Interaction among <i>CYP2C8</i>, <i>EPHX2</i>, and <i>CYP4A11</i> Gene Variants Significantly Increases the Risk for Ischemic Stroke in Chinese Populations

Abstract

Aim: Ischemic stroke (IS) is a multifactorial disease caused by environmental risk factors and genetic susceptibility. However, few studies have assessed whether gene -gene interactions among cytochrome P450 (CYP) pathway genes influence the risk of IS. The aim of the present study was to investigate the association of 10 variants of eight CYP pathway genes with IS and to determine whether these gene -gene interactions increase the risk of IS. Methods: Ten variants of eight CYP pathway genes were examined using mass spectrometry methods in 396 patients with IS and 378 controls. Gene -gene interactions were analyzed using generalized multifactor dimensionality reduction (GMDR) methods. Results: Apart fro m variant rs9333025, there were no significant differences in the genotype distributions of the other nine variants between the two groups using the single -locus analytical approach. However, the GMDR analysis showed a significant gene -gene interaction among rs17110453, rs751141, and rs9333025, which scored 10 for cross-validation consistency and nine for the sign test (p 0.011). Individual patients with the combination of 17110453CC, rs751141GG, and rs9333025GG had a significantly higher risk for IS than those with the combination of 17110453AA, rs751141AA, and rs9333025AA [odds ratio (OR) 2.86, 95% confidence interval (CI): 1.24 -7.26, p 0.004]. Logistic regression analysis showed that certain gene -gene interactions among rs17110453, rs751141, and rs9333025 predict a higher risk for IS (OR 2.36, 95% CI: 1.228 -5.297, p 0.005). Conclusion:The three-loci interaction may confer a higher risk for IS. The combinatorial analysis used in this study may be helpful to elucidate complex genetic risk factors for IS.

Association of Cytochrome P450 Genetic Variants with Clopidogrel Resistance and Outcomes in Acute Ischemic Stroke

“…One possible explanation for this may be because the two genes encode enzymes that participate in the modulation of clopidogrel pharmacokinetics and pharmacodynamics, which is one of the principal pathogenic factors of clopidogrel response. Our previous studies have shown that the interaction of CYP rs17110453, rs751141, and rs9333025 may confer a higher risk for IS 19, 37) . A possible explanation for these CYP gene SNP interactions may be the three CYP gene encode enzymes that participate in arachidonic acid metabolism, which is one of the principal pathogenic factors of IS.…”

“…Genotyping was performed on genomic DNA extracted from periphery blood using the matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) method according to our previous study 19) . In brief, each SNP was amplified using two specific PCR primers and one extension primer.…”

“…Gene–gene interaction was assessed using a generalized multifactor dimensionality reduction (GMDR) program (beta version 0.7, ) 18, 19) . GMDR computed the maximum likelihood estimates and the scores of all individuals under the null hypothesis.…”

“…Moreover, the effects of individual locialone on clopidogrel resistance may be too small to be observed. Thus, the investigation of multiple gene – gene interactions is necessary to be able to understand the genetic basis of clopidogrel resistance risk in IS patients using alternative analytical methods, such as the generalized multifactor dimensionality reduction (GMDR) approach 18, 19) . We therefore hypothesized that relevant CYP genetic variants and interaction among these variants contribute to clopidogrel resistance and the outcome of acute IS patients treated with clopidogrel.…”

Interaction among COX-2, P2Y1 and GPIIIa gene variants is associated with aspirin resistance and early neurological deterioration in Chinese stroke patients

“…It is possible that the effects of each locus alone may be too small to be detected in relatively small patient groups, and only specific combinations of multiple variants were found to significantly contribute to AR. Thus, investigating multiple gene-gene interactions using the generalized multifactor dimensionality reduction (GMDR) approach may be required to accurately characterize the genetic etiology of AR [22, 23]. However, no such studies investigating the effect of gene-gene interactions on AR have been reported.…”