title: Genetic polymorphisms of ALOX5AP and CYP3A5 increase susceptibility to ischemic stroke and are associated with atherothrombotic events in stroke patients.
abstract: BACKGROUND
  The contributions of gene-gene interactions to pathogenesis of stroke remain largely elusive. The present study was designed to investigate the associations between genetic variations and ischemic stroke risk, the roles of gene-gene interactions in ischemic stroke, and their associations with atherothrombotic events.
  
  
  METHODS
  Among 396 patients with ischemic stroke and 378 controls, we examined 8 variants from 5 genes, including ALOX5AP-SG13S32 (rs9551963), SG13S42 (rs4769060), SG13S89 (rs4769874), SG13S114 (rs10507391), EPHX2 G860A (rs751141), CYP2C9*2 C430T (rs1799853), CYP2C9*3 A1075C (rs1057910), and CYP3A5 A6986G (rs776746), using matrix-assisted laser desorption/ionization time of flight mass spectrometry. Gene-gene interactions were determined by the generalized multifactor dimensionality reduction (GMDR) method. All ischemic stroke patients were followed up 12 months for atherothrombotic events, including recurrent ischemic stroke and other vascular events.
  
  
  RESULTS
  Single-gene variant analysis showed no significant differences in the genotype distributions of the 8 variants between the 2 groups. However, the GMDR analysis showed a significant interaction between rs10507391 and rs776746, in those cases carrying rs10507391 AA and rs776746 GG, the risk of ischemic stroke increased by 2.014 times (95% confidence interval [CI], 1.896-6.299; P = .006), and the atherothrombotic events occurred more frequently in those patients during follow-up period (P < .001). Multiple Cox regression analysis showed that the interaction between rs10507391 AA and rs776746 GG was an independent risk factor for atherothrombotic events (relative risk = 2.921; 95% CI, 1.118-7.012; P = .008).
  
  
  CONCLUSIONS
  The interaction between rs10507391 and rs776746 increases the susceptibility to ischemic stroke and is associated with atherothrombotic events in stroke patients.
authors.affiliation: Department of Neurology, People's Hospital of Deyang City, Deyang, 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, China.
authors.forename: Biao
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Neurology, People's Hospital of Deyang City, Deyang, China.
authors.forename: Chun
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Neurology, People's Hospital of Deyang City, Deyang, China.
authors.forename: Duanxiu
authors.initials: D
authors.lastname: Liao
authors.affiliation: Department of Neurology, Third Affiliated Hospital of Wenzhou Medical College, Wenzhou, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Lin
authors.affiliation: Department of Neurology, Third Affiliated Hospital of Wenzhou Medical College, Wenzhou, China.
authors.forename: Lifen
authors.initials: L
authors.lastname: Chi
mesh_terms: D058927:5-Lipoxygenase-Activating Proteins / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D050197:Atherosclerosis / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics* / Q000401:mortality; D002545:Brain Ischemia / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics* / Q000401:mortality; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D002681:China; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016016:Proportional Hazards Models; D012008:Recurrence; D012307:Risk Factors; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D020521:Stroke / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics* / Q000401:mortality; D013927:Thrombosis / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics* / Q000401:mortality
chemical_list: D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A
keywords: 5-lipoxygenase activating protein; GMDR; Stroke; cytochrome P450; genetics; variants