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Pharmacogenomic and pharmacoepigenomic analysis in individuals with familial hypercholesterolemia

Grant number: 16/25637-0
Support type:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): May 01, 2017
Field of knowledge:Health Sciences - Pharmacy
Principal Investigator:Rosario Dominguez Crespo Hirata
Grantee:Carolina Dagli Hernandez
Home Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated scholarship(s):19/19009-4 - In silico functionality prediction analysis of pharmacogenes and development of a pharmacogenetic score for Brazilian Familial Hypercholesterolemia patients, BE.EP.DD


Familial Hypercholesterolemia (FH) is a primary dyslipidemia with frequent monogenic inheritance resulting from functional mutations in the Low Density Lipoprotein Receptor (LDLR), apolipoprotein B (APOB) and Proprotein convertase subtilisin/kexin type 9 (PCSK9) genes, which codify proteins that regulate cholesterol homeostasis. The first-line treatment consists of the use of statins, such as atorvastatin and rosuvastatin. However, there is great inter-individual variability in the response, with some being resistant to treatment and others with serious adverse events, such as myopathy and hepatotoxicity. The response to statins can vary between 10% and 70%, being partly attributed to polymorphisms in the LDLR, PCSK9, APOE and HMGCR genes, among others. Objective: To study the association of genetic variants in individuals with FH with the response to lipid-lowering drugs and their interaction with the profile of circulating microRNAs. Patients and methods: Subjects with HF will be recruited at the Dante Pazzanese Institute of Cardiology (IDPC-SP). Biodemographic, clinical and treatment data will be collected from medical records and interviews. The clinical response will be assessed by reaching or not the therapeutic target (decrease of 50% of LDL cholesterol level), according to the level of cardiovascular risk. Adverse events and potential drug interactions will also be identified in the pharmacotherapy analysis. Blood samples will be collected for laboratory tests, DNA sequencing (molecular diagnosis of HF), and analysis of serum miRNAs. The genomic DNA will be extracted and the exon of 61 genes will be sequenced using the MiSeq Reagent kit (300 cycles) and the MiSeq (Illumina) equipment. The analysis of global expression of miRNAs will be performed in 10 HF individuals (with and without pharmacological response) by PCR array. Differentially expressed miRNAs will be analyzed in the other samples by qPCR. Statistical analysis of the results will be performed using the programs SPSS 20 (SPSS Inc.) and GraphPad Prism, version 1.03 (Sigma).Expected results and study contribution: We expect to identify the presence of known and new genetic variants related to the response to statins and to describe possible drug interactions related to the therapeutic response. The miRNA analysis of these patients may help to answer possible gaps in the relationship between the therapeutic response and pharmacogenes. With the results of this study, we hope to contribute to expand the possibilities of new pharmacotherapies and personalized therapy. (AU)