Genetic insights into lipid traits and atherosclerosis risk: a Mendelian randomization and polygenic risk score analysis

Background: Atherosclerosis (AS) is a leading cause of cardiovascular diseases, with lipid metabolism disorders playing a key role in its development. This study used Mendelian randomization (MR) analysis to examine the causal links between four lipid traits [high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TG), and total cholesterol (TC)] and AS risk, and also investigated the polygenic risk score (PRS) and potential molecular mechanisms. Methods: Genome-Wide Association Study GWAS summary data for lipid traits from the Integrative Epidemiology Unit IEU and Finngen databases were used for MR analysis to assess the causal link between lipid traits and AS risk. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing (bulk RNA-seq) data were used to evaluate the PRS of AS. Drug enrichment analysis and molecular docking were performed to identify potential drug targets. Results: Higher HDL levels were associated with a decreased risk of AS (OR = 0.8038, P = 0.000014), while higher LDL, TC, and TG levels were linked to increased AS risk (OR = 1.0147, P = 9.95 × 10 −13 ; OR = 1.0163, P = 8.98 × 10 −16 ; OR = 1.0087, P = 4.32 × 10 −4 ). Drug enrichment analysis highlighted potential drug targets, including HMGCR binding with STIGMASTEROL and Benzofurans. PRS analysis revealed that multiple lipid metabolism-related genes influence AS susceptibility. Conclusion: The study demonstrated a clear causal relationship between lipid traits and AS risk. Higher HDL levels were associated with a reduced risk, while higher LDL, TC, and TG levels increase AS risk. The role of lipid metabolism genes in AS pathogenesis was underscored by PRS analysis.