Linkage disequilibrium between tumor necrosis factor (TNF)-alpha-308 G/A promoter and TNF-beta NcoI polymorphisms: Association with TNF-alpha response of granulocytes to endotoxin stimulation

Crit Care Med. 2003 Jan;31(1):211-4. doi: 10.1097/00003246-200301000-00032.


Objective: Controversial data have been reported on the association between the tumor necrosis factor (TNF)-alpha-308 G[U279C]A promoter polymorphism or the TNF-alpha I polymorphism with TNF-alpha plasma concentrations. The purpose of this study was to evaluate whether there is a linkage disequilibrium between the two polymorphisms. Moreover, the influence of these polymorphisms on the TNF-alpha synthesis of activated granulocytes was studied.

Design: Analysis of TNF-alpha concentrations of human whole blood after endotoxin stimulation.

Setting: Medical research laboratory.

Patients: Healthy human volunteers.

Interventions: None.

Measurements and main results: Healthy human volunteers were genotyped for both TNF polymorphisms by means of polymerase chain reaction. TNF-alpha plasma concentrations were determined with chemiluminescence after incubation of whole blood with endotoxin. A strong (p <.0001) linkage disequilibrium was found for the TNF-beta I and the TNF-alpha-308 genetic polymorphisms. Almost all individuals homozygous for the TNF-B2 allele of the TNF-beta I polymorphism were also TNF-alpha-308 G homozygotes. Carriers of the TNF-alpha-308 genotype AG had a significantly higher TNF-alpha production capacity than G homozygotes. The TNF-beta I genotype TNF-B1/TNF-B2 was associated with significantly higher TNF-alpha concentrations than the genotype TNF-B2/TNF-B2. Individuals homozygous for the TNF-B2 and the TNF-alpha-308 G alleles had a significantly reduced TNF-alpha response compared with individuals heterozygous for both TNF polymorphisms.

Conclusions: A linkage disequilibrium between the two TNF polymorphisms was found. This study revealed a significant association between genotype and phenotype for both TNF polymorphisms. Heterozygosity for both TNF polymorphisms is associated with an increased TNF-alpha response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Granulocytes / metabolism
  • Humans
  • In Vitro Techniques
  • Likelihood Functions
  • Linkage Disequilibrium*
  • Lipopolysaccharides
  • Lymphotoxin-alpha / genetics*
  • Polymorphism, Genetic*
  • Promoter Regions, Genetic / genetics
  • Shock, Septic / genetics*
  • Shock, Septic / metabolism
  • Statistics, Nonparametric
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / genetics*


  • Lipopolysaccharides
  • Lymphotoxin-alpha
  • Tumor Necrosis Factor-alpha