A miRNA signature linked to high lipoprotein (a) and coronary calcification in familial hypercholesterolaemia.

Background: High lipoprotein(a) [Lp(a)] levels are associated with increased coronary artery calcification (CAC) in familial hypercholesterolaemia (FH) patients. However, mechanisms linking high Lp(a) with CAC remain poorly understood. In this study, we have performed a bioinformatics and system biology analysis to identify miRNAs and their target genes involved in Lp(a)-associated atherosclerotic lesion and coronary calcification in FH patients.

Methods: Patients with a genetic diagnosis of FH (n = 24) from the SAFEHEART were included in the study. Plasma miRNA signature was obtained using Affymetrix miRNA microarrays from patients with FH grouped using an Lp(a) cut-off of (>50 mg/dL) and presence or absence of coronary artery calcification [CCS(+) or CCS(-)]. In silico analyses were performed to identify potential miRNA target genes.

Results: Forty-two miRNAs had > 1.5-fold difference in their detection levels when grouped by Lp(a) [FH-Lp(a)> 50 (n = 9) vs FH-Lp(a)< 50 (n = 15)]. Among these, 9 miRNAs were associated with CCS(+) (miR-1228-5p, miR-3940-5p, miR-1237-5p, miR-3196, miR-6765-5p, miR-6786-5p, miR-4486, miR-6821-5p and miR-1908-5p). In silico analysis, identified 68 target genes of these 9 miRNAs in lipid and atherosclerosis pathways (KEGG code: hsa05417). Network analysis revealed seven target genes (AKT3, APAF1, BCL2L1, TRAF6, MYD88, STAT3, and CASP9) with stronger interactions and higher binding probability for the nine-miRNA signature, mainly linked to lipid metabolism, inflammation and calcification processes.

Conclusion: Our results identify a miRNA signature that regulates atherosclerotic processes associated with high Lp(a) levels and CAC in asymptomatic FH patients. These findings offer new insights into the underlying mechanisms and highlight potential therapeutic targets.