Papafili Anastasia, Hill Michael R, Brull David J, McAnulty Robin J, Marshall Richard P, Humphries Steve E, Laurent Geoffrey J
Centre for Respiratory Research, Department of Medicine, Royal Free and University College Medical School, The Rayne Institute, London, UK.
Arterioscler Thromb Vasc Biol. 2002 Oct 1;22(10):1631-6. doi: 10.1161/01.atv.0000030340.80207.c5.
Cyclooxygenase (COX)-2 is a key regulatory enzyme in the synthesis of prostanoids associated with trauma and inflammation. We investigated the COX-2 gene for functional variants that may influence susceptibility to disease.
The promoter of COX-2 was screened for variants in healthy subjects by use of polymerase chain reaction-based methods. Promoter activity was investigated by using reporter expression experiments in human lung fibroblasts. Patients undergoing coronary artery bypass graft surgery, with measurements of plasma markers linked to COX-2 activity, were genotyped for association studies. A common COX-2 promoter variant, -765G>C, was found and shown to be carried by >25% of a group of healthy UK subjects. The -765C allele had significantly lower promoter activity compared with -765G, basally (28+/-3% lower, P<0.005) and in serum-stimulated cells (31+/-2% lower, P<0.005). In patients subjected to coronary artery bypass graft surgery, the magnitude of rise in levels of C-reactive protein (CRP) was strongly genotype dependent. Compared with -765G homozygotes, patients carrying the -765C allele had significantly lower plasma CRP levels at 1 to 4 days after surgery (14% lower at the peak of CRP levels on day 3, P<0.05 for all time points).
For several acute and chronic inflammatory diseases, -765G>C may influence the variability of response observed.
环氧化酶（COX）-2是与创伤和炎症相关的前列腺素合成中的关键调节酶。我们研究了COX-2基因中可能影响疾病易感性的功能变异。
采用基于聚合酶链反应的方法，在健康受试者中筛选COX-2启动子的变异。通过在人肺成纤维细胞中进行报告基因表达实验来研究启动子活性。对接受冠状动脉搭桥手术的患者进行基因分型以进行关联研究，同时测量与COX-2活性相关的血浆标志物。发现了一种常见的COX-2启动子变异，即-765G>C，在一组英国健康受试者中，携带该变异的比例超过25%。与-765G相比，-765C等位基因的启动子活性显著降低，在基础状态下（低28±3%，P<0.005）以及血清刺激的细胞中（低31±2%，P<0.005）。在接受冠状动脉搭桥手术的患者中，C反应蛋白（CRP）水平升高的幅度强烈依赖于基因型。与-765G纯合子相比，携带-765C等位基因的患者在术后1至4天的血浆CRP水平显著较低（在术后第3天CRP水平峰值时低14%，所有时间点P<0.05）。
对于几种急慢性炎症性疾病，-765G>C可能会影响所观察到的反应变异性。
