Ross Stephanie, Eikelboom John, Anand Sonia S, Eriksson Niclas, Gerstein Hertzel C, Mehta Shamir, Connolly Stuart J, Rose Lynda, Ridker Paul M, Wallentin Lars, Chasman Daniel I, Yusuf Salim, Paré Guillaume
Population Health Research Institute, Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada Population Genomics Program, Chanchlani Research Centre, McMaster University, Hamilton, Ontario, Canada Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada.
Population Health Research Institute, Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
Eur Heart J. 2014 Sep 1;35(33):2242-8a. doi: 10.1093/eurheartj/ehu168. Epub 2014 May 5.
A genetic variant (rs20417) of the PTGS2 gene, encoding for COX-2, has been associated with decreased COX-2 activity and a decreased risk of cardiovascular disease (CVD). However, this genetic association and the role of COX-2 in CVD remain controversial.
The association of rs20417 with CVD was prospectively explored in 49 232 subjects (ACTIVE-A, CURE, epiDREAM/DREAM, ONTARGET, RE-LY, and WGHS) and the effect of potentially modifiable risk factors on the genetic association was further explored in 9363 INTERHEART participants. The effect of rs20417 on urinary thromboxane and prostacyclin metabolite concentrations was measured in 117 healthy individuals. Carriage of the rs20417 minor allele was associated with a decreased risk of major CVD outcomes (OR = 0.78, 95% CI: 0.70-0.87; P = 1.2 × 10(-5)). The genetic effect was significantly stronger in aspirin users (OR: 0.74, 95% CI: 0.64-0.84; P = 1.20 × 10(-5)) than non-users (OR: 0.87, 95% CI: 0.72-1.06; P = 0.16) (interaction P-value: 0.0041). Among patients with previous coronary artery disease (CAD), rs20417 carriers had a stronger protective effect on risk of major adverse events when compared with individuals without previous CAD (interaction P-value: 0.015). Carriers had significantly lower urinary levels of thromboxane (P = 0.01) and prostacyclin (P = 0.01) metabolites when compared with non-carriers.
The rs20417 polymorphism is associated with a reduced risk of major cardiovascular events and lower levels of thromboxane and prostacyclin. Our results suggest that a genetic decrease in COX-2 activity may be beneficial with respect to CVD risk, especially, in higher risk patients on aspirin.
编码环氧化酶 - 2（COX - 2）的PTGS2基因的一个基因变异（rs20417）与COX - 2活性降低及心血管疾病（CVD）风险降低相关。然而，这种基因关联以及COX - 2在CVD中的作用仍存在争议。
在49232名受试者（ACTIVE - A、CURE、epiDREAM/DREAM、ONTARGET、RE - LY和WGHS）中前瞻性地探究rs20417与CVD的关联，并在9363名INTERHEART参与者中进一步探究潜在可改变风险因素对该基因关联的影响。在117名健康个体中测量rs20417对尿血栓素和前列环素代谢物浓度的影响。携带rs20417次要等位基因与主要CVD结局风险降低相关（比值比[OR]=0.78，95%置信区间[CI]：0.70 - 0.87；P = 1.2×10⁻⁵）。在阿司匹林使用者中，基因效应（OR：0.74，95%CI：0.64 - 0.84；P = 1.20×10⁻⁵）显著强于非使用者（OR：0.87，95%CI：0.72 - 1.06；P = 0.16）（交互P值：0.0041）。在既往有冠状动脉疾病（CAD）的患者中，与无既往CAD的个体相比，rs20417携带者对主要不良事件风险具有更强的保护作用（交互P值：0.015）。与非携带者相比，携带者的尿血栓素（P = 0.01）和前列环素（P = 0.01）代谢物水平显著更低。
rs20417多态性与主要心血管事件风险降低及血栓素和前列环素水平降低相关。我们的结果表明，COX - 2活性的基因降低可能对CVD风险有益，尤其是在服用阿司匹林的高风险患者中。
