title: Clinical and genetic association of serum paraoxonase and arylesterase activities with cardiovascular risk.
abstract: OBJECTIVE
  Diminished serum paraoxonase and arylesterase activities (measures of paraoxonase-1 [PON-1] function) in humans have been linked to heightened systemic oxidative stress and atherosclerosis risk. The clinical prognostic use of measuring distinct PON-1 activities has not been established, and the genetic determinants of PON-1 activities are not known.
  
  
  RESULTS
  We established analytically robust high-throughput assays for serum paraoxonase and arylesterase activities and measured these in 3668 stable subjects undergoing elective coronary angiography without acute coronary syndrome and were prospectively followed for major adverse cardiovascular events (MACE= death, myocardial infarction, stroke) over 3 years. Low serum arylesterase and paraoxonase activities were both associated with increased risk for MACE, with arylesterase activity showing greatest prognostic value (quartile 4 versus quartile 1; hazard ratio 2.63; 95% CI, 1.97-3.50; P<0.01). Arylesterase remained significant after adjusting for traditional risk factors, C-reactive protein, and creatinine clearance (hazard ratio, 2.20; 95% CI, 1.60-3.02; P<0.01), predicted future development of MACE in both primary and secondary prevention populations, and reclassified risk categories incrementally to traditional clinical variables. A genome-wide association study identified distinct single nucleotide polymorphisms within the PON-1 gene that were highly significantly associated with serum paraoxonase (1.18×10(-303)) or arylesterase (4.99×10(-116)) activity but these variants were not associated with either 3-year MACE risk in an angiographic cohort (n=2136) or history of either coronary artery disease or myocardial infarction in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis consortium (n≈80 000 subjects).
  
  
  CONCLUSIONS
  Diminished serum arylesterase activity, but not the genetic determinants of PON-1 functional measures, provides incremental prognostic value and clinical reclassification of stable subjects at risk of developing MACE.
authors.affiliation: Department of Cell Biology, Center for Cardiovascular Diagnostics and Prevention, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: W H Wilson
authors.initials: WH
authors.lastname: Tang
authors.forename: Jaana
authors.initials: J
authors.lastname: Hartiala
authors.forename: Yiying
authors.initials: Y
authors.lastname: Fan
authors.forename: Yuping
authors.initials: Y
authors.lastname: Wu
authors.forename: Alexandre F R
authors.initials: AF
authors.lastname: Stewart
authors.forename: Jeanette
authors.initials: J
authors.lastname: Erdmann
authors.forename: Sekar
authors.initials: S
authors.lastname: Kathiresan
authors.forename: Robert
authors.initials: R
authors.lastname: Roberts
authors.forename: Ruth
authors.initials: R
authors.lastname: McPherson
authors.forename: Hooman
authors.initials: H
authors.lastname: Allayee
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
mesh_terms: D000368:Aged; D043303:Aryldialkylphosphatase / Q000097:blood* / Q000235:genetics*; D015415:Biomarkers / Q000097:blood; D002265:Carboxylic Ester Hydrolases / Q000097:blood* / Q000235:genetics*; D002318:Cardiovascular Diseases / Q000201:enzymology / Q000453:epidemiology* / Q000235:genetics / Q000401:mortality; D016009:Chi-Square Distribution; D003324:Coronary Artery Disease / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics; D015536:Down-Regulation; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D057166:High-Throughput Screening Assays; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009203:Myocardial Infarction / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics; D009820:Ohio / Q000453:epidemiology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D020521:Stroke / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics; D013997:Time Factors
chemical_list: D015415:Biomarkers; D002265:Carboxylic Ester Hydrolases; C019734:arylesterase; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human