NAD(P)H oxidase polymorphism (C242T) and high HDL cholesterol associate with recurrent coronary events in postinfarction patients

Corsetti, James P.; Ryan, D. H.; Moss, Arthur J.; Zaręba, Wojciech; Sparks, Charles E.

doi:10.1016/j.atherosclerosis.2006.12.007

Cited by 26 publications

(40 citation statements)

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“…Clinical and laboratory characterization of the postinfarction study population are essentially the same as reported previously 7,9 with notable features including that: 77.7% were male; 78.0% were white; and they were overweight (mean BMI, 27.7Ϯ4.93 kg/m 2 ). Mean blood marker levels outside standard reference ranges included HDL (…”

Section: Study Populationmentioning

confidence: 57%

“…Gradient gel electrophoresis was used to fractionate LDL particles according to size 9 with approximate size ranges (nm) as follows: LDL1, 26.4 to 29; LDL2, 25.5 to 26.4; LDL3, 24.2 to 25.5; and LDL4, 21.0 to 24.2.…”

Section: Blood Markersmentioning

confidence: 99%

“…Additionally, we sought to assess risk within the subgroup potentially associated with a set of thrombogenic, inflammatory, and metabolic blood markers. We did this by graphically analyzing recurrent coronary event rates as a function of serum total cholesterol and triglyceride levels using outcome event mapping, [7][8][9] an exploratory data analysis tool that allows identification of patient subgroups based on risk.…”

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confidence: 99%

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Plasminogen Activator Inhibitor-1 Polymorphism (4G/5G) Predicts Recurrence in Nonhyperlipidemic Postinfarction Patients

Corsetti

Ryan

Moss

et al. 2008

ATVB

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Objective-Nonhyperlipidemic postinfarction patients are at high risk for recurrent coronary events by virtue of incident myocardial infarction (MI); however, few studies assess risk beyond incident MI. The aim of this study was to assess such risk as a function of 37 atherosclerosis-associated genetic polymorphisms and 17 blood marker variables. Methods and Results-Screening of polymorphisms in nonhyperlipidemic postinfarction patients revealed significant risk only for the 4G/5G insertion/deletion polymorphism in the promoter of the plasminogen-activator inhibitor-1 (PAI-1) gene. Outcome event mapping, an exploratory data analysis tool, was then applied to define a subgroup (182 patients from total study population of 846 nondiabetic patients) exhibiting maximal functional dependence of risk on the PAI-1 polymorphism. Cox multivariable regression analyses within the subgroup adjusted for significant clinical covariates and medication use as a function of the PAI-1 polymorphism and 17 atherosclerosis-associated blood markers revealed significant risk for patients homozygous for the 4G allele (hazard ratio 4.30, 95% CI 1.98 to 9.33, Pϭ0.00023), and lack of significant risk-association with any blood marker. Conclusions-In a subgroup of normolipidemic postinfarction patients, only the PAI-1 4G/5G polymorphism was associated with recurrent risk from a set of atherosclerosis-associated genetic polymorphisms and blood markers. A lthough hypercholesterolemic postinfarction patients are at high risk for recurrent coronary events, normocholesterolemic postinfarction patients suffer recurrent events as well. 1 Beyond incident myocardial infarction (MI), traditional and nontraditional risk factors play a role 2,3 although little specific information is available especially for normolipidemic postinfarction patients. 4 In a previous report on nondiabetic patients of the Thrombogenic Factors and Recurrent Coronary Events (THROMBO) postinfarction study, when lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) was included in models, it resulted in replacement of apolipoprotein B (apoB) as the only risk factor of recurrent coronary events from a set of thrombogenic, inflammatory, and metabolic blood markers. 5 To determine predictors of risk for recurrent events in normolipidemic postinfarction patients, we studied nondiabetic THROMBO patients (nϭ846) as a function of a set of 37 genetic markers associated with cardiovascular disease (CVD) followed by studies with a set of 17 thrombogenic, inflammatory, and metabolic blood markers. 5 Preliminary screening of genetic markers in normolipidemic (cholesterol Ͻ5.17 mmol/L, triglycerides Ͻ1.69 mmol/L) study patients revealed most significant risk for the 4G/5G insertion/deletion polymorphism (4 or 5 sequential guanosines, respectively) of plasminogen activator inhibitor-1 (PAI-1), a major inhibitor of fibrinolysis. The polymorphism is located in the gene promoter region (chromosome 7) and results in allele-specific responses to multiple agents. 6 Accordingly, studies have shown th...

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Section: Study Populationmentioning

confidence: 57%

Section: Blood Markersmentioning

confidence: 99%

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confidence: 99%

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Plasminogen Activator Inhibitor-1 Polymorphism (4G/5G) Predicts Recurrence in Nonhyperlipidemic Postinfarction Patients

Corsetti

Ryan

Moss

et al. 2008

ATVB

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“…Opposite findings were observed in a more recent study in which the prevalence of p22phox genotypes was analyzed in a cohort of 663 post-MI patients over a 26-month follow-up. 21 In patients defined with a high risk for recurrences (nϭ103), based on high cholesterol and C-reactive protein levels, the prevalence of the T allele was significantly Our results showed a significantly lower recurrence of cardiovascular deaths, nonfatal MI, and revascularization procedures in patients carrying the T allele (CT and TT genotypes) compared to those carrying the CC genotype. However, after controlling for classical risk factors, only the risk of revascularization procedures remained significantly associated with the T allele.…”

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confidence: 48%

Section: Discussionmentioning

confidence: 99%

C242T Polymorphism of NADPH Oxidase p22phox and Recurrence of Cardiovascular Events in Coronary Artery Disease

Arca¹,

Conti²,

Mestice³

et al. 2008

ATVB

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Objectives-The common C242T polymorphism in the gene for the p22phox subunit of NADPH oxidase has been reported to be negatively associated with oxidative stress, but whether it confers prognostic information is not yet clear. Methods and Results-The incidence of major adverse cardiovascular events (MACE) were determined in 237 patients with coronary stenosis during a median follow-up of 7.8 years. The p22phox genotypes were evaluated in 213 patients (89.9%) by polymerase chain reaction and RsaI. digestion. Plasma levels of 8-hydroxy-2Ј-deoxyguanosine (8-OHdG), a marker of oxidative stress, were also measured. In the univariate analysis, patients with CT/TT genotypes showed reduced recurrence of cardiovascular deaths, nonfatal MI, and revascularization procedures compared with homozygous carriers of the C allele. After controlling for confounders, a significantly lower risk of new revascularization procedures (HRϭ0.31, 95% CI 0.12 to 0.70; Pϭ0.014) remained associated with the T allele. The Kaplan-Meier analysis showed a longer survival free from fatal and nonfatal MI in carriers of T allele (PϽ0.001). The presence of the 242T allele was associated with significantly reduced plasma concentrations of 8-OHdG. Conclusions-The 242T allele was a predictor of lower risk of recurrence of cardiovascular events in high-risk patients and was associated with reduced systemic oxidative stress. Key Words: NADPH oxidase Ⅲ polymorphisms Ⅲ oxidative markers Ⅲ atherosclerosis Ⅲ cardiovascular risk Ⅲ follow-up study T he beneficial effects of LDL cholesterol-lowering therapy in the prevention of coronary artery disease (CAD) are well established. 1 However, despite intensive LDL cholesterol (LDL-C) reduction, a significant proportion of coronary patients still develop cardiovascular events. 2 Therefore, factors in addition to LDL-C that may contribute to the residual cardiovascular risk have received greater attention in recent years.Reactive oxygen species (ROS) play a prominent role in the pathophysiology of atherosclerosis. 3,4 Compelling evidence indicates that the major source of ROS in the artery wall is related to the activity of NADPH oxidase. 5 NADPH oxidase is composed of membrane (gp22 phox and gp91phox) and cytosolic (gp40 phox, gp47 phox, gp67 phox and rac1) subunits that assemble on the cellular surface to generate superoxide anions. 3 NADPH oxidase is expressed in human atherosclerotic plaque where it promotes oxidative stress and, eventually, plaque progression and instability. 6 Experimental studies demonstrated reduced formation of atherosclerotic lesions in animals knocked-out for gp47 phox compared to wild-type animals. 7 The role of NADPH oxidase in vascular disease is less evident in humans.The identification of the functional C242T polymorphism of the p22phox subunit, in which the T allele is associated with lower production of superoxide anions, 8 -11 allowed further analysis of the role of NADPH oxidase in the atherogenic process. Subjects carrying the T allele (CT and TT genotypes) were hypothesized...

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Epidemiology

2011

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NAD(P)H oxidase polymorphism (C242T) and high HDL cholesterol associate with recurrent coronary events in postinfarction patients

Cited by 26 publications

References 25 publications

Plasminogen Activator Inhibitor-1 Polymorphism (4G/5G) Predicts Recurrence in Nonhyperlipidemic Postinfarction Patients

Plasminogen Activator Inhibitor-1 Polymorphism (4G/5G) Predicts Recurrence in Nonhyperlipidemic Postinfarction Patients

C242T Polymorphism of NADPH Oxidase p22phox and Recurrence of Cardiovascular Events in Coronary Artery Disease

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