Association of TNF2, a TNF-alpha promoter polymorphism, with septic shock susceptibility and mortality: a multicenter study

JAMA. 1999 Aug 11;282(6):561-8. doi: 10.1001/jama.282.6.561.


Context: Tumor necrosis factor alpha (TNF-alpha) is believed to be a cytokine central to pathogenesis of septic shock. TNF2, a polymorphism within the TNF-alpha gene promoter, has been associated with enhanced TNF-alpha production and negative outcome in some severe infections.

Objectives: To investigate the frequency of the TNF2 allele in patients with septic shock and to determine whether the allele is associated with the occurrence and outcome of septic shock.

Design: Multicenter case-control study conducted from March 1996 to June 1997.

Setting: Seven medical intensive care units in university hospitals.

Subjects: Eighty-nine patients with septic shock and 87 healthy unrelated blood donors.

Main outcome measures: Frequency of the TNF2 allele among patients with septic shock and among those who died and the level of corresponding TNF-alpha concentrations.

Results: Mortality among patients with septic shock was 54%, consistent with the predicted mortality from the Simplified Acute Physiologic Score (SAPS II) value. The polymorphism frequencies of the controls and the patients with septic shock differed only at the TNF2 allele (39% vs 18% in the septic shock and control groups, respectively, P =.002). Among the septic shock patients, TNF2 polymorphism frequency was significantly greater among those who had died (52% vs 24% in the survival group, P =.008). Concentrations of TNF-alpha were higher in 68% and 52% with the TNF2 and TNF1 polymorphisms, respectively, but their median values (48 pg/mL vs 29 pg/mL) were not statistically different (P = .31). After controlling for age and the probability of death, derived by the SAPS II score, multiple logistic regression analysis showed that, for the same rank of SAPS II value, patients with the TNF2 allele had a 3.7-fold risk of death (95% confidence interval, 1.37-10.24).

Conclusion: The TNF2 allele is strongly associated with susceptibility to septic shock and death due to septic shock.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Base Sequence
  • Case-Control Studies
  • Disease Susceptibility
  • Electrophoresis
  • Female
  • Gene Frequency
  • Genotype
  • HLA Antigens / genetics
  • Humans
  • Logistic Models
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Polymerase Chain Reaction
  • Polymorphism, Genetic*
  • Promoter Regions, Genetic* / genetics
  • Risk
  • Sequence Analysis, DNA
  • Severity of Illness Index
  • Shock, Septic / immunology*
  • Shock, Septic / mortality
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / genetics*


  • HLA Antigens
  • Tumor Necrosis Factor-alpha