Figarska Sylwia M, Vonk Judith M, Boezen H Marike
Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Physiol Genomics. 2014 Jun 15;46(12):411-7. doi: 10.1152/physiolgenomics.00178.2013. Epub 2014 May 1.
The nuclear factor (erythroid-derived 2)-like 2 (NFE2L2 or NRF2) gene regulates transcription of enzymes involved in cellular detoxification and lipids homeostasis. NFE2L2 is associated with pathophysiology of atherosclerosis and chronic obstructive pulmonary disease (COPD). Therefore we studied the relation between NFE2L2 and all-cause, cardiovascular, and COPD mortality and its associations with triglyceride and cholesterol levels. We genotyped five tagging single nucleotide polymorphisms (SNPs) (rs4243387, rs2364723, rs13001694, rs1806649, and rs6726395) in NFE2L2 in 1,390 subjects from the Vlagtwedde-Vlaardingen cohort. Participants were examined in 1989/1990 and followed up till the vital status evaluation on December 31st, 2008. Associations between SNPs and mortality were estimated by Cox proportional hazards regression, and associations between SNPs and triglyceride and cholesterol levels were tested with linear regression. After 18 yr, 284 (20.4%) subjects had died, 107 from cardiovascular disease and 20 from COPD. Minor allele carriers of rs13001694 had a significantly reduced risk of all-cause mortality compared with wild types: hazard ratio (HR) 0.8 [95% confidence interval (CI) 0.6 to 1.0]. Minor allele carriers of rs2364723 had significantly reduced risk of cardiovascular mortality: HR = 0.5 (95% CI: 0.3-0.7). This result was consistent in stratified analyses: females 0.4 (0.2-0.7), males 0.6 (0.3-0.9), never smokers 0.5 (0.2-1.1), ever smokers 0.5 (0.3-0.8). Minor allele carriers of rs1806649 had a markedly reduced COPD mortality: HR = 0.3 (95% CI: 0.1-0.9). Rs2364723 was associated with lower triglyceride levels. None of the SNPs was associated with cholesterol levels. This study shows for the first time that NFE2L2 is associated with reduced risk of all-cause, cardiovascular and COPD mortality in humans.
核因子（红系衍生2）样2（NFE2L2或NRF2）基因调控参与细胞解毒和脂质稳态的酶的转录。NFE2L2与动脉粥样硬化和慢性阻塞性肺疾病（COPD）的病理生理学相关。因此，我们研究了NFE2L2与全因死亡率、心血管疾病死亡率和COPD死亡率之间的关系，以及它与甘油三酯和胆固醇水平的关联。我们对来自Vlagtwedde-Vlaardingen队列的1390名受试者的NFE2L2基因中的五个标签单核苷酸多态性（SNP）（rs4243387、rs2364723、rs13001694、rs1806649和rs6726395）进行了基因分型。参与者在1989/1990年接受检查，并随访至2008年12月31日的生命状态评估。通过Cox比例风险回归估计SNP与死亡率之间的关联，并通过线性回归测试SNP与甘油三酯和胆固醇水平之间的关联。18年后，284名（20.4%）受试者死亡，其中107人死于心血管疾病，20人死于COPD。与野生型相比，rs13001694的次要等位基因携带者全因死亡率风险显著降低：风险比（HR）为0.8 [95%置信区间（CI）为0.6至1.0]。rs2364723的次要等位基因携带者心血管疾病死亡率风险显著降低：HR = 0.5（95% CI：0.3 - 0.7）。这一结果在分层分析中是一致的：女性为0.4（0.2 - 0.7），男性为0.6（0.3 - 0.9），从不吸烟者为0.5（0.2 - 1.1），曾经吸烟者为0.5（0.3 - 0.8）。rs1806649的次要等位基因携带者COPD死亡率显著降低：HR = 0.3（95% CI：0.1 - 0.9）。rs2364723与较低的甘油三酯水平相关。没有一个SNP与胆固醇水平相关。这项研究首次表明，NFE2L2与人类全因、心血管疾病和COPD死亡率风险降低相关。
