ABSTRACT
WHAT IS KNOWN: SLCO1B1 polymorphisms have been reported to affect the responses to statin therapy. However, the association of these polymorphisms and lipid-lowering responses has been inconsistent. OBJECTIVE: To investigate the effect of SLCO1B1 c.388A>G, c.521T>C and g.89595T>C polymorphisms on the lipid-lowering response to simvastatin therapy in Thai hypercholesterolaemic patients. METHODS: Three hundred and 91 hypercholesterolaemic patients in Southern Thailand were enrolled and treated with simvastatin 20 or 40 mg per day. Among them, 191 and 200 patients were treated for 3 and 12 months, respectively. Serum lipids were measured before and after the treatment. SLCO1B1 c.388A>G, c.521T>C and g.89595T>C polymorphisms were analysed using polymerase chain reaction-high-resolution melting (PCR-HRM). RESULTS: The allele frequencies of the SLCO1B1 c.388A>G, c.521T>C and g.89595T>C polymorphisms in Thai hypercholesterolaemic patients were 74.9%, 11.8% and 37.2%, respectively. After treatment with 20-40 mg simvastatin daily for 3 and 12 months, TC, TG and LDL-C concentrations were significantly lower than at baseline (P < .05). However, there was no a significant change in serum HDL-C after simvastatin treatment for 3 and 12 months (P > .05). Moreover, there was no association between SLCO1B1 c.388A>G, c.521T>C and g.89595T>C polymorphisms and lipid-lowering response to 3 and 12 months of either 20 or 40 mg/day simvastatin treatment. WHAT IS NEW AND CONCLUSION: SLCO1B1 c.388A>G, c.521T>C and g.89595T>C polymorphisms may not be useful as genetic markers of lipid-lowering response to simvastatin therapy in Thai hypercholesterolaemic patients.
Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hypercholesterolemia/drug therapy , Hypercholesterolemia/genetics , Lipids/blood , Liver-Specific Organic Anion Transporter 1/genetics , Polymorphism, Single Nucleotide/genetics , Simvastatin/therapeutic use , Adult , Aged , Aged, 80 and over , Alleles , Biomarkers/blood , Female , Gene Frequency/genetics , Humans , Hypercholesterolemia/blood , Male , Middle Aged , ThailandABSTRACT
Induction of manganese superoxide dismutase (MnSOD) in response to oxidative stress has been well established in animals, tissues, and cell culture. However, the role of the human MnSOD (hMnSOD) promoter in stimulus-dependent activation of transcription is unknown. The hMnSOD promoter lacks both a TATA and a CAAT box but possesses several GC motifs. In a previous study, we showed that the basal promoter contains multiple Sp1 and AP-2 binding sites and that Sp1 is essential for the constitutive expression of the hMnSOD gene. In this study, we identified an Egr-1 binding site in the basal promoter of hMnSOD. We also found that the basal promoter is responsive to 12-O-tetradecanoylphorbol-13-acetate (TPA)-activated hMnSOD transcription in the human hepatocarcinoma cell line HepG2. The contributions of these binding sites and the roles of the transcription factors Egr-1, AP-2, and Sp1 in the activation of hMnSOD transcription by TPA were investigated by site-directed mutation analysis, Western blotting, and overexpression of transcription factors. The results showed that Sp1 plays a positive role for both basal and TPA-activated hMnSOD transcription, whereas overexpression of Egr-1 has a negative role in the basal promoter activity without any effect on TPA-mediated activation of hMnSOD transcription.
