Quantile-specific heritability of 8-isoprostane and the modulating effects of smoking, alcohol, cardiovascular disease and diabetes on 8-isoprostane-gene interactions

Abstract

BackgroundUrinary 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. MethodTo test whether genetic effects on 8-isoprostane concentrations are quantile-dependent, quantile-specific offspring-parent (βOP) and full-sib regression slopes (βFS) 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 = 2βOP/(1+rspouse) and h2 = {(1+8rspouseβFS)0.5-1}/(2rspouse)). ResultsSpouse 8-isoprostane concentrations were weakly concordant (rspouse = 0.06). 8-isoprostane heritability (h2±SE) increased significantly with increasing percentiles of its distribution (Plinear trend = 0.0009, Pquadratic trend = 0.0007, Pcubic trend = 0.003) when estimated from βOP, and when estimated from βFS (Plinear trend = 0.005, Pquadratic trend = 0.09, Pcubic trend = 0.06). Compared to the 10th percentile, βOP-estimated h2 was over 22-fold greater at the 90th percentile (Pdifference = 9.2 × 10−5), and 5.3-fold greater when estimated from βFS (Pdifference = 0.004). Significantly higher 8-isoprostane heritability in smokers than nonsmokers (0.352 ± 0.147 vs. 0.061 ± 0.036, Pdifference = 0.01), and heavier than lighter drinkers (0.449 ± 0.216 vs. 0.078 ± 0.037, Pdifference = 0.01) were eliminated when corrected for the higher 8-isoprostane concentrations of the smokers and heavier drinkers. ConclusionHeritability 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.