Pharmacogenetic interaction between paraoxonase-1 gene promoter polymorphism C-107T and statin.

Objective: The aims of this study were to compare the impact of transcription factors, together with statin, on the paraoxonase promoter alleles defined by the C(-107T) polymorphism and to more clearly define regions of the paraoxonase promoter implicated in the actions of transcription factors.

Methods: Expression studies of promoter alleles were performed with reporter gene cassettes transfected into HepG2 cells, complemented by nuclease protection assays, electrophoretic mobility shift assays and statin therapy in patients.

Results: One region only of the minimal promoter fragment that up-regulates activity was protected by transcription factors and nuclear extracts. It spanned nucleotides -119 to -100, encompassing the C(-107)T polymorphism. Sp1 was effective alone in protecting this region, with its effect greatly enhanced by SREBP-2. The protective effect was much stronger for the C vs. T promoter allele. Expression studies confirmed the stimulatory influence of SREBP-2 was significantly stronger for the C promoter. Simvastatin up-regulated promoter activity of the C allele, but had a minor effect on the T allele. Hypercholesterolemic patients homozygous for the C allele showed a significant increase in serum paraoxonase-1 activity and mass during treatment with simvastatin, whereas patients homozygous for the T allele showed no increase.

Conclusions: The study has delimited the region responsive to transcription factors to a sequence surrounding the C(-107)T polymorphism of the paraoxonase-1 gene, and demonstrated an interaction at this sequence between Sp1 and SREBP-2. SREBP-2 and statin strongly up-regulated the C, but not the T allele. The results suggest a pharmacogenetic interaction between the promoter and simvastatin, which can influence serum paraoxonase in patients.