HDL-bound microRNAs modulating cholesterol efflux and homeostasis and incidence of acute myocardial infarction: A population-based case-cohort study

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ABSTRACT Background HDL particles can carry microRNAs (miRNAs), capable of regulating gene expression connected to HDL functions. Despite links to some cardiovascular risk factors, miRNA association with incident acute myocardial infarction (AMI) remains unclear. Objectives Our aim was to elucidate the association between HDL-bound miRNAs (HDL-miRNAs) and incident AMI using a non-targeted approach in a population-based study. Methods We conducted a case-cohort study including 247 participants from the REGICOR cohort in northeastern Spain (51 AMI cases and a random sample of 196 participants, including seven overlapping AMI cases). HDL-miRNAs were isolated from apolipoprotein B-depleted serum and quantified by whole-genome miRNA sequencing. Associations between HDL-miRNAs and incident AMI were assessed using multivariable Cox proportional hazards model. For AMI-associated HDL-miRNAs ( p -value <0.10), we retrieved their experimentally validated targets and assessed pathway enrichment of these targets via over-representation analysis. Results Two HDL-miRNAs were associated with incident AMI after FDR correction: miR-628-3p (HR 1.69, 95% CI 1.30 to 2.19) and miR-28-3p (HR 1.58, 95% CI 1.21 to 2.06). Nine additional HDL-miRNAs were nominally associated with AMI incidence ( p -value <0.05), eight with a direct association (miR-93-5p, miR-26b-5p, miR-106a-5p, miR-126-3p, miR-15b-5p, let-7a-5p, let-7e-5p, and let-7f-5p) and one with an inverse association (miR-361-5p). These miRNAs regulate the expression of genes in pathways involved in cholesterol regulation, particularly cholesterol efflux and homeostasis. The AMI group exhibited higher variance and a greater number of significant and strong correlations. Conclusions Two HDL-miRNAs (miR-628-3p and miR-28-3p) were significantly associated with AMI incidence. A tighter coregulatory network in cases was observed, underscoring their potential clinical utility in risk prediction and cardiovascular prevention. Clinical Perspective What Is New? In a population-based case-cohort study we profiled the HDL-bound miRNome and found two miRNAs (miR-628-3p and miR-28-3p) associated with incident AMI. The use of HDL-enriched serum fractions provided a focused analysis on HDL functionality. These miRNAs regulate the expression of genes in pathways involved in cholesterol efflux and homeostasis ( ABCA1, ARL4C, SIRT1, NFKBIA, ANXA2, LRP6 ) and show a tighter coregulatory network among significant miRNAs among cases, supporting biological coherence. What Are the Clinical Implications? HDL-miRNA signatures may complement traditional risk factors to refine AMI risk stratification and provide a rationale for HDL-guided, miRNA-targeted preventive interventions using HDL-like delivery platforms.

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