Synergistic association of DNA repair relevant gene polymorphisms with the risk of coronary artery disease in northeastern Han Chinese

Abstract

Evidence is mounting suggesting that DNA damage is implicated in the development and progression of atherosclerosis. To yield more information, we focused on six well-characterized polymorphisms from four DNA repair-relevant candidate genes, viz. XRCC1 (rs1799782 and rs25487), XRCC3 (rs861539), MTHFR (rs1801133 and rs4846049), and NQO1 (rs1800566), to identify and characterize their potential gene-to-gene interactions in susceptibility to coronary artery disease (CAD) in Han Chinese. This was a hospital-based case-control study involving 1142 patients diagnosed with CAD and 1106 age- and gender-matched controls. All participants were angiographically confirmed. Risk estimates were expressed as odds ratio (OR) and 95% confidence interval (95% CI). All six examined polymorphisms met Hardy-Weinberg equilibrium. Overall there were significant differences in the genotype/allele distributions of MTHFR gene rs1801133 and rs4846049 (both P ≤ 0.005), and in the genotype distributions of XRCC1 gene rs1799782 (P = 0.002) between patients and controls. The adjusted risk of having CAD was more evident for rs1799782 (OR = 1.53; 95% CI: 1.16-2.02; P = 0.003), rs1801133 (OR = 1.54; 95% CI: 1.22-1.94; P < 0.001), and rs4846049 (OR = 1.74; 95% CI: 1.13-2.69; P = 0.013) under the recessive model. Interaction analyses indicated that the overall best multifactor dimensionality reduction (MDR) model included rs4846049, rs1801133, and rs1799782, and this model had a maximal testing accuracy of 0.6885 and a cross-validation consistency of 10 out of 10 (P = 0.0030). Further interaction entropy graph bore out the validity of this MDR model. Taken together, our findings demonstrate a contributory role of genetic defects in XRCC1 and MTHFR genes, both individually and interactively, in the development of CAD in Han Chinese.