Background: Myocardial infarction (MI) can range from mild to severe cardiovascular events and typically develops through complex interactions between genetic and lifestyle factors. Objectives: We aimed to understand the genetic predisposition associated with MI through genetic correlation, colocalization analysis, and cells’ gene expression values to develop more effective prevention and treatment strategies to reduce its burden. Methods: A polygenic risk score (PRS) was employed to estimate the genetic risk for MI and to analyze the dietary interactions with PRS that affect MI risk in adults over 45 years (n = 58,701). Genetic correlation (rg) between MI and metabolic syndrome-related traits was estimated with linkage disequilibrium score regression. Single-cell RNA sequencing (scRNA-seq) analysis was performed to investigate cellular heterogeneity in MI-associated genes. Results: Ten significant genetic variants associated with MI risk were related to cardiac, immune, and brain functions. A high PRS was associated with a threefold increase in MI risk (OR: 3.074, 95% CI: 2.354–4.014, p < 0.001). This increased the risk of MI plus obesity, hyperglycemia, dyslipidemia, and hypertension by about twofold after adjusting for MI-related covariates (p < 0.001). The PRS interacted with moderate fat intake (>15 energy percent), alcohol consumption (<30 g/day), and non-smoking, reducing MI risk in participants with a high PRS. MI was negatively correlated with the consumption of olive oil, sesame oil, and perilla oil used for cooking (rg = −0.364). MI risk was associated with storkhead box 1 (STOX1) and vacuolar protein sorting-associated protein 26A (VPS26A) in atrial and ventricular cardiomyocytes and fibroblasts. Conclusions: This study identified novel genetic variants and gene expression patterns associated with MI risk, influenced by their interaction with fat and alcohol intake, and smoking status. Our findings provide insights for developing personalized prevention and treatment strategies targeting this complex clinical presentation of MI.
