Association study of 230 polymorphisms in 60 candidate genes and response to atorvastatin

• Grant number: 08/06667-9
• Support Opportunities: Regular Research Grants
• Start date: December 01, 2008
• End date: November 30, 2010
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Rosario Dominguez Crespo Hirata
• Grantee: Rosario Dominguez Crespo Hirata
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• City of the host institution: São Paulo

Abstract

The pharmacotherapy with statins, HMG-CoA reductase inhibitors, is an advance on hypercholesterolemia and atherosclerosis treatment with considerable benefits in reduction of the cardiovascular risk. However, the individual variability in response to therapy is a constant problem in the clinical practice. Several factors should be considered in the variability interpretations such as health status of the patient, prognosis, severity of the disease, quality of the prescribed medicine, adverse effects and the genetic profile of the patient. The genetic contribution in the benefit of the treatment for the patient and the occurence of adverse effects have brought a hughe recognition as an important issue to be investigated. In this matter, this study aims to investigate the farmacogenetics of the atorvastatin, potent lowering-cholesterol medicine, in our population. To achieve this objective, we sellected 230 polymorphisms in three main classes of genes (n=60): genes associated to farmacokinetics (absorption, distribution and metabolism), genes associated to pharmacodynamics (mechanism of action) and genes associated with the development of atherosclerosis. Two-hundred normolipidemic individuals and 250 individuals with hypercholesterolemia (HC) were included in the study. The HC individuals were treated with atorvastatin (10 mg/day/4 weeks). Blood samples were collected for genomic DNA extraction and measurements of the biochemical parameters. The gene polymorphisms will be analyzed by the genotyping system SNPlexTM that allows elavuate 48 polymorphisms simultaneously for each DNA sample. The polymorphisms that were not compatible with this system will be analyzed by the allelic discrimination system by real-time PCR TaqMan®. The results from this study may contribute with the kowledge of factors related to the interindividual variability of the response to statins. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

RODRIGUES, A. C.; SOBRINO, B.; GENVIGIR, F. D. V.; WILLRICH, M. A. V.; ARAZI, S. S.; DOREA, E. L.; BERNIK, M. M. S.; BERTOLAMI, M.; FALUDI, A. A.; BRION, M. J.; et al. Genetic variants in genes related to lipid metabolism and atherosclerosis, dyslipidemia and atorvastatin response. Clinica Chimica Acta, v. 417, p. 8-11, FEB 18 2013. (08/06667-9)

RODRIGUES, ALICE C.; PERIN, PAULA M. S.; PURIM, SHEILA G.; SILBIGER, VIVIAN N.; GENVIGIR, FABIANA D. V.; WILLRICH, MARIA ALICE V.; ARAZI, SIMONE S.; LUCHESSI, ANDRE D.; HIRATA, MARIO H.; BERNIK, MARCIA M. S.; et al. Pharmacogenetics of OATP Transporters Reveals That SLCO1B1 c.388A > G Variant Is Determinant of Increased Atorvastatin Response. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 12, n. 9, p. 5815-5827, SEP 2011. (08/06667-9)

WILLRICH, MARIA ALICE V.; RODRIGUES, ALICE C.; CERDA, ALVARO; GENVIGIR, FABIANA D. V.; ARAZI, SIMONE S.; DOREA, EGIDIO L.; BERNIK, MARCIA M. S.; BERTOLAMI, MARCELO C.; FALUDI, ANDRE; LARGURA, ALVARO; et al. Effects of atorvastatin on CYP3A4 and CYP3A5 mRNA expression in mononuclear cells and CYP3A activity in hypercholeresterolemic patients. Clinica Chimica Acta, v. 421, p. 157-163, JUN 5 2013. (08/06667-9)