A disintegrin and metalloprotease 33 and chronic obstructive pulmonary disease pathophysiology
- Margot M E Gosman1,
- H Marike Boezen2,
- Cleo C van Diemen2,
- Jiska B Snoeck-Stroband3,
- Thérèse S Lapperre4,
- Pieter S Hiemstra4,
- Nick H T ten Hacken1,
- Jan Stolk1,
- Dirkje S Postma1,
- the GLUCOLD Study Group
- 1Department of Pulmonology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
- 2Department of Epidemiology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
- 3Departments of Public Health and Primary Care, Leiden University Medical Centre, Leiden, The Netherlands
- 4Departments of Pulmonology, Leiden University Medical Centre, Leiden, The Netherlands
- Correspondence to:
Professor D S Postma
Department of Pulmonology, University Medical Centre Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands;
- Received 17 February 2006
- Accepted 12 September 2006
- Published Online First 7 November 2006
Background: Chronic obstructive pulmonary disease (COPD) is a respiratory disorder with increasing prevalence and mortality. It is associated with airway obstruction, increased airway hyper-responsiveness (AHR), and ongoing airway and lung inflammation dominated by CD8 lymphocytes and neutrophils. Single-nucleotide polymorphisms (SNPs) in a disintegrin and metalloprotease 33 (ADAM33) gene have been associated with AHR and COPD.
Objective: To assess whether SNPs in ADAM33 are associated with the severity of AHR and airway inflammation in COPD.
Methods: Eight SNPs in ADAM33 (F+1, Q-1, S_1, S_2, ST+5, T_1, T_2, V_4) were genotyped in 111 patients with COPD (96 males, 69 current smokers, mean (standard deviation (SD)), aged 62 (8) years, median pack-years 42 (IQR 31–55), mean postbronchodilator forced expiratory volume in 1 s (FEV1)% predicted 63 (9). Provocative concentration of methacholine causing a decrease in FEV1 of 20% (PC20 methacholine), sputum and bronchial biopsies were collected.
Results: Patients with the ST+5 AA genotype had more severe AHR, higher numbers of sputum inflammatory cells and CD8 cells in bronchial biopsies than patients with the GG genotype (p = 0.03, 0.05 and 0.01, respectively). CD8 cell numbers were lower in patients carrying the minor allele of SNP T_1 and T_2, and homozygotic minor variants of SNP S_2 compared with the wild type (p = 0.02, 0.01 and 0.02, respectively).
Conclusions: This is the first study revealing that SNPs in a gene that confers susceptibility to COPD in the general population—that is, ADAM33—are associated with AHR and airway inflammation in COPD. These findings constitute an important step forward in linking gene polymorphisms with COPD pathophysiology, thereby possibly contributing to better treatments for this progressive and disabling disease in the future.
- ADAM33, a disintegrin and metalloprotease 33
- AHR, airway hyper-responsiveness
- COPD, chronic obstructive pulmonary disease
- FEV, forced expiratory volume
- PC20, 20% fall in forced expiratory volume in 1 s
- SNP, single nucleotide polymorphism
Published Online First 7 November 2006
Funding: This work was supported by Netherlands Organisation for Scientific Research (NWO), The Netherlands Asthma Foundation (NAF; 37.97.74; NAF3.2.02.51), GlaxoSmithKline (NL), Leiden University Medical Centre (LUMC), and University of Groningen (RUG).
Competing interests: None.