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Genomics, epigenomics and pharmacogenomics characterization of familial hypercholesterolemia in the Brazilian population

Grant number: 16/12899-6
Support type:Research Projects - Thematic Grants
Duration: March 01, 2018 - February 29, 2024
Field of knowledge:Health Sciences - Pharmacy
Principal researcher:Mario Hiroyuki Hirata
Grantee:Mario Hiroyuki Hirata
Home Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Pesquisadores principais:
( Atuais )
Dorotéia Rossi Silva Souza
Pesquisadores principais:
( Anteriores )
Patricia Moriel
Assoc. researchers:Alexandre da Costa Pereira ; Amanda Guerra de Moraes Rego Souza ; André Arpad Faludi ; André Ducati Luchessi ; Andrei Carvalho Sposito ; Augusto Ducati Luchessi ; Emilio Hideyuki Moriguchi ; Marcelo Chiara Bertolami ; Renata Gorjao ; Rosario Dominguez Crespo Hirata ; Tania Cristina Pithon Curi ; Vivian Nogueira Silbiger
Associated scholarship(s):22/04697-5 - Standardization of total RNA extraction and amplification for the analysis of long non-coding RNA (lncRNA) expression, BP.IC
22/01054-6 - Analysis of variants at splicing sites in patients with Familial Hypercholesterolemia, BP.IC
21/11205-9 - Development of new drugs based on the structure of essential proteins for cholesterol synthesis and metabolism, integrating genetic studies and molecular modeling of dyslipidemic patients, BP.PD
+ associated scholarships 21/11655-4 - Influence of APOB variants on binding and uptake by cellular HepG2 receptors, BP.IC
19/17340-5 - Human SLPI protein production in Chlamydomonas reinhardtii and its application in cardiology, BP.PD
21/02585-2 - Functional characterization of variants in the APOB gene in patients with Familial Hypercholesterolemia, BP.DD
20/13339-0 - Elaboration of libraries for high-throughput sequencing and primary data analysis, BP.TT
20/06490-3 - Search a new PCSK9 inhibitor using techniques of drug planning based on a target structure, BP.IC
19/16967-4 - Standardization of PCR and sequencing methods for DNA methylation analysis of LDLR, PCSK9 and LDLRAP1, BP.IC
18/11917-6 - Development of a specific pipeline of bioinformatics, BP.PD
18/21686-1 - Optimization and standardization of circulating microRNA isolation from patients with Familial Hypercholesterolemia, BP.IC
18/11966-7 - Library construction for next-generation sequencing and primary data analysis, BP.TT - associated scholarships


Familial hypercholesterolemia (FH) is an autosomal dominant disease with genetic basis not fully understood yet. This study aims to investigate the genomics, epigenomics and pharmacogenomics bases of monogenic and polygenic FH. Patients with FH diagnosed phenotypically will be recruited in six research centers from different regions of Brazil. The methods include: (i) Ultra deep DNA sequencing of the major genes related to FH and other primary dyslipidemias using MiSeq equipment (Illumina); (ii) functional analysis of new variants in the LDLR, APOB and PCSK9 genes by flow cytometry, to study interaction with LDL receptors in primary lymphocytes and directed mutagenesis studies using CRISPR/Cas9 in HepG2 and HUVEC cells; (iii) differential expression of circulating miRNAs in plasma samples by PCR array; (iv) methylation profile of the LDLR, APOB and PCSK9 genes in leukocytes by DNA pyrosequencing; (v) pharmacogenomic analysis including genes involved in metabolism and response to lowering-cholesterol drugs. Bioinformatics analysis will be performed using the MiSeq Reporter and CLC Genomic Workbench. This study is pioneer in the country and its realization in the highly mixed Brazilian population is innovative and challenging. The results of this study will contribute to the knowledge of the molecular basis of FH, to provide elements to improve the genetic diagnosis and personalized therapy of affected patients, and to enable the creation of a national database of genomic data to assist in the orientation of molecular diagnostics procedure for patients with FH and their families. It will also contribute to the training of human resources, research consolidation and integration of the institutions involved. (AU)

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Scientific publications (4)
(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)
DAGLI-HERNANDEZ, CAROLINA; COSTA DE FREITAS, RENATA CAROLINE; RODRIGUES MARCAL, ELISANGELA DA SILVA; GONCALVES, RODRIGO MARQUES; FALUDI, ANDRE ARPAD; BORGES, JESSICA BASSANI; BASTOS, GISELE MEDEIROS; LOS, BRUNA; MORI, AUGUSTO AKIRA; BORTOLIN, RAUL HERNANDES; et al. Late response to rosuvastatin and statin-related myalgia due to SLCO1B1, SLCO1B3, ABCB11, and CYP3A5 variants in a patient with Familial Hypercholesterolemia: a case report. ANNALS OF TRANSLATIONAL MEDICINE, v. 9, n. 1, . (16/25637-0, 16/12899-6)
ALMEIDA, VITOR MEDEIROS; CHAUDHURI, APALA; CARDOSO, MARCUS VINICIUS CANGUSSU; MATSUYAMA, BRUNO YASUI; FERREIRA, GLAUCIO MONTEIRO; GOULART TROSSINI, GUSTAVO HENRIQUE; SALINAS, ROBERTO KOPKE; LORIA, J. PATRICK; MARANA, SANDRO ROBERTO. Role of a high centrality residue in protein dynamics and thermal stability. Journal of Structural Biology, v. 213, n. 3, . (19/24112-9, 17/25543-8, 18/25952-8, 16/12899-6)
DOS SANTOS, BENEDITO MATHEUS; FERREIRA, GLAUCIO MONTEIRO; TAVARES, MAURICIO TEMOTHEO; DE BONA, JULIO CESAR; HIRATA, MARIO HIROYUKI; DE PAULA, VANDERLUCIA FONSECA; SATURNINO, KLAUS CASARO; SOARES, ANDREIMAR MARTINS; MENDES, MIRIAN MACHADO. Antiophidic activity of the secondary metabolite lupeol isolated from Zanthoxylum monogynum. Toxicon, v. 193, p. 38-47, . (19/06172-4, 16/12899-6, 19/24112-9)

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