Genomics, epigenomics and pharmacogenomics of familial hypercholesterolemia (FHBGEP): A study protocol.
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Borges Jéssica Bassani, Oliveira Victor Fernandes de, Ferreira Glaucio Monteiro, Los Bruna, Barbosa Thais Kristini Almendros Afonso, Marçal Elisangela da Silva Rodrigues, Dagli-Hernandez Carolina, de Freitas Renata Caroline Costa, Bortolin Raul Hernandes, Mori Augusto Akira, Hirata Thiago Dominguez Crespo, Nakaya Helder Takashi Imoto, Bastos Gisele Medeiros, Thurow Helena Strelow, Gonçalves Rodrigo Marques, Araujo Daniel Branco de, Zatz Henry Paulo, Bertolami Adriana, Faludi André Arpad, Bertolami Marcelo Chiara, Sousa Amanda Guerra de Moraes Rego, França João Ítalo Dias, Jannes Cinthia Elim, Pereira Alexandre da Costa, Nakazone Marcelo Arruda, Souza Dorotéia Rossi Silva, Carmo Tayanne Silva, Sampaio Marcelo Ferraz, Gorjão Renata, Pithon-Curi Tania Cristina, Moriel Patricia, Silbiger Vivian Nogueira, Luchessi André Ducati, de Araújo Jéssica Nayara Góes, Naslavsky Michel Satya, Wang Jaqueline Yu Ting, Kronenberger Thales, Cerda Alvaro, Lin-Wang Hui Tzu, Garofalo Adriana Regina, Fajardo Cristina Moreno, Hirata Rosario Dominguez Crespo, Hirata Mario Hiroyuki
Аннотация
OBJECTIVES: The study protocol FHBGEP was design to investigate the main genomic, epigenomic, and pharmacogenomic factors associated with FH and polygenic hypercholesterolemia (PH).
METHODS: FH patients will be enrolled at six research centers in Brazil. An exon-targeted gene strategy will be used to sequence a panel of 84 genes related to FH, PH, pharmacogenomics and coronary artery disease. Variants in coding and regulatory regions will be identified using a proposed variant discovery pipeline and classified according to the American College Medical Genetics guidelines. Functional effects of variants in FH-related genes will be investigated by in vitro studies using lymphocytes and cell lines (HepG2, HUVEC and HEK293FT), CRISPR/Cas9 mutagenesis, luciferase reporter assay and other technologies. Functional studies in silico, such as molecular docking, molecular dynamics, and conformational analysis, will be used to explore the impact of novel variants on protein structure and function. DNA methylation profile and differential expression of circulating non-coding RNAs (miRNAs and lncRNAs) will be analyzed in FH patients and normolipidemic subjects (control group). The influence of genomic and epigenomic factors on metabolic and inflammatory status will be analyzed in FH patients. Pharmacogenomic studies will be conducted to investigate the influence of genomic and epigenomic factors on response to statins in FH patients.
SUMMARY: The FHBGEP protocol has the potential to elucidate the genetic basis and molecular mechanisms involved in the pathophysiology of FH and PH, particularly in the Brazilian population. This pioneering approach includes genomic, epigenomic and functional studies, which results will contribute to the improvement of the diagnosis, prognosis and personalized therapy of FH patients.