Protective effect of the G-765C COX-2 polymorphism on subclinical atherosclerosis and inflammatory markers in asymptomatic subjects with cardiovascular risk factors

Abstract

Background: Cyclooxygenase (COX)-2, a key regulatory enzyme in prostanoid synthesis, plays an important role in inflammatory processes. The À765G > C COX-2 polymorphism has been associated with lower promoter activity in vitro and reduced levels of C-reactive protein (CRP) in atherosclerotic carriers of the C allele. However, its pathophysiological relevance in vivo has not been fully elucidated. Methods and results:We assessed the À 765G > C polymorphism and COX-2 expression in 220 asymptomatic subjects free of cardiovascular disease, in relation to global vascular risk, carotid intima-media thickness (IMT), and inflammatory markers (fibrinogen, Creactive protein [CRP], von Willebrand factor [vWF] and interleukin-6 [IL-6]). Genotype frequencies were: CC (7.7%), CG (34.5%), GG (57.7%). Among hypercholesterolemic subjects (n = 140), C allele carriers had lower COX-2 expression ( p < 0.05), reduced carotid IMT ( p < 0.01) and diminished levels of inflammatory markers CRP, vWF and IL-6 ( p < 0.05), as compared to GG homozygous subjects. The association between carotid IMT and COX-2 polymorphism remained significant after adjusting for cardiovascular risk factors and inflammatory markers ( p = 0.008). Conclusions: In asymptomatic hypercholesterolemic subjects the C allele of À 765G > C COX-2 polymorphism was associated with lower COX-2 expression, and reduced subclinical atherosclerosis and systemic inflammation compared with GG homozygous, thus conferring atherosclerosis protection in this cardiovascular risk population. D

LPS-mediated production of pro/anti-inflammatory cytokines and eicosanoids in whole blood samples: Biological effects of +896A/G TLR4 polymorphism in a Sicilian population of healthy subjects

“…SNPs Biological effect TLR4 (NM-138554.1) +896A/G (Asp299Gly; rs4986790) Determining a single amino acid substitution in the extracellular receptor domain and, hence, a blunted innate/inflammatory response to both foreign pathogens and endogenously generated inflammatory ligands ) PTGS2 (NM-000963) (Cox-2 gene) À765G/C (rs20417) Located within a putative binding site for the transcription factor Sp1, determining a reduction in the expression of Cox-2 enzyme (Cipollone et al, 2004;Orbe et al, 2006) …”

“…Changes in eicosanoid levels are also correlated with SNPs in the promoter region of PTGS2 and 5-Lo genes, respectively codifying the cyclooxygenase-(Cox)-2 and 5-lipoxygenase (5-Lo), enzymes involved in arachidonic acid metabolism. Two functional (À765G/C PTGS2 and À1708G/A 5-Lo) SNPs have recently been identified and associated with the major age-related diseases (Candore et al, 2007a,b;Caruso et al, 2009;Cipollone et al, 2004;In et al, 1997;Orbe et al, 2006). To clarify and confirm the possible pathophysiological effects of +896A/G TLR4 SNP (Balistreri et al, 2004(Balistreri et al, , 2010, we analysed the levels of IL-6, TNF-a, IL-10 and eicosanoids (LTB4 and PGE2) in LPS-stimulated whole blood samples in vitro of 50 young healthy Sicilians, screened for the presence of +896A/G TLR4 SNP.…”

Cox-2 gene polymorphism and IL-6 levels in coronary artery disease

“…Cox-2, a key regulatory enzyme in prostanoid synthesis, plays important roles in inflammatory processes. Cox-2 (-765G > C) polymorphism has been associated with lower promoter activity (Papafili et al, 2002;Orbe et al, 2006).…”

“…The Cox-2 (-765G > C) polymorphism was previously found to be associated with lower promoter activity (Papafili et al, 2002;Orbe et al, 2006).…”

A review of gene-drug interactions for nonsteroidal anti-inflammatory drug use in preventing colorectal neoplasia

“…59 The À765G4C polymorphism is relatively frequent (minor allele frequency B17%) 38 and has been shown to suppress COX2 promoter activity, 60 although not consistently so. 44 In atherosclerosis, patients with the À765CC genotype possess significantly lower levels of C-reactive protein and interleukin-6, biomarkers of inflammatory disease. Abbreviations: het, heterozygous; hzv, homozygous variant; wt, wild type.…”