Genetic Risk Factors for Atherosclerosis: What's New in Genomic Medicine?

Atherosclerosis remains the leading cause of cardiovascular morbidity and mortality worldwide. While traditional risk factors such as dyslipidemia, hypertension, and smoking contribute significantly, genetic predisposition accounts for a substantial portion of inter-individual variability in disease susceptibility. Recent advances in genomic medicine have revolutionized our understanding of the inherited basis of atherosclerosis, identifying more than 250 genome-wide association study (GWAS) loci that implicate key pathways including lipid metabolism, inflammation, vascular remodeling, and smooth muscle cell (SMC) plasticity. In this review, we provide a comprehensive update on the genetic architecture of atherosclerosis, highlighting major loci such as LPA, CDKN2A/B, SORT1, PCSK9, and newly emerging candidates like PDGFD and ZEB2. We explore how polygenic risk scores (PRS) enable individualized risk stratification, and how integrative multi-omics approaches—including epigenomics, expression quantitative trait loci (eQTLs), single-cell transcriptomics, and spatial profiling—are unveiling causal mechanisms across diverse vascular cell types. Special attention is given to gene–environment interactions, the epigenetic regulation of atherogenesis, and the rise of functional genomics using CRISPR-based editing and RNA-targeted therapeutics. We further discuss how genetic discoveries are being translated into clinical innovation, with therapies targeting PCSK9, ANGPTL3, and LPA already in use or late-stage development. Finally, we outline future directions toward truly personalized cardiovascular prevention and therapy, leveraging polygenic profiling, gene-editing technologies, and systems biology. DOI: https://doi.org/10.52783/jchr.v15.i2.7753