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.
Authors: Berran Yucesoy; Michael L Kashon; Victor J Johnson; Zana L Lummus; Kara Fluharty; Denyse Gautrin; André Cartier; Louis-Philippe Boulet; Joaquin Sastre; Santiago Quirce; Susan M Tarlo; Maria-Jesus Cruz; Xavier Munoz; Michael I Luster; David I Bernstein Journal: J Immunotoxicol Date: 2015-09-04 Impact factor: 3.000
Authors: Karen W Makar; Elizabeth M Poole; Alexa J Resler; Brenna Seufert; Karen Curtin; Sarah E Kleinstein; David Duggan; Richard J Kulmacz; Li Hsu; John Whitton; Christopher S Carlson; Christine F Rimorin; Bette J Caan; John A Baron; John D Potter; Martha L Slattery; Cornelia M Ulrich Journal: Cancer Causes Control Date: 2013-12 Impact factor: 2.506