UBC James Hogg Research Centre, Providence Heart + Lung Institute, St. Paul's Hospital, Vancouver, British Columbia, Canada.
Physiol Genomics. 2012 Aug 1;44(15):754-63. doi: 10.1152/physiolgenomics.00027.2012. Epub 2012 Jun 12.
An oxidant-antioxidant imbalance in the lung contributes to the development of chronic obstructive pulmonary disease (COPD) that is caused by a complex interaction of genetic and environmental risk factors. Nuclear erythroid 2-related factor 2 (NFE2L2 or NRF2) is a critical molecule in the lung's defense mechanism against oxidants. We investigated whether polymorphisms in the NFE2L2 pathway affected the rate of decline of lung function in smokers from the Lung Health Study (LHS)(n = 547) and in a replication set, the Vlagtwedde-Vlaardingen cohort (n = 533). We selected polymorphisms in NFE2L2 in genes that positively or negatively regulate NFE2L2 transcriptional activity and in genes that are regulated by NFE2L2. Polymorphisms in 11 genes were significantly associated with rate of lung function decline in the LHS. One of these polymorphisms, rs11085735 in the KEAP1 gene, was previously shown to be associated with the level of lung function in the Vlagtwedde-Vlaardingen cohort but not with decline of lung function. Of the 23 associated polymorphisms in the LHS, only rs634534 in the FOSL1 gene showed a significant association in the Vlagtwedde-Vlaardingen cohort with rate of lung function decline, but the direction of the association was not consistent with that in the LHS. In summary, despite finding several nominally significant polymorphisms in the LHS, none of these associations were replicated in the Vlagtwedde-Vlaardingen cohort, indicating lack of effect of polymorphisms in the NFE2L2 pathway on the rate of decline of lung function.
肺部氧化还原失衡导致慢性阻塞性肺疾病（COPD）的发生，这是由遗传和环境风险因素的复杂相互作用引起的。核红细胞 2 相关因子 2（NFE2L2 或 NRF2）是肺部对抗氧化剂防御机制中的关键分子。我们研究了 NFE2L2 通路中的多态性是否会影响来自肺健康研究（LHS）的吸烟者（n=547）和复制组，Vlagtwedde-Vlaardingen 队列（n=533）的肺功能下降速度。我们选择了正向或负向调节 NFE2L2 转录活性的 NFE2L2 通路中的基因和受 NFE2L2 调节的基因中的多态性。LHS 中 11 个基因的多态性与肺功能下降速度显著相关。KEAP1 基因中的 rs11085735 多态性先前与 Vlagtwedde-Vlaardingen 队列的肺功能水平相关，但与肺功能下降无关。在 LHS 中 23 个相关多态性中，只有 FOSL1 基因中的 rs634534 在 Vlagtwedde-Vlaardingen 队列中与肺功能下降速度呈显著相关，但关联方向与 LHS 不一致。总之，尽管在 LHS 中发现了几个名义上显著的多态性，但在 Vlagtwedde-Vlaardingen 队列中没有一个得到复制，这表明 NFE2L2 通路中的多态性对肺功能下降速度没有影响。
