Genomic copy number determines functional expression of {beta}-defensin 2 in airway epithelial cells and associates with chronic obstructive pulmonary disease

Am J Respir Crit Care Med. 2010 Jul 15;182(2):163-9. doi: 10.1164/rccm.200905-0767OC. Epub 2010 Apr 8.


Rationale: Copy number variations of the cluster of beta-defensin genes have been associated with psoriasis and inflammatory bowel disease. Controversy still exists on whether the beta-defensins genes determine susceptibility for chronic obstructive pulmonary disease (COPD).

Objectives: We investigated whether genomic copy number variations of the beta-defensin gene cluster have a functional role in airway epithelial cells and associate with the presence of COPD.

Methods: Baseline and inflammatory induced transcript expression of DEFB4 was studied in nasal epithelial cell cultures and its effect on Pseudomonas aeruginosa inhibition was assessed. Subsequently, relevant functional cut-offs for copy numbers were used to explore associations with COPD in two independent case-control studies.

Measurements and main results: Copy number variation in the beta-defensin encoding genes correlated with baseline mRNA DEFB4 expression levels (R(2) = 0.96; P = 0.02), with a plateau effect from five copies or more. Only when higher copy numbers of beta-defensin genes were present, transcription was significantly up-regulated by tumor necrosis factor-alpha (P < 0.0001), which resulted in better antimicrobial activity in vitro. When comparing healthy smokers with COPD patients, a copy number greater than or equal to 5 was associated with increased risk for COPD with an adjusted odds ratio of 1.8 (confidence interval, 1.1-2.8; P = 0.02), which was confirmed by a second independent case-control study.

Conclusions: Genomic copy number variation of beta-defensin encoding genes has a functional role in airway epithelial cells, which may contribute to the pathogenesis of COPD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Case-Control Studies
  • Cells, Cultured
  • Diploidy
  • Epithelial Cells / metabolism*
  • Female
  • Gene Dosage*
  • Genetic Predisposition to Disease
  • Genetic Variation*
  • Humans
  • Interleukin-8 / metabolism
  • Male
  • Middle Aged
  • Nasal Mucosa / cytology
  • Polymerase Chain Reaction
  • Pseudomonas aeruginosa
  • Pulmonary Disease, Chronic Obstructive / genetics*
  • RNA, Messenger / metabolism
  • Up-Regulation
  • beta-Defensins / genetics*


  • DEFB4A protein, human
  • Interleukin-8
  • RNA, Messenger
  • beta-Defensins