Dataset Information

P22phox C242T Single-Nucleotide Polymorphism Inhibits Inflammatory Oxidative Damage to Endothelial Cells and Vessels.

ABSTRACT: BACKGROUND:The NADPH oxidase, by generating reactive oxygen species, is involved in the pathophysiology of many cardiovascular diseases and represents a therapeutic target for the development of novel drugs. A single-nucleotide polymorphism, C242T of the p22(phox) subunit of NADPH oxidase, has been reported to be negatively associated with coronary heart disease and may predict disease prevalence. However, the underlying mechanisms remain unknown. METHODS AND RESULTS:With the use of computer molecular modeling, we discovered that C242T single-nucleotide polymorphism causes significant structural changes in the extracellular loop of p22(phox) and reduces its interaction stability with Nox2 subunit. Gene transfection of human pulmonary microvascular endothelial cells showed that C242T p22(phox) significantly reduced Nox2 expression but had no significant effect on basal endothelial O2 (.-) production or the expression of Nox1 and Nox4. When cells were stimulated with tumor necrosis factor-? (or high glucose), C242T p22(phox) significantly inhibited tumor necrosis factor-?-induced Nox2 maturation, O2 (.-) production, mitogen-activated protein kinases and nuclear factor ?B activation, and inflammation (all P<0.05). These C242T effects were further confirmed using p22(phox) short-hairpin RNA-engineered HeLa cells and Nox2(-/-) coronary microvascular endothelial cells. Clinical significance was investigated by using saphenous vein segments from non-coronary heart disease subjects after phlebotomies. TT (C242T) allele was common (prevalence of ?22%) and, in comparison with CC, veins bearing TT allele had significantly lower levels of Nox2 expression and O2 (.-) generation in response to high-glucose challenge. CONCLUSIONS:C242T single-nucleotide polymorphism causes p22(phox) structural changes that inhibit endothelial Nox2 activation and oxidative response to tumor necrosis factor-? or high-glucose stimulation. C242T single-nucleotide polymorphism may represent a natural protective mechanism against inflammatory cardiovascular diseases.

SUBMITTER: Meijles DN

PROVIDER: S-EPMC6485513 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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p22phox C242T Single-Nucleotide Polymorphism Inhibits Inflammatory Oxidative Damage to Endothelial Cells and Vessels.

Meijles Daniel N DN Fan Lampson M LM Ghazaly Maziah M MM Howlin Brendan B Krönke Martin M Brooks Gavin G Li Jian-Mei JM

Circulation 20160509 24

<h4>Background</h4>The NADPH oxidase, by generating reactive oxygen species, is involved in the pathophysiology of many cardiovascular diseases and represents a therapeutic target for the development of novel drugs. A single-nucleotide polymorphism, C242T of the p22(phox) subunit of NADPH oxidase, has been reported to be negatively associated with coronary heart disease and may predict disease prevalence. However, the underlying mechanisms remain unknown.<h4>Methods and results</h4>With the use ...[more]

PMID: 27162237

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Project description:BackgroundObservational and experimental studies have thus far been unable to resolve whether the CYBA C242T polymorphism is associated with coronary artery disease (CAD). Therefore, we undertook a comprehensive meta-analysis to more precisely evaluate the influence of this polymorphism on CAD and potential biases.MethodsWe screened MEDLINE, Embase, CNKI, Wanfang and CBM up to January 2013 and extracted data from 22 studies with 9,279 CAD patients and 9,349 controls. A random-effects model was exploited to synthesize the inconsistent outcomes of the individual studies, while addressing between-study heterogeneity and publication bias.ResultsThe CYBA C242T polymorphism conformed to Hard-Weinberg Equilibrium for all studies (P>0.05). Overall comparison of the T allele with the C allele produced a non-significant risk estimate for CAD but with striking heterogeneity (T versus C: P = 0.87, OR = 0.99, 95%CI 0.89-1.11, P(heterogeneity)<0.0001, I² = 67.8%). However, subgroup analysis by ethnicity documented that the T allele carriers had a marginal risk increase (21%) of CAD among Caucasians (recessive genetic model: P = 0.05, 95%CI 1.00-1.46, P(heterogeneity) = 0.15, I² = 29.1%). Then data were divided into study design, the significance of CAD risk increase was substantially strengthened in matched case-control studies (allele comparison: P = 0.02, OR = 1.13, 95%CI 1.02-1.26, P(heterogeneity) = 0.24, I² = 21.6%).Further meta-regression analysis identified that a large proportion of heterogeneity was explained by body mass index (BMI) (P = 0.03, OR = 1.07, 95%CI 1.01-1.15) and study design (P = 0.03, OR = 1.30, 95%CI 1.02-1.64).There was no obvious publication bias as verified by funnel plot and Egger's linear regression test (t = -0.25, P = 0.81 for allele comparison).ConclusionTaken together, our results suggested the CYBA C242T polymorphism might be a risk-conferring factor on developing CAD and BMI and study design were probable sources of between-study heterogeneity.

Project description:BackgroundEpidemiological 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 findingsSystematic 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/significanceThis 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.

Dataset Information

P22phox C242T Single-Nucleotide Polymorphism Inhibits Inflammatory Oxidative Damage to Endothelial Cells and Vessels.

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p22phox C242T Single-Nucleotide Polymorphism Inhibits Inflammatory Oxidative Damage to Endothelial Cells and Vessels.

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