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The tumor necrosis factor polymorphism TNF (-308) is associated with susceptibility to meningococcal sepsis, but not

Robert C Read1, Dawn M Teare, Alison C Pridmore

  • 1Section of Infection, Inflammation and Immunity, University of Sheffield Medical School, Sheffield, United Kingdom. r.c.read@sheffield.ac.uk

Critical Care Medicine
|February 27, 2009
PubMed
Abstract

Insights

The tumor necrosis factor (-308) gene variant may increase susceptibility to meningococcal disease. However, this genetic factor does not impact the likelihood of death from the infection.

Area of Science:

  • Genetics
  • Immunology
  • Infectious Diseases

Background:

  • Meningococcal sepsis is a severe infection with significant mortality.
  • The tumor necrosis factor (TNF) gene, particularly the -308 promoter polymorphism, is investigated for its role in inflammatory responses.
  • Understanding genetic predispositions to meningococcal disease is crucial for public health.

Purpose of the Study:

  • To investigate the association between the TNF (-308) promoter polymorphism and susceptibility to, or death from, meningococcal sepsis.
  • To explore the functional relevance of the TNF (-308) genotype in response to Neisseria meningitidis infection.

Main Methods:

  • An association study was conducted with 1321 patients diagnosed with invasive meningococcal disease and 1280 healthy blood donor controls.
  • DNA genotyping was performed for the TNF (-308) polymorphism and eight other markers in linkage disequilibrium.
  • In vitro experiments measured TNF secretion and mRNA expression in macrophages from volunteers with known TNF (-308) genotypes upon exposure to Neisseria meningitidis.

Main Results:

  • The TNF (-308) genotype did not influence the likelihood of death from meningococcal disease.
  • Patients with meningococcal disease were more likely to be homozygous for the rare TNF (-308) allele (OR=1.93) and less likely to be heterozygous (OR=0.79) compared to controls, suggesting a role in susceptibility.
  • Macrophages from individuals homozygous for the rare TNF (-308) allele exhibited higher TNF mRNA expression and secretion after N. meningitidis exposure.

Conclusions:

  • The TNF (-308) genotype influences cellular TNF secretion in response to Neisseria meningitidis.
  • This genetic variation may play a role in susceptibility to meningococcal disease.
  • The TNF (-308) genotype does not appear to affect the fatality rate of meningococcal infection.

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