Genetic variants in genes related to lipid metabolism and atherosclerosis, dyslipidemia and atorvastatin response.

OBJECTIVE: Using candidate gene approach, we have investigated the effect of single nucleotide polymorphism (SNP) in genes related to lipid metabolism and atherosclerosis on dyslipidemia and atorvastatin response. METHODS: The study included 157 patients treated with atorvastatin and 145 controls. Genomic DNA was isolated and genotyped using SNPlex technology. RESULTS: Allele and genotype disease association test revealed that APOB rs693 (OR: 2.2 [1.5-3.2], p=0.0001) and CD36 rs1984112 (OR: 3.7 [1.9-7.0], p=0.0002) SNPs were independent risk factors for hypercholesterolemia. Only APOB rs693 T variant allele was associated with increased LDL cholesterol levels (>160mg/dL). After atorvastatin treatment (10mg/day/4weeks), LIPC -514T allele was positively associated with LDL cholesterol reduction. CONCLUSION: The current study reinforces the current knowledge that carrying APOB rs693 is an independent risk factor for dyslipidemia and higher LDL levels. Furthermore, we found that a variant of CD36 was associated with dyslipidemia as a risk (rs1984112) factor. Finally, atorvastatin response could be predicted by LIPC -514C>T SNP and physical activity. In conclusion, our data evidences the contribution of genetic markers and their interaction with environmental factor in the variability of statin response.

Potentiated cytotoxic effects of statins and ajoene in murine melanoma cells.

Because statins and ajoene inhibit the 3-hydroxy-3-methyl-glutaryl coenzyme A reductase, we evaluated the hypothesis that the cytotoxic effect of these compounds may be potentiated when both are used in combination on tumor cells. We showed that cotreatment of the murine melanoma B16F10 cell with statins (atorvastatin and pravastatin) and ajoene, all at nontoxic doses, dramatically increased their cytotoxicity. B16F10 cell death induced by statins, but not by ajoene, was prevented by mevalonate and geranylgeranylpyrophosphate. To our knowledge, this is the first report that the combination of statins and ajoene, which alters the mevalonate pathway, might potentiate their cytotoxic effects on tumor cells.

The genetic determinants of atorvastatin response.

The statins or HMG-CoA reductase inhibitors are considered one of the most effective classes of drugs for reducing LDL and total cholesterol. Although, statin treatment has beneficial effects in the prevention of cardiovascular disease, considerable inter-individual variation exists in response to statin therapy, as well as in the incidence of adverse effects. Genetic factors contribute to patients' inter-variability in the lipid-lowering response to statins,drug-interactions and the occurrence of muscle damage havebeen reported. However, studies investigating aspects of pharmacokinetics, pharmacodynamics and disease-related genes have found no association that could impact on the decisions to treat with statins. Improved strategies that assess the simultaneous influence of multiple relevant susceptibility factors on disease risk (eg, diet, lifestyle and gene effects) are required. Data from pharmacogenetics studies investigating the association between gene variation and drug response and/or susceptibility to adverse effects are promising and are expected to impact on the clinical treatment of hypercholesterolemia.