title: Polymorphisms in catechol-O-methyltransferase modify treatment effects of aspirin on risk of cardiovascular disease.
abstract: OBJECTIVE
  Catechol-O-methyltransferase (COMT), a key enzyme in catecholamine metabolism, is implicated in cardiovascular, sympathetic, and endocrine pathways. This study aimed to confirm preliminary association of COMT genetic variation with incident cardiovascular disease (CVD). It further aimed to evaluate whether aspirin, a commonly used CVD prevention agent, modified the potential association of COMT with incident CVD.
  
  
  RESULTS
  We examined COMT polymorphism rs4680 (MAF [minor allele frequency], 0.47), encoding a nonsynonymous methionine-to-valine substitution, in the Women's Genome Health Study (WGHS), a large population-based cohort of women with randomized allocation to aspirin or vitamin E when compared with placebo and 10-year follow-up. Rs4680 effects were confirmed with COMT polymorphism rs4818 and also examined in Coronary ARtery DIsease Genome-wide Replication and Meta-analysis/The Coronary Artery Disease Genetics Consortium, consortia for genome-wide association studies of coronary artery disease. Among WGHS women allocated to placebo (135 events/n=5811), the rs4680 valine allele was protective against incident CVD relative to the methionine (hazard ratio [HR; 95% confidence interval {CI}], 0.66 [0.51-0.84]; P=0.0007); an association also observed in Coronary ARtery DIsease Genome-wide Replication and Meta-analysis and The Coronary Artery Disease Genetics Consortium (combined P=2.4×10(-5)). In the WGHS, the rs4680 association was abolished by randomized allocation to aspirin, such that valine/valine women experienced higher CVD rates with aspirin allocation when compared with placebo (HR [95% CI], 1.85 [1.05-3.25]; P=0.033), whereas methionine/methionine women experienced lower rates (HR [95% CI], 0.60 [0.39-0.93]; P=0.023). Allocation to vitamin E also conferred higher but nonsignificant CVD rates on valine/valine (HR [95% CI], 1.50 [0.83-2.70]; P=0.180) when compared with significantly lower rates on methionine/methionine (HR [95% CI], 0.53 [0.34-0.84]; P=0.006) women. Rs4818 results were similar.
  
  
  CONCLUSIONS
  Common COMT polymorphisms were associated with incident CVD, and this association was modified by randomized allocation to aspirin or vitamin E. Replication of these findings is required.
authors.affiliation: From the Program in Placebo Studies, Division of General Medicine and Primary Care, Department of Medicine, Beth Israel Deaconess Medical Center (K.T.H., R.B.D., I.K., T.J.K.), Division of Preventative Medicine, Brigham and Women's Hospital (J.E.B., P.M.R., D.I.C.), and Department of Medicine, Brigham and Women's Hospital (J.L.), Harvard Medical School, Boston, MA (K.T.H., R.B.D., I.K., T.J.K, J.E.B., P.M.R., D.I.C, J.L., M.A.M.); Department of Cardiovascular Sciences, Clinical Research Centre, Glenfield General Hospital, University of Leicester, Leicester, United Kingdom (C.P.N., N.J.S.); Department of Psychology, Plymouth University, Plymouth, United Kingdom (I.K.); and Cardiovascular Epidemiology Research Unit, Division of Cardiology, Beth Israel Deaconess Medical Center, Harvard Medical School and Harvard School of Public Health Boston, MA (M.A.M.). kthall@bidmc.harvard.edu.
authors.forename: Kathryn T
authors.initials: KT
authors.lastname: Hall
authors.affiliation: From the Program in Placebo Studies, Division of General Medicine and Primary Care, Department of Medicine, Beth Israel Deaconess Medical Center (K.T.H., R.B.D., I.K., T.J.K.), Division of Preventative Medicine, Brigham and Women's Hospital (J.E.B., P.M.R., D.I.C.), and Department of Medicine, Brigham and Women's Hospital (J.L.), Harvard Medical School, Boston, MA (K.T.H., R.B.D., I.K., T.J.K, J.E.B., P.M.R., D.I.C, J.L., M.A.M.); Department of Cardiovascular Sciences, Clinical Research Centre, Glenfield General Hospital, University of Leicester, Leicester, United Kingdom (C.P.N., N.J.S.); Department of Psychology, Plymouth University, Plymouth, United Kingdom (I.K.); and Cardiovascular Epidemiology Research Unit, Division of Cardiology, Beth Israel Deaconess Medical Center, Harvard Medical School and Harvard School of Public Health Boston, MA (M.A.M.).
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Nelson
authors.affiliation: From the Program in Placebo Studies, Division of General Medicine and Primary Care, Department of Medicine, Beth Israel Deaconess Medical Center (K.T.H., R.B.D., I.K., T.J.K.), Division of Preventative Medicine, Brigham and Women's Hospital (J.E.B., P.M.R., D.I.C.), and Department of Medicine, Brigham and Women's Hospital (J.L.), Harvard Medical School, Boston, MA (K.T.H., R.B.D., I.K., T.J.K, J.E.B., P.M.R., D.I.C, J.L., M.A.M.); Department of Cardiovascular Sciences, Clinical Research Centre, Glenfield General Hospital, University of Leicester, Leicester, United Kingdom (C.P.N., N.J.S.); Department of Psychology, Plymouth University, Plymouth, United Kingdom (I.K.); and Cardiovascular Epidemiology Research Unit, Division of Cardiology, Beth Israel Deaconess Medical Center, Harvard Medical School and Harvard School of Public Health Boston, MA (M.A.M.).
authors.forename: Roger B
authors.initials: RB
authors.lastname: Davis
authors.affiliation: From the Program in Placebo Studies, Division of General Medicine and Primary Care, Department of Medicine, Beth Israel Deaconess Medical Center (K.T.H., R.B.D., I.K., T.J.K.), Division of Preventative Medicine, Brigham and Women's Hospital (J.E.B., P.M.R., D.I.C.), and Department of Medicine, Brigham and Women's Hospital (J.L.), Harvard Medical School, Boston, MA (K.T.H., R.B.D., I.K., T.J.K, J.E.B., P.M.R., D.I.C, J.L., M.A.M.); Department of Cardiovascular Sciences, Clinical Research Centre, Glenfield General Hospital, University of Leicester, Leicester, United Kingdom (C.P.N., N.J.S.); Department of Psychology, Plymouth University, Plymouth, United Kingdom (I.K.); and Cardiovascular Epidemiology Research Unit, Division of Cardiology, Beth Israel Deaconess Medical Center, Harvard Medical School and Harvard School of Public Health Boston, MA (M.A.M.).
authors.forename: Julie E
authors.initials: JE
authors.lastname: Buring
authors.affiliation: From the Program in Placebo Studies, Division of General Medicine and Primary Care, Department of Medicine, Beth Israel Deaconess Medical Center (K.T.H., R.B.D., I.K., T.J.K.), Division of Preventative Medicine, Brigham and Women's Hospital (J.E.B., P.M.R., D.I.C.), and Department of Medicine, Brigham and Women's Hospital (J.L.), Harvard Medical School, Boston, MA (K.T.H., R.B.D., I.K., T.J.K, J.E.B., P.M.R., D.I.C, J.L., M.A.M.); Department of Cardiovascular Sciences, Clinical Research Centre, Glenfield General Hospital, University of Leicester, Leicester, United Kingdom (C.P.N., N.J.S.); Department of Psychology, Plymouth University, Plymouth, United Kingdom (I.K.); and Cardiovascular Epidemiology Research Unit, Division of Cardiology, Beth Israel Deaconess Medical Center, Harvard Medical School and Harvard School of Public Health Boston, MA (M.A.M.).
authors.forename: Irving
authors.initials: I
authors.lastname: Kirsch
authors.affiliation: From the Program in Placebo Studies, Division of General Medicine and Primary Care, Department of Medicine, Beth Israel Deaconess Medical Center (K.T.H., R.B.D., I.K., T.J.K.), Division of Preventative Medicine, Brigham and Women's Hospital (J.E.B., P.M.R., D.I.C.), and Department of Medicine, Brigham and Women's Hospital (J.L.), Harvard Medical School, Boston, MA (K.T.H., R.B.D., I.K., T.J.K, J.E.B., P.M.R., D.I.C, J.L., M.A.M.); Department of Cardiovascular Sciences, Clinical Research Centre, Glenfield General Hospital, University of Leicester, Leicester, United Kingdom (C.P.N., N.J.S.); Department of Psychology, Plymouth University, Plymouth, United Kingdom (I.K.); and Cardiovascular Epidemiology Research Unit, Division of Cardiology, Beth Israel Deaconess Medical Center, Harvard Medical School and Harvard School of Public Health Boston, MA (M.A.M.).
authors.forename: Murray A
authors.initials: MA
authors.lastname: Mittleman
authors.affiliation: From the Program in Placebo Studies, Division of General Medicine and Primary Care, Department of Medicine, Beth Israel Deaconess Medical Center (K.T.H., R.B.D., I.K., T.J.K.), Division of Preventative Medicine, Brigham and Women's Hospital (J.E.B., P.M.R., D.I.C.), and Department of Medicine, Brigham and Women's Hospital (J.L.), Harvard Medical School, Boston, MA (K.T.H., R.B.D., I.K., T.J.K, J.E.B., P.M.R., D.I.C, J.L., M.A.M.); Department of Cardiovascular Sciences, Clinical Research Centre, Glenfield General Hospital, University of Leicester, Leicester, United Kingdom (C.P.N., N.J.S.); Department of Psychology, Plymouth University, Plymouth, United Kingdom (I.K.); and Cardiovascular Epidemiology Research Unit, Division of Cardiology, Beth Israel Deaconess Medical Center, Harvard Medical School and Harvard School of Public Health Boston, MA (M.A.M.).
authors.forename: Joseph
authors.initials: J
authors.lastname: Loscalzo
authors.affiliation: From the Program in Placebo Studies, Division of General Medicine and Primary Care, Department of Medicine, Beth Israel Deaconess Medical Center (K.T.H., R.B.D., I.K., T.J.K.), Division of Preventative Medicine, Brigham and Women's Hospital (J.E.B., P.M.R., D.I.C.), and Department of Medicine, Brigham and Women's Hospital (J.L.), Harvard Medical School, Boston, MA (K.T.H., R.B.D., I.K., T.J.K, J.E.B., P.M.R., D.I.C, J.L., M.A.M.); Department of Cardiovascular Sciences, Clinical Research Centre, Glenfield General Hospital, University of Leicester, Leicester, United Kingdom (C.P.N., N.J.S.); Department of Psychology, Plymouth University, Plymouth, United Kingdom (I.K.); and Cardiovascular Epidemiology Research Unit, Division of Cardiology, Beth Israel Deaconess Medical Center, Harvard Medical School and Harvard School of Public Health Boston, MA (M.A.M.).
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.affiliation: From the Program in Placebo Studies, Division of General Medicine and Primary Care, Department of Medicine, Beth Israel Deaconess Medical Center (K.T.H., R.B.D., I.K., T.J.K.), Division of Preventative Medicine, Brigham and Women's Hospital (J.E.B., P.M.R., D.I.C.), and Department of Medicine, Brigham and Women's Hospital (J.L.), Harvard Medical School, Boston, MA (K.T.H., R.B.D., I.K., T.J.K, J.E.B., P.M.R., D.I.C, J.L., M.A.M.); Department of Cardiovascular Sciences, Clinical Research Centre, Glenfield General Hospital, University of Leicester, Leicester, United Kingdom (C.P.N., N.J.S.); Department of Psychology, Plymouth University, Plymouth, United Kingdom (I.K.); and Cardiovascular Epidemiology Research Unit, Division of Cardiology, Beth Israel Deaconess Medical Center, Harvard Medical School and Harvard School of Public Health Boston, MA (M.A.M.).
authors.forename: Paul M
authors.initials: PM
authors.lastname: Ridker
authors.affiliation: From the Program in Placebo Studies, Division of General Medicine and Primary Care, Department of Medicine, Beth Israel Deaconess Medical Center (K.T.H., R.B.D., I.K., T.J.K.), Division of Preventative Medicine, Brigham and Women's Hospital (J.E.B., P.M.R., D.I.C.), and Department of Medicine, Brigham and Women's Hospital (J.L.), Harvard Medical School, Boston, MA (K.T.H., R.B.D., I.K., T.J.K, J.E.B., P.M.R., D.I.C, J.L., M.A.M.); Department of Cardiovascular Sciences, Clinical Research Centre, Glenfield General Hospital, University of Leicester, Leicester, United Kingdom (C.P.N., N.J.S.); Department of Psychology, Plymouth University, Plymouth, United Kingdom (I.K.); and Cardiovascular Epidemiology Research Unit, Division of Cardiology, Beth Israel Deaconess Medical Center, Harvard Medical School and Harvard School of Public Health Boston, MA (M.A.M.).
authors.forename: Ted J
authors.initials: TJ
authors.lastname: Kaptchuk
authors.affiliation: From the Program in Placebo Studies, Division of General Medicine and Primary Care, Department of Medicine, Beth Israel Deaconess Medical Center (K.T.H., R.B.D., I.K., T.J.K.), Division of Preventative Medicine, Brigham and Women's Hospital (J.E.B., P.M.R., D.I.C.), and Department of Medicine, Brigham and Women's Hospital (J.L.), Harvard Medical School, Boston, MA (K.T.H., R.B.D., I.K., T.J.K, J.E.B., P.M.R., D.I.C, J.L., M.A.M.); Department of Cardiovascular Sciences, Clinical Research Centre, Glenfield General Hospital, University of Leicester, Leicester, United Kingdom (C.P.N., N.J.S.); Department of Psychology, Plymouth University, Plymouth, United Kingdom (I.K.); and Cardiovascular Epidemiology Research Unit, Division of Cardiology, Beth Israel Deaconess Medical Center, Harvard Medical School and Harvard School of Public Health Boston, MA (M.A.M.).
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Chasman
mesh_terms: D019943:Amino Acid Substitution; D001241:Aspirin / Q000494:pharmacology / Q000627:therapeutic use*; D002318:Cardiovascular Diseases / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics / Q000517:prevention & control*; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D055106:Genome-Wide Association Study; D006801:Humans; D015994:Incidence; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D011446:Prospective Studies; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors; D014810:Vitamin E / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D014810:Vitamin E; C588010:COMT protein, human; D002394:Catechol O-Methyltransferase; D001241:Aspirin
keywords: aspirin; catecholamines; vitamin E