Work

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

Year: 2025

Type: article

Abstract: Background: 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. Methods: 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. Results: 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 (p < 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. Conclusions: 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.

Source: Nutrients

DOI: 10.3390/nu17091411

Authors: Meiling Liu, Junyu Zhou, Sunmin Park

Institutions: Hoseo University, Shanxi Institute of Science and Technology, Peking University

Language: English

Topic: Lipoproteins and Cardiovascular Health

Subfield: Surgery

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,499