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 Al (P < 0.005, both substrates). The paraoxonase-1 promoter C - 107T and Q192R polymorphisms influenced SP and, together with apolipoprotein Al, were highly significant, independent determinants in regression models. There was an interaction between apolipoprotein Al 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 Al 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. (c) 2005 Lippincott Williams & Wilkins.