Abstract | OBJECTIVE: 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.
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Authors | Thilo Menges, Inke R König, Hamid Hossain, Simon Little, Svetlin Tchatalbachev, Felix Thierer, Holger Hackstein, Isolda Franjkovic, Thorsten Colaris, Florian Martens, Katja Weismüller, Tanja Langefeld, Jürgen Stricker, Gunter Hempelmann, Pieter E Vos, Andreas Ziegler, Bram Jacobs, Trinad Chakraborty, Gregor Bein |
Journal | Critical care medicine
(Crit Care Med)
Vol. 36
Issue 5
Pg. 1456-62, e1-6
(May 2008)
ISSN: 1530-0293 [Electronic] United States |
PMID | 18434886
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Tumor Necrosis Factor-alpha
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Topics |
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Female
- Humans
- Male
- Middle Aged
- Polymorphism, Single Nucleotide
- Prospective Studies
- Systemic Inflammatory Response Syndrome
(complications, genetics, mortality)
- Tumor Necrosis Factor-alpha
(genetics)
- Wounds and Injuries
(complications)
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