Effects of 5 ' regulatory-region polymorphisms on paraoxonase-gene (PON1) expression

Human HDL-associated paraoxonase (PON1) hydrolyzes a number of toxic organo phosphorous compounds and reduces oxidation of LDLs and HDLs. These propert ies of PON1 account for its ability to protect against pesticide poisonings and atherosclerosis. PON1 also hydrolyzes a number of lactone and cyclic-c arbonate drugs. Among individuals in a population, PON1 levels vary widely. We previously identified three polymorphisms in the PON1 regulatory region that affect expression levels in cultured human hepatocytes. In this study , we determined the genotypes of three regulatory-region polymorphisms for 376 white individuals and examined their effect on plasma-PON1 levels, dete rmined by rates of phenylacetate hydrolysis. The -108 polymorphism had a si gnificant effect on PON1-activity level, whereas the -162 polymorphism had a lesser effect. The -909 polymorphism, which is in linkage disequilibrium with the other sites, appears to have little or no independent effect on PO N1-activity level in vivo. Other studies have found that the L55M polymorph ism in the PON1-coding region is associated with differences in both PON1-m RNA and PON1-activity levels. The results presented here indicate that the L55M effect of lowered activity is not due to the amino acid change but is, rather, largely due to linkage disequilibrium with the -108 regulatory-reg ion polymorphism. The codon 55 polymorphism marginally appeared to account for 15.3% of the variance in PON1 activity, but this dropped to 5% after ad justments for the effects of the -108 and Q192R polymorphisms were made. Th e -108C/T polymorphism accounted for 22.8% of the observed variability in P ON1-expression levels, which was much greater than that attributable to the other PON1 polymorphisms. We also identified four sequence differences in the 3' UTR of the PON1 mRNA.