Mariam Ramadan, Amie Jobe, Ranjit Vijayan
Cardiovascular disease (CVD) remains the leading global cause of mortality, with diet as a major modifiable determinant of risk. However, substantial interindividual variability in lipid, glycemic, inflammatory, and blood pressure responses to dietary interventions suggests that uniform dietary recommendations may not optimally benefit all individuals. Nutrigenomics and nutrigenetics provide mechanistic and genetic frameworks to explain this heterogeneity by linking dietary exposures to gene expression, epigenetic remodeling, and genotype-dependent metabolic responses. In this context, this review synthesizes evidence on genome-wide interaction analyses, Mendelian randomization, and emerging multi-omics research. Across major dietary exposures, including fat, carbohydrates, sodium, and plant-derived bioactive compounds, genetic variation in pathways governing lipid transport and metabolism, glucose regulation, circadian biology, blood pressure control, and oxidative stress/repair has been associated with cardiometabolic responses. Mediterranean and low-fat/hypocaloric interventions demonstrate genotype-dependent changes in cardiometabolic biomarkers and, in some studies, transcriptomic signatures. Similarly, sodium sensitivity could be partly genetically influenced, supported by genome-wide interaction evidence, controlled sodium-feeding trials, and genetic causal inference. At the translational level, personalized nutrition trials indicate potential added benefit when dietary advice is genotype-informed, although reported benefits are generally incremental and often limited to intermediate cardiometabolic markers rather than validated cardiovascular outcomes. Generalizability is also constrained by methodological heterogeneity and limited population diversity. Accordingly, broader validation, standardization, and equitable implementation strategies are required before routine clinical adoption.