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

Epigenomics. 2021 May;13(10):779-791. doi: 10.2217/epi-2020-0462. Epub 2021 Apr 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.

Keywords: 3′UTR variants; PCSK9; epigenomics; familial hypercholesterolemia; functional analysis; microRNAs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Child
  • Female
  • Genetic Variation
  • HEK293 Cells
  • Hep G2 Cells
  • Humans
  • Hyperlipoproteinemia Type II / genetics*
  • Hyperlipoproteinemia Type II / metabolism
  • Male
  • MicroRNAs*
  • Middle Aged
  • Proprotein Convertase 9 / genetics*
  • Proprotein Convertase 9 / metabolism
  • RNA, Messenger*
  • Young Adult

Substances

  • 3' Untranslated Regions
  • MicroRNAs
  • RNA, Messenger
  • PCSK9 protein, human
  • Proprotein Convertase 9