Promoter polymorphisms of human paraoxonase PON1 gene and serum paraoxonase activities and concentrations

Paraoxonase (PON) is a serum enzyme with a wide species distribution. It pr otects lipoproteins from toxic oxidative modifications and is an antiathero genic mechanism of major potential. Activity levels of PON are major determ inants of the protective function; consequently, factors that influence PON levels ore of particular relevance. The present study has identified 3 pol ymorphisms in the promoter region of the human PON1 gene. Cell transfection studies have revealed their variable impact on promoter activity, with up to 2-fold differences in reporter gene expression. Genotyping studies have established that the polymorphisms are frequent in the population, a findin g that is consistent with a major impact on PON concentrations. The physiol ogical relevance of the polymorphisms was underlined by showing that they a re associated with highly significant differences in serum concentrations a nd activities of PON. The study thus firmly establishes a genetic basis for variations in serum PON levels and, consequently, serum PON activity. It i s consistent with the suggestion that variations in a major antioxidant fun ction of high density lipoprotein are, to an important degree, genetically determined.