Paraoxonase-1 promoter polymorphism C--107T and serum apolipoprotein AI interact to modulate serum paraoxonase-1 status.

OBJECTIVES: The objective was to examine the hypothesis that modifications to paraoxonase-1 specific activity (SP, activity per unit mass peptide) could contribute to serum paraoxonase-1 status, a determinant of the clinical efficacy of the enzyme. METHODS: Enzyme activities and concentrations were determined in a large population (n=912) of patients and controls. SP were subsequently examined as a function of paraoxonase-1 gene polymorphisms, plasma lipids and lipoproteins, and physiological and pathophysiological parameters. RESULTS: Pathophysiological parameters (diabetes, metabolic syndrome, smoking, aging) did not promote variations in paraoxonase-1 SP, whilst coronary disease lowered SP (P<0.003). No serum lipid, apolipoprotein or lipoprotein component had an impact on specific activity, with the exception of apolipoprotein AI (P<0.005, both substrates). The paraoxonase-1 promoter C--107T and Q192R polymorphisms influenced SP and, together with apolipoprotein AI, were highly significant, independent determinants in regression models. There was an interaction between apolipoprotein AI and the C--107T polymorphism, which significantly modulated SP and serum paraoxonase-1 status. CONCLUSIONS: Enzyme inactivation giving rise to modulated activity per unit mass of peptide is not a major contributor to pathological effects of disease on serum paraoxonase-1 status. The C--107T polymorphism and serum apolipoprotein AI have major impacts individually on SP and also provide an example of gene-environment interaction to modulate such activities. These effects accentuate the differences between--107C and--107T allele carriers in terms of serum paraoxonase-1 status. The data underline the complexity of the factors that determine serum paraoxonase-1 status and suggest that the latter would benefit from therapeutic modulation of serum high density lipoproteins.

Small, dense lipoprotein particles and reduced paraoxonase-1 in patients with the metabolic syndrome.

The presence of the metabolic syndrome (World Health Organization definition) and its association with lipoprotein abnormalities suggestive of greater susceptibility to oxidative stress have been analyzed in patients with angiographically defined coronary artery disease. The odds ratio for the presence of the metabolic syndrome was significantly higher in coronary artery disease-positive patients (P < 0.001). The metabolic syndrome was also associated with more severe coronary disease (P < 0.01). Patients with the metabolic syndrome had significantly decreased low-density lipoprotein-cholesterol/apolipoprotein B and high-density lipoprotein-cholesterol/apolipoprotein AI ratios, indicative of the presence of small, dense lipoprotein particles. The syndrome was also associated with reduced concentrations and activities of the antioxidant enzyme, paraoxonase-1. The metabolic syndrome is characterized by smaller, denser lipoprotein particles that increase their susceptibility to oxidative modifications and diminished serum paraoxonase-1, which is a major determinant of the antioxidant capacity of high-density lipoproteins. These may be contributory factors to the increased presence and severity of coronary disease in such patients.