Analysis of paraoxonase (PON1) L55M status requires both genotype and phenotype

Paraoxonase (PON1) is tightly associated with high-density lipoprotein particles and is believed to contribute to the prevention of atherosclerosis by metabolizing oxidized lipids. PON1 also hydrolyses the bioactive oxon forms of organophosphorus pesticides such as parathion, diazinon and chlorpyrifos. Two common polymorphisms have been identified in the coding sequence of human PON1: L55M and R192Q. Several previous studies have found that the presence of the PON1(R192) allele raises the risk of cardiovascular disease while others found no correlation. The studies, however, have focused on the genotype of PON1 and not the expression level of the protein. We found that the PON1 expression level in plasma, as determined by the rates of paraoxon and diazoxon hydrolysis, varies widely among individuals and within a genotype. Previous studies found that individuals having Met at PON1(55) have lower levels of both PON1 mRNA and activity. In this study, we determined the plasma activity levels of PON1 and examined the relationships between PON1(55) genotype and PON1 level. As with PON1(192), we found considerable overlap in activity among the PON155 genotypes. Of the 317 individuals whose PON1 status was determined in this study, 48.9% were PON1(Q192) homozygotes. Analysis of the PON1(QQ192) population showed that while the average PON1 activity (diazoxon hydrolysis) was 12266 U/L for PON1(LL55) and 7777 U/L for PON1(MM55), a given PON1(MM55) individual could have more than twice the activity of a PON1(LL55) individual. PON1 status, which includes PON1 level as well as PON1(192) genotype, may be a better predictor for cardiovascular disease or organophosphate susceptibility than PON1 genotype alone. Pharmacogenetics 10:453-460 (C) 2000 Lippincott Williams & Wilkins.