title: Sepsis syndrome and death in trauma patients are associated with variation in the gene encoding tumor necrosis factor.
abstract: 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.
  
  
  METHODS
  Prospective cohort study; validation in an external replication sample.
  
  
  METHODS
  Tertiary academic medical center.
  
  
  METHODS
  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.
  
  
  METHODS
  None.
  
  
  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.
authors.affiliation: Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, Justus-Liebig-University, Giessen, Germany.
authors.forename: Thilo
authors.initials: T
authors.lastname: Menges
authors.forename: Inke R
authors.initials: IR
authors.lastname: König
authors.forename: Hamid
authors.initials: H
authors.lastname: Hossain
authors.forename: Simon
authors.initials: S
authors.lastname: Little
authors.forename: Svetlin
authors.initials: S
authors.lastname: Tchatalbachev
authors.forename: Felix
authors.initials: F
authors.lastname: Thierer
authors.forename: Holger
authors.initials: H
authors.lastname: Hackstein
authors.forename: Isolda
authors.initials: I
authors.lastname: Franjkovic
authors.forename: Thorsten
authors.initials: T
authors.lastname: Colaris
authors.forename: Florian
authors.initials: F
authors.lastname: Martens
authors.forename: Katja
authors.initials: K
authors.lastname: Weismüller
authors.forename: Tanja
authors.initials: T
authors.lastname: Langefeld
authors.forename: Jürgen
authors.initials: J
authors.lastname: Stricker
authors.forename: Gunter
authors.initials: G
authors.lastname: Hempelmann
authors.forename: Pieter E
authors.initials: PE
authors.lastname: Vos
authors.forename: Andreas
authors.initials: A
authors.lastname: Ziegler
authors.forename: Bram
authors.initials: B
authors.lastname: Jacobs
authors.forename: Trinad
authors.initials: T
authors.lastname: Chakraborty
authors.forename: Gregor
authors.initials: G
authors.lastname: Bein
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D018746:Systemic Inflammatory Response Syndrome / Q000150:complications / Q000235:genetics* / Q000401:mortality*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D014947:Wounds and Injuries / Q000150:complications*
chemical_list: D014409:Tumor Necrosis Factor-alpha