Genetic polymorphisms of ALOX5AP and CYP3A5 increase susceptibility to ischemic stroke and are associated with atherothrombotic events in stroke patients

J Stroke Cerebrovasc Dis. 2015 Mar;24(3):521-9. doi: 10.1016/j.jstrokecerebrovasdis.2014.09.035. Epub 2014 Dec 19.

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.

Keywords: 5-lipoxygenase activating protein; GMDR; Stroke; cytochrome P450; genetics; variants.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Lipoxygenase-Activating Proteins / genetics*
  • Aged
  • Aged, 80 and over
  • Atherosclerosis / diagnosis
  • Atherosclerosis / enzymology
  • Atherosclerosis / genetics*
  • Atherosclerosis / mortality
  • Brain Ischemia / diagnosis
  • Brain Ischemia / enzymology
  • Brain Ischemia / genetics*
  • Brain Ischemia / mortality
  • Case-Control Studies
  • Chi-Square Distribution
  • China
  • Cytochrome P-450 CYP3A / genetics*
  • Female
  • Gene Frequency
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Humans
  • Logistic Models
  • Male
  • Middle Aged
  • Multivariate Analysis
  • Odds Ratio
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Prognosis
  • Proportional Hazards Models
  • Recurrence
  • Risk Factors
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Stroke / diagnosis
  • Stroke / enzymology
  • Stroke / genetics*
  • Stroke / mortality
  • Thrombosis / diagnosis
  • Thrombosis / enzymology
  • Thrombosis / genetics*
  • Thrombosis / mortality

Substances

  • 5-Lipoxygenase-Activating Proteins
  • ALOX5AP protein, human
  • CYP3A5 protein, human
  • Cytochrome P-450 CYP3A