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Stroke is the second leading cause of death in developed countries.Ischemic stroke (IS), the most common type of stroke, s a multi-factorial disease caused by a combination of environmental risk factors and genetic susceptibilities.Recent genome-wide association studies have identified a number of genetic variants associated with increased risk of stroke.However, only a few studies have assessed the effects of gene-gene interactions among cytochrome P450 (CYP) pathway genes on the risk of stroke.The present study aims to investigate the association of the 7 variants of 6 CYP pathway genes with IS in a Chinese population consisting of 396 patients with IS and 378 controls healthy volunteers.The 7 variants from 6 genes,CYP2J2 rs10889160, CYP2C8 rs17110453, CYP2C8 rs1934980, CYP2C9 rs1799853, CYP2C9 rs1057910, CYP3A5 rs776746, EPHX2 rs751141, were examined using the matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) methods.Gene-gene interactions were analyzed using generalized multifactor dimensionality reduction (GMDR) methods.Single-gene variant analysis showed no significant differences in the genotype distributions of the 7 variants between ischemic stroke patients and controls.However, the GMDR analysis showed a significant gene-gene interaction between rs17110453 and rs751141, with scores of 10 and 9 for the cross-validation consistency and the sign test, respectively (P =0.0167).A 1.86-fold increased risk for IS was detected in individuals carrying the genotypes of rs17110453CC and rs751141GG (adjusted for age, hypertension, and diabetes mellitus; 95% CI: 1.216-2.896, P=0.005).The combinational analysis used in this study may be helpful in the elucidation of genetic risk factors for common and complex diseases such as IS.