Interactions Among CYP2C8, EPHX2, and CYP4A11 Variants and CYP Plasma Metabolite Levels in Ischemic Stroke.

AIM: To better understand the relationship between the interactions among rs17110453, rs751141, and rs9333025 variants and plasma levels of cytochrome P450 (CYP) metabolites, i.e.,20-hydroxyeicosatetraenoic acid (20-HETE), epoxyeicosatrienoic acids (EETs), and dihydroxyeicosatrienoic acids (DiHETEs) in ischemia stroke (IS). METHODS: We measured plasma CYP metabolite levels in 218 acute IS cases and 126 controls, and a subset of samples were assessed to further understand the association between relevant variants and IS risk in our previous study. We assessed the associations between variant interactions and levels of 20-HETE, EETs, and DiHETEs as well as the associations between levels of 20-HETE, EETs, and DiHETEs and IS risk after adjusting for other potential confounders. Furthermore, the association between variant interactions and IS risk after adjusting for other covariates, including CYP metabolites levels, was evaluated. RESULTS: The interactions among variants rs17110453, rs751141, and rs9333025 were significantly associated with high 20-HETE, high DiHETEs, and low EETs after adjusting for the status of diabetes mellitus and hypertension. High 20-HETE, high DiHETEs, and low EETs were independent risk factors for IS after adjusting for hypertension, diabetes mellitus, and the interactions among rs17110453, rs751141, and rs9333025. Furthermore, the interactions among rs17110453, rs751141, and rs9333025 were significantly associated with a higher risk of IS after adjusting for CYP metabolites (OR=2.02, 95% CI: 1.28-5.27, P=0.007). CONCLUSION: The association between the interactions among rs17110453, rs751141, and rs9333025 and IS risk in Chinese population may be partly but not exclusively mediated by plasma levels of 20-HETE, EETs, and DHETs. Further well-designed studies are warranted to replicate this finding.

Interaction Between CYP4F2 rs2108622 and CPY4A11 rs9333025 Variants Is Significantly Correlated with Susceptibility to Ischemic Stroke and 20-Hydroxyeicosatetraenoic Acid Level.

AIMS: To investigate the association of four variants of two CYP ω-hydroxylase genes and 20-hydroxyeicosatetraenoic acid (HETE) levels with ischemic stroke (IS) and whether gene-gene interactions between these genes increase the risk of IS. METHODS: Three hundred ninety-six patients with IS and 378 controls were genotyped for rs2269231, rs9333025, rs2108622, and rs3093135. Gene-gene interactions were analyzed using generalized multifactor dimensionality reduction (GMDR) methods. The 20-HETE levels was measured in 218 IS patients and 126 controls. RESULTS: The frequency of the GG genotype of rs9333025 was significantly higher in IS patients than in controls (p < 0.001). The GMDR analysis showed a significant gene-gene interaction between rs9333025 and rs2108622 (p = 0.0116). This gene-gene interaction predicted a significantly higher risk of IS in individuals carrying the genotypes of rs9333025 GG and rs2108622 GG (odds ratio = 1.92, 95% confidence interval = 1.12-4.26, p = 0.007). The plasma levels of 20-HETE were significantly higher in IS patients than in controls, and IS patients carrying the genotype combination of rs9333025 GG and rs2108622 GG had higher 20-HETE levels than IS patients with other combinations of the two variants. CONCLUSION: CYP4A1l rs9333025 GG and CYP4F2 rs2108622 GG two-loci interaction significantly increases the risk for IS and an elevated 20-HETE level.

CYP Genetic Variants, CYP Metabolite Levels, and Symptomatic Carotid Stenosis in Ischemic Stroke Patients.

AIM: To evaluate the relationship between CYP genetic polymorphisms and CYP metabolite levels with carotid artery stenosis in acute ischemic stroke (IS) patients. METHODS: Eleven single nucleotide polymorphisms (SNPs) of seven CYP genes were genotyped in 136 IS patients with carotid stenosis and 158 patients without carotid stenosis. CYP plasma metabolite levels [20-hydroxyeicosatetraenoic acid (HETE), total epoxyeicosatrienoic acids (EETs), and dihydroxyeicosatrienoic acids (DiHETEs)] were assessed in a subsample of 90 patients with carotid stenosis and 96 patients without carotid stenosis. We evaluated the relationship between assessed variants and carotid stenosis risk, variants with CYP metabolite levels, and variants in mediating the differences of CYP metabolite levels between patients with carotid stenosis and those without. Additionally, gene-gene interactions were analyzed to assess the interactive role of the assessed variants in affecting CYP metabolite levels and risk of carotid stenosis. RESULTS: The genotypes of rs17110453CC, rs751141GG, and rs9333025GG were significantly associated with carotid stenosis risk. Also these polymorphisms were associated with CYP plasma metabolite levels in patients with carotid stenosis. There was a significant gene-gene interaction between rs17110453 and rs9333025 in affecting the risk of carotid stenosis. Patients with rs17110453CC and rs9333025GG had a significantly higher risk of carotid stenosis than those with 17110453AA and rs9333025AA (OR=2.12, 95% CI: 1.13-7.26, P=0.013). CONCLUSIONS: Specific CYP450 gene SNPs and their interactions are associated with CYP450 plasma metabolite levels, which may partially explain their associations with carotid stenosis. Further studies are needed to validate our findings.

Cytochrome P450 Genetic Variants and Their Metabolite Levels Associated with Plaque Stability in Patients with Ischemic Stroke.

AIM: Cytochrome P450s (CYP450) enzymes regulate inflammation and atherosclerosis and can affect carotid plaque stability in patients with ischemic stroke (IS). This study aimed to investigate the association of CYP450 genetic variants with CYP plasma metabolite levels and plaque stability in patients with IS. METHODS: Eleven single nucleotide polymorphisms (SNPs) of CYP genes and their plasma metabolite [20-hydroxyeicosatetraenoic acid (HETE), total epoxyeicosatrienoic acids (EETs), and dihydroxyeicosatrienoic acids (DiHETEs)] levels were measured in 396 patients with IS who underwent high-resolution B-mode ultrasound carotid plaque detection and were stratified into the following groups: non-carotid plaque and carotid plaque groups. The carotid plaque was further classified into subgroups of echolucent plaque (ELP) and echogenic plaque (EGP). RESULTS: Among the 396 patients with IS, 294 cases (74%) had plaques. The frequency of rs17110453CC, rs751141 GG, and rs9333025 GG genotypes was significantly higher in patients with plaque than those without plaque. The CC, GG, GG, and GG genotypes of rs17110453, rs776746, rs751141, and rs9333025 polymorphisms were independently associated with ELP (OR, 2.62 [1.34-5.26]; OR, 1.89 [1.16-3.58]; OR, 3.12 [1.27-7.13]; and OR, 2.06 [1.34-6.33], respectively). These polymorphisms were also associated with CYP plasma metabolite levels. Patients with ELP have also shown significantly higher levels of 20-HETE and DiHETEs, but lower levels of EETs. CONCLUSIONS: Our data demonstrates that CYP450 SNPs are associated with plasma CYP450 metabolite levels and echolucent plaques, indicating that these SNPs may be potential markers for plaque instability.

Interaction among CYP2C8, EPHX2, and CYP4A11 Gene Variants Significantly Increases the Risk for Ischemic Stroke in Chinese Populations.

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.

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

AIMS: 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. MAIN 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. KEY FINDINGS: 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). SIGNIFICANCE: 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.

Cytochrome 4A11 Genetic Polymorphisms Increase Susceptibility to Ischemic Stroke and Associate with Atherothrombotic Events After Stroke in Chinese.

To evaluate the associations between four single-nucleotide polymorphisms (SNPs) in CYP4A11 and CYP4F2 and ischemic stroke (IS), and between these variants and atherothrombotic events after stroke. IS patients (n=396) and controls (n=378) were genotyped for two CYP4A11 SNPs (rs2269231 and rs9333025) and two CYP4F2 SNPs (rs2108622 and rs3093135). Patients were followed up for 12 months after the stroke for the atherothrombotic events. The frequency of the rs9333025 GG genotype was significantly higher in IS patients than in controls. Logistic regression analysis showed that the presence of rs9333025 GG in patients was associated with significantly higher risk of IS. Cox regression analysis revealed that the rs9333025 GG genotype was an independent risk factor for atherothrombotic events after stroke. The rs9333025 GG genotype increases patients' susceptibility to IS and is associated with high frequencies of atherothrombotic events in stroke patients.

Clopidogrel plus aspirin prevents early neurologic deterioration and improves 6-month outcome in patients with acute large artery atherosclerosis stroke.

AIMS: To evaluate the effects of treatments with clopidogrel plus aspirin (dual therapy) on early neurological deterioration (END) and outcomes at 6 months in patients with acute large artery atherosclerosis (LAA) stroke. METHODS: A total of 574 patients with LAA stroke were randomly assigned to receive either dual therapy or aspirin alone (monotherapy). The primary outcome was END. Secondary outcomes included recurrent ischemic stroke (RIS) and outcomes at 6 months. RESULTS: The prevalence of END and RIS was lower in patients on dual therapy than in those on monotherapy during the 30 days. At 6 months, dual therapy improved outcomes among older patients and those with symptomatic stenosis in the posterior circulation and basilar artery. CONCLUSION: Clopidogrel plus aspirin is superior to aspirin alone for reducing END and RIS within 30 days and improves outcomes in certain subgroups at 6 months.

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

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.