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 nucleoticles - 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.