The C242T Polymorphism of the NAD(P)H Oxidase p22phox Subunit Is Associated with an Enhanced Risk for Cerebrovascular Disease at a Young Age

Division of Molecular and Clinical Neurobiology, Department of Psychiatry, Ludwig Maximilian University, Munich, Germany.
Cerebrovascular Diseases (Impact Factor: 3.75). 10/2008; 26(4):430-3. DOI: 10.1159/000155639
Source: PubMed

ABSTRACT Oxidative stress has been proposed as a major contributing factor for vascular disease, that acts independently from its participation in predisposing disorders such as diabetes and arterial hypertension. A functionally relevant C242T polymorphism of the CYBA gene encoding the NAD(P)H oxidase p22(phox) subunit, is supposed to lead to an abnormal reduction in the generation of reactive oxygen species in vascular smooth-muscle and endothelial cells.
We investigated the p22(phox) C242T single-nucleotide polymorphism by polymerase chain reaction in consecutive patients with ischemic stroke or transient ischemic attack under the age of 50 (n = 161) and in population-based control subjects (n = 136).
Homozygosity for the T variant was associated with an enhanced risk for cerebral ischemia (odds ratio 3.85, confidence interval 1.39-10.64) after adjusting for classical risk factors. Risk for cerebral ischemia was not increased in heterozygous subjects.
The p22(phox) C242T single-nucleotide polymorphism is associated with stroke risk. This finding supports the hypothesis that oxidative stress may contribute to stroke pathogenesis.

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    • "Secondly, we performed sensitivity analysis by limiting the meta-analysis to studies in agreement with HWE. One study [27] deviating from HWE was excluded. The corresponding pooled ORs and 95%CIs were not substantively altered (allelic model: OR = 1.15, 95%CI = 0.84–1.58; "
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    ABSTRACT: Epidemiological studies have evaluated the association between nicotinamide adenine dinucleotide phosphate (NADPH) oxidase p22(phox) C242T polymorphism and risk of ischemic cerebrovascular disease (ICVD), but the results remain inconclusive. This meta-analysis was therefore designed to clarify these controversies. Systematic searches of electronic databases Embase, PubMed and Web of Science, as well as hand searching of the references of identified articles and the meeting abstracts were performed. Statistical analyses were performed using software Review Manager (Version 5.1.7) and Stata (Version 11.0). The pooled odds ratios (ORs) with 95% confidence intervals (95%CIs) were performed. Fixed or random effects model was separately used depending on the heterogeneity between studies. Publication bias was tested by Begg's funnel plot and Egger's regression test. A total of 6 studies including 1,948 cases and 2,357 controls were combined showing no statistical evidence of association between NADPH oxidase p22(phox) C242T polymorphism and overall ICVD (allelic model: OR = 1.08, 95%CI = 0.93-1.26; additive model: OR = 1.33, 95%CI = 0.81-2.17; dominant model: OR = 1.00, 95%CI = 0.86-1.15; recessive model: OR = 1.06, 95%CI = 0.77-1.45). Significant association was found in large-artery atherosclerotic stroke subgroup (allelic model: OR = 1.12, 95%CI = 0.88-1.41; additive model: OR = 1.36, 95%CI = 0.60-3.09; dominant model: OR = 1.25, 95%CI = 0.74-2.11; recessive model: OR = 2.17, 95%CI = 1.11-4.23). No statistical evidence of significant association was observed for small-vessel occlusive stroke, as well as Asian subgroup and Caucasian subgroup. Statistical powers on the combined sample size (total and subgroup) were all lower than 80%. This meta-analysis indicates that NADPH oxidase p22(phox) C242T polymorphism is more associated with large-artery atherosclerotic stroke than small-vessel occlusive stroke. However, this conclusion should be interpreted with caution due to the small sample size. Larger sample-size studies with homogeneous ICVD patients and well-matched controls are required.
    PLoS ONE 02/2013; 8(2):e56478. DOI:10.1371/journal.pone.0056478 · 3.23 Impact Factor
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    ABSTRACT: Oxidative stress has been implicated in the pathogenesis of neurologic and psychiatric diseases. The brain is particularly vulnerable to oxidative damage due to high oxygen consumption, low antioxidant defense, and an abundance of oxidation-sensitive lipids. Production of reactive oxygen species (ROS) by mitochondria is generally thought to be the main cause of oxidative stress. However, a role for ROS-generating NADPH oxidase NOX enzymes has recently emerged. Activation of the phagocyte NADPH oxidase NOX2 has been studied mainly in microglia, where it plays a role in inflammation, but may also contribute to neuronal death in pathologic conditions. However, NOX-dependent ROS production can be due to the expression of other NOX isoforms, which are detected not only in microglia, but also in astrocytes and neurons. The physiologic and pathophysiologic roles of such NOX enzymes are only partially understood. In this review, we summarize the present knowledge about NOX enzymes in the central nervous system and their involvement in neurologic and psychiatric diseases.
    Antioxidants & Redox Signaling 04/2009; 11(10):2481-504. DOI:10.1089/ARS.2009.2578 · 7.41 Impact Factor
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    ABSTRACT: Reactive oxygen species play an important role in the physiology and pathology of cerebral arteries, including ischaemic stroke. The cytochrome b-245 alpha gene (CYBA) encodes cytochrome b-245 alpha light chain (p22phox peptide), a critical element of NAD(P)H oxidases, the most important source of superoxide anion in the cerebral arteries. To search for genetic factors associated with paediatric ischaemic stroke, the possible association between CYBA gene C242T polymorphism and the disease was evaluated. The study group consisted of 238 individuals: children with ischaemic stroke (n = 70), their biological parents (n = 118) and children without any symptoms of stroke (n = 50). The C242T polymorphism was genotyped using polymerase chain reaction - restriction fragment length methodology. To evaluate the possible association between polymorphism and stroke, the transmission disequilibrium test and the case-control method were applied. The C242 allele was transmitted more frequently than 242T (62.2% vs. 37.8%) but observed frequencies did not differ significantly from expected (p = 0.10). There were also no significant differences in allele and genotype distribution between patients and control subjects (patients: CC - 50.0%, CT - 38.6%, TT - 11.4% vs. controls: CC - 52.0%, CT - 36.0%, TT - 12.0%). The study did not show that the C242T polymorphism of the CYBA gene is a risk factor of ischaemic stroke in children.
    Neurologia i neurochirurgia polska 01/2010; 44(5):453-8. DOI:10.1016/S0028-3843(14)60135-3 · 0.64 Impact Factor
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