Objective-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. Methods and Results-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, Ϫ765GϾC, was found and shown to be carried by Ͼ25% of a group of healthy UK subjects. The Ϫ765C allele had significantly lower promoter activity compared with Ϫ765G, basally (28Ϯ3% lower, PϽ0.005) and in serum-stimulated cells (31Ϯ2% lower, PϽ0.005). 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 Ϫ765G homozygotes, patients carrying the Ϫ765C 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, PϽ0.05 for all time points). Key Words: cyclooxygenase-2 Ⅲ promoter variant Ⅲ coronary artery bypass graft surgery Ⅲ C-reactive protein Ⅲ inflammation C yclooxygenase (COX) is a key regulatory enzyme in eicosanoid metabolism, converting free arachidonic acid to prostaglandin (PG)H 2 , from which a number of prostanoids, including PGE 2 , PGI 2 , PGD 2 , and thromboxane, are produced. 1 The prostanoids are important mediators in the control of normal tissue homeostasis and regulate inflammation in response to trauma or infection. 2 Two isoforms of COX have been identified, COX-1 and COX-2, which have common and specific roles. 3 COX-1 is expressed constitutively in most cell types; however, COX-2 is inducible on cell activation and is mainly expressed at sites of inflammation. COX-2 expression is raised in several pathophysiological states, and the use of COX inhibitors to reduce COX-2 activity has proven beneficial in attenuating chronic inflammatory conditions, such as arthritis and inflammatory bowel disease. 4,5 Several million people worldwide regularly use COX inhibitors. Regular use has been shown to decrease the relative risk of developing cardiovascular disease, stroke, and colorectal cancer. 5,6 See page 1516
Conclusions-ForAlthough COX-2 is widely accepted as a proinflammatory agonist and is therefore a suitable target for treating chronic inflammatory disease, there is increasing evidence to suggest that COX-2 has other roles, including anti-inflammatory, antifibrotic, and antithrombotic properties. 7-9 These alternative roles challenge the dogma that COX-2 is ubiquitously a foe, and indeed, there is evidence indicating that with certain tissue injuries, a limited expression of COX-2 can result in pathology, as in pulmonary fibrosis. 8,10 It also appears that COX-...