Research Progress and Clinical Translation Potential of Coronary Atherosclerosis Diagnostic Markers from a Genomic Perspective

Abstract

Objective: Coronary atherosclerosis (CAD) is characterized by arterial intima lipid deposition, chronic inflammation, and fibrous tissue proliferation, leading to arterial wall thickening and lumen narrowing. As the primary cause of coronary heart disease and acute coronary syndrome, CAD significantly impacts global health. Recent genetic studies have demonstrated CAD's polygenic and multifactorial nature, providing molecular insights for early diagnosis and risk assessment. This review analyzes recent advances in CAD-related genetic markers and evaluates their diagnostic potential, focusing on their applications in diagnosis and risk stratification within precision medicine. Methods: We conducted a systematic review of CAD genomic studies from PubMed and Web of Science databases, analyzing findings from genome-wide association studies (GWASs), gene sequencing, transcriptomics, and epigenomics research. Results: GWASs and sequencing studies have identified key genetic variations associated with CAD, including JCAD/KIAA1462, GUCY1A3, PCSK9, and SORT1, which regulate inflammation, lipid metabolism, and vascular function. Transcriptomic and epigenomic analyses have revealed disease-specific gene expression patterns, DNA methylation signatures, and regulatory non-coding RNAs (miRNAs and lncRNAs), providing new approaches for early detection. Conclusions: While genetic marker research in CAD has advanced significantly, clinical implementation faces challenges including marker dynamics, a lack of standardization, and integration with conventional diagnostics. Future research should prioritize developing standardized guidelines, conducting large-scale prospective studies, and enhancing multi-omics data integration to advance genomic diagnostics in CAD, ultimately improving patient outcomes through precision medicine.

Keywords: coronary atherosclerosis; early diagnosis; epigenomics; gene markers; genome-wide association study; genomics; precision medicine; transcriptomics.

Figure 1

Pathological cascade in coronary atherosclerosis development. This figure illustrates the progression of coronary atherosclerosis, beginning with vascular endothelial cell (VEC) dysfunction caused by genetic predispositions (e.g., JCAD, NOS3), oxidative stress factors (arterial shear stress, dyslipidemia, and smoking), and familial hypercholesterolemia (PCSK9, LDLR, APOB). LDL infiltration into the arterial wall promotes foam cell formation, driven by impaired LDL metabolism (SORT1). The resulting inflammatory response involves cytokines such as TNF-α, IL-6, and MCP-1, which stimulate smooth muscle cell (SMC) proliferation and migration. These processes contribute to vascular remodeling, lumen narrowing, and fibrous cap formation, which may ultimately lead to rupture, foam cell apoptosis, and advanced atherosclerotic lesions.

Figure 2

GWAS-identified genes and their role in coronary artery disease pathophysiology. This figure highlights the molecular pathways involving key genes identified through GWASs that contribute to coronary artery disease (CAD). Lipid metabolism: Genes such as PCSK9 and LDLR regulate low-density lipoprotein (LDL) cholesterol levels. Gain-of-function mutations in PCSK9 lead to hypercholesterolemia and increased CAD risk by affecting LDL uptake and degradation. Endothelial cell function: The JCAD/KIAA1462 gene encodes a protein critical for endothelial cell adhesion and vascular integrity. Variants impair endothelial cell function, promoting CAD development. Smooth muscle contraction/relaxation: The GUCY1A3 gene encodes soluble guanylyl cyclase (sGC), a mediator of smooth muscle relaxation. Mutations disrupt vascular tone and contribute to CAD risk. Inflammatory response: Genes like IL6R influence cytokine signaling, contributing to vascular inflammation and lesion progression. MicroRNAs such as miR-126 and miR-33 further modulate inflammatory and lipid transport pathways.

Figure 3

Clinical applications of genetic markers in coronary artery disease. This figure summarizes the integration of genetic markers and their clinical utility in diagnosing and managing coronary artery disease (CAD) across different stages. Genetic markers and miRNAs: Key markers such as PCSK9, SORT1, JCAD, NOS3, and associated miRNAs (miR-148a, miR-33, miR-122) are identified from blood samples. These markers are linked to lipid metabolism, vascular inflammation, and endothelial function, contributing to CAD risk stratification and management. Risk stratification: Patients are categorized into high-risk (e.g., PCSK9/SORT1 mutations), intermediate-risk (e.g., JCAD/NOS3 variants), and low-risk groups based on genetic profiles, guiding interventions such as statins, PCSK9 inhibitors, or regular monitoring. Disease stage diagnosis: Genetic and inflammatory markers like IL6R, NOS2A, and IL1Ars2297518 are utilized to differentiate between early-stage CAD (characterized by inflammatory infiltration with markers like IL-6 and TNF-α) and advanced-stage CAD (associated with plaque rupture and infarction, mediated by MMP-9). Clinical applications: These markers facilitate early disease detection, dynamic monitoring of disease progression, and personalized interventions to reduce CAD risk and improve patient outcomes.