C242T Polymorphism Of P22 Phox Gene Research Articles

Association between p22PHOX gene C242T polymorphism and hypertension in end-stage kidney disease patients.

Oxidative stress plays an important role in hypertension associated vascular damage. It is mediated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation. The C242T polymorphism in the p22PHOX gene encoding essential subunit of NADPH oxidase was associated with CVD, hypertension, and endothelial function. The aim of this study was to assess a potential association of C242T polymorphism with hypertension in end-stage kidney disease (ESKD) patients. DNA samples from 495 patients were genotyped by polymerase chain reaction (PCR) with subsequent cleavage with Rsa I restriction endonuclease. There were no significant differences in genotype and allele distribution between ESKD patients and healthy controls. When patients were stratified into male and female subgroups, there were no differences in the frequency of the T allele (0.35 and 0.34, respectively). Genotype and allele frequencies were also comparable between HY+ and HY- subgroups. We analyzed whether there were any differences between genders in the effect of C242T polymorphism on the presence of hypertension by comparing HY+ males with normotensive males and HY+ females with normotensive females. No difference in polymorphism distribution was found in female subgroup. The significant differences were observed in males. In HY+ subgroup, the frequencies of T allele and TT genotype were higher than in HY- males, with OR 1.91 (1.31-2.8), p = 0.0008 and OR 4.2 (1.67-10.6), p = 0.002, respectively. In conclusion, this is the first study to demonstrate significant association of the p22PHOX gene polymorphism with hypertension in male ESKD patients, with T allele as a risk factor for hypertension.

Association of the NAD(P)H oxidase p22 phox gene C242T polymorphism with type 2 diabetes mellitus, diabetic nephropathy, and carotid atherosclerosis with type 2 diabetes mellitus: A meta-analysis

BackgroundSeveral epidemiological studies have evaluated the association between the NAD(P)H oxidase p22 phox gene C242T polymorphism and the risk of type 2 diabetes mellitus (T2DM), diabetic nephropathy (DN), and carotid atherosclerosis with T2DM (CA), but the results are inconclusive. This meta-analysis was therefore designed to clarify these controversies. MethodsSystematic searches were performed using electronic databases such as MEDLINE, PubMed, EMBASE, and China National Knowledge Infrastructure, as well as through manual searching of the references of identified articles. A total of 11 publications were eligible for this meta-analysis after running a search on the NAD(P)H oxidase p22 phox gene C242T polymorphism, including 7 with outcomes for T2DM, 7 with outcomes for DN, and 3 with outcomes for CA. The pooled odds ratio (OR) with a 95% confidence interval (CI) was calculated using a fixed effects model (FEM) or a random effects model (REM). Publication bias was tested by Begg's funnel plot analysis. Sensitivity analysis was also performed. ResultsThe results showed a significant association between the NAD(P)H oxidase p22 phox gene C242T polymorphism and T2DM risk in the allelic model (REM: OR=1.23, 95% CI=1.06–1.43), additive model (FEM: OR=1.61, 95% CI=1.14–2.26), and recessive model (FEM: OR=1.50, 95% CI=1.10–2.05). A significant association was also observed for DN in the allelic model (REM: OR=1.25, 95% CI=1.06–1.47), additive model (FEM: OR=1.61, 95% CI=1.08–2.38), and dominant model (REM: OR=1.26, 95% CI=1.03–1.54). However, no association was observed for CA. Similar results were obtained in subgroup analysis based on ethnicity. ConclusionsResults of this meta-analysis suggest that the NAD(P)H oxidase p22 phox gene 242T allele might be associated with an increased risk of T2DM and DN, but not CA.

NADPH oxidase p22phox C242T polymorphism and ischemic cerebrovascular disease: an updated meta-analysis.

BackgroundA growing number of studies on the associations between nicotinamide adenine dinucleotide phosphate (NADPH) oxidase p22phox C242T polymorphism and risk of ischemic cerebrovascular disease have recently been published, but the results remain inconsistent.Material/MethodsWe performed an updated meta-analysis to evaluate this association. Eight case-control studies were included, involving 2045 cases and 2102 controls. Heterogeneity was assessed by the Q test and the I2 statistic. Begg and Egger’s tests were conducted to evaluate publication bias. Odds ratio (OR) was tested to identify the associations.ResultsSignificant associations between p22phox gene C242T polymorphism and ischemic cerebrovascular disease (ICVD) risk were observed in the allelic genetic model (OR=1.33, 95% confidence interval [CI] 1.00–1.77, p=0.048). No statistical significant association was found in the dominant model (OR=0.74, 95% CI 0.54–1.02, p=0.064) and recessive model (OR=1.40, 95% CI 0.89–2.19, p=0.146). Subgroup analysis showed an association in European populations for recessive model (OR=2.13, 95% CI 1.06–4.26, p=0.034) and no significant evidence of association in Asian populations was found (dominant model: OR=0.64, 95% CI 0.41–1.00, p=0.05; recessive model: OR=0.98, 95% CI 0.53–1.81, p=0.948; allelic model: OR=1.51, 95% CI 0.98–2.32, p=0.061).Conclusionsp22phox gene C242T polymorphism was associated with ICVD risk in the allelic genetic model, as well as in European populations for recessive model. No evidence showed association between p22phox gene C242T polymorphism and ICVD risk in the dominant model and recessive model. Furthermore, no association existed in Asian populations for any of the 3 genetic models and European populations in the dominant model and allelic model.

C242T Polymorphism of P22phox Gene of the Nox: A Putative Pathological Risk Factor for Stroke in Kashmiri Population

Background and purpose: NADPH oxidase (Nox) is a multicomponent enzyme responsible for the generation of reactive oxygen species (ROS). The p22phox is a key component of the cytochrome b558 of Nox and is essential for the activation of this enzyme, which by generating reactive oxygen species (ROS) is involved in the pathogenesis of many inflammatory diseases. The Nox-mediated excessive ROS production can damage tissue and represents an important cause of injury in many chronic inflammatory disorders including rheumatoid arthritis, atherosclerosis, lung injury and inflammation-associated cancer. An intensive expression of the p22phox has been reported in human atherosclerotic arteries. However, studies on the association of the C242T polymorphism in the p22phox gene with cerebrovascular disease (CVD) have produced conflicting results, and the relation of this polymorphism with CVD is not well known in a population with acquired risk factors enhancing the Nox-dependent superoxide production. We investigated the relevance of C242T polymorphism of p22phox gene to stroke, the maiden study directed in ethnic Kashmiri subjects. Methods: The study included 100 cases suffering from stroke (both ischemic and hemorrhagic stroke) and 120 controls. DNA was isolated from peripheral leukocytes and the genomic analysis of C242T polymorphism was done by PCR-RFLP. Results: We found T allele frequency of 38% in cases and 14% in controls (p<0.0001). Hemorrhagic stroke T allele frequency was 41% (p<0.0001) and Ischemic stroke T allele frequency was 34% (p<0.0001). Conclusion: The presence of T allele was associated with higher risk of stroke. The prevalence of T allele was significantly higher in stroke patients (p<0.0001) irrespective of type which demonstrates that C242T polymorphism of p22phox gene plays an important role in the stroke in Kashmiri population.

C242T polymorphism of the NADPH oxidase p22PHOX gene and its association with endothelial dysfunction in asymptomatic individuals with essential systemic hypertension

Vascular oxidative stress is an important factor in hypertension-associated vascular damage and is mediated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation. The C242T polymorphism at the p22PHOX gene affects binding of p22PHOX to heme, leading to variants of NADPH oxidase that produce different levels of reactive oxygen species (ROS). Specific variations in ROS are associated with an altered risk of developing cardiovascular disease. In the present study, 140 permanent Kashmiri-resident individuals were recruited (75 with essential systemic hypertension and 65 normotensive controls). Endothelial function was assessed non-invasively using high-resolution ultrasonography of the brachial artery. Endothelium-dependent vasoreactivity was expressed in terms of flow-mediated dilation. The TT genotype was identified in 2% of hypertensive and 7% of normotensive individuals. Frequency of the T-allele was not observed as significantly different between hypertensive and normotensive individuals (P=0.24; OR=0.4; 95% CI, 0.07-2.2). Blood pressure or the prevalence of hypertension did not vary between C242T p22PHOX genotypes or in the presence or absence of the T-allele.

C242T polymorphism of NADPH oxidase p22phox gene reduces the risk of coronary artery disease in a random sample of Egyptian population

The p22phox protein subunit is essential for NADPH oxidase activity. The prevalence of C242T variants of p22phox gene was studied in 101 healthy Egyptian controls and 104 acute myocardial infarction (AMI) Egyptian patients. Contribution of oxidative stress, represented by serum oxidized-LDL (ox-LDL), in development of AMI was also examined and correlated with C242T gene variants. Genotyping and ox-LDL were assessed by PCR-RFLP and ELISA. Results showed that wild type CC genotype is prevalent in 27 % of controls; CT and TT are in 72 and 1 %. In patients, the distribution was 40.2, 59.8 and 0 % for CC, CT and TT; respectively, showing a significant difference (p = 0.0259). Serum ox-LDL levels were higher in patients than controls (p ≤ 0.0001). Subjects having CT genotype had lower levels of ox-LDL than CC genotype (p ≤ 0.005). C242T polymorphism of p22phox gene of NADPH oxidase is a novel genetic marker associated with reduced susceptibility to AMI.

Association of the C242T polymorphism in the NAD(P)H oxidase P22 phox gene with type 2 diabetes mellitus risk: a meta-analysis

Objectives:A number of epidemiological studies have explored the association between NAD(P)H oxidase P22 phox gene C242T (rs4673) polymorphism and susceptibility to type 2 diabetes mellitus (T2DM), but the results are still debatable. Therefore, we conducted a meta-analysis to assess the potential association between the NAD(P)H oxidase P22 phox gene C242T polymorphism and T2DM risk.Methods:Electronic literature searches of the PubMed, Embase, Web of Science, CBMdisc, CNKI and Google Scholar were performed up to June 15, 2013. Additionally, hand searching of the references of identified articles was performed. Data analyses were carried out by Stata 11.0.Results:Seven studies were included in the final meta-analysis, covering a total of 1661 T2DM cases and 1265 controls. The results showed evidence for significant association between the NAD(P)H oxidase P22 phox gene C242T polymorphism and T2DM risk (for T/T vs. T/C: OR = 1.61, 95% CI = 1.14–2.26, p = 0.007; for T/T vs. T/C + C/C: OR = 1.50, 95% CI = 1.10–2.05, p = 0.009). In the subgroup analysis, there was also evidence for significant association between the NAD(P)H oxidase P22 phox gene C242T polymorphism and T2DM risk, either for Asians (T/T vs. T/C + C/C: OR = 1.74, 95% CI = 1.15–2.64, p = 0.009) or for non-Asians (for T allele vs C allele: OR = 1.30, 95% CI = 1.04–1.61, p = 0.02).Conclusions:The present meta-analysis indicates that the NAD(P)H oxidase P22 phox gene 242 T allele might be associated with an increased T2DM risk.

Association of the −262C/T polymorphism in the catalase gene promoter and the C242T polymorphism of the NADPH oxidase P22phox gene with essential arterial hypertension in patients with diabetes mellitus type 2

Aim: The aim of the present study was to test the association between genetic polymorphisms with functional effects on redox regulation: the −262C/T of the catalase gene promoter (rs1001179), the C242T of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase P22phox gene (rs4673), and the 594C/T polymorphism of the glutathione peroxidase gene (rs1050450) and arterial hypertension (AH) in patients with type 2 diabetes.Methods: 810 Slovenian subjects (Caucasians) with type 2 diabetes were enrolled in the cross-sectional study. Genotypes were determined by real-time PCR.Results: Univariate analysis failed to demonstrate an association between either the −262C/T of the catalase gene promoter (rs1001179) or the C242T polymorphism of the P22phox gene (rs4673) or the 594C/T polymorphism of the glutathione peroxidase gene (rs1050450) and AH. After adjustment for age, body mass index, fibrinogen level and high sensitivity C-reactive protein level, rs4673 was found to be an independent risk factor for AH in subjects with type 2 diabetes, whereas rs1001179 and rs1050450 were not.Conclusion: According to the results of cross-sectional study, the tested polymorphism of the NADPH oxidase P22phox gene (rs4673) was found to be associated with the development of AH, indicating that the oxidative stress gene NADPH oxidase might be implicated in the pathogenesis of AH in subjects with type 2 diabetes.

Association between the C242T polymorphism of p22phox gene and ischemic stroke: A meta-analysis

Recently, increasing studies have been focused on the association between the p22phox gene C242T polymorphism and ischemic stroke (IS). However, the results were controversial. As far as we know, there is no previous systematic review or meta-analysis concerning this association. Thus, we conducted this meta-analysis to evaluate this association. The strength of association was evaluated by the odds ratio (OR) with the corresponding 95% confidence intervals (CIs). Heterogeneity was assessed by Q-test and the I2 statistic. Publication bias was tested using funnel plots and Egger's regression test. Cumulative meta-analysis was performed to assess the trend in pooled OR over time. There was no significant association of the p22phox gene C242T polymorphism with IS in the overall analysis and subgroup analysis by ethnicity and subtypes of IS. However, statistical significance was found in the dominant model (OR: 1.57, 95%CI: 1.18–2.09), codominant model (OR: 1.62, 95%CI: 1.20–2.17) and allelic model (OR: 1.44, 95%CI: 1.11–1.87) among the hospital-based studies. The cumulative meta-analysis also suggested no trend of association between this polymorphism and IS from 2007 to 2011 as more data accumulated over time. Our meta-analysis indicated that the p22phox gene C242T polymorphism is unrelated to the risk of IS in the overall analysis and subgroup analysis by ethnicity and subtypes of IS. However, statistical significance was found in the subgroup analysis by source of controls among the hospital-based studies.

Association of p22phox gene C242T polymorphism with coronary artery disease: A meta-analysis

Introduction The C242T polymorphism of p22phox gene (rs4673) has been linked to the reduced coronary artery disease (CAD) risk, but results in the published literatures are controversial. A meta-analysis was performed to assess the effect of this polymorphism on the CAD risk. Methods A comprehensive search was conducted to identify all studies on the association of p22phox gene C242T polymorphism with CAD risk. The fixed or random effect pooled measure was selected based on the homogeneity test among studies. Heterogeneity among studies was evaluated using Q test and the I 2 of Higgins and Thompson. Meta-regression was used to explore the sources of between-study heterogeneity. Publication bias was estimated using modified Egger's linear regression test proposed by Harbord etal. Results We identified 15 published articles including 6273 CAD cases and 5045 controls. In this studied overall and non-Asian populations, we didn't found any significant association of p22phox gene C242T polymorphism with CAD in any of codominant, dominant, and recessive models. Only in Asian population, both fixed effect model (FEM) and random effect model (REM) indicated the significant protective effect both in codominant (FEM: OR = 0.771, 95%CI: 0.681-0.873; REM: OR = 0.751, 95%CI: 0.607-0.930) and dominant (FEM: OR = 0.714, 95%CI: 0.621-0.822; REM: OR = 0.694, 95%CI: 0.538-0.895) models with strong evidence for between-study heterogeneity ( I 2 = 52.6% for codominant and I 2 = 56.5% for dominant), but not in recessive model. No evidence of publication bias was detected. Conclusions The results suggested a significant heterogeneity across ethnicities about the relationship between the T allele of p22phox gene C242T polymorphism and reduced CAD risk, with a significant protective effect only in Asian population that needs to be confirmed by further studies.

NAD(P)H oxidase p22phox gene C242T polymorphism, nitric oxide production, salt sensitivity and cardiovascular risk factors in Hispanics

Mutations in the NAD(P)H oxidase gene may be associated with abnormal superoxide generation, nitric oxide (NO) availability and cardiovascular diseases. We investigated the prevalence of the NAD(P)H oxidase p22phox gene C242T polymorphism, and its possible association with blood pressure, NO production, salt sensitivity and cardiovascular risk factors in Hispanics. Genotype frequencies were as follows: CC, 52.9%; CT, 40.3%; and TT, 6.8%. There were no significant differences in systolic blood pressure, diastolic blood pressure, age, weight, fasting and post-load glucose levels, LDL and HDL cholesterol, triglyceride and urinary albumin levels in subjects with CC, CT or the TT genotypes. Presence of the T allele was associated with increased salt sensitivity in women, but not in men. NO metabolite excretion was markedly decreased both in women and men with the TT genotype (CC: 868+/-79 micromol/day; CT: 839+/-75 micromol/day; TT: 534+/-78 micromol/day; P<0.05). In conclusion, the prevalence of the NAD(P)H oxidase p22phox gene C242T polymorphism in Venezuelans was comparable to that of Caucasians, but different from that of Chinese and Japanese. Although the T allele was not associated with cardiovascular risk factors, hyperinsulinaemia or hypertension, in women, it appeared to be a genetic susceptibility factor for salt sensitivity. Both in women and men, the p22phox gene may play a role in the genetic control of NO levels.

Cardiac Remodeling: Mechanism and Treatment

Barry Greenberg, MD, ed 569 pages. New York, NY: Taylor and Francis; 2006. $199.95. ISBN 0-8247-2387-2. The appreciation that the myocardium changes shape and structure in response to disease has been appreciated for more than a century. The German anatomists including Krehl, Romberg, Aschoff, and Tawara debated the morphological changes occurring in the heart related to function at the end of the last century. The seminal work of Linzbach1 described the changes in myocyte size in response to aging and to hypertension, valvular heart disease, and heart failure. Because the cardiomyocyte is considered to be “terminally differentiated,” it must respond to disease by adapting to change by modifying its molecular and …

A beneficial effect of simvastatin on DNA damage in 242T allele of the NADPH oxidase p22phox in hypercholesterolemic patients

Background The effect of simvastatin on DNA damage in hypercholesterolemic patients was investigated, and the relationship between the C242T polymorphism of the NADPH oxidase p22phox gene and the antioxidant effects of simvastatin was examined. Methods Simvastatin (20–40 mg /day) was administered for 8 weeks in 72 hypercholesterolemic patients. DNA damage in lymphocytes was quantified using single-cell gel electrophoresis (COMET assay) by measuring tail DNA (%), tail length (μm) and tail moment (tail length × % tail DNA / 100). Results Simvastatin significantly reduced DNA damage as expressed by tail DNA (%, p < 0.001), tail length (μm, p < 0.001) and tail moment on the DNA in lymphocytes ( p < 0.001) after 8 weeks. The frequencies of the C242T genotypes for CC, TC, and TT were 75.0%, 23.6% and 1.4% in the subjects. In the presence of the 242T allele, there were higher levels of baseline DNA damage and also a greater improvement in the DNA damage after 8 week simvastatin treatment compared with the CC homozygotes. Conclusion Simvastatin significantly reduced DNA damage of hypercholesterolemic patients. This study showed that simvastatin has a beneficial effect on the improvement of DNA damage in patients with the 242T allele of NADPH oxidase p22phox gene.

The C242T p22phox polymorphism and endothelium-dependent vasodilation in subjects with hypercholesterolaemia.

Oxidative stress plays a major pathogenetic role in cardiovascular disease. The C242T variant of the CYBA gene encoding the p22phox subunit of the NAD(P)H oxidase, a major source of superoxide production, has been shown to be associated with coronary artery disease and with vascular superoxide production in human veins ex vivo. Since superoxide degrades nitric oxide (NO), we hypothesized that the C242T variant influences endothelium-dependent vasodilation of the human forearm vasculature in vivo. In the present study, 90 subjects with elevated cholesterol levels were stratified for the C242T polymorphism of the CYBA p22phox gene. Endothelium-dependent and -independent vasodilation were assessed by plethysmographic monitoring of forearm blood flow responses to intra-arterial infusion of acetylcholine and sodium nitroprusside respectively. N(G)-Monomethyl-L-arginine (L-NMMA) was infused to analyse NO-mediated basal vascular tone. Baseline parameters (age, gender, blood pressure, body mass index, cholesterol level) were similar across the genotypes. No differences in forearm blood flow responses to the intra-arterial infusion of acetylcholine, sodium nitroprusside or L-NMMA were found across the CYBA p22phox genotypes. Our sample size of n =90 had a power of >80% (beta=0.20) with a P value of <0.05 (alpha=0.05) to detect a difference greater than 156% in the forearm blood flow response to acetylcholine across genotypes (S.D. 336%; average increase in forearm blood flow=514%). In conclusion, at a power of 80%, our study excludes a major effect of the C242T CYBA p22phox polymorphism on acetylcholine-mediated endothelium-dependent vasodilation and basal NO-mediated vascular tone of the human forearm circulation in subjects with hypercholesterolaemia.

Genetic factors associated with endothelial dysfunction affect the early onset of coronary artery disease in Korean males

The maintenance of balance between nitric oxide (NO) and the superoxide anion is required for proper functioning of the endothelium. To investigate the relationship between genetic factors associated with endothelial function and the development of coronary artery disease (CAD), endothelial nitric oxide synthase (ecNOS) gene a/b polymorphism and NADH/NADPH oxidase p22 phox gene C242T polymorphism were examined in 305 Korean male CAD patients and 215 healthy male control subjects. The beta-fibrinogen gene H1/H2 polymorphism was also analyzed. Both ecNOS a/b and p22 phox C242T polymorphisms were found to be associated with the development of CAD in the study population (p=0.020 and 0.011, respectively). When the association was analyzed by age, statistical significance was retained only in those <51 years (p=0.021 and 0.025 for the a/b and the C242T polymorphism, respectively) and not in those >51 years of age (p=0.155 and 0.278 respectively). However, the distribution of the beta-fibrinogen H1/H2 genotypes was not found to be associated with the development of CAD in either the < or =50 (p = 0.611) or >50 groups (p = 0.188). The ecNOS gene a/b polymorphism and the NADH/NADPH oxidase p22 phox gene C242T polymorphism were found to be significantly associated with the development of CAD in Korean male patients less than 51 years old.