Interaction among CYP2C8, EPHX2, and CYP4A11 Gene Variants Significantly Increases the Risk for Ischemic Stroke in Chinese Populations

Aim: Ischemic stroke (IS) is a multifactorial disease caused by environmental risk factors and genetic susceptibility. However, few studies have assessed whether gene-gene interactions among cytochrome P450 (CYP) pathway genes influence the risk of IS. The aim of the present study was to investigate the association of 10 variants of eight CYP pathway genes with IS and to determine whether these gene-gene interactions increase the risk of IS. Methods: Ten variants of eight CYP pathway genes were examined using mass spectrometry methods in 396 patients with IS and 378 controls. Gene-gene interactions were analyzed using generalized multifactor dimensionality reduction (GMDR) methods. Results: Apart from variant rs9333025, there were no significant differences in the genotype distributions of the other nine variants between the two groups using the single-locus analytical approach. However, the GMDR analysis showed a significant gene-gene interaction among rs17110453, rs751141, and rs9333025, which scored 10 for cross-validation consistency and nine for the sign test (p=0.011). Individual patients with the combination of 17110453CC, rs751141GG, and rs9333025GG had a significantly higher risk for IS than those with the combination of 17110453AA, rs751141AA, and rs9333025AA [odds ratio (OR)=2.86, 95% confidence interval (CI): 1.24-7.26, p=0.004]. Logistic regression analysis showed that certain gene -gene interactions among rs17110453, rs751141, and rs9333025 predict a higher risk for IS (OR=2.36, 95% CI: 1.228-5.297, p=0.005). Conclusion: The three-loci interaction may confer a higher risk for IS. The combinatorial analysis used in this study may be helpful to elucidate complex genetic risk factors for IS.