title: Both paraoxonase-1 genotype and activity do not predict the risk of future coronary artery disease; the EPIC-Norfolk Prospective Population Study.
abstract: BACKGROUND
  Paraoxonase-1 (PON1) is an antioxidant enzyme, that resides on high-density lipoprotein (HDL). PON1-activity, is heavily influenced by the PON1-Q192R polymorphism. PON1 is considered to protect against atherosclerosis, but it is unclear whether this relation is independent of its carrier, HDL. In order to evaluate the atheroprotective potential of PON1, we assessed the relationships among PON1-genotype, PON1-activity and risk of future coronary artery disease (CAD), in a large prospective case-control study.
  
  
  RESULTS
  Cases (n = 1138) were apparently healthy men and women aged 45-79 years who developed fatal or nonfatal CAD during a mean follow-up of 6 years. Controls (n = 2237) were matched by age, sex and enrollment time. PON1-activity was similar in cases and controls (60.7+/-45.3 versus 62.6+/-45.8 U/L, p = 0.3) and correlated with HDL-cholesterol levels (r = 0.16, p<0.0001). The PON1-Q192R polymorphism had a profound impact on PON1-activity, but did not predict CAD risk (Odds Ratio [OR] per R allele 0.98[0.84-1.15], p = 0.8). Using conditional logistic regression, quartiles of PON1-activity showed a modest inverse relation with CAD risk (OR for the highest versus the lowest quartile 0.77[0.63-0.95], p = 0.01; p-trend = 0.06). PON1-activity adjusted for Q192R polymorphism correlated better with HDL-cholesterol (r = 0.26, p<0.0001) and more linearly predicted CAD risk (0.79[0.64-0.98], p = 0.03; p-trend = 0.008). However, these relationships were abolished after adjustment for HDL (particles-cholesterol-size) and apolipoproteinA-I (0.94[0.74-1.18], p-trend = 0.3).
  
  
  CONCLUSIONS
  This study, shows that PON1-activity inversely relates to CAD risk, but not independent of HDL, due to its close association with the HDL-particle. These data strongly suggest that a low PON1-activity is not a causal factor in atherogenesis.
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands. r.s.birjmohun@amc.uva.nl
authors.forename: Rakesh S
authors.initials: RS
authors.lastname: Birjmohun
authors.forename: Menno
authors.initials: M
authors.lastname: Vergeer
authors.forename: Erik S G
authors.initials: ES
authors.lastname: Stroes
authors.forename: Manjinder S
authors.initials: MS
authors.lastname: Sandhu
authors.forename: Sally L
authors.initials: SL
authors.lastname: Ricketts
authors.forename: Michael W
authors.initials: MW
authors.lastname: Tanck
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Wareham
authors.forename: J Wouter
authors.initials: JW
authors.lastname: Jukema
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.forename: Kay-Tee
authors.initials: KT
authors.lastname: Khaw
authors.forename: S Matthijs
authors.initials: SM
authors.lastname: Boekholdt
mesh_terms: D000368:Aged; D043303:Aryldialkylphosphatase / Q000235:genetics*; D001317:Austria / Q000453:epidemiology; D016022:Case-Control Studies; D003324:Coronary Artery Disease / Q000201:enzymology* / Q000453:epidemiology / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012307:Risk Factors
chemical_list: D043303:Aryldialkylphosphatase; C468406:PON1 protein, human