A Disintegrin and Metalloproteinase 33 and Chronic Obstructive Pulmonary Disease Pathophysiology

Margot M E Gosman ¹, H Marike Boezen ¹, Cleo C van Diemen ¹, Jiska B Snoeck-Stroband ², Therese S Lapperre ², Pieter S Hiemstra ², Nick H Ten Hacken ¹, Jan Stolk ³ and Dirkje S Postma ^1*

¹ University Medical Center Groningen, Netherlands
² Leiden University Medical Center, Netherlands
³ University Medical Center Leiden, Netherlands

^* To whom correspondence should be addressed. E-mail: d.s.postma{at}int.azg.nl.

Accepted 12 September 2006

Abstract

Rationale: Chronic obstructive pulmonary disease (COPD) is a respiratory disorder with increasing prevalence and mortality. It is associated with airway obstruction, increased airway hyperresponsiveness (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 with 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 age 62 years (SD=8), median pack-years 42 (IQR 31-55), mean postbronchodilator FEV1% predicted 63 (SD=9)). 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, p=0.05, p=0.01, respectively). CD8+ cell numbers were lower in subjects carrying the minor allele of SNP T_1 and T_2, and homozygous minor variants of SNP S_2 compared to the wild-type (p=0.02, p=0.01, p=0.02, respectively).

Conclusions: This is the first study demonstrating that SNPs in a gene that confers susceptibility to COPD in the general population, i.e. 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 future treatments for this progressive and disabling disease.

Keywords: ADAM33, COPD, Hyperresponsiveness, Inflammation, Pathophysiology

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