Genomic Copy Number Determines Functional Expression of β-Defensin 2 in Airway Epithelial Cells and Associates with Chronic Obstructive Pulmonary Disease

Rationale Copy number variations of the cluster of p-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 p-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 P-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 p-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 p-defensin encoding genes has a functional role in airway epithelial cells, which may contribute to the pathogenesis of COPD.