Centre for Inflammation and Tissue Repair, University College London, London, United Kingdom;
Centre for Respiratory Medicine, University College London, London, United Kingdom; and.
Am J Physiol Lung Cell Mol Physiol. 2014 Aug 15;307(4):L311-6. doi: 10.1152/ajplung.00128.2014. Epub 2014 Jun 27.
Proteinase-activated receptor-1 (PAR-1) plays a key role in mediating the interplay between coagulation and inflammation in response to injury. The aim of this study was to investigate the role of the promoter single-nucleotide polymorphism (SNP) rs2227744G>A in modulating PAR-1/F2R gene expression in the context of chronic obstructive pulmonary disease (COPD) and COPD exacerbations. The function of the rs2227744G>A SNP was investigated by using reporter gene assays. The frequency of the polymorphism in the UK population was assessed by genotyping 8,579 healthy individuals from the Whitehall II and English Longitudinal Study of Ageing cohorts. The rs2227744G>A SNP was genotyped in a carefully phenotyped cohort of 203 COPD cases and matched controls. The results were further replicated in two different COPD cohorts. The minor allele of the rs2227744G>A polymorphism was found to increase F2R expression by 2.6-fold (P < 0.001). The rs2227744G>A SNP was not significantly associated with COPD, or with lung function, in all cohorts. The minor allele of the SNP was found to be associated with protection from frequent exacerbations (P = 0.04) in the cohort of COPD patients for which exacerbation frequency was available. Considering exacerbations as a continuous variable, the presence of the minor allele was associated with a significantly lower COPD exacerbation rate (3.03 vs. 1.98 exacerbations/year, Mann-Whitney U-test P = 0.04). Taken together, these data do not support a role for the rs2227744G>A F2R polymorphism in the development of COPD but suggest a protective role for this polymorphism from frequent exacerbations. Studies in separate cohorts to replicate these findings are warranted.
蛋白酶激活受体-1（PAR-1）在介导损伤反应中凝血和炎症的相互作用中发挥关键作用。本研究旨在研究启动子单核苷酸多态性（SNP）rs2227744G>A 在慢性阻塞性肺疾病（COPD）和 COPD 加重的情况下调节 PAR-1/F2R 基因表达中的作用。通过使用报告基因检测研究 rs2227744G>A SNP 的功能。通过对来自 Whitehall II 和英国老龄化纵向研究队列的 8579 名健康个体进行基因分型来评估英国人群中多态性的频率。在经过精心表型分析的 203 例 COPD 病例和匹配对照的队列中对 rs2227744G>A SNP 进行了基因分型。结果在两个不同的 COPD 队列中得到了进一步验证。发现 rs2227744G>A 多态性的次要等位基因使 F2R 表达增加 2.6 倍（P<0.001）。在所有队列中，rs2227744G>A SNP 与 COPD 或肺功能均无显著相关性。在有 COPD 加重频率可用的 COPD 患者队列中，发现 SNP 的次要等位基因与频繁加重的保护作用相关（P=0.04）。考虑到加重作为连续变量，存在次要等位基因与 COPD 加重率显著降低相关（3.03 次/年与 1.98 次/年，Mann-Whitney U 检验 P=0.04）。总的来说，这些数据不支持 rs2227744G>A F2R 多态性在 COPD 发病机制中的作用，但表明该多态性对频繁加重具有保护作用。有必要在单独的队列中进行研究以复制这些发现。
