A disintegrin and metalloprotease 33 and chronic obstructive pulmonary disease pathophysiology.
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 (FEV(1))% predicted 63 (9). Provocative concentration of methacholine causing a decrease in FEV(1) of 20% (PC(20) 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.
Gosman
Margot M E
MM
Department of Pulmonology, University Medical Centre Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands.
Boezen
H Marike
HM
van Diemen
Cleo C
CC
Snoeck-Stroband
Jiska B
JB
Lapperre
Thérèse S
TS
Hiemstra
Pieter S
PS
Ten Hacken
Nick H T
NH
Stolk
Jan
J
Postma
Dirkje S
DS
D051722:ADAM Proteins / Q000235:genetics*; D000704:Analysis of Variance; D001706:Biopsy; D001980:Bronchi / Q000473:pathology; D016535:Bronchial Hyperreactivity / Q000235:genetics*; D001991:Bronchitis / Q000235:genetics; D004804:Eosinophils / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008407:Mast Cells / Q000378:metabolism; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics*; D013183:Sputum / Q000166:cytology
D051722:ADAM Proteins; C450441:ADAM33 protein, human