School of Public Health, The Institute for Chemical Carcinogenesis, The State Key Lab of Respiratory Disease, Guangzhou Medical University, 195 Dongfengxi Road, Guangzhou 510182, China.
Hum Genet. 2013 Apr;132(4):451-60. doi: 10.1007/s00439-013-1264-9. Epub 2013 Jan 16.
Lung inflammation is the major pathogenetic feature for both chronic obstructive pulmonary disease (COPD) and lung cancer. The nuclear factor-kappa B (NFκB) and its inhibitor (IκB) play crucial roles in inflammatory. Here, we tested the hypothesis that single nucleotide polymorphisms (SNPs) in NFκB/IκB confer consistent risks for COPD and lung cancer. Four putative functional SNPs (NFκB1: -94del>insATTG; NFκB2: -2966G>A; IκBα: -826C>T, 2758G>A) were analyzed in southern and validated in eastern Chineses to test their associations with COPD risk in 1,511 COPD patients and 1,677 normal lung function controls, as well as lung cancer risk in 1,559 lung cancer cases and 1,679 cancer-free controls. We found that the -94ins ATTG variants (ins/del + ins/ins) in NFκB1 conferred an increased risk of COPD (OR 1.27, 95% CI 1.06-1.52) and promoted COPD progression by accelerating annual FEV1 decline (P = 0.015). The 2758AA variant in IκBα had an increased risk of lung cancer (OR 1.53, 95% CI 1.30-1.80) by decreasing IκBα expression due to the modulation of microRNA hsa-miR-449a but not hsa-miR-34b. Furthermore, both adverse genotypes exerted effect on increasing lung cancer risk in individuals with pre-existing COPD, while the -94del>insATTG did not in those without pre-existing COPD. However, no significant association with COPD or lung cancer was observed for -2966G>A and -826C>T. Our data suggested a common susceptible mechanism of inflammation in lung induced by genetic variants in NFκB1 (-94del>ins ATTG) or IκBα (2758G>A) to predict risk of COPD or lung cancer.
肺部炎症是慢性阻塞性肺疾病（COPD）和肺癌的主要发病特征。核因子-κB（NFκB）及其抑制剂（IκB）在炎症中起着至关重要的作用。在这里，我们检验了一个假设，即 NFκB/IκB 中的单核苷酸多态性（SNP）赋予 COPD 和肺癌的一致风险。我们分析了四个假定的功能性 SNP（NFκB1：-94del>insATTG；NFκB2：-2966G>A；IκBα：-826C>T，2758G>A），并在南方进行了验证，在东部中国人中进行了验证，以测试它们与 1511 例 COPD 患者和 1677 例正常肺功能对照者的 COPD 风险的关联，以及与 1559 例肺癌病例和 1679 例无癌症对照者的肺癌风险的关联。我们发现，NFκB1 中的-94ins ATTG 变体（ins/del + ins/ins）增加了 COPD 的风险（OR 1.27，95%CI 1.06-1.52），并通过加速每年 FEV1 下降来促进 COPD 的进展（P=0.015）。IκBα 中的 2758AA 变体由于 microRNA hsa-miR-449a 的调节而降低了 IκBα 的表达，从而增加了肺癌的风险（OR 1.53，95%CI 1.30-1.80），但不影响 hsa-miR-34b。此外，在患有预先存在的 COPD 的个体中，这两种不利基因型都对增加肺癌风险产生了影响，而在没有预先存在的 COPD 的个体中，-94del>insATTG 则没有。然而，-2966G>A 和-826C>T 与 COPD 或肺癌均无显著相关性。我们的数据表明，NFκB1（-94del>ins ATTG）或 IκBα（2758G>A）中的遗传变异在肺部引起的炎症的共同易感性机制可以预测 COPD 或肺癌的风险。
