Functional analysis of PCSK9 3 ' UTR variants and mRNA-miRNA interactions in patients with familial hypercholesterolemia

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Los, Bruna ; Borges, Jessica B. ; Oliveira, Victor F. ; Freitas, Renata C. C. ; Dagli-Hernandez, Carolina ; Bortolin, Raul H. ; Goncalves, Rodrigo M. ; Faludi, Andre A. ; Rodrigues, Alice C. ; Bastos, Gisele M. ; Jannes, Cinthia E. ; Pereira, Alexandre C. ; Hirata, Rosario D. C. ; Hirata, Mario H.

• Document type: Journal article
• Source: Epigenomics; v. 13, n. 10, p. 13-pg., 2021-04-26.

Abstract

Aim: Functional analysis of PCSK9 3 ' UTR variants and mRNA-miRNA interactions were explored in patients with familial hypercholesterolemia (FH). Materials & methods: PCSK9 3 ' UTR variants were identified by exon-targeted gene sequencing. Functional effects of 3 ' UTR variants and mRNA-miRNA interactions were analyzed using in silico and in vitro studies in HEK293FT and HepG2 cells. Results: Twelve PCSK9 3 ' UTR variants were detected in 88 FH patients. c.*75C >T and c.*345C >T disrupted interactions with miR-6875, miR-4721 and miR-564. Transient transfection of the c.*345C >T decreased luciferase activity in HEK293FT cells. miR-4721 and miR-564 mimics reduced PCSK9 expression in HepG2 cells. Conclusion: PCSK9 c.*345C >T has a possible role as loss-of-function variant. miR-4721 and miR-564 downregulate PCSK9 and may be useful to improve lipid profile in FH patients. (AU)

• FAPESP's process: 16/12899-6 - Genomics, epigenomics and pharmacogenomics characterization of familial hypercholesterolemia in the Brazilian population
• Grantee: Mario Hiroyuki Hirata
• Support Opportunities: Research Projects - Thematic Grants