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Functional characterization of variants in the APOB gene in patients with Familial Hypercholesterolemia

Grant number: 21/02585-2
Support Opportunities:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): April 01, 2021
Effective date (End): January 31, 2024
Field of knowledge:Health Sciences - Pharmacy - Toxicological Analysis
Principal Investigator:Mario Hiroyuki Hirata
Grantee:Vanessa Barbosa Malaquias
Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:16/12899-6 - Genomics, epigenomics and pharmacogenomics characterization of familial hypercholesterolemia in the Brazilian population, AP.TEM


Familial Hypercholesterolemia (FH) is an autosomal dominant hereditary disease that predisposes early to Atherosclerosis and the development of cardiovascular diseases, including Acute Coronary Syndrome and Stroke. Laboratory characterized by elevation of low-density lipoprotein cholesterol (LDL-c e 190 mg/dL) and total cholesterol (TC e 310 mg/dL) and by clinical manifestations such as tendon xanthomas, xanthelasmas, and corneal arcus. The molecular diagnosis of FH is defined mainly to variants in the LDLR, APOB, and PCSK9 genes. New sequencing technologies have helped to identify a large number of new variants related to FH, however, the mechanisms by which these variations interfere with cholesterol metabolism are not well defined. This study aims to evaluate in silico and in vitro variants in the APOB gene identified by exomic ultra-sequencing in patients with Familial Hypercholesterolemia. Biological activity will be assessed using isolated and fluorescently labeled LDL uptake profiles from patients with variants with potential pathogenicity, by in silico analysis and in in vitro models of HepG2 and HUVEC cells. It is expected that the study will contribute to the identification and validation of variants that cause Hypercholesterolemia, associating it with the clinical phenotype, and thus contributing to elucidate the pathophysiological mechanisms of Hypercholesterolemia and the previous identification of the risk of developing cardiovascular diseases. (AU)

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