Abstract
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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