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. Methods and Results— The promoter of COX-2 was screened for varia...
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| Published in | Arteriosclerosis, thrombosis, and vascular biology Vol. 22; no. 10; pp. 1631 - 1636 |
|---|---|
| Main Authors | , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Philadelphia, PA
Lippincott
01.10.2002
Hagerstown, MD American Heart Association, Inc |
| Subjects | |
| Online Access | Get full text |
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| 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. |
|---|---|
| AbstractList | 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.OBJECTIVECyclooxygenase (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).METHODS AND RESULTSThe 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.CONCLUSIONSFor several acute and chronic inflammatory diseases, -765G>C may influence the variability of response observed. 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. 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. 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. |
| Author | Papafili, Anastasia Marshall, Richard P. Brull, David J. McAnulty, Robin J. Humphries, Steve E. Hill, Michael R. Laurent, Geoffrey J. |
| Author_xml | – sequence: 1 givenname: Anastasia surname: Papafili fullname: Papafili, Anastasia organization: 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 – sequence: 2 givenname: Michael R. surname: Hill fullname: Hill, Michael R. organization: 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 – sequence: 3 givenname: David J. surname: Brull fullname: Brull, David J. organization: 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 – sequence: 4 givenname: Robin J. surname: McAnulty fullname: McAnulty, Robin J. organization: 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 – sequence: 5 givenname: Richard P. surname: Marshall fullname: Marshall, Richard P. organization: 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 – sequence: 6 givenname: Steve E. surname: Humphries fullname: Humphries, Steve E. organization: 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 – sequence: 7 givenname: Geoffrey J. surname: Laurent fullname: Laurent, Geoffrey J. organization: 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 |
| BackLink | http://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=13977987$$DView record in Pascal Francis https://www.ncbi.nlm.nih.gov/pubmed/12377741$$D View this record in MEDLINE/PubMed |
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| CODEN | ATVBFA |
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| Keywords | Human Prostaglandin-endoperoxide synthase Enzyme Pathogenesis Acute Genetic variant Exploration Genotype Inflammation Gene expression Genetic determinism Phenotype Aortocoronary Gene Bypass Surgery Graft Oxidoreductases |
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| PublicationTitle | Arteriosclerosis, thrombosis, and vascular biology |
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| References | (e_1_3_3_38_2) 1985; 5 e_1_3_3_17_2 e_1_3_3_16_2 e_1_3_3_18_2 (e_1_3_3_36_2) 1980; 2 e_1_3_3_13_2 e_1_3_3_12_2 e_1_3_3_37_2 e_1_3_3_15_2 e_1_3_3_34_2 (e_1_3_3_5_2) 1998; 582 e_1_3_3_14_2 e_1_3_3_35_2 e_1_3_3_32_2 e_1_3_3_33_2 e_1_3_3_11_2 e_1_3_3_30_2 (e_1_3_3_46_2) 1990; 115 e_1_3_3_10_2 e_1_3_3_31_2 e_1_3_3_40_2 e_1_3_3_6_2 e_1_3_3_8_2 e_1_3_3_7_2 e_1_3_3_28_2 e_1_3_3_9_2 (e_1_3_3_19_2) 2001; 299 e_1_3_3_27_2 e_1_3_3_29_2 e_1_3_3_24_2 (e_1_3_3_39_2) 1995; 762 e_1_3_3_23_2 e_1_3_3_26_2 e_1_3_3_45_2 e_1_3_3_25_2 e_1_3_3_2_2 e_1_3_3_20_2 e_1_3_3_43_2 e_1_3_3_1_2 e_1_3_3_44_2 e_1_3_3_4_2 e_1_3_3_22_2 e_1_3_3_41_2 e_1_3_3_3_2 e_1_3_3_21_2 e_1_3_3_42_2 12377724 - Arterioscler Thromb Vasc Biol. 2002 Oct 1;22(10):1516-8 |
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| Snippet | Objective—
Cyclooxygenase (COX)-2 is a key regulatory enzyme in the synthesis of prostanoids associated with trauma and inflammation. We investigated the COX-2... 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... OBJECTIVE: Cyclooxygenase (COX)-2 is a key regulatory enzyme in the synthesis of prostanoids associated with trauma and inflammation. We investigated the COX-2... |
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| SubjectTerms | 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 |
| Subtitle | Evidence of Role in Acute-Phase Inflammatory Response |
| Title | Common Promoter Variant in Cyclooxygenase-2 Represses Gene Expression |
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