title: Association of cyclooxygenase-2 genetic variant with cardiovascular disease.
abstract: OBJECTIVE
  A genetic variant (rs20417) of the PTGS2 gene, encoding for COX-2, has been associated with decreased COX-2 activity and a decreased risk of cardiovascular disease (CVD). However, this genetic association and the role of COX-2 in CVD remain controversial.
  
  
  RESULTS
  The association of rs20417 with CVD was prospectively explored in 49 232 subjects (ACTIVE-A, CURE, epiDREAM/DREAM, ONTARGET, RE-LY, and WGHS) and the effect of potentially modifiable risk factors on the genetic association was further explored in 9363 INTERHEART participants. The effect of rs20417 on urinary thromboxane and prostacyclin metabolite concentrations was measured in 117 healthy individuals. Carriage of the rs20417 minor allele was associated with a decreased risk of major CVD outcomes (OR = 0.78, 95% CI: 0.70-0.87; P = 1.2 × 10(-5)). The genetic effect was significantly stronger in aspirin users (OR: 0.74, 95% CI: 0.64-0.84; P = 1.20 × 10(-5)) than non-users (OR: 0.87, 95% CI: 0.72-1.06; P = 0.16) (interaction P-value: 0.0041). Among patients with previous coronary artery disease (CAD), rs20417 carriers had a stronger protective effect on risk of major adverse events when compared with individuals without previous CAD (interaction P-value: 0.015). Carriers had significantly lower urinary levels of thromboxane (P = 0.01) and prostacyclin (P = 0.01) metabolites when compared with non-carriers.
  
  
  CONCLUSIONS
  The rs20417 polymorphism is associated with a reduced risk of major cardiovascular events and lower levels of thromboxane and prostacyclin. Our results suggest that a genetic decrease in COX-2 activity may be beneficial with respect to CVD risk, especially, in higher risk patients on aspirin.
authors.affiliation: Population Health Research Institute, Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada Population Genomics Program, Chanchlani Research Centre, McMaster University, Hamilton, Ontario, Canada Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Ross
authors.affiliation: Population Health Research Institute, Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Eikelboom
authors.affiliation: Population Health Research Institute, Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada Population Genomics Program, Chanchlani Research Centre, McMaster University, Hamilton, Ontario, Canada Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Sonia S
authors.initials: SS
authors.lastname: Anand
authors.affiliation: Department of Medical Sciences, Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden.
authors.forename: Niclas
authors.initials: N
authors.lastname: Eriksson
authors.affiliation: Population Health Research Institute, Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Hertzel C
authors.initials: HC
authors.lastname: Gerstein
authors.affiliation: Population Health Research Institute, Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Shamir
authors.initials: S
authors.lastname: Mehta
authors.affiliation: Population Health Research Institute, Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Connolly
authors.affiliation: Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Lynda
authors.initials: L
authors.lastname: Rose
authors.affiliation: Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA Harvard Medical School, Boston, MA, USA.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Ridker
authors.affiliation: Department of Medical Sciences, Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Wallentin
authors.affiliation: Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA Harvard Medical School, Boston, MA, USA.
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Chasman
authors.affiliation: Population Health Research Institute, Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Salim
authors.initials: S
authors.lastname: Yusuf
authors.affiliation: Population Health Research Institute, Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada Population Genomics Program, Chanchlani Research Centre, McMaster University, Hamilton, Ontario, Canada Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada Thrombosis and Atherosclerosis Research Institute, Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada pareg@mcmaster.ca.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Paré
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000031:analogs & derivatives / Q000652:urine; D000368:Aged; D001241:Aspirin / Q000627:therapeutic use; D051546:Cyclooxygenase 2 / Q000235:genetics*; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D015337:Multicenter Studies as Topic; D009203:Myocardial Infarction / Q000188:drug therapy / Q000235:genetics* / Q000652:urine; D011110:Polymorphism, Genetic / Q000235:genetics*; D011446:Prospective Studies; D016032:Randomized Controlled Trials as Topic; D020521:Stroke / Q000188:drug therapy / Q000235:genetics* / Q000652:urine; D013929:Thromboxane B2 / Q000031:analogs & derivatives / Q000652:urine
chemical_list: D016861:Cyclooxygenase Inhibitors; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; C028290:2,3-dinor-6-ketoprostaglandin F1alpha; C049235:11-dehydro-thromboxane B2; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D001241:Aspirin
keywords: Aspirin; Genetics; Myocardial infarction; Pharmacogenetics; Stroke