Abstract
Paroxonase-1 (PON1) is a key enzyme that inhibits low-density lipoprotein oxidation and consequently atherogenesis. Here, we assessed whether low serum PON1 activity associates with incident cardiovascular disease (CVD) in subjects with high levels of high-density cholesterol (HDL-C) and C-reactive protein (CRP), a marker of low-grade systemic inflammation. Cox proportional-hazards modeling of incident CVD risk (11 years mean follow-up) adjusted for relevant clinical and biomarker covariates was performed on a population-based study (N = 7766) stratified into three groups: low CRP—(LR; event rate 4.9%); low HDL-C/high CRP—(HR1; event rate 14.4%); and high HDL-C/high CRP—(HR2; event rate 7.6%). Modeling results for PON1 activity in HR2 were significant and robust (hazard ratio/SD unit—0.68, 95% CI 0.55–0.83, p = 0.0003), but not so for LR and HR1. Analyses in HR2 of the interaction of PON1 with HDL-C, apoA-I, apoA-II, and apoE levels were significant only for PON1 with apoE (hazard ratio—1.77, 95% CI 1.29–2.41, p = 0.0003). Subsequent subgroup analysis revealed inverse risk dependence for apoE at low PON1 levels. In conclusion, in a population-based study of subjects with concurrently high HDL-C and CRP levels, low serum PON1 activity associates with incident CVD risk with risk accentuated at low apoE levels.
Highlights
Paraoxonases make up a family of three enzymes (PON1, PON2, and PON3) with predominantly lactonase activity, each of which has been shown to manifest anti-atherogenic properties
Results of chi square testing, unadjusted ANOVA, and ANOVA adjusted for gender and age revealed significant differences among the low risk (LR), high risk 1 (HR1), and high-risk 2 (HR2) groups for all variables except ethanol use
Subsequent post-hoc testing revealed pair-wise significant differences between LR, HR1, and HR2 for all continuous variables except for: nonHDL-C (LR versus HR2, p = 0.078J.)C,litnr
Summary
Paraoxonases make up a family of three enzymes (PON1, PON2, and PON3) with predominantly lactonase activity, each of which has been shown to manifest anti-atherogenic properties. In light of the key role of PON1 in inhibiting oxidative changes in the HDL lipidome that acts to preserve anti-atherogenic functionality of HDL as described above, we hypothesized that low PON1 levels in subjects with high levels of HDL-C in the setting of chronic low-level inflammation would be at increased risk for CVD To test this hypothesis, we studied risk of incident CVD in subjects having concurrently high HDL-C and CRP levels as an indicator of chronic low grade inflammation in comparison to two other subject groups, one with low HDL-C and high CRP levels and the other with “normal” HDL-C and low CRP levels. The present study was carried out in the frame of the prospective Prevention of Renal and Vascular End-stage Disease (PREVEND) cohort study
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