Genomics, epigenomics and pharmacogenomics of familial hypercholesterolemia (FHBGEP): A study protocol

Jéssica Bassani Borges; Victor Fernandes de Oliveira; Glaucio Monteiro Ferreira; Bruna Los; Thais Kristini Almendros Afonso Barbosa; Elisangela da Silva Rodrigues Marçal; Carolina Dagli-Hernandez; Renata Caroline Costa de Freitas; Raul Hernandes Bortolin; Augusto Akira Mori; Thiago Dominguez Crespo Hirata; Helder Takashi Imoto Nakaya; Gisele Medeiros Bastos; Helena Strelow Thurow; Rodrigo Marques Gonçalves; Daniel Branco de Araujo; Henry Paulo Zatz; Adriana Bertolami; André Arpad Faludi; Marcelo Chiara Bertolami; Amanda Guerra de Moraes Rego Sousa; João Ítalo Dias França; Cinthia Elim Jannes; Alexandre da Costa Pereira; Marcelo Arruda Nakazone; Dorotéia Rossi Silva Souza; Tayanne Silva Carmo; Marcelo Ferraz Sampaio; Renata Gorjão; Tania Cristina Pithon-Curi; Patricia Moriel; Vivian Nogueira Silbiger; André Ducati Luchessi; Jéssica Nayara Góes de Araújo; Michel Satya Naslavsky; Jaqueline Yu Ting Wang; Thales Kronenberger; Alvaro Cerda; Hui Tzu Lin-Wang; Adriana Regina Garofalo; Cristina Moreno Fajardo; Rosario Dominguez Crespo Hirata; Mario Hiroyuki Hirata

doi:10.1016/j.sapharm.2020.10.007

Genomics, epigenomics and pharmacogenomics of familial hypercholesterolemia (FHBGEP): A study protocol

Res Social Adm Pharm. 2021 Jul;17(7):1347-1355. doi: 10.1016/j.sapharm.2020.10.007. Epub 2020 Oct 29.

Authors

Jéssica Bassani Borges¹, Victor Fernandes de Oliveira², Glaucio Monteiro Ferreira³, Bruna Los⁴, Thais Kristini Almendros Afonso Barbosa⁵, Elisangela da Silva Rodrigues Marçal⁶, Carolina Dagli-Hernandez⁷, Renata Caroline Costa de Freitas⁸, Raul Hernandes Bortolin⁹, Augusto Akira Mori¹⁰, Thiago Dominguez Crespo Hirata¹¹, Helder Takashi Imoto Nakaya¹², Gisele Medeiros Bastos¹³, Helena Strelow Thurow¹⁴, Rodrigo Marques Gonçalves¹⁵, Daniel Branco de Araujo¹⁶, Henry Paulo Zatz¹⁷, Adriana Bertolami¹⁸, André Arpad Faludi¹⁹, Marcelo Chiara Bertolami²⁰, Amanda Guerra de Moraes Rego Sousa²¹, João Ítalo Dias França²², Cinthia Elim Jannes²³, Alexandre da Costa Pereira²⁴, Marcelo Arruda Nakazone²⁵, Dorotéia Rossi Silva Souza²⁶, Tayanne Silva Carmo²⁷, Marcelo Ferraz Sampaio²⁸, Renata Gorjão²⁹, Tania Cristina Pithon-Curi³⁰, Patricia Moriel³¹, Vivian Nogueira Silbiger³², André Ducati Luchessi³³, Jéssica Nayara Góes de Araújo³⁴, Michel Satya Naslavsky³⁵, Jaqueline Yu Ting Wang³⁶, Thales Kronenberger³⁷, Alvaro Cerda³⁸, Hui Tzu Lin-Wang³⁹, Adriana Regina Garofalo⁴⁰, Cristina Moreno Fajardo⁴¹, Rosario Dominguez Crespo Hirata⁴², Mario Hiroyuki Hirata⁴³

Affiliations

¹ School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil; Institute Dante Pazzanese of Cardiology, Sao Paulo, Brazil. Electronic address: [email protected].
² School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil. Electronic address: [email protected].
³ School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil; Institute Dante Pazzanese of Cardiology, Sao Paulo, Brazil. Electronic address: [email protected].
⁴ School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil. Electronic address: [email protected].
⁵ School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil. Electronic address: [email protected].
⁶ School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil. Electronic address: [email protected].
⁷ School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil. Electronic address: [email protected].
⁸ School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil. Electronic address: [email protected].
⁹ School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil. Electronic address: [email protected].
¹⁰ School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil. Electronic address: [email protected].
¹¹ School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil. Electronic address: [email protected].
¹² School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil. Electronic address: [email protected].
¹³ Institute Dante Pazzanese of Cardiology, Sao Paulo, Brazil; Real e Benemerita Associação Portuguesa de Beneficiência, Sao Paulo, Brazil. Electronic address: [email protected].
¹⁴ School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil. Electronic address: [email protected].
¹⁵ Institute Dante Pazzanese of Cardiology, Sao Paulo, Brazil. Electronic address: [email protected].
¹⁶ Institute Dante Pazzanese of Cardiology, Sao Paulo, Brazil. Electronic address: [email protected].
¹⁷ Institute Dante Pazzanese of Cardiology, Sao Paulo, Brazil. Electronic address: [email protected].
¹⁸ Institute Dante Pazzanese of Cardiology, Sao Paulo, Brazil. Electronic address: [email protected].
¹⁹ Institute Dante Pazzanese of Cardiology, Sao Paulo, Brazil. Electronic address: [email protected].
²⁰ Institute Dante Pazzanese of Cardiology, Sao Paulo, Brazil. Electronic address: [email protected].
²¹ Institute Dante Pazzanese of Cardiology, Sao Paulo, Brazil. Electronic address: [email protected].
²² Institute Dante Pazzanese of Cardiology, Sao Paulo, Brazil. Electronic address: [email protected].
²³ Heart Institute, University of Sao Paulo, Sao Paulo, Brazil. Electronic address: [email protected].
²⁴ Heart Institute, University of Sao Paulo, Sao Paulo, Brazil. Electronic address: [email protected].
²⁵ Sao Jose do Rio Preto Medical School, Sao Jose do Rio Preto, Brazil. Electronic address: [email protected].
²⁶ Sao Jose do Rio Preto Medical School, Sao Jose do Rio Preto, Brazil. Electronic address: [email protected].
²⁷ Sao Jose do Rio Preto Medical School, Sao Jose do Rio Preto, Brazil. Electronic address: [email protected].
²⁸ Real e Benemerita Associação Portuguesa de Beneficiência, Sao Paulo, Brazil. Electronic address: [email protected].
²⁹ Cruzeiro do Sul University, Sao Paulo, Brazil. Electronic address: [email protected].
³⁰ Cruzeiro do Sul University, Sao Paulo, Brazil. Electronic address: [email protected].
³¹ Faculty of Pharmaceutical Sciences, University of Campinas, Campinas, Brazil. Electronic address: [email protected].
³² Department of Clinical and Toxicological Analyses, Federal University of Rio Grande do Norte, Natal, Brazil. Electronic address: [email protected].
³³ Department of Clinical and Toxicological Analyses, Federal University of Rio Grande do Norte, Natal, Brazil. Electronic address: [email protected].
³⁴ Northeast Biotechnology Network (RENORBIO), Graduate Program in Biotechnology, Federal University of Rio Grande do Norte, Natal, Brazil. Electronic address: [email protected].
³⁵ Human Genome and Stem-Cell Research Center, Biosciences Institute, University of Sao Paulo, Sao Paulo, Brazil. Electronic address: [email protected].
³⁶ Human Genome and Stem-Cell Research Center, Biosciences Institute, University of Sao Paulo, Sao Paulo, Brazil. Electronic address: [email protected].
³⁷ Department of Internal Medicine VIII, University Hospital Tübingen, Tübingen, Germany. Electronic address: [email protected].
³⁸ Center of Excellence in Translational Medicine, BIOREN, Department of Basic Sciences, Universidad de La Frontera, Temuco, Chile. Electronic address: [email protected].
³⁹ Institute Dante Pazzanese of Cardiology, Sao Paulo, Brazil. Electronic address: [email protected].
⁴⁰ Institute Dante Pazzanese of Cardiology, Sao Paulo, Brazil. Electronic address: [email protected].
⁴¹ School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil. Electronic address: [email protected].
⁴² School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil. Electronic address: [email protected].
⁴³ School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil. Electronic address: [email protected].

PMID: 33129683
DOI: 10.1016/j.sapharm.2020.10.007

Abstract

Background: Familial hypercholesterolemia (FH) is a genetic disease that affects millions of people worldwide.

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.

Keywords: Epigenomics; Familial hypercholesterolemia; Genomics; Pharmacogenomics; Polygenic hypercholesterolemia.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Brazil
Epigenomics
Genomics
Humans
Hyperlipoproteinemia Type II* / drug therapy
Hyperlipoproteinemia Type II* / genetics
Molecular Docking Simulation
Pharmacogenetics