Genetic Polymorphisms of Oxidative Stress Regulatory Genes and Their Association with Coronary Artery Disease Risk

Coronary artery disease (CAD) remains a leading cause of morbidity and mortality worldwide. Its development results from a complex interaction between environmental risk factors and genetic susceptibility. Evidence indicates that oxidative stress, defined as a state in which free radical production exceeds antioxidant defenses, plays an important role in atherogenesis by promoting endothelial dysfunction, lipid oxidation, vascular inflammation and plaque instability. This review summarizes current knowledge on polymorphisms of the most important genes involved in reactive oxygen species generation and antioxidant defense. Several variants have been associated with CAD, hypertension, carotid atherosclerosis and other cardiovascular phenotypes, although the direction and strength of associations often differ across populations. In many cases, functional effects include altered enzyme activity, changes in promoter activity, reduced nitric oxide bioavailability or impaired antioxidant capacity. The evidence is heterogeneous: many candidate-gene studies are small, differ in ancestry, phenotype definitions and genetic models and are affected by limited replication and publication bias. Among the variants discussed, NOS3 rs3918226 and GPX1 rs1050450, rs1800668 and rs3811699 showed genome-wide significant associations with CAD in a large-scale genome-wide association study.The variants reviewed have no established role in CAD risk stratification and their added value beyond established clinical risk factors and validated genome-wide CAD polygenic risk scores has not been tested.