Gosman Margot M E, Boezen H Marike, van Diemen Cleo C, Snoeck-Stroband Jiska B, Lapperre Thérèse S, Hiemstra Pieter S, Ten Hacken Nick H T, Stolk Jan, Postma Dirkje S
Department of Pulmonology, University Medical Centre Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands.
Thorax. 2007 Mar;62(3):242-7. doi: 10.1136/thx.2006.060988. Epub 2006 Nov 7.
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.
To assess whether SNPs in ADAM33 are associated with the severity of AHR and airway inflammation in COPD.
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.
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).
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.
慢性阻塞性肺疾病（COPD）是一种患病率和死亡率不断上升的呼吸系统疾病。它与气道阻塞、气道高反应性（AHR）增加以及以CD8淋巴细胞和中性粒细胞为主的持续性气道和肺部炎症有关。解整合素金属蛋白酶33（ADAM33）基因中的单核苷酸多态性（SNP）与AHR和COPD相关。
评估ADAM33基因中的SNP是否与COPD中AHR的严重程度和气道炎症相关。
对111例COPD患者（96例男性，69例当前吸烟者，平均（标准差（SD））年龄62（8）岁，中位吸烟包年数42（四分位间距31 - 55），支气管扩张剂后1秒用力呼气容积（FEV₁）预测值平均为63（9））的ADAM33基因中的8个SNP（F +1、Q -1、S_1、S_2、ST +5、T_1、T_2、V_4）进行基因分型。收集引起FEV₁下降20%的乙酰甲胆碱激发浓度（PC₂₀乙酰甲胆碱）、痰液和支气管活检组织。
与GG基因型患者相比，ST +5 AA基因型患者的AHR更严重，支气管活检组织中的痰液炎症细胞和CD8细胞数量更多（分别为p = 0.03、0.05和0.01）。与野生型相比，携带SNP T_1和T_2的次要等位基因以及SNP S_2的纯合次要变异体的患者CD8细胞数量更低（分别为p = 0.02、0.01和0.02）。
这是第一项揭示在普通人群中赋予COPD易感性的基因——即ADAM33——中的SNP与COPD中的AHR和气道炎症相关的研究。这些发现是将基因多态性与COPD病理生理学联系起来的重要一步，从而可能有助于未来更好地治疗这种进行性致残疾病。
