Pharmacogenomics study: effects of hypolipidemic drugs on gene expression of transcription factors involved in cholesterol regulation

Abstract

The inhibitors of the cholesterol synthesis (statins) and absorption (ezetimibe) are potent hypolipidemic drugs. Pharmacogenetic studies have demonstrated that polymorphisms of the genes that regulate plasma cholesterol (LDLR, APOB, APOE and others) are related to differences in response to these therapeutic agents. The genes involved in the cholesterol synthesis (HMGCR), uptake (LDLR) e absorption (NPC1L1) are activated by binding of transcription factors and other regulatory proteins, such as Sterol Regulatory Element–Binding Protein 1 e 2 (SREBF1, SREBF2) and cleavage-activating protein (SCAP), to sterol response elements (SREs) in the promoter region of these genes. Polymorphisms of the SREBF1 e SCAP genes have been associated with differences in response to statins, however the molecular mechanisms are not completely elucidated yet.The aim of this study is to investigate the effects of hypolipidemic drugs on expression of transcription factors and target genes of hypolipidemic drugs. For this purpose, 200 hypercholesterolemic individuals (100 diabetics and 100 non-diabetics) will be sellected. These individuals will be treated with ezetimibe (10 mg/day/4weeks), sinvastatin (10 mg/day/4weeks) and combined therapy (sinvastatin + ezetimibe, 10 mg/day/4weeks). Blood samples will be collected for evaluation of the lipid profile, glucose, insulin, HBA1c, ALT and CK, and for extraction of genomic DNA and total RNA. The mRNA expression and polymorphisms of the genes SREBF1, SREBF2, SCAP, HMGCR, LDLR e NPC1L1 will be analyzed by Real Time RT-PCR and PCR-RFLP, respectivelly, in order to investigate the relationships between gene polymorphims and expresion and response to hypolipidemic drugs. We expected that the results of this study will contribute to the elucidation of the mechanisms involved in the farmacogenomics of hypolipidemic drugs and can became useful tools for prescription and therapeutic monitoring of hypercholesterolemic and diabetic patients in order to reduce the risk for cardiovascular diseases. (AU)