Heart disease continues to be the leading cause of death in the United States, killing about 695,000 people in 2021, ahead of cancer and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)1. In the United States, the average annual direct and indirect cost of cardiovascular disease (CVD) was an estimated $378.0 billion in 2017-2018; the estimated direct costs have more than doubled in the last two decades2. Fatty acids (FAs), which can be obtained exogenously through the diet or produced endogenously through de novo lipogenesis (DNL), play a critical role in heart health by helping maintain lipid balance and regulate inflammatory processes. FAs can be oxygenated to produce oxylipins which are bioactive, act as lipid mediators, and are thought to be a potential explanation for the diverse effects of polyunsaturated FAs (PUFAs)3, 4. FA and oxylipin synthesis are highly regulated processes in which genes exert substantial influence. Genetic variation contributes to the activity and efficiency of enzymes responsible for FA and oxylipin metabolism as well as the functionality of receptors specific to FAs and oxylipins. The field of precision nutrition has developed to understand how one's diet and their genes interact to affect the way the body responds to food. This dissertation aims to address how a person's genes affect the way the body responds to food, specifically fats and FAs, to provide individualized nutrition guidance in CVD prevention and treatment. In Study 1, we explore the pivotal role of free fatty acid receptor 4 (FFAR4 (human); Ffar4 (mouse)) in the context of myocardial infarction (MI), focusing particularly on its impact on the early oxylipin response to cardiac ischemia/reperfusion (I/R) injury. Previous research has established the relevance of Ffar4 in metabolic and inflammatory pathways and found cardiac function improves 7 days after ischemic insult, prompting an in-depth analysis of the complex milieu of cardiac ischemia. To unravel the intricate connections, a murine model was employed, subjecting mice to cardiac ischemia followed by only 3 days of reperfusion while scrutinizing the influence of Ffar4 on oxylipin dynamics. The study was designed to meticulously assess the response to I/R injury, unraveling gene- and sex-specific variations in the oxylipin response. Additionally, to bridge the translational gap, the analysis extended to the UK Biobank (UKB) cohort. This human component aimed to elucidate the association of FFAR4 single nucleotide polymorphisms (SNPs) with MI and ischemic CVDs. The murine experimentation uncovered a Ffar4-dependent response, particularly concerning LA-derived oxylipins, to I/R injury. While animals with systemic deletion of Ffar4 had higher LA alcohols and epoxides than wildtype prior to injury, I/R injury ablated the differences in oxylipin profile. Sex-specific differences also emerged from the analysis, shedding light on distinct molecular mechanisms operating in male and female mice. However, the human analysis found FFAR4-dependent higher risk for stroke in women; no other FFAR4-dependent differences in disease incidence were found which may suggest genetic variation is not the cause of downstream differences due implicating FFAR4. In essence, this research underscores the intricate involvement of FFAR4 in the oxylipin responses to cardiac ischemia. The study provides valuable insights into potential sex-specific mechanisms of oxylipin response while acknowledging the inherent disparities between murine and human response to cardiovascular (CV) challenges. These complexities emphasize the multifaceted role of the FFAR4 in CVD. In Study 2, we investigate substrate competition between saturated FAs (SFAs) and PUFAs as ligands for FFAR4 and the downstream impact on metabolic outcomes, specifically related to metabolic syndrome (MetSyn), MI, and death. The study utilizes data from the UKB cohort including various demographic and health-related variables as well as FA measurements. The statistical methods involve linear regression models and Cox-proportional hazard models to explore the relationships between SFAs and PUFAs, as well as their interaction on MetSyn risk factors, MI, and death. The study reveals that the association of PUFAs with lower triglycerides (TG), higher high-density lipoprotein cholesterol (HDL-c), lower waist circumference (WC), and lower blood pressure (BP) depends on the levels of SFAs. Unexpectedly, when stratified by PUFA level higher SFAs are associated with metabolically beneficial outcomes, contrary to common perceptions. The study also uncovers differences by racial/ethnic group membership, showing distinct responses to SFAs and PUFAs among White, Black, and Asian participants. The findings challenge the simplistic view that reducing SFAs and increasing PUFAs uniformly benefit metabolic health. Instead, the findings suggest that individual differences in participant characteristics, including in racial/ethnic group membership, play a crucial role in how SFAs and PUFAs influence metabolic outcomes. A more nuanced approach to dietary recommendations that considers the intricate interplay between specific FAs and their impact on diverse populations may allow researchers to better address the risks for CVD. In Study 3, we focus on the fatty acid desaturase (FADS) genes, which play a regulatory role in PUFA metabolism. The FADS genes (FADS1 and FADS2) have two major haplotypes (haplotype D and haplotype A) which vary in prevalence across populations. Functional analyses indicate that haplotype D is more efficient in synthesis of longer chain PUFA in both the omega-3 ([omega]3) and omega-6 ([omega]6) pathways. The study specifically examines variant rs174547 in FADS1 as a proxy for the FADS genes. This variant has been associated with CV health outcomes leading to the hypothesis that 1) the association between FADS and lipid outcomes depends on FAs (moderation) and 2) the effect of FADS on outcomes occurs through FAs (mediation). The analysis uses the UKB dataset to explore the interplay between FADS and FAs on lipid outcomes including total cholesterol (TC), HDL-c, low-density lipoprotein cholesterol (LDL-c), and TGs. The research employs a statistical framework to quantify the extent to which FAs mediate or moderate the relationship between FADS and lipid biomarkers. Results reveal evidence of moderation and/or mediation (or suppression) effects. For instance, out of the 28 tests of moderation, 19 models have evidence that a FA modifies the effect of FADS on lipid outcomes. Additionally, there are 12 models with evidence of mediation; for example, DHA acts as a mediator for the association between FADS and HDL-c, indicating that the influence of FADS on HDL-c is explained by the level of DHA, and non-LA [omega]6-PUFA suppresses the association between FADS and LDL-c. The study provides valuable insights into the complex interactions between FADS, FAs, and CV health. By analyzing FADS as a case study, the research demonstrates an analytical framework that can be applied to understand similar relationships in other genetic contexts. The findings underscore the need to consider individual variations in FA metabolism to optimize dietary recommendations for CV health. Collectively, this research sheds light on the multifaceted interplay between PUFAs, genetic factors, and CV health. The conditional associations based on FA profiles emphasize the potential for dietary modifications to address health disparities rooted in individual genotypes, as well as social and environmental factors. These findings challenge broad dietary recommendations and advocate for a more personalized approach to disease prevention and treatment strategies. The implications extend beyond CV health, prompting a reevaluation of how individualized nutrition guidance can be integrated into broader public health initiatives.