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.