Published online before print July 18, 2002, doi: 10.1161/01.ATV.0000030340.80207.C5
© 2002 American Heart Association, Inc.
Atherosclerosis |
Common Promoter Variant in Cyclooxygenase-2 Represses Gene Expression
Evidence of Role in Acute-Phase Inflammatory Response
From the Centre for Respiratory Research (A.P., M.R.H., R.J.M., R.P.M., G.J.L.) and the Centre for Cardiovascular Genetics (D.J.B., S.E.H.), Department of Medicine, Royal Free and University College Medical School, The Rayne Institute, London, UK.
Correspondence to Michael R. Hill, DPhil, Centre for Respiratory Research, Department of Medicine, Royal Free and University College Medical School, The Rayne Institute, 5 University St, London WC1E 6JJ, UK. E-mail michael.hill{at}ucl.ac.uk
Abstract
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, -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).
Conclusions— For several acute and chronic inflammatory diseases, -765G>C may influence the variability of response observed.
Key Words: cyclooxygenase-2 • promoter variant • coronary artery bypass graft surgery • C-reactive protein • inflammation
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