CYP2C8 rs17110453 and EPHX2 rs751141 two-locus interaction increases susceptibility to ischemic stroke

•The potential association of CYP pathway gene variants with IS was investigated.•Rs17110453 and rs751141 two-locus interaction increased susceptibility to IS.•Carrying rs17110453CC and rs751141GG showed a 1.86-fold increased risk for IS.•GMDR analysis may be helpful in the elucidation of genetic risk factors for IS.

AimsIschemic stroke (IS) is a multifactorial disease caused by a combination of environmental risk factors and genetic susceptibilities. However, few studies have assessed the effects of gene–gene interactions among cytochrome P450 (CYP) pathway genes on the risk of stroke. The present study investigated the association of seven variants of six CYP pathway genes with IS in a Chinese population.Main methodsA total of 396 patients with IS and 378 controls were genotyped for seven variants from six CYP pathway genes, including CYP2J2 rs10889160, CYP2C8 rs17110453, CYP2C8 rs1934980, CYP2C9 rs1799853, CYP2C9 rs1057910, and CYP3A5 rs776746, as well as epoxide hydrolase 2 (EPHX2) rs751141, using 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.Key findingsSingle-gene variant analysis showed no significant differences in the genotype distributions of the seven variants between IS patients and healthy volunteers. However, GMDR analysis showed a significant gene–gene interaction between rs17110453 and rs751141, with scores of 10 and 9 for the cross-validation consistency and 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).SignificanceThe CYP2C8 rs17110453 and EPHX2 rs751141 two-locus interaction confers a significantly higher risk for IS. 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.