Genetic determinants of lipid metabolism in cardioprotection: From mechanisms to clinical practice

Atherosclerotic cardiovascular diseases continue to be the leading causes of morbidity and mortality globally. Disorders of lipoprotein metabolism contribute significantly to the development of atherosclerosis, which begins with the subendothelial retention of plasma-derived apolipoprotein B-containing lipoproteins, particularly low-density lipoprotein (LDL) and its remnants. Elevated LDL cholesterol levels and triglycerides, coupled with low high-density lipoprotein (HDL) cholesterol levels, are critical risk factors for atherosclerotic cardiovascular diseases. Landmark epidemiological studies have identified dyslipidemia as a key modifiable risk factor for these diseases, elucidating the essential role of lipid abnormalities in atherogenesis and highlighting significant opportunities for cardiovascular disease prevention and risk stratification. Genetic epidemiology studies have shown that lifelong low levels of LDL due to genetic variations markedly reduce the risk of atherosclerotic cardiovascular diseases. Recent advancements in lipid-lowering pharmacology are increasingly informed by genetic studies that reveal naturally occurring mutations offering lifelong cardioprotection. Furthermore, these genetic studies have facilitated the development of novel therapeutics and enhanced the prediction of potential side effects, variability in individual drug responses, and improved risk stratification. This narrative review article aims to summarize key genetic variants that influence lipid metabolism and examine their therapeutic potential in cardiovascular therapy. Given the central role of atherosclerosis in determining cardiovascular risk, it is vital to consider lipid metabolism in the context of genetic factors that affect individual susceptibility to hyperlipidemia. Defining cardioprotective genetic determinants is equally important, as it may provide a foundation for therapeutic strategies by emphasizing protective mechanisms.