Functional Analysis of <i>PCSK9</i> 3′UTR Variants and mRNA–miRNA Interactions in Patients with Familial Hypercholesterolemia

Abstract

<b>Aim:</b> Functional analysis of <i>PCSK9</i> 3'UTR variants and mRNA-miRNA interactions were explored in patients with familial hypercholesterolemia (FH). <b>Materials & methods:</b><i>PCSK9</i> 3'UTR variants were identified by exon-targeted gene sequencing. Functional effects of 3'UTR variants and mRNA-miRNA interactions were analyzed using <i>in silico</i> and <i>in vitro</i> studies in HEK293FT and HepG2 cells. <b>Results:</b> Twelve <i>PCSK9</i> 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 <i>PCSK9</i> expression in HepG2 cells. <b>Conclusion:</b><i>PCSK9</i> c.*345C >T has a possible role as loss-of-function variant. miR-4721 and miR-564 downregulate <i>PCSK9</i> and may be useful to improve lipid profile in FH patients.