Abstract

BACKGROUND: Urinary 8-isoprostane provides a significantly heritable measure of oxidative stress. Prior reports suggest that genetic variants may modulate oxidative stress due to smoking, other environmental factors, and disease. Alternatively, these apparent modulations may reflect a dependence of genetic effects on 8-isoprostane concentrations. METHOD: To test whether genetic effects on 8-isoprostane concentrations are quantile-dependent, quantile-specific offspring-parent (β_OP) and full-sib regression slopes (β_FS) were estimated by applying quantile regression to the age- and sex-adjusted creatinine-standardized urinary 8-isoprostane concentrations of Framingham Heart Study families. Quantile-specific heritabilities were calculated as h² = 2β_OP/(1+r_spouse) and h² = {(1+8r_spouseβ_FS)^0.5-1}/(2r_spouse)). RESULTS: Spouse 8-isoprostane concentrations were weakly concordant (r_spouse = 0.06). 8-isoprostane heritability (h²±SE) increased significantly with increasing percentiles of its distribution (P_{linear trend} = 0.0009, P_{quadratic trend} = 0.0007, P_{cubic trend} = 0.003) when estimated from β_OP, and when estimated from β_FS (P_{linear trend} = 0.005, P_{quadratic trend} = 0.09, P_{cubic trend} = 0.06). Compared to the 10th percentile, β_OP-estimated h² was over 22-fold greater at the 90th percentile (P_difference = 9.2 × 10^-5), and 5.3-fold greater when estimated from β_FS (P_difference = 0.004). Significantly higher 8-isoprostane heritability in smokers than nonsmokers (0.352 ± 0.147 vs. 0.061 ± 0.036, P_difference = 0.01), and heavier than lighter drinkers (0.449 ± 0.216 vs. 0.078 ± 0.037, P_difference = 0.01) were eliminated when corrected for the higher 8-isoprostane concentrations of the smokers and heavier drinkers. CONCLUSION: Heritability of oxidative stress as measured by 8-isoprostane is quantile-dependent, which may contribute to the larger reported effects on oxidative stress by UCP2 -866G > A, IL6 -572C > G and LTA 252A > G polymorphisms in smokers than nonsmokers, by the UCP2 -866G > A polymorphism in coronary heart disease patients, by the ESRRG rs1890552 A > G polymorphism in type 2 diabetics, by the CYBA 242C > T polymorphism after exercise training, by the PLIN 11482G > A/14995A > T haplotype before weight loss, and by the CYBA -930A > G and GSTP1 I105V haplotypes in patients with pulmonary edema.