Dept of Thoracic Medicine, Haukeland University Hospital, Bergen, Norway.
Eur Respir J. 2011 Feb;37(2):255-63. doi: 10.1183/09031936.00091709. Epub 2010 Jun 18.
Lack of reproducibility of findings has been a criticism of genetic association studies on complex diseases, such as chronic obstructive pulmonary disease (COPD). We selected 257 polymorphisms of 16 genes with reported or potential relationships to COPD and genotyped these variants in a case-control study that included 953 COPD cases and 956 control subjects. We explored the association of these polymorphisms to three COPD phenotypes: a COPD binary phenotype and two quantitative traits (post-bronchodilator forced expiratory volume in 1 s (FEV₁) % predicted and FEV₁/forced vital capacity (FVC)). The polymorphisms significantly associated to these phenotypes in this first study were tested in a second, family-based study that included 635 pedigrees with 1,910 individuals. Significant associations to the binary COPD phenotype in both populations were seen for STAT1 (rs13010343) and NFKBIB/SIRT2 (rs2241704) (p<0.05). Single-nucleotide polymorphisms rs17467825 and rs1155563 of the GC gene were significantly associated with FEV₁ % predicted and FEV₁/FVC, respectively, in both populations (p<0.05). This study has replicated associations to COPD phenotypes in the STAT1, NFKBIB/SIRT2 and GC genes in two independent populations, the associations of the former two genes representing novel findings.
研究结果缺乏可重复性一直是复杂疾病（如慢性阻塞性肺疾病，COPD）遗传关联研究的批评点。我们选择了 16 个与 COPD 有报道或潜在关系的基因中的 257 个多态性，并在一项包括 953 例 COPD 病例和 956 例对照的病例对照研究中对这些变体进行了基因分型。我们探讨了这些多态性与三种 COPD 表型的关联：COPD 二分表型和两个定量性状（支气管扩张剂后 1 秒用力呼气量（FEV₁）占预计值的百分比和 FEV₁/用力肺活量（FVC））。在这项首次研究中，与这些表型显著相关的多态性在第二个基于家族的研究中进行了测试，该研究包括 635 个家系，共 1910 人。在两个群体中，STAT1（rs13010343）和 NFKBIB/SIRT2（rs2241704）的多态性与 COPD 二分表型显著相关（p<0.05）。在两个群体中，GC 基因的单核苷酸多态性 rs17467825 和 rs1155563 与 FEV₁ %预测值和 FEV₁/FVC 分别显著相关（p<0.05）。本研究在两个独立的群体中复制了 STAT1、NFKBIB/SIRT2 和 GC 基因与 COPD 表型的关联，前两个基因的关联代表了新的发现。
