Background
Paraoxonase-1 (PON1) is a potent antioxidant enzyme bound to high-density lipoprotein (HDL). Its activity, but not its concentration, is controlled by the PON1 Q192R polymorphism. PON1 is considered to protect against atherogenesis, but it is unclear whether this relation is independent of its carrier, HDL.
Objective
To evaluate the predictive value of PON1 for coronary artery disease (CAD) we assessed PON1 activity and genotype (Q192R polymorphism) in a large cohort.
Methods and results
We performed a case-control study nested in the prospective EPIC-Norfolk cohort. 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 and sex. Serum PON1 activity was lower in cases vs. controls (59.9 ± 44.6 U/L vs. 63.4 ± 46.7 U/L, p=0.020) and correlated with HDL cholesterol (r= 0.16, p<0.0001). Whereas the PON1 Q192R polymorphism strongly controlled PON1 activity (QQ: 27 ± 9, QR: 87 ± 27 and RR 152 ± 44 U/L), it was not related to the risk of future CAD (Odds Ratio [OR] per R allele 0.98 [0.84–1.15], p=0.84). Using conditional logistic regression, quartiles of PON1 activity showed a modest inverse relation with CAD risk (OR for the highest vs. the lowest quartile 0.77 [0.63– 0.95], p=0.013; p for trend over quartiles 0.064). PON1 activity adjusted for Q192R genotype - a proxy for PON1 concentration -correlated better with HDL cholesterol (r=0.29, p<0.0001) and strongly predicted CAD risk (OR for the highest versus the lowest quartile 0.72 (0.58 – 0.91), p for trend over quartiles = 0.005). However, this relation was abolished after adjustment for HDL related parameters (HDL particle number, HDL cholesterol, HDL size and apolipoprotein A-I; OR for highest vs. lowest quartile 0.87 [0.66 –1.16], p for trend over quartiles = 0.13).
Conclusion
In the largest prospective study to date, we show that PON1 activity inversely relates to CAD risk, but not independently of HDL, presumably due to its close association with the HDL particle. Since the Q192R polymorphism profoundly affects lifelong PON1 activity, our inability to demonstrate a relation between the Q192R polymorphism and CAD risk suggests that PON1 activity is not a causal factor in atherogenesis.
Paraoxonase 1 gene (Q192R) polymorphism confers susceptibility to coronary artery disease in type 2 diabetes patients: Evidence from case-control studies