Tumor necrosis factor-{alpha} rs361525 polymorphism is associated with increased local production and downstream inflammation in chronic obstructive pulmonary disease

Am J Respir Crit Care Med. 2010 Jul 15;182(2):192-9. doi: 10.1164/rccm.200912-1846OC. Epub 2010 Mar 18.


Rationale: Chronic obstructive pulmonary disease (COPD) has a genetic component, explaining susceptibility. Tumor necrosis factor (TNF)-alpha polymorphisms have been associated with COPD, but it is unclear if genotype influences clinical phenotype, protein expression, and bioactivity.

Objectives: To determine if a functional polymorphism was important by assessing TNF-alpha expression and activity and its association with clinical severity over time.

Methods: Patients with COPD with rs361525 polymorphism were matched to patients with COPD without rs361525 polymorphism. TNF-alpha, its antagonists, and downstream mediators were measured in plasma and sputum. To determine TNF-alpha bioactivity, IL-8 secretion from primary bronchial epithelial cells (PBECs) was measured, and neutrophil migration was assessed using sputum from both subject groups in the presence and absence of TNF-alpha antibody. Subjects were followed annually and compared.

Measurements and main results: Patients with polymorphism had more chronic bronchitis, a lower body mass index, and a greater annual decline in FEV(1) than patients with COPD without rs361525 polymorphism. TNF-alpha concentrations were 100-fold higher in airway secretions from the patients with the rs361525 polymorphism, with no difference in TNF-alpha antagonists. Their lung secretions contained more IL-8 and myeloperoxidase, consistent with downstream inflammation. Sputum from patients with rs361525 polymorphism induced greater secretion of IL-8 from PBECs and increased neutrophil migration. These effects could be abrogated by TNF-alpha antibody, demonstrating the bioactivity of TNF-alpha in lung secretions from this group.

Conclusions: This TNF-alpha polymorphism is associated with clinical features of disease including progression. There is clear evidence of TNF-alpha overexpression and bioactivity with neutrophilic inflammation. The polymorphism is likely to be a factor that influences a COPD disease phenotype and its progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Body Mass Index
  • Bronchi / cytology
  • Bronchitis / epidemiology
  • Case-Control Studies
  • Cell Movement
  • Disease Progression
  • Epithelial Cells / metabolism
  • Female
  • Forced Expiratory Volume
  • Genotype
  • Humans
  • Interleukin-8 / metabolism
  • Male
  • Middle Aged
  • Neutrophils / physiology
  • Peroxidase / metabolism
  • Phenotype
  • Polymorphism, Genetic*
  • Pulmonary Disease, Chronic Obstructive / genetics*
  • Severity of Illness Index
  • Sputum / metabolism
  • Tumor Necrosis Factor-alpha / genetics*
  • Tumor Necrosis Factor-alpha / metabolism


  • Interleukin-8
  • Tumor Necrosis Factor-alpha
  • Peroxidase