Abstract Body: Cardiovascular diseases (CVDs) are complex, multifactorial conditions that require personalized assessment and treatment. Advancements in multi-omics technologies, most importantly whole-genome sequencing (WGS) and RNA sequencing (RNA-seq) have provided translational researchers with a comprehensive view of the human genome and transcriptome. The efficient synthesis and analysis of multimodal data that characterizes genetic variants alongside expression patterns linked to emerging phenotypes, can reveal novel biomarkers and enable the segmentation of patient populations based on personalized risk factors. In this study, we present a cutting-edge and groundbreaking methodology rooted in the integration of traditional bioinformatics, classical statistics, and multimodal artificial intelligence (AI) and machine learning (ML) techniques. Our approach has the potential to uncover the intricate mechanisms underlying CVD, enabling patient-specific risk and response profiling. We sourced transcriptomic expression data and single nucleotide polymorphisms (SNPs) from both CVD patients and healthy controls. By integrating these multi-omics datasets with clinical and demographic information, we generated patient-specific profiles. Utilizing our robust feature selection approach, we identified a signature of transcriptomic features and SNPs that are effective predictors of CVD. Differential expression analysis, combined with minimum redundancy maximum relevance feature selection, highlighted biomarkers that explain the disease phenotype. This approach prioritizes both biological relevance and efficiency in ML. We employed Combination Annotation Dependent Depletion (CADD) scores and allele frequencies to identify variants with pathogenic characteristics in CVD patients. Classification models trained on this signature demonstrated high-accuracy predictions for CVD. The best performing of these models was an XGBoost classifier optimized via Bayesian hyperparameter tuning, which was able to correctly classify all patients in our test dataset. Using SHapley Additive exPlanations, we created risk assessments for patients, offering further contextualization of these predictions in a clinical setting. A comprehensive literature review revealed that a substantial portion of the diagnostic biomarkers identified have previously been associated with CVD. Summarized results are presented in the figure attached.