Common Promoter Variant in Cyclooxygenase-2 Represses Gene Expression Evidence of Role in Acute-Phase Inflammatory Response

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 22; no. 10; pp. 1631 - 1636
• Main Authors: Papafili, Anastasia, Hill, Michael R., Brull, David J., McAnulty, Robin J., Marshall, Richard P., Humphries, Steve E., Laurent, Geoffrey J.
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA Lippincott 01.10.2002; Hagerstown, MD American Heart Association, Inc
• Subjects: 5' Flanking Region - genetics; Acute-Phase Reaction - genetics; Alleles; Biological and medical sciences; C-Reactive Protein - metabolism; Cell Line; Coronary Artery Bypass - methods; Coronary Artery Disease - blood; Coronary Artery Disease - surgery; Cyclooxygenase 2; DNA - analysis; DNA Mutational Analysis; Gene Expression Regulation - genetics; Genetic Predisposition to Disease; Genetic Variation - genetics; Genetic Variation - physiology; Genotype; Humans; Isoenzymes - genetics; Isoenzymes - physiology; Male; Medical sciences; Membrane Proteins; Middle Aged; Peroxidases - genetics; Peroxidases - physiology; Promoter Regions, Genetic - genetics; Promoter Regions, Genetic - physiology; Prostaglandin-Endoperoxide Synthases - genetics; Prostaglandin-Endoperoxide Synthases - physiology; Random Allocation; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Surgery of the heart; Transfection; Human; Prostaglandin-endoperoxide synthase; Enzyme; Pathogenesis; Acute; Genetic variant; Exploration; Genotype; Inflammation; Gene expression; Genetic determinism; Phenotype; Aortocoronary; Gene; Bypass; Surgery; Graft; Oxidoreductases
• ISSN: 1079-5642; 1524-4636; 1524-4636
• DOI: 10.1161/01.ATV.0000030340.80207.C5

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.