Dataset Information

Association between NADPH oxidase p22(phox) C242T polymorphism and ischemic cerebrovascular disease: a meta-analysis.

ABSTRACT:

Background

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.

Methodology/principal findings

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%.

Conclusions/significance

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.

SUBMITTER: Li BH

PROVIDER: S-EPMC3569432 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Association between NADPH oxidase p22(phox) C242T polymorphism and ischemic cerebrovascular disease: a meta-analysis.

Li Bing-Hu BH Zhang Li-Li LL Zhang Bei-Bei BB Yin Yan-Wei YW Dai Li-Meng LM Pi Yan Y Guo Lu L Gao Chang-Yue CY Fang Chuan-Qin CQ Wang Jing-Zhou JZ Li Jing-Cheng JC

PloS one 20130211 2

<h4>Background</h4>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.<h4>Methodology/principal findings</h4>Systematic searches of electronic databases Embase, PubMed and Web of Science, as well as hand searching of the references of i ...[more]

PMID: 23409188

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Project description:The reactive oxygen-generating NADPH oxidases (Noxes) function in a variety of biological roles, and can be broadly classified into those that are regulated by subunit interactions and those that are regulated by calcium. The prototypical subunit-regulated Nox, Nox2, is the membrane-associated catalytic subunit of the phagocyte NADPH-oxidase. Nox2 forms a heterodimer with the integral membrane protein, p22phox, and this heterodimer binds to the regulatory subunits p47phox, p67phox, p40phox and the small GTPase Rac, triggering superoxide generation. Nox-organizer protein 1 (NOXO1) and Nox-activator 1 (NOXA1), respective homologs of p47phox and p67phox, together with p22phox and Rac, activate Nox1, a non-phagocytic homolog of Nox2. NOXO1 and p22phox also regulate Nox3, whereas Nox4 requires only p22phox. In this study, we have assembled and analyzed amino acid sequences of Nox regulatory subunit orthologs from vertebrates, a urochordate, an echinoderm, a mollusc, a cnidarian, a choanoflagellate, fungi and a slime mold amoeba to investigate the evolutionary history of these subunits.Ancestral p47phox, p67phox, and p22phox genes are broadly seen in the metazoa, except for the ecdysozoans. The choanoflagellate Monosiga brevicollis, the unicellular organism that is the closest relatives of multicellular animals, encodes early prototypes of p22phox, p47phox as well as the earliest known Nox2-like ancestor of the Nox1-3 subfamily. p67phox- and p47phox-like genes are seen in the sea urchin Strongylocentrotus purpuratus and the limpet Lottia gigantea that also possess Nox2-like co-orthologs of vertebrate Nox1-3. Duplication of primordial p47phox and p67phox genes occurred in vertebrates, with the duplicated branches evolving into NOXO1 and NOXA1. Analysis of characteristic domains of regulatory subunits suggests a novel view of the evolution of Nox: in fish, p40phox participated in regulating both Nox1 and Nox2, but after the appearance of mammals, Nox1 (but not Nox2) became independent of p40phox. In the fish Oryzias latipes, a NOXO1 ortholog retains an autoinhibitory region that is characteristic of mammalian p47phox, and this was subsequently lost from NOXO1 in later vertebrates. Detailed amino acid sequence comparisons identified both putative key residues conserved in characteristic domains and previously unidentified conserved regions. Also, candidate organizer/activator proteins in fungi and amoeba are identified and hypothetical activation models are suggested.This is the first report to provide the comprehensive view of the molecular evolution of regulatory subunits for Nox enzymes. This approach provides clues for understanding the evolution of biochemical and physiological functions for regulatory-subunit-dependent Nox enzymes.

Dataset Information

Association between NADPH oxidase p22(phox) C242T polymorphism and ischemic cerebrovascular disease: a meta-analysis.

Background

Methodology/principal findings

Conclusions/significance

Publications

Association between NADPH oxidase p22(phox) C242T polymorphism and ischemic cerebrovascular disease: a meta-analysis.

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