title: CYP2C8 rs17110453 and EPHX2 rs751141 two-locus interaction increases susceptibility to ischemic stroke.
abstract: OBJECTIVE
  Ischemic 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.
  
  
  METHODS
  A 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.
  
  
  RESULTS
  Single-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).
  
  
  CONCLUSIONS
  The 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.
authors.affiliation: Department of Neurology, People's Hospital of Deyang City, Deyang 618000, Sichuan, China. Electronic address: yixingyang64@126.com.
authors.forename: Xingyang
authors.initials: X
authors.lastname: Yi
authors.affiliation: Department of Neurology, People's Hospital of Deyang City, Deyang 618000, Sichuan, China. Electronic address: 1842942576@qq.com.
authors.forename: Biao
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Neurology, People's Hospital of Deyang City, Deyang 618000, Sichuan, China.
authors.forename: Chun
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Neurology, People's Hospital of Deyang City, Deyang 618000, Sichuan, China.
authors.forename: Duanxiu
authors.initials: D
authors.lastname: Liao
authors.affiliation: Department of Neurology, Third Affiliated Hospital of Wenzhou Medical College, Wenzhou 325200, Zhejiang, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Lin
authors.affiliation: Department of Neurology, Third Affiliated Hospital of Wenzhou Medical College, Wenzhou 325200, Zhejiang, China.
authors.forename: Lifen
authors.initials: L
authors.lastname: Chi
mesh_terms: D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D002545:Brain Ischemia / Q000150:complications* / Q000235:genetics; D065727:Cytochrome P-450 CYP2C8 / Q000235:genetics*; D004851:Epoxide Hydrolases / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods; D020521:Stroke / Q000235:genetics*
chemical_list: D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D004851:Epoxide Hydrolases; C506428:EPHX2 protein, human
keywords: Cytochrome P450; Generalized multifactor dimensionality reduction; Genetics; Interaction; Stroke; Variants