PON 2 gene variants are associated with clinical manifestations of cardiovascular disease in familial hypercholesterolemia patients

Abstract

Paraoxonase is an enzyme associated with the high-density lipoprotein (HDL) particle. It catalyses the hydrolysis of organophosphates and protects LDL from oxidative modification in vitro by hydrolyzing lipid peroxides, suggestive of a role for paraoxonase in the development of atherosclerosis. Two frequent mutations at the paraoxonase gene locus (PON 1) underlie the leucine (Leu allele) → methionine (Met allele) and the glutamine(Gln allele) → arginine(Arg allele) aminoacid substitutions at residues 55 and 192, respectively. These polymorphisms have been associated with increased risk for cardiovascular disease (CVD) in several studies, while others have not found this association. Recently, another member of the PON gene family designated PON 2 has been identified. While the PON 2 gene product is expressed ubiquitously, its physiological role is unknown. A common polymorphism at codon 311 (Cys→Ser) in the PON 2 gene has been described. In our study we assessed the frequency and genotype distribution of the PON 1 and PON 2 polymorphisms in 197 patients with familial hypercholesterolemia (FH), to determine the possible association between these mutations and susceptibility for CVD. The FH cohort group was divided into subjects with ( n=83) and without ( n=114) definite clinical manifestations of CVD (FH-Symptomatic and FH-Asymptomatic respectively). The control population consisted of 201 healthy normolipidemic blood donors. All subjects in this study were of Caucasian background. Genotypes were identified by PCR based analysis. With regard to the PON 1 polymorphisms 55 and 192, no different distributions of allele frequencies were found between the groups studied. However, we did show an association between the PON 2 311 polymorphism and CVD. The frequencies of PON 2 Ser 311 carriers (Ser/Ser and Cys/Ser) between FH-Symptomatic and both FH-Asymptomatic and controls did show a significant difference ( P=0.01 and P=0.02 respectively). In the FH-Symptomatic population, surprisingly, no subjects were homozygous for PON 2 Cys 311, whereas in the FH-Asymptomatic population nine persons (7.9%) and in the control group 12 persons (6.0%) were homozygous. Our data indicate that the common PON 2 polymorphism is associated with clinical manifestations of CVD in FH patients. While PON 2 Ser 311 carriers seem to be at risk, subjects with the Cys/Cys 311 genotype are likely to be protected against the development of premature CVD.