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Association of TNF2, a TNF- Promoter Polymorphism, With Septic Shock Susceptibility and Mortality

A Multicenter Study

Jean-Paul Mira, MD; Alain Cariou, MD; Franck Grall, MD; Christophe Delclaux, MD; Marie-Reine Losser, MD; Fahrad Heshmati, MD; Christine Cheval, MD; Mehran Monchi, MD; Jean-Louis Teboul, MD, PhD; Florence Riché, MD; Ghislaine Leleu, MD; Laurence Arbibe, MD, PhD; Alexandre Mignon, MD, PhD; Marc Delpech, MD, PhD; Jean-François Dhainaut, MD, PhD

JAMA. 1999;282:561-568.

Context  Tumor necrosis factor alpha (TNF-) is believed to be a cytokine central to pathogenesis of septic shock. TNF2, a polymorphism within the TNF- gene promoter, has been associated with enhanced TNF- 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- 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- 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.

Author Affiliations: Intensive Care Unit (Drs Mira, Cariou, Monchi, Arbibe, Mignon, and Dhainaut) and Laboratory of Biochemical Genetics (Drs Grall and Delpech), Cochin Port-Royal University Hospital; Intensive Care Units of Lariboisière University Hospital (Drs Losser and Riché), Saint-Joseph University Hospital (Dr Cheval), Kremlin-Bicètre University Hospital (Dr Teboul), Saint-Louis University Hospital (Dr Leleu), and Cochin-Hospital Blood Bank (Dr Heshmati), Paris, France; and Mondor University Hospital, Créteil, France (Dr Delclaux).

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