Common promoter variant in cyclooxygenase-2 represses gene expression: evidence of role in acute-phase inflammatory response.
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.


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.
Papafili
Anastasia
A
Centre for Respiratory Research, Department of Medicine, Royal Free and University College Medical School, The Rayne Institute, London, UK.
Hill
Michael R
MR
Brull
David J
DJ
McAnulty
Robin J
RJ
Marshall
Richard P
RP
Humphries
Steve E
SE
Laurent
Geoffrey J
GJ
D024506:5' Flanking Region / Q000235:genetics; D000210:Acute-Phase Reaction / Q000235:genetics*; D000483:Alleles; D002097:C-Reactive Protein / Q000378:metabolism; D002460:Cell Line; D001026:Coronary Artery Bypass / Q000379:methods; D003324:Coronary Artery Disease / Q000097:blood / Q000601:surgery; D051546:Cyclooxygenase 2; D004247:DNA / Q000032:analysis; D004252:DNA Mutational Analysis; D005786:Gene Expression Regulation / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000235:genetics* / Q000502:physiology; D005838:Genotype; D006801:Humans; D007527:Isoenzymes / Q000235:genetics* / Q000502:physiology; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D010544:Peroxidases / Q000235:genetics / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000235:genetics* / Q000502:physiology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics* / Q000502:physiology; D011897:Random Allocation; D014162:Transfection
D007527:Isoenzymes; D008565:Membrane Proteins; D002097:C-Reactive Protein; D004247:DNA; D010544:Peroxidases; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases