Sepsis syndrome and death in trauma patients are associated with variation in the gene encoding tumor necrosis factor.

OBJECTIVE: 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 postulate that variation of the gene coding for tumor necrosis factor (TNF)-alpha is associated with increased occurrence of sepsis syndrome and mortality in trauma patients. DESIGN: Prospective cohort study; validation in an external replication sample. SETTING: Tertiary academic medical center. PATIENTS: We included 159 severely traumatized patients from a single center. Serial blood samples were analyzed for serum concentrations of TNF-alpha and lymphotoxin-alpha (LTA). 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 28 patients by whole genome-based profiling and validated the results. INTERVENTIONS: None. MEASUREMENTS AND MAIN 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 = 5.0 x 10(-5)), with development of sepsis syndrome (odds ratio 7.14, two-sided p = 1.2 x 10(-6); external validation sample [n = 76]: odds ratio 3.3, one-sided p = .03), and with fatal outcome (odds ratio 7.65, two-sided p = 1.9 x 10(-6)). Carriage of the TNF rs1800629 A allele was associated with differential expression of genes representing stronger proinflammatory and apoptotic responses compared with 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.

In vivo application of histone deacetylase inhibitor trichostatin-a impairs murine male meiosis.

In vivo application of histone deacetylase (HDAC) inhibitor trichostatin-A (TSA) in mice results in male infertility. To get more insight into the mechanisms underlying this phenomenon, we performed a genome-wide expression analysis and investigated HDAC activity and degree of histone H3 and H4 acetylation in murine testes after TSA treatment. A significant decrease in HDAC activity and a weak increase in histone acetylation could be demonstrated at 2.5, 5.0, and 7.5 hours after TSA application. Gene expression analysis revealed 507 significantly regulated genes. Transcripts expressed in the somatic cells of the testis (Sertoli, Leydig, peritubular cells, and testis macrophages) or extratubular matrix were regulated as early as 2.5 hours after TSA application, whereas very few meiosis-specific genes were modulated after TSA treatment. In addition, members of the p53-noxa-caspase-3 proapoptotic pathway were regulated early. Applying in-situ hybridization, caspase-3-mRNA was found only in apoptotic spermatocytes, whereas TRP53/p53- and PMAIP1/noxa-mRNA could be demonstrated in spermatogonia and spermatocytes. Our data suggest that TSA impaired male meiosis, possibly through an indirect mechanism implicating somatic cells of the testis.