A miRNA signature linked to high lipoprotein (a) and coronary calcification in familial hypercholesterolaemia
Rafael Escate1,2, Juan F Sánchez Muñoz-Torrero3, Marta Mauri4
1Institut Recerca Sant Pau, (IR-HSCSP), Barcelona, Spain.
Insights
High lipoprotein(a) [Lp(a)] levels are linked to coronary artery calcification (CAC) in familial hypercholesterolaemia (FH). This study identified a miRNA signature regulating these atherosclerotic processes, offering potential therapeutic targets.
Area of Science:
- Cardiovascular Biology
- Genetics
- Bioinformatics
Background:
- Elevated lipoprotein(a) [Lp(a)] is a risk factor for coronary artery calcification (CAC) in familial hypercholesterolaemia (FH) patients.
- The precise mechanisms linking high Lp(a) to CAC remain incompletely understood.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying Lp(a)-associated atherosclerotic lesions and coronary calcification in FH patients.
- To identify microRNAs (miRNAs) and their target genes involved in these pathological processes using bioinformatics and systems biology approaches.
Main Methods:
- Analysis of plasma miRNA profiles from 24 FH patients stratified by Lp(a) levels and presence/absence of CAC.
- Utilized Affymetrix miRNA microarrays for miRNA signature detection.
- Performed in silico analyses to identify miRNA target genes within lipid and atherosclerosis pathways.
Main Results:
- Identified 42 differentially expressed miRNAs based on Lp(a) levels.
- Discovered a signature of 9 miRNAs associated with CAC in FH patients.
- Network analysis revealed seven key target genes (AKT3, APAF1, BCL2L1, TRAF6, MYD88, STAT3, CASP9) involved in lipid metabolism, inflammation, and calcification.
Conclusions:
- A specific miRNA signature is identified that regulates atherosclerotic processes linked to high Lp(a) and CAC in FH patients.
- These findings provide novel insights into the molecular underpinnings of Lp(a)-associated cardiovascular disease.
- The identified miRNAs and target genes represent potential therapeutic targets for managing FH and preventing CAC.
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.
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