Investigation of the causal effect and molecular signatures of serum hydroxyvitamin D on atherosclerosis: a Mendelian randomization and transcriptomic approach

Arterial atherosclerosis is a common cardiovascular disease with serious health impact. Growing evidence suggests that serum hydroxyvitamin D may influence its progression. Investigating the causal relationship and underlying mechanisms between vitamin D and atherosclerosis is essential for developing effective prevention and treatment strategies. We conducted Mendelian randomization analysis with stringent single-nucleotide polymorphism selection to assess causal relationships. We analyzed transcriptomic datasets to identify differentially expressed genes (DEGs) and genes related to vitamin D metabolism. Feature selection was performed using Least Absolute Shrinkage and Selection Operator regression, Support Vector Machine-Recursive Feature Elimination, and random forest algorithms. Receiver operating characteristic (ROC) curves were used to evaluate diagnostic performance, and a nomogram was constructed for predictive modeling. Immune cell infiltration was assessed via CIBERSORT, while Gene Set Enrichment Analysis (GSEA) was employed to explore key pathways. Quantitative real-time PCR validated gene expression. Mendelian randomization analysis confirmed that 25-hydroxyvitamin D acted a protective factor against coronary atherosclerosis. We identified 1,195 DEGs and 33 vitamin D-related genes, with four key genes demonstrating strong diagnostic accuracy in ROC curve analysis. Immune profiling revealed significant differences in nine immune cell types, and GSEA highlighted critical biological pathways involved in disease progression. The nomogram model showed high predictive performance. This multi-omics study establishes a causal relationship between serum hydroxyvitamin D levels and atherosclerosis while uncovering potential biomarkers and pathogenic mechanisms through analyses of gene expression, immune infiltration, and signaling pathways. These findings provide valuable insights into atherosclerosis research and may help guide future therapeutic strategies.