of the stress hormone system and a global impact on the function of immune cells and brain areas associated with stress regulation. This first identification of molecular mechanisms of genotype-directed long-term environmental reactivity will also critically contribute to designing more effective treatment strategies for stress-related disorders. Effects of FKBP5 rs1360780 genotype x environment interaction on peripheral blood mRNA expression of GR responsive genes, as measured by gene expression arrays, were explored in 129 individuals (child abuse/risk allele carrier N = 40, child abuse/protective allele carrier N = 15; and no child abuse/risk allele carrier N = 60, no child abuse/protective allele carrier N = 14). In all 129 individuals, 1627 transcripts showed a significant correlation with plasma cortisol concentrations, suggesting their GR responsiveness. The correlation of 76 of these transcripts with cortisol plasma levels showed significant differences when stratifying by FKBP5 genotype in individuals with child abuse (Fisher z score ≥ 1.96) For these 76 transcripts, the mean absolute correlation coefficient with plasma cortisol was R = 0.23 in the risk allele carriers with child abuse, that is those exhibiting a demethylation of FKBP5 intron 7 as compared to R = 0.74 in the carriers of the protective genotype with child abuse where intron 7 methylation remains largely stable. This indicates a relative GR-resistance in the trauma exposed FKBP5 risk allele vs. protective genotype carriers. These 76 transcripts did not show a genotype-dependent difference in correlation coefficients in non-trauma exposed individuals suggesting that exposure to early trauma enhances FKBP5 genotype-dependent effect of GR sensitivity, most likely by epigenetic mechanisms. These findings suggest that the combination of FKBP5 risk allele carrier status and early trauma exposure alters the stress hormone-dependent regulation of several genes in peripheral blood cells, and might thereby enhance the reported association of early trauma with immune and inflammatory dysregulation, further promoting system-wide symptoms of stress-related disorders.

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Gene Expression Profiling of Patients with a Variation in the TNF-alpha gene and suffering from Multiple Trauma

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