Short (GT)_n repeats in heme oxygenase-1 gene promoter are associated with lower risk of coronary heart disease in subjects with high levels of oxidative stress

摘要

Although (GT) _n repeats in heme oxygenase-1 (HO-1) promoter may modulate gene transcriptional activity, the association between (GT) _n repeats polymorphism and risk of coronary heart disease (CHD) from different levels of oxidative stress (OS) is unknown. We determined the allelic frequencies of (GT) _n repeats in the HO-1 gene promoter and plasma malonaldehyde (MDA) as biomarkers of OS in 2,298 pairs of CHD patients and controls in the Chinese population. Furthermore, we measured MDA in culture mediums and HO-1 expressions levels in cell lysates of endothelial cells carrying various (GT) _n genotypes under different concentrations of H₂O₂. Compared with L/L genotype (>25 repeats) carriers, the adjusted odd ratios for S/S genotype (≤25 repeats) in subjects with different levels of OS (MDA 2.91 μmol/L) were 1.06 (95%CI, 0.75 to 1.49), 0.79 (95%CI, 0.55 to 1.12), and 0.60 (95%CI, 0.44 to 0.81), respectively (P _interaction = 0.002). In biological experiments, compared with endothelial cells carrying L/L genotype, cells with S/S genotype did not have a significantly higher HO-1 expression under 0 μmol/L H₂O₂, but displayed a significantly higher HO-1 expression under 50 μmol/L H₂O₂ (P _interaction = 0.003). S/S genotype in HO-1 gene promoter is associated with a lower risk of CHD in subjects with higher levels of OS, because under conditions of high OS, the S/S genotype has higher levels of HO-1, an antioxidant.