Interaction of paraoxonase-192 polymorphism with low HDL-cholesterol in coronary artery disease risk.

Introduction: Coronary artery disease (CAD) is the main cause of mortality in developed countries. Increased lipid peroxidation is associated with accelerated progression of atherosclerosis. Paraoxonase (PON1) is an antioxidant enzyme bound to high-density lipoprotein (HDL), which protects against lipid peroxidation and coronary artery disease. PON1 activity is under genetic control and its molecular basis is a polymorphism in the PON1 gene that shows two common isoforms: the wild Q form (192 Gln) with high ability to protect LDL from lipid peroxidation in vitro, and the mutated R (Arg) form with lower ability. Aim: To explore the interaction of the R allele of the paraoxonase gene and low HDL-cholesterol concentrations in CAD risk. Methods: The study population consisted of 818 individuals, 298 coronary patients, aged 55.0±10.3 years, 78.9% male, and 520 age and gender matched healthy controls, aged 53.3±11.7 years, 72.5% male. Low HDL-cholesterol was defined as <0.90 mmol/l in men and <1.11 mmol/l in women. Comparisons of genotypes between cases and controls were performed by a chi-square test. Statistical significance was accepted at p<0.05. Odds ratios and 95% confidence intervals for the RR genotypes and HDL-deficient subjects were computed using univariate analysis (2x2 tables). To determine the interaction between the RR paraoxonase genotype and HDL-deficient subjects, we used 4x2 epidemiologic tables and synergy measures: the additive model (Rothman's synergy index, SI) and multiplicative model (Khoury's synergy index, SIM). The relative excess risk due to interaction (RERI) and the attributable proportion (AP) due to interaction (Rothman) were calculated. Results: The PON1 RR192 polymorphism was associated with coronary heart disease (OR=1.61; p=0.043) in the whole population. HDL-deficient subjects with the RR192 genotype showed increased risk for CAD (OR=17.38; p<0.0001) compared to those with normal HDL and RR192 (OR=1.39; p=0.348) and HDL-deficient subjects not carrying the RR genotype (OR=7.79; p<0.0001). Synergy measures were SI=2.3, SIM=1.6; RERI=9.2. Conclusion: These data suggest the existence of a synergistic effect of the PON1 RR192 genotype (with lower antioxidant ability) and HDL-deficient subjects in risk for development of CAD. The AP due to this interaction was 0.53, meaning that 53% of CAD was explained by this interaction.