Polymorphisms in the human paraoxonase (PON1) promoter

Paraoxonase (PON1) is a protein component of high-density lipoprotein (HDL) particles that protects against oxidative damage to both low-density lipop rotein and HDL and detoxifies organophosphorus pesticides and nerve agents. A wide range of expression levels of PON1 among individuals has been obser ved. We examined the promoter region of PON1 for genetic factors that might affect PON1 activity levels. We conducted a deletion analysis of the PON1 promoter region in transient transfection assays and found that cell-type s pecific promoter elements for liver and kidney are present in the first 200 bp upstream of the coding sequence. Sequence analysis of DNA from a BAC cl one and a YAC clone identified five polymorphisms in the first 1000 bases u pstream of the coding region at positions -108, -126, -162, -832 and -909. Additionally, the promoter sequences of two individuals expressing high lev els of PON1 and two individuals expressing low levels of PON1 were analysed , The two polymorphisms at -126 and -832 had no apparent effect on expressi on level in the reporter gene assay. The polymorphisms at position -909, -1 62 (a potential NF-1 transcription factor binding site) and -108 (a potenti al SP1 binding site) each have approximately a two-fold effect on expressio n level. The expression level effects of the three polymorphisms appear not to be strictly additive and may depend on context effects. Pharmacogenetic s 11:77-84 (C) 2001 Lippincott Williams & Wilkins.