APOA2 (apolipoprotein A2) is a structural component of high-density lipoprotein (HDL) that stabilizes HDL particles and regulates their metabolism 1. The protein facilitates cholesterol binding, efflux, and transport, with involvement in HDL particle assembly and maintenance of cholesterol homeostasis. PPARα activation increases APOA2 production as part of its mechanism for raising plasma HDL levels 1. APOA2 exhibits significant gene-diet interactions, particularly with saturated fat intake. The APOA2 -265T>C polymorphism shows consistent interactions with dietary saturated fat across three independent populations, where individuals carrying the CC genotype with high saturated fat intake (≥22 g/day) demonstrate a 6.2% greater BMI increase and 1.84-fold higher obesity odds compared to TT+TC carriers 2. Similarly, the rs5082 variant demonstrates genotype-dependent weight-loss responses to low-carbohydrate versus low-fat diets 3. Disease relevance includes metabolic and cardiovascular pathophysiology. Mediterranean diet studies demonstrate APOA2 genetic variants interact with dietary interventions to influence cardiovascular disease and diabetes risk 45. APOA2 polymorphisms also associate with altered HDL and APOA1 levels, particularly in obese individuals 6. Emerging evidence implicates APOA2 in neurodegenerative disease, as proteogenomic analysis identified APOA2 among dysregulated proteins in Parkinson's disease pathogenesis 7, and in hepatocellular carcinoma, where APOA2 mRNA stability modulates immune checkpoint regulation via the SAMD4B-APOA2-PD-L1 axis 8.