UBC James Hogg Research Center, Providence Heart + Lung Institute, St, Paul's Hospital, Vancouver, B.C., Canada.
BMC Med Genet. 2011 Sep 8;12:117. doi: 10.1186/1471-2350-12-117.
Oxidative stress induced by smoking is considered to be important in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). Heme oxygenase-1 (HMOX1) is an essential enzyme in heme catabolism that is induced by oxidative stress and may play a protective role as an antioxidant in the lung. We determined whether HMOX1 polymorphisms were associated with lung function in COPD patients and whether the variants had functional effects.
We genotyped five single nucleotide polymorphisms (SNPs) in the HMOX1 gene in Caucasians who had the fastest (n = 278) and the slowest (n = 304) decline of FEV1 % predicted, selected from smokers in the NHLBI Lung Health Study. These SNPs were also studied in Caucasians with the lowest (n = 535) or the highest (n = 533) baseline lung function. Reporter genes were constructed containing three HMOX1 promoter polymorphisms and the effect of these polymorphisms on H2O2 and hemin-stimulated gene expression was determined. The effect of the HMOX1 rs2071749 SNP on gene expression in alveolar macrophages was investigated.
We found a nominal association (p = 0.015) between one intronic HMOX1 SNP (rs2071749) and lung function decline but this did not survive correction for multiple comparisons. This SNP was in perfect linkage disequilibrium with rs3761439, located in the promoter of HMOX1. We tested rs3761439 and two other putatively functional polymorphisms (rs2071746 and the (GT)n polymorphism) in reporter gene assays but no significant effects on gene expression were found. There was also no effect of rs2071749 on HMOX1 gene expression in alveolar macrophages.
We found no association of the five HMOX1 tag SNPs with lung function decline and no evidence that the three promoter polymorphisms affected the regulation of the HMOX1 gene.
吸烟引起的氧化应激被认为在慢性阻塞性肺疾病（COPD）的发病机制中很重要。血红素加氧酶-1（HMOX1）是血红素分解代谢中必不可少的酶，它受氧化应激诱导，在肺部可能作为抗氧化剂发挥保护作用。我们确定了 HMOX1 多态性是否与 COPD 患者的肺功能有关，以及这些变体是否具有功能效应。
我们在 NHLBI 肺健康研究中选择了吸烟人群中 FEV1%预计值下降最快（n = 278）和最慢（n = 304）的白种人，对 HMOX1 基因中的 5 个单核苷酸多态性（SNP）进行了基因分型。还在基线肺功能最低（n = 535）或最高（n = 533）的白种人中研究了这些 SNP。构建了包含三个 HMOX1 启动子多态性的报告基因，并确定了这些多态性对 H2O2 和血红素刺激基因表达的影响。研究了 HMOX1 rs2071749 单核苷酸多态性对肺泡巨噬细胞基因表达的影响。
我们发现一个内含子 HMOX1 SNP（rs2071749）与肺功能下降之间存在名义关联（p = 0.015），但在进行多次比较校正后未得到证实。该 SNP 与位于 HMOX1 启动子内的 rs3761439 完全连锁不平衡。我们在报告基因检测中测试了 rs3761439 以及另外两个假定的功能多态性（rs2071746 和（GT）n 多态性），但未发现对基因表达有显著影响。rs2071749 也未对肺泡巨噬细胞中 HMOX1 基因表达产生影响。
我们没有发现 5 个 HMOX1 标签 SNP 与肺功能下降有关，也没有证据表明三个启动子多态性影响 HMOX1 基因的调控。
