NADPH Oxidase p22phox C242T Polymorphism and Ischemic Cerebrovascular Disease: An Updated Meta-Analysis

A 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.  We 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.  Significant 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).  p22phox 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.

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CRITICAL ISSUES
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The first Nox enzyme to be cloned and characterised was termed gp91phox (or Nox2), because it is the catalytic unit of the phagocytic respiratory burst oxidase, which is important for non-specific host defence against invading microbes. This protein exists in a macromolecular complex with p22phox, another membrane subunit that stabilises gp91phox and interacts with the cytosolic regulatory factor p47phox. p47phox has two tandem SH3 groups that interact with auto-inhibitory domains to maintain the protein in an inactive state. Upon phosphorylation of p47phox by protein kinase C, this interaction is lost, and the SH3 groups and proline-rich tail are exposed and bind to the membrane subunits and a second regulatory cytosolic subunit, p67phox. p67phox, in turn, serves as a binding site for the small molecular weight G protein Rac, which modulates enzyme activity.1

Originally, gp91phox was thought to be restricted to phagocytic cells. Recent work, however, indicates that gp91phox is expressed at low, but functionally important levels in many tissues. More importantly, in …

title: Oxidative stress and cardiovascular risk: the role of vascular NAD(P)H oxidase and its genetic variants
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title: p22phox Is a Critical Component of the Superoxide-generating NADH/NADPH Oxidase System and Regulates Angiotensin IIinduced Hypertrophy in Vascular Smooth Muscle Cells*
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title: Polymorphism of the NADH/NADPH oxidase p22 phox gene in patients with coronary artery disease.
abstract: Oxidative stress in the vasculature has been implicated in the pathogenesis of coronary artery disease (CAD). NADH/NADPH oxidase is a key enzyme of superoxide production in the vasculature. p22 phox, an essential component of NADH/NADPH oxidase, has four types of polymorphism. The C242T polymorphism changes histidine-72 to tyrosine, located in the potential heme-binding sites, whereas A640G polymorphism is located in the 3' untranslated region.



We investigated whether these polymorphisms were associated with risk of CAD by use of restriction fragment length polymorphism (RFLP). The prevalence of the TC + TT genotype of the C242T polymorphism was significantly more frequent in control subjects (n=201) than in the patients with CAD (n=201). The odds ratio of the TC + TT versus CC genotype of the C242T polymorphism between control subjects and case patients was 0.49 (95% CI, 0.28 to 0.87) (P=.015). The prevalence of the genotypes of the A640G polymorphism was not different between groups. The association of C242T polymorphism of the p22 phox gene with CAD was statistically significant and independent of other risk factors.



The mutation of the potential heme-binding site of the p22 phox gene may reduce susceptibility to CAD. Our observations suggest that the C242T polymorphism of the p22 phox gene is a novel genetic marker that has a protective effect on coronary risk.

title: NADH/NADPH oxidase p22phox C242T polymorphism and coronary artery disease in the Australian population
abstract: Oxidative stress induced by the superoxide anion (.O2−) has been implicated in atherogenesis. The NADH/NADPH oxidase system is involved in .O2− production and p22 phox is an essential component of that system.

title: C242T Polymorphism of NADPH Oxidase p22 PHOX Gene and Ischemic Cerebrovascular Disease in the Japanese Population
abstract: Superoxide has been implicated in the pathogenesis of ischemic stroke and atherosclerosis. NADPH oxidase, a major source of superoxide generation in neutrophils and the vascular system, plays a critical role in ischemic injury and atherogenesis. Recently, an association between the C242T polymorphism of p22 PHOX, an essential component of NADPH oxidase, and coronary artery disease (CAD) has been reported in several studies. To investigate the relationship between the C242T polymorphism of p22 PHOX and ischemic cerebrovascular disease (CVD), we conducted a case-control study. We recruited 226 CVD patients (atherothrombotic infarction, lacunar infarction, and transient ischemic attack) and 301 control subjects and analyzed C242T polymorphism of p22 PHOX by detection of restriction fragment length polymorphism. The TC+TT genotype frequencies in the CVD group and control group were 21.7% and 13.3%, respectively, and the prevalence of the TC+TT genotype was significantly ...

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title: NADPH Oxidase Polymorphisms in Cerebral Small Vessel Disease
abstract: 1 Lovett JK, Dennis MS, Sandercock PA, Bamford J, Warlow CP, Rothwell PM: Very early risk of stroke after a first transient ischemic attack. Stroke 2003; 34:e138–e140. 2 Lovett JK, Coull AJ, Rothwell PM: Early risk of recurrence by subtype of ischemic stroke in population-based incidence studies. Neurology 2004; 62: 569–573. 3 Fairhead JF, Mehta Z, Rothwell PM: Population-based study of delays in carotid imaging and surgery and the risk of recurrent stroke. Neurology 2005; 65: 371–375. 4 Lovblad KO, Laubach HJ, Baird AE, et al: Clinical experience with diffusion-weighted MR in patients with acute stroke.  Early ischemic lesion recurrence within a week after acute ischemic stroke.  Recent advances in management of transient ischaemic attacks and minor ischaemic strokes. Lancet Neurol 2006; 5: 323–331. 8 Demchuk AM: Acute secondary stroke prevention trials in minor stroke/TIA: prime time for magnetic resonance imaging.  2006; 1: 91–93. 9 Coutts SB, Hill MD, Simon JE, Sohn CH, Scott JN, Demchuk AM: Silent ischemia in minor stroke and TIA patients identified on MR imaging. Neurology 2005; 65: 513–517. 10 Kang DW, Latour LL, Chalela JA, Dambrosia JA, Warach S: Early and late recurrence of ischemic lesion on MRI: evidence for a prolonged stroke-prone state? Neurology 2004; 63: 2261–2265. 11 World Health Organization: Cerebrovascular Diseases – Prevention, Treatment and Rehabilitation. Geneva,  Rothwell PM, Coull AJ, Giles MF, et al: Change in stroke incidence, mortality, case-fatality, severity, and risk factors in Oxfordshire, UK, from 1981 to 2004 (. Lancet 2004;  Rothwell PM, Gutnikov SA, Warlow CP: Reanalysis of the final results of the European Carotid Surgery Trial. Stroke 2003; 34: 514–523. 14 Kang DW, Chalela JA, Ezzeddine MA, Warach S: Association of ischemic lesion patterns on early diffusion-weighted imaging with TOAST stroke subtypes.  Neurol 2003; 60: 1730–1734. 15 Baird AE, Lovblad KO, Schlaug G, Edelman RR, Warach S: Multiple acute stroke syndrome: marker of embolic disease? Neurology 2000; 54: 674–678. 16 Wong KS, Gao S, Chan YL, et al: Mechanisms of acute cerebral infarctions in patients with middle cerebral artery stenosis: a diffusionweighted imaging and microemboli monitoring study.

title: Functional effects of NAD(P)H oxidase p22(phox) C242T mutation in human leukocytes and association with thrombotic cerebral infarction.
abstract: Previous study showed that polymorphism of the NAD(P)H oxidase p22(phox) gene is associated with atherosclerosis, although others could not confirm such association. We investigated the association between p22(phox) C242T polymorphism and thrombotic cerebral infarction and the role of this polymorphism on superoxide-production activity in human neutrophils and promyelocytic HL-60 cells as a model system.



PCR-RFLP analysis revealed that genotype and allele frequencies of C242T polymorphism in 120 patients with thrombotic cerebral infarction and 177 control subjects. The superoxide-production activity in neutrophils was determined by cytochrome c reduction assay. To clarify the role of p22(phox) C242T polymorphism on NAD(P)H oxidase activity, we used transgenic HL-60 cells transfected with expression plasmids carrying p22(phox) cDNAs with or without C242T polymorphism.



Genotype and allele frequencies of C242T polymorphism in patients and control subjects were not significantly different. The superoxide-production activity in neutrophils with T allele was higher than in neutrophils without T allele. Moreover, expression analysis showed that superoxide-production activity in p22(phox) C242T-expressing HL-60 cells were significantly higher than in p22(phox)-expressing HL-60 cells.



We conclude that C242T of p22(phox) gene is not involved in thrombotic cerebral infarction but more likely in increased NAD(P)H oxidase activity in phagocytes.

title: NAD(P)H oxidase p22phox C242T polymorphism and ischemic stroke in Japan: the Fukuoka Stroke Registry and the Hisayama study
abstract: The C242T polymorphism of p22phox, a component of NAD(P)H oxidase, may have an impact on cardiovascular diseases; however, the association between this polymorphism and brain infarction is not fully understood. Here, we investigate the relationship between the C242T polymorphism and brain infarction in Japan. We recruited 1055 patients with brain infarction and 1055 control subjects. A chi‐squared test revealed that the T‐allele frequency was lower in patients with cardioembolic infarction (5.6%) than in control subjects (11.0%, P < 0.001); however, allele frequencies in patients with lacunar and atherothrombotic infarction (11.2%) were not significantly different from those in control subjects (11.0%). A multivariate‐adjusted conditional logistic regression analysis also revealed no association between CT + TT genotype, and lacunar and atherothrombotic infarction (odds ratio = 0.97, 95% confidence interval: 0.72–1.32). To investigate the functional effects of the C242T polymorphism, we examined superoxide production in COS‐7 cells cotransfected with Nox4 and p22phox of each genotype. The superoxide‐producing activity in those cells expressing p22phox with the T allele was not significantly different from that in cells expressing p22phox with the C allele. The present results suggest that the p22phox C242T polymorphism may have a protective effect against cardioembolic infarction, but is not related to lacunar and atherothrombotic infarction in Japan.

title: The C242T polymorphism of the gene encoding cytochrome b-245 alpha is not associated with paediatric ischaemic stroke: family-based and case-control study.
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.

title: The C242T Polymorphism of the NAD(P)H Oxidase p22phox Subunit Is Associated with an Enhanced Risk for Cerebrovascular Disease at a Young Age
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 p22phox 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 p22phox 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 p22phox C242T single-nucleotide polymorphism is associated with stroke risk. This finding supports the hypothesis that oxidative stress may contribute to stroke pathogenesis.

title: Correlation between NAD(P)H oxidase p22phox C242T polymorphism and cerebral infarction
abstract: To investigate the distribution of the gene polymorphism and allele frequency of the NAD(P)H oxidase p22phox C242T,and evaluate the relationship between the polymorphism and cerebral infarction among Han population in Shanghai. The gene C242T was detected by polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP) technique in 176 cerebral infarction patients and 131 healthy elders.The frequency distribution of allele was calculated. The serum triglyeride(TG),high density lipoprotein cholesterol(HDL-C),low density lipoprotein cholesterol(LDL-C),blood glucose level and blood pressure in cerebral infarction patients were much higher than those in the healthy elders(P0.05).However,the genotype distributions of the cerebral infarction patients were 92.05%(CC),7.95%(CT) and 0(TT).The genotype distributions of the healthy elders were 93.89%(CC),5.34%(CT) and 0.76%(TT).The allele frequency in the cerebral infarction patients was distributed as 96.02%(C) and 3.98%(T),while that in the healthy elders was distributed as 96.56%(C) and 3.44%(T).There was no significant difference in genotype and allele frequency distribution between the cerebral infarction patients and the healthy elders(P0.05).Conclusions The NAD(P)H oxidase p22phox C242T polymorphism might not associate with cerebral infarction.

title: Association of the C242T polymorphism in the NADPH oxidase p22 phox gene with carotid atherosclerosis in Slovenian patients with type 2 diabetes
abstract: Oxidative stress plays an important role in the pathogenesis of diabetes and its complications. Genetic variations of enzymes producing reactive oxygen species could change their activity, thus contributing to the susceptibility to oxidative stress. The aim of this study was to examine the role of the NADPH oxidase C242T polymorphism in the development of carotid atherosclerosis in patients with type 2 diabetes. 286 diabetic patients and 150 healthy controls were enrolled in the study. Carotid atherosclerosis was quantified ultrasonographically as carotid intima-media thickness, plaque score (0–6) and plaque type (1–5). Diabetic patients were divided into low and high risk groups based on ultrasound phenotypes of carotid atherosclerosis. Genotypes were determined by real-time PCR. Levels of 8-hydroxy-2-deoxyguanosine (8-OHdG) were measured by enzyme-linked immunosorbent assay (ELISA). Diabetic patients demonstrated a statistically significant difference compared to healthy controls in the following parameters: age, BMI, waist circumference, smoking prevalence, glucose, triglyceride and 8-OHdG serum levels. Control subjects had significantly higher levels of HDL, LDL and total cholesterol than diabetics (p < 0.001). The NADPH C242T polymorphism was not related with clinical characteristics, lipid parameters and 8-OHdG serum levels. We found no significant difference in the NADPH genotype distribution between diabetics and controls (p = 0.19) nor between low and high risk subgroups of diabetics (mean CIMT: p = 0.67; plaque score: p = 0.49, plaque type: p = 0.56). In the present study the NADPH C242T polymorphism was not associated with the degree of oxidative stress and carotid atherosclerosis. Further studies will show if it can be used as a genetic marker for carotid atherosclerosis in diabetic patients.

title: Association between NADPH Oxidase p22phox C242T Polymorphism and Ischemic Cerebrovascular Disease: A Meta-Analysis
abstract: Epidemiological studies have evaluated the association between nicotinamide adenine dinucleotide phosphate (NADPH) oxidase p22phox 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 p22phox 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 p22phox 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.

title: Meta-analysis of genetic association studies.
abstract: Meta-analysis, a statistical tool for combining results across studies, is becoming popular as a method for resolving discrepancies in genetic association studies. Persistent difficulties in obtaining robust, replicable results in genetic association studies are almost certainly because genetic effects are small, requiring studies with many thousands of subjects to be detected. In this article, we describe how meta-analysis works and consider whether it will solve the problem of underpowered studies or whether it is another affliction visited by statisticians on geneticists. We show that meta-analysis has been successful in revealing unexpected sources of heterogeneity, such as publication bias. If heterogeneity is adequately recognized and taken into account, meta-analysis can confirm the involvement of a genetic variant, but it is not a substitute for an adequately powered primary study.

title: An analysis of Methylenetetrahydrofolate reductase and Glutathione S-transferase omega-1 genes as modifiers of the cerebral response to ischemia
abstract: BackgroundCerebral ischemia involves a series of reactions which ultimately influence the final volume of a brain infarction. We hypothesize that polymorphisms in genes encoding proteins involved in these reactions could act as modifiers of the cerebral response to ischemia and impact the resultant stroke volume. The final volume of a cerebral infarct is important as it correlates with the morbidity and mortality associated with non-lacunar ischemic strokes.MethodsThe proteins encoded by the methylenetetrahydrofolate reductase (MTHFR) and glutathione S-transferase omega-1 (GSTO-1) genes are, through oxidative mechanisms, key participants in the cerebral response to ischemia. On the basis of these biological activities, they were selected as candidate genes for further investigation. We analyzed the C677T polymorphism in the MTHFR gene and the C419A polymorphism in the GSTO-1 gene in 128 patients with non-lacunar ischemic strokes.ResultsWe found no significant association of either the MTHFR (p = 0.72) or GSTO-1 (p = 0.58) polymorphisms with cerebral infarct volume.ConclusionOur study shows no major gene effect of either the MTHFR or GSTO-1 genes as a modifier of ischemic stroke volume. However, given the relatively small sample size, a minor gene effect is not excluded by this investigation.

title: Superoxide Production and Expression of Nox Family Proteins in Human Atherosclerosis
abstract: NAD(P)H oxidases are important sources of superoxide in the vasculature, the activity of which is associated with risk factors for human atherosclerosis. This study was designed to investigate the localization of superoxide production and the expression of the Nox family of NAD(P)H oxidase proteins (gp91phox, Nox1, and Nox4) in nonatherosclerotic and atherosclerotic human coronary arteries. In coronary artery segments from explanted human hearts, we examined intracellular superoxide production with dihydroethidium. In nonatherosclerotic coronary arteries, superoxide was present homogenously throughout the intima, media, and adventitia. In atherosclerotic arteries, there was an additional intense area of superoxide in the plaque shoulder, which is rich in macrophages and &agr;-actin–positive cells. p22phox colocalized with gp91phox mainly in macrophages, whereas Nox4 was found only in nonphagocytic vascular cells. Expression of gp91phox and p22phox mRNA was associated with the severity of atherosclerosis. gp91phox correlated with the plaque macrophage content, whereas Nox4 correlated with the content of &agr;-actin–positive cells. Nox1 expression was low both in human coronary arteries and isolated vascular cells. Several Nox proteins, including gp91phox and Nox4, may contribute to increased intracellular oxidative stress in human coronary atherosclerosis in a cell-specific manner and thus may be involved in the genesis and progression of human coronary atherosclerotic disease.

title: Functional Effect of the C242T Polymorphism in the NAD(P)H Oxidase p22phox Gene on Vascular Superoxide Production in Atherosclerosis
abstract: BackgroundIncreased superoxide anion production increases oxidative stress and reduces nitric oxide bioactivity in vascular disease states. NAD(P)H oxidase is an important source of superoxide in human blood vessels, and some studies suggest a possible association between polymorphisms in the NAD(P)H oxidase CYBA gene and atherosclerosis; however, no functional data address this hypothesis. We examined the relationships between the CYBA C242T polymorphism and direct measurements of superoxide production in human blood vessels. Methods and ResultsVascular NAD(P)H oxidase activity was determined in human saphenous veins obtained from 110 patients with coronary artery disease and identified risk factors. Immunoblotting, reverse-transcription polymerase chain reaction, and DNA sequencing showed that p22phox protein, mRNA, and 242C/T allelic variants are expressed in human blood vessels. Vascular superoxide production, both basal and NADH-stimulated, was highly variable between patients, but the presence of the CYBA 242T allele was associated with significantly reduced vascular NAD(P)H oxidase activity, independent of other clinical risk factors for atherosclerosis. ConclusionsAssociation of the CYBA 242T allele with reduced NAD(P)H oxidase activity in human blood vessels suggests that genetic variation in NAD(P)H oxidase components may play a significant role in modulating superoxide production in human atherosclerosis.

title: Association of NAD(P)H oxidase p22 phox gene variation with advanced carotid atherosclerosis in Japanese type 2 diabetes.
abstract: To evaluate the association between the C242T polymorphism of the p22 phox gene, an essential component of NAD(P)H oxidase in the vasculature, with intima-media thickness (IMT) of the carotid artery and risk factors for atherosclerosis in type 2 diabetic subjects.



C242T polymorphism of the p22 phox gene was detected by polymerase chain reaction-restriction fragment-length polymorphism in 200 Japanese type 2 diabetic subjects and 215 nondiabetic subjects. We examined the association with this mutation and carotid atherosclerosis as well as the patients' clinical characteristics and the level of 8-hydroxy-2'deoxyguanosine (8-OHdG) as an index of oxidative DNA damage.



The diabetic subjects with the TC+TT genotypes displayed a significantly lower average IMT (1.13 +/- 0.31 vs. 1.31 +/- 0.34 mm; P = 0.0099) and a not significantly lower serum 8-OHdG level than those with the CC genotype, despite no difference in the risk factors. Stepwise multiple regression analysis showed that the risk factors for increased IMT in the diabetic subjects were systolic blood pressure (P = 0.0042) and p22 phox CC genotype (P = 0.0151). In nondiabetic subjects, the average IMT of the TC+TT group was not different from that of the CC group (0.85 +/- 0.14 vs. 0.94 +/- 0.30 mm, P = 0.417). Fasting plasma insulin concentration (41.4 +/- 15.6 vs. 64.2 +/- 59.4 pmol/l, P = 0.0098) and insulin resistance index of homeostasis model assessment (HOMA-R) (1.58 +/- 0.66 vs. 2.60 +/- 2.56, P = 0.0066) were significantly lower in the TC+TT group than in the CC group.



These results show that the C242T mutation in the p22 phox gene is associated with progression of asymptomatic atherosclerosis in the subjects with type 2 diabetes and is also associated with insulin resistance in nondiabetic subjects.