Dissecting miRNA–Gene Networks to Map Clinical Utility Roads of Pharmacogenomics-Guided Therapeutic Decisions in Cardiovascular Precision Medicine

Abstract

MicroRNAs (miRNAs) create systems networks and gene-expression circuits through molecular signaling and cell interactions that contribute to health imbalance and the emergence of cardiovascular disorders (CVDs). Because the clinical phenotypes of CVD patients present a diversity in their pathophysiology and heterogeneity at the molecular level, it is essential to establish genomic signatures to delineate multifactorial correlations, and to unveil the variability seen in therapeutic intervention outcomes. The clinically validated miRNA biomarkers, along with the relevant SNPs identified, have to be suitably implemented in the clinical setting in order to enhance patient stratification capacity, to contribute to a better understanding of the underlying pathophysiological mechanisms, to guide the selection of innovative therapeutic schemes, and to identify innovative drugs and delivery systems. In this article, the miRNA–gene networks and the genomic signatures resulting from the SNPs will be analyzed as a method of highlighting specific gene-signaling circuits as sources of molecular knowledge which is relevant to CVDs. In concordance with this concept, and as a case study, the design of the clinical trial GESS (NCT03150680) is referenced. The latter is presented in a manner to provide a direction for the improvement of the implementation of pharmacogenomics and precision cardiovascular medicine trials.

De novo DNA methylation induced by circulating extracellular vesicles from acute coronary syndrome patients

“…For the first time, ACS-EVs induced significant activation of SYP, CHL1 and SHB genes (p<0.05), for which the literature never showed a CVDs involvement. Considering the above evidence and in according with previous studies, our findings underlie the potential stress-response role of ACS-EVs [65][66][67][68][69]. Our hypothesis that circulating EVs from ACS patients are secreted in response to cell damage and carry stress-response effects molecules is also supported by the observed correlations between clinical parameters, such as serum TnT and total cholesterol levels and changes in gene expression by PBMCs from the same patients upon EV-ACS treatment (Fig.…”

Expression of ATP-binding cassette subfamily B member 1 gene in peripheral blood of patients with acute myocardial infarction

“…In all stages of atherosclerosis, more than 190 microRNAs are involved in regulating 160 different genes. MicroRNA is involved in atherosclerosis-related molecular pathways, including endothelial dysfunction, cell adhesion, proliferation, lipid uptake, and outflow, production of inflammatory mediators, activation of platelets, and plaque formation [ 39 ].…”

Cost-Effectiveness of Pharmacogenomics-Guided Prescribing to Prevent Gene-Drug-Related Deaths: A Decision-Analytic Model

“…Additionally, both the Clinical Pharmacogenetics Implementation Consortium (CPIC) ( Relling and Klein, 2011 ; Relling et al, 2020 ) and the Dutch Pharmacogenetics Working Group (DPWG) ( Swen et al, 2008 ; Swen et al, 2011 ; Swen et al, 2018 ) have developed guidelines on incorporating PGx results into drug prescribing. Appropriate sub-groups have previously been identified for PGx testing, including cardiovascular ( Chatzopoulou et al, 2022 ) (supportive-)oncology ( Patel, 2021 ; Patel et al, 2021 ), geriatric and polypharmacy patients ( Brixner et al, 2016 ). Nevertheless, ambiguity remains regarding whether and which PGx tests should be prioritized for implementation into routine care ( Roden et al, 2018 ).…”