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SMALL RNA SEQ PROFILE IN PATIENTS WITH AND WITHOUT FAMILIAL HYPERCHOLESTEROLEMIA TREATED WITH PCSK9 INHIBITOR
Topic: Atherosclerosis
Type: Poster - doctors
Dlouhá D.1, Hucková P.2, Blaha V.3, Chytilová Š.4, Bláha M.5, Hubáček J.2

1 Centrum experimentální medicíny, Institut klinické a experimentální medicíny, Prague, 2 Centrum experimentální medicíny, Institut klinické a experimentální medicíny, Praha, 3 III. interní gerontometabolická klinika, Fakultní nemocnice Hradec Králové, Hradec Králové, 4 Oddělení elektronických informačních zdrojů a datové vědy OI, Institut klinické a experimentální medicíny, Prague, 5 IV. Interní hematologická klinika, Fakultní nemocnice Hradec Králové, Hradec Králové


Background: Heterozygous familial hypercholesterolemia (HeFH) is relatively frequent (1:300), life-threatening genetic disorder characterized by an elevated serum level of low-density lipoprotein cholesterol and accelerated atherosclerotic cardiovascular diseases. Small RNAs are non-coding molecules known to play a pivotal role in posttranscriptional regulation of gene expression. The aim of our study was to compare miRNA Seq profile in HeFH and non-FH patients under PCSK9 inhibitor (PCSK9i) treatment.
Methods: From 30 patients (age 62±9.6 years; women 33.3%) involved in study, eight subjects were genetically diagnosed as HeHF (age 56.3±14.5; men 14.3%). Plasma samples were collected before the start of PCSK9i treatment, and then at 3rd, 6th and 12th month of treatment. Total RNA was extracted from of plasma, miRNA sequencing libraries were prepared and examined by the next-generation sequencing.
Results: Totally 103 differently expressed miRNAs (DE-miRNAs; Padj < 0.05) were detected between HeFH vs. non-FH patients across follow-up time points (FUs). Fifteen DE-miRNAs between HeFH vs. non-FH were found in all FUs. In a total group of subjects, concentration of 24 miRNA significantly changed (P < 0.05) during one year of PCSK9i treatment. 309 genes as potential targets of DE-miRNAs between HeFH vs. non-FH, and 254 validated genes of DE-miRNAs, if both groups analyzed together, were identified. GSEA identified these targets are involved mainly in FoxO signaling, PI3K-Akt signaling, TGF-beta signaling and EGFR tyrosine kinase inhibitor resistance pathways (all FDR q-value <0.05).
Conclusions: Circulating miRNome is affected both by FH genotype as well as by PCSK9i treatment. Potentially influenced genes to be regulated by DE-miRNAs are members of signaling pathways related to extracellular matrix regulation, inflammation, and vascular pathology.