Genetic Variants, Bioactive Compounds, and PCSK9 Inhibitors in Hyper-LDL-Cholesterolemia: A GWAS and In Silico Study on Cardiovascular Disease Risk

<b>Background:</b> Hyper-LDL-cholesterolemia is a key contributor to cardiovascular diseases (CVDs), and both genetic predisposition and lifestyle influence it. This study aimed to develop personalized strategies for managing hyper-LDL-cholesterolemia by integrating polygenic risk scores (PRSs), genetic variants, and bioactive compound interactions, leveraging a precision medicine approach. <b>Methods:</b> A cohort of 58,701 Korean adults, including 8966 individuals with hyper-LDL-cholesterolemia (LDL ≥ 160 mg/dL) or undergoing treatment with hypocholesterolemic agents, was analyzed to investigate the interplay between genetic risk and lifestyle factors. The PRS was constructed using three key variants: PCSK9 (rs151193009), CELSR2 (rs11102967), and APOE (rs7412). Gene-lifestyle interactions were assessed, focusing on energy intake and physical activity. Computational molecular docking was utilized to investigate how bioactive compounds differentially interact with the wild-type and mutant forms of PCSK9 (Arg93Cys) and APOE (Arg176Cys), focusing on variations in binding affinity. <b>Results:</b> Hyper-LDL-cholesterolemia was associated with a 1.3-fold increased risk of CVD. The PRS showed a significant association with a 3.45-fold higher likelihood of developing both elevated LDL cholesterol and reduced HDL cholesterol levels. Lifestyle interactions revealed that high energy intake and physical inactivity significantly amplified the genetic risk (<i>p</i> < 0.05). In silico analysis demonstrated that bioactive compounds, notably prodelphinidin trimer, exhibited enhanced binding affinity with wild-type PCSK9 (Arg93Cys), while several compounds preferentially targeted the mutated PCSK9, suggesting potential avenues for genotype-specific therapies. <b>Conclusions:</b> This study emphasizes the combined influence of genetic predispositions and lifestyle behaviors on developing hyper-LDL-cholesterolemia, and highlights potential bioactive compounds as personalized therapeutic targets. By integrating genomic data, lifestyle analysis, and molecular docking, this research provides a foundation for precision interventions tailored to an individual's genetic and metabolic profile, paving the way for more effective and personalized management of dyslipidemia and associated CVD risk.