Genetic contributions to plasma total antioxidant activity

Oxidative stress plays important roles in a wide spectrum of pathological p rocesses, such as atherosclerosis. Although several environmental factors a re documented to influence redox metabolism, relatively little is known abo ut genetic effects. In the present study, we evaluated genetic contribution s to variation in plasma total antioxidant status (TAS), a measure of perox yl-scavenging capacity, in 1337 members of 40 Mexican American families. TA S levels were significantly lower in women than in men (1.675 +/-0.004 vers us 1.805 +/-0.005 mmol/L, respectively; P <0.001), and there was a signific ant decline of TAS levels with age in men but not in women (P <0.01 for the interaction). Quantitative genetic analysis indicated the heritability of TAS levels to be 0.509 +/-0.052; ie, approximate to 51% of the residual var iance (after covariate adjustment) in TAS levels was due to the additive ef fects of genes (P <0.001). We have further observed a significant gene-by-s moking interaction (P <0.05). Additive genetic effects account for 83% of t he residual phenotypic variance in TAS levels among smokers, but they accou nt for only 49% in nonsmokers. However, genes contributing to TAS variation are the same in smokers and nonsmokers. Our study for the first time demon strates that TAS, an indicator of redox homeostasis, is under strong geneti c control, especially among smokers. With appropriate tools, such as genome screening, it should be possible to localize genes that regulate redox hom eostasis and, ultimately, identify the DNA sequence variants predisposing s ubjects to oxidative damage.