ABSTRACT
PURPOSE: The American College of Medical Genetics and Genomics (ACMG) recommends the return of pathogenic and likely pathogenic (P/LP) secondary findings from exome and genome sequencing. The latest version (ACMG secondary finding [SF] v3.0) includes 14 additional genes. We interrogated the ClinSeq cohort for variants in these genes to determine the additional yield in unselected individuals. METHODS: Exome data from 1473 individuals (60% White, 34% African American or Black, 6% other) were analyzed. We restricted our analyses to coding variants; +1,+2,-1, and -2 splice site variants; and the pathogenic GAA variant, NM_000152.5:c.-32-13T>G. Variants were assessed with slightly modified ACMG/Association of Molecular Pathology guidelines. RESULTS: A total of 25 P/LP variants were identified. In total, 7 individuals had P/LP variants in genes recommended for return of heterozygous variants, namely HNF1A (1), PALB2 (3), TMEM127 (1), and TTN (2). In total, 4 individuals had a homozygous variant in a gene recommended for biallelic variant return, namely HFE, NM_000410.3(HFE):c.845G>A p.Cys282Tyr. A total of 17 P/LP variants were identified in the heterozygous state in genes recommended only for biallelic variant reporting and were not returned. The frequency of returnable P/LP variants did not significantly differ by race. CONCLUSION: Using the ACMG SF v3.0, the returnable P/LP variant frequency increased in the ClinSeq cohort by 22%, from 3.4% (n = 50, ACMG SF v2.0) to 4.1% (n = 61, ACMG SF v3.0).
Subject(s)
Genetic Variation , Genomics , Exome/genetics , Genetic Variation/genetics , Humans , Mutation , Exome SequencingABSTRACT
Costello syndrome (CS) is a multisystem disorder caused by heterozygous germline mutations in the HRAS proto-oncogene. Respiratory system complications have been reported in individuals with CS, but a comprehensive description of the full spectrum and incidence of respiratory symptoms in these patients is not available. Here, we report the clinical course of four CS patients with respiratory complications as a major cause of morbidity. Review of the literature identified 56 CS patients with descriptions of their neonatal course and 17 patients in childhood/adulthood. We found that in the neonatal period, respiratory complications are seen in approximately 78% of patients with transient respiratory distress reported in 45% of neonates. Other more specific respiratory diagnoses were reported in 62% of patients, the majority of which comprised disorders of the upper and lower respiratory tract. Symptoms of upper airway obstruction were reported in CS neonates but were more commonly diagnosed in childhood/adulthood (71%). Analysis of HRAS mutations and their respiratory phenotype revealed that the common p.Gly12Ser mutation is more often associated with transient respiratory distress and other respiratory diagnoses. Respiratory failure and dependence on mechanical ventilation occurs almost exclusively with rare mutations. In cases of prenatally diagnosed CS, the high incidence of respiratory complications in the neonatal period should prompt anticipatory guidance and development of a postnatal management plan. This may be important in cases involving rarer mutations. Furthermore, the high frequency of airway obstruction in CS patients suggests that otorhinolaryngological evaluation and sleep studies should be considered. © 2016 Wiley Periodicals, Inc.
Subject(s)
Costello Syndrome/genetics , Proto-Oncogene Proteins p21(ras)/genetics , Respiratory System Abnormalities/genetics , Costello Syndrome/complications , Costello Syndrome/diagnosis , Costello Syndrome/physiopathology , Female , Germ-Line Mutation , Humans , Infant, Newborn , Male , Phenotype , Pregnancy , Proto-Oncogene Mas , Respiratory System Abnormalities/complications , Respiratory System Abnormalities/diagnosis , Respiratory System Abnormalities/physiopathologyABSTRACT
The diagnosis of Angelman syndrome (AS) is based on clinical features and genetic testing. Developmental delay, severe speech impairment, ataxia, atypical behavior and microcephaly by two years of age are typical. Feeding difficulties in young infants and obesity in late childhood can also be seen. The NIH Angelman-Rett-Prader-Willi Consortium and others have documented genotype-phenotype associations including an increased body mass index in children with uniparental disomy (UPD) or imprinting center (IC) defects. We recently encountered four cases of infantile obesity in non-deletion AS cases, and therefore examined body mass measures in a cohort of non-deletion AS cases. We report on 16 infants and toddlers (ages 6 to 44 months; 6 female, and 10 male) with severe developmental delay. Birth weights were appropriate for gestational age in most cases, >97th% in one case and not available in four cases. The molecular subclass case distribution consisted of: UPD (n = 2), IC defect (n = 3), UPD or IC defect (n = 3), and UBE3A mutation (n = 8). Almost all (7 out of 8) UPD, IC and UPD/IC cases went on to exhibit >90th% age- and gender-appropriate weight for height or BMI within the first 44 months. In contrast, no UBE3A mutation cases exhibited obesity or pre-obesity measures (percentiles ranged from <3% to 55%). These findings demonstrate that increased body mass may be evident as early as the first year of life and highlight the utility of considering the diagnosis of AS in the obese infant or toddler with developmental delay, especially when severe. Although a mechanism explaining the association of UPD, and IC defects with obesity has not been identified, recognition of this correlation may inform investigation of imprinting at the PWS/AS locus and obesity.
Subject(s)
Angelman Syndrome/genetics , Angelman Syndrome/pathology , Body Weight , Genomic Imprinting , Uniparental Disomy/genetics , Uniparental Disomy/pathology , Cephalometry , Child , Female , Humans , Infant , MaleABSTRACT
The RASopathies are a family of developmental disorders caused by heritable defects of the RAS/MAPK signaling pathway. While the postnatal presentation of this group of disorders is well known, the prenatal and neonatal findings are less widely recognized. We report on the perinatal presentation of 10 patients with Noonan syndrome (NS), nine with Cardiofaciocutaneous syndrome (CFCS) and three with Costello syndrome (CS), in conjunction with the results of a comprehensive literature review. The majority of perinatal findings in NS, CS, and CFCS are shared: polyhydramnios; prematurity; lymphatic dysplasia; macrosomia; relative macrocephaly; respiratory distress; hypotonia, as well as cardiac and renal anomalies. In contrast, fetal arrhythmia and neonatal hypoglycemia are relatively specific to CS. NS, CS, and CFCS should all be considered as a possible diagnosis in pregnancies with a normal karyotype and ultrasound findings of a RASopathy. Recognition of the common perinatal findings of these disorders should facilitate both their prenatal and neonatal diagnosis.
Subject(s)
Costello Syndrome/diagnosis , Ectodermal Dysplasia/diagnosis , Failure to Thrive/diagnosis , Heart Defects, Congenital/diagnosis , Noonan Syndrome/diagnosis , Phenotype , Abnormalities, Multiple , Costello Syndrome/genetics , DNA Mutational Analysis , Diagnosis, Differential , Ectodermal Dysplasia/genetics , Facies , Failure to Thrive/genetics , Female , Heart Defects, Congenital/genetics , Humans , Infant, Newborn , Male , Mutation , Neonatal Screening , Noonan Syndrome/genetics , Prenatal DiagnosisABSTRACT
BACKGROUND: Recognition of biological patterns holds promise for improved identification of patients at risk for myocardial infarction (MI) and death. We hypothesized that identifying high- and low-risk patterns from a broad spectrum of hematologic phenotypic data related to leukocyte peroxidase-, erythrocyte- and platelet-related parameters may better predict future cardiovascular risk in stable cardiac patients than traditional risk factors alone. METHODS AND RESULTS: Stable patients (n=7369) undergoing elective cardiac evaluation at a tertiary care center were enrolled. A model (PEROX) that predicts incident 1-year death and MI was derived from standard clinical data combined with information captured by a high-throughput peroxidase-based hematology analyzer during performance of a complete blood count with differential. The PEROX model was developed using a random sampling of subjects in a derivation cohort (n=5895) and then independently validated in a nonoverlapping validation cohort (n=1474). Twenty-three high-risk (observed in > or =10% of subjects with events) and 24 low-risk (observed in > or =10% of subjects without events) patterns were identified in the derivation cohort. Erythrocyte- and leukocyte (peroxidase)-derived parameters dominated the variables predicting risk of death, whereas variables in MI risk patterns included traditional cardiac risk factors and elements from all blood cell lineages. Within the validation cohort, the PEROX model demonstrated superior prognostic accuracy (78%) for 1-year risk of death or MI compared with traditional risk factors alone (67%). Furthermore, the PEROX model reclassified 23.5% (P<0.001) of patients to different risk categories for death/MI when added to traditional risk factors. CONCLUSIONS: Comprehensive pattern recognition of high- and low-risk clusters of clinical, biochemical, and hematologic parameters provided incremental prognostic value in stable patients having elective diagnostic cardiac catheterization for 1-year risks of death and MI.
Subject(s)
Myocardial Infarction/epidemiology , Peroxidases/blood , Aged , Angioplasty, Balloon, Coronary , Cardiovascular Diseases/blood , Cardiovascular Diseases/enzymology , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/genetics , Cohort Studies , Female , Follow-Up Studies , Hematology/methods , Humans , Male , Medical History Taking , Middle Aged , Myocardial Infarction/blood , Myocardial Infarction/enzymology , Myocardial Infarction/mortality , Predictive Value of Tests , Prognosis , Prospective Studies , Reproducibility of Results , Risk Factors , Survival Rate , Time Factors , Troponin T/bloodABSTRACT
BACKGROUND: Although myeloperoxidase (MPO) monitoring is predictive for cardiovascular outcomes in suspected acute coronary syndromes, the value of serial testing is unknown. METHODS: We investigated the relationship between serial MPO concentrations in 490 individuals with acute chest pain and incident major adverse cardiac events (MACE) during 6 months of follow-up. We measured MPO with the CardioMPO assay, and cardiac troponin I (cTnI), with the Abbott Architect assay. RESULTS: Plasma MPO concentrations during the first 16 h were higher in individuals who experienced MACE. Higher MPO quartiles predicted a greater likelihood of 6-month MACE at baseline [OR (95% CI), 2.4 (1.4-4.1), P = 0.001 for highest vs lowest quartile] and all subsequent time points, with strongest predictive ability found in 16-h postbaseline samples [9.9 (4.7-20.9), P < 0.001 for highest vs lowest quartile]. MPO was predictive for MACE among individuals whose cTnI remained within reference intervals (<0.028 µg/L). The lowest rate of missed cases was found when MPO was <640 pmol/L at baseline and all other time points. Serial MPO monitoring predicted MACE risk better than baseline MPO measurements alone (c statistic 0.813 vs 0.602; P = 0.002), including in individuals whose cTnI remained within reference intervals (c statistic 0.903; P = 0.009). Combined serial cTnI and MPO testing improved accuracy for predicting 6-month MACE, reduced the number of missed MACE events from cTnI testing alone, and improved risk classification in 26.1% of patients. CONCLUSIONS: MPO concentrations are predictive of outcome up to 16 h after presentation with chest pain and predict events missed by cTnI testing, supporting a potential role in rapid patient triage.
Subject(s)
Acute Coronary Syndrome/diagnosis , Chest Pain/diagnosis , Peroxidase/blood , Aged , Angina, Unstable/diagnosis , Biomarkers/blood , Cohort Studies , Female , Humans , Male , Middle Aged , Myocardial Infarction/diagnosis , ROC Curve , Reference Values , Risk Assessment , Troponin I/bloodABSTRACT
Left ventricular (LV) remodeling after myocardial infarction (MI) results in LV dilation, a major cause of congestive heart failure and sudden cardiac death. Ischemic injury and the ensuing inflammatory response participate in LV remodeling, leading to myocardial rupture and LV dilation. Myeloperoxidase (MPO), which accumulates in the infarct zone, is released from neutrophils and monocytes leading to the formation of reactive chlorinating species capable of oxidizing proteins and altering biological function. We studied acute myocardial infarction (AMI) in a chronic coronary artery ligation model in MPO null mice (MPO(-/-)). MPO(-/-) demonstrated decreased leukocyte infiltration, significant reduction in LV dilation, and marked preservation of LV function. The mechanism appears to be due to decreased oxidative inactivation of plasminogen activator inhibitor 1 (PAI-1) in the MPO(-/-), leading to decreased tissue plasmin activity. MPO and PAI-1 are shown to have a critical role in the LV response immediately after MI, as demonstrated by markedly delayed myocardial rupture in the MPO(-/-) and accelerated rupture in the PAI-1(-/-). These data offer a mechanistic link between inflammation and LV remodeling by demonstrating a heretofore unrecognized role for MPO and PAI-1 in orchestrating the myocardial response to AMI.
Subject(s)
Myocardial Infarction/metabolism , Peroxidase/metabolism , Plasminogen Activator Inhibitor 1/metabolism , Serine Proteinase Inhibitors/metabolism , Ventricular Remodeling , Animals , Collagen/metabolism , Coronary Circulation , Enzyme Activation , Humans , Inflammation , Leukocyte Common Antigens/metabolism , Leukocytes/metabolism , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Myocardium/cytology , Myocardium/metabolism , Myocardium/pathology , Oxidation-Reduction , Peroxidase/genetics , Survival Rate , Time FactorsABSTRACT
Conventional biomarker discovery focuses mostly on the identification of single markers and thus often has limited success in disease diagnosis and prognosis. This study proposes a method to identify an optimized protein biomarker panel based on MS studies for predicting the risk of major adverse cardiac events (MACE) in patients. Since the simplicity and concision requirement for the development of immunoassays can only tolerate the complexity of the prediction model with a very few selected discriminative biomarkers, established optimization methods, such as conventional genetic algorithm (GA), thus fails in the high-dimensional space. In this paper, we present a novel variant of GA that embeds the recursive local floating enhancement technique to discover a panel of protein biomarkers with far better prognostic value for prediction of MACE than existing methods, including the one approved recently by FDA (Food and Drug Administration). The new pragmatic method applies the constraints of MACE relevance and biomarker redundancy to shrink the local searching space in order to avoid heavy computation penalty resulted from the local floating optimization. The proposed method is compared with standard GA and other variable selection approaches based on the MACE prediction experiments. Two powerful classification techniques, partial least squares logistic regression (PLS-LR) and support vector machine classifier (SVMC), are deployed as the MACE predictors owing to their ability in dealing with small scale and binary response data. New preprocessing algorithms, such as low-level signal processing, duplicated spectra elimination, and outliner patient's samples removal, are also included in the proposed method. The experimental results show that an optimized panel of seven selected biomarkers can provide more than 77.1% MACE prediction accuracy using SVMC. The experimental results empirically demonstrate that the new GA algorithm with local floating enhancement (GA-LFE) can achieve the better MACE prediction performance comparing with the existing techniques. The method has been applied to SELDI/MALDI MS datasets to discover an optimized panel of protein biomarkers to distinguish disease from control.
Subject(s)
Algorithms , Biomarkers/blood , Cardiovascular Diseases/diagnosis , Diagnosis, Computer-Assisted/methods , Aged , Biomarkers/chemistry , Cardiovascular Diseases/blood , Female , Humans , Male , Middle Aged , Predictive Value of Tests , Proteome/chemistry , Risk Assessment/methods , Spectrometry, Mass, Matrix-Assisted Laser Desorption-IonizationABSTRACT
OBJECTIVE: Familial combined hyperlipidemia (FCHL) characterized by high serum total cholesterol and/or triglycerides (TGs) is a common dyslipidemia predisposing to coronary artery disease (CAD). Recently, the upstream transcription factor 1 (USF1) was linked and associated with FCHL and TGs in Finnish FCHL families. Here we examined the previously associated rs3737787 SNP in extended Dutch FCHL families (n=532) and in a cohort of US subjects who underwent diagnostic coronary angiography (n=1533). METHODS AND RESULTS: In males of the Dutch FCHL families, we observed significant sex-dependent associations between the common allele of rs3737787 and FCHL, TGs, and related metabolic traits (P=0.02 to 0.006). In the U.S. Whites, sex-dependent associations with TGs and related metabolic traits were observed for the common allele of rs3737787 in males (P=0.04 to 0.02) and rare allele in females (P=0.05 to 0.002). This intriguing relationship was further supported by the highly significant genotype x sex interactions observed for TGs in the Dutch and TGs and body mass index (BMI) in U.S. White subjects with CAD (P=0.0005 to 0.00004). CONCLUSIONS: These data show that USF1 influences several cardiovascular risk factors in a sex-dependent manner in Dutch FCHL families and U.S. Whites with CAD. A significant interaction between sex and genotype was shown to affect TGs and BMI.
Subject(s)
Coronary Artery Disease/genetics , Hyperlipidemia, Familial Combined/genetics , Polymorphism, Single Nucleotide , Triglycerides/blood , Upstream Stimulatory Factors/genetics , White People/genetics , Adult , Aged , Body Mass Index , Cohort Studies , Coronary Angiography , Coronary Artery Disease/blood , Coronary Artery Disease/diagnostic imaging , Coronary Artery Disease/physiopathology , Female , Gene Frequency , Genetic Predisposition to Disease , Humans , Hyperlipidemia, Familial Combined/blood , Hyperlipidemia, Familial Combined/complications , Hyperlipidemia, Familial Combined/physiopathology , Male , Metabolic Syndrome/complications , Metabolic Syndrome/genetics , Middle Aged , Netherlands , Phenotype , Risk Factors , Severity of Illness Index , Sex Distribution , Sex Factors , United States , Upstream Stimulatory Factors/metabolismABSTRACT
CONTEXT: Paraoxonase 1 (PON1) is reported to have antioxidant and cardioprotective properties. The relationship between PON1 genotypes and functional activity with systemic measures of oxidative stress and cardiovascular disease (CVD) risk in humans has not been systematically investigated. OBJECTIVE: To investigate the relationship of genetic and biochemical determinants of PON1 activity with systemic measures of oxidative stress and CVD risk in humans. DESIGN, SETTING, AND PARTICIPANTS: The association between systemic PON1 activity measures and a functional polymorphism (Q192R) resulting in high PON1 activity with prevalent CVD and future major adverse cardiac events (myocardial infarction, stroke, or death) was evaluated in 1399 sequential consenting patients undergoing diagnostic coronary angiography between September 2002 and November 2003 at the Cleveland Clinic. Patients were followed up until December 2006. Systemic levels of multiple structurally defined fatty acid oxidation products were also measured by mass spectrometry in 150 age-, sex-, and race-matched patients and compared with regard to PON1 genotype and activity. MAIN OUTCOME MEASURES: Relationship between a functional PON1 polymorphism and PON1 activity with global indices of systemic oxidative stress and risk of CVD. RESULTS: The PON1 genotype demonstrated significant dose-dependent associations (QQ192 > QR192 > RR192) with decreased levels of serum PON1 activity and with increased levels of systemic indices of oxidative stress. Compared with participants with either the PON1 RR192 or QR192 genotype, participants with the QQ192 genotype demonstrated an increased risk of all-cause mortality (43/681 deaths [6.75%] in RR192 and QR192 and 62/584 deaths [11.1%] in QQ192; adjusted hazard ratio, 2.05; 95% confidence interval [CI], 1.32-3.18) and of major adverse cardiac events (88/681 events [13.6%] in RR192 and QR192 and 102/584 events [18.0%] in QQ192; adjusted hazard ratio, 1.48; 95% CI, 1.09-2.03; P = .01). The incidence of major adverse cardiac events was significantly lower in participants in the highest PON1 activity quartile (23/315 [7.3%]) and 235/324 [7.7%] for paraoxonase and arylesterase, respectively) compared with those in the lowest activity quartile (78/311 [25.1%] and 75/319 [23.5%]; P < .001 for paraoxonase and arylesterase, respectively). The adjusted hazard ratios for major adverse cardiac events between the highest and lowest PON1 activity quartiles were, for paraoxonase, 3.4 (95% CI, 2.1-5.5; P < .001) and for arylesterase, 2.9 (95% CI, 1.8-4.7; P < .001) and remained independent in multivariate analysis. CONCLUSION: This study provides direct evidence for a mechanistic link between genetic determinants and activity of PON1 with systemic oxidative stress and prospective cardiovascular risk, indicating a potential mechanism for the atheroprotective function of PON1.
Subject(s)
Aryldialkylphosphatase/genetics , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/genetics , Oxidative Stress/physiology , Polymorphism, Genetic , Aged , Aryldialkylphosphatase/blood , Cardiovascular Diseases/blood , Chromatography, High Pressure Liquid , Female , Fluorescence Polarization , Humans , Logistic Models , Male , Middle Aged , Polymerase Chain Reaction , Prognosis , Proportional Hazards Models , Prospective Studies , Risk Factors , Tandem Mass SpectrometryABSTRACT
OBJECTIVES: To assess carotid intima media thickness (IMT) and cardiac biomarkers in HIV infected children on antiretroviral therapy (ART). METHODS: This was a single site, cross sectional, controlled observational study. We assessed carotid IMT, homocysteine, high-sensitivity C-reactive protein and myeloperoxidase levels in HIV infected children on stable ART for >or= 6 months. Carotid IMT was reported as internal carotid artery (ICA) and common carotid artery (CCA) thickness; left and right sides were measured separately. Groups were compared using appropriate two-sample tests. RESULTS: Of the 62 subjects enrolled, 31 were HIV positive (50%), 66% were female, and 69% were African-American. Median CD4% was 32% and 26 patients (84%) had HIV-1 RNA< 400 copies/ml. Sixteen patients had been taking protease inhibitors for a median duration of 27 months. None had hypertension or smoked. HIV infected children had higher HOMA-IR, waist-to-hip ratio, cholesterol, triglycerides, myeloperoxidase and lower homocysteine levels. Left and right CCA IMT, and left and right ICA IMT were significantly higher in the HIV infected group. Significant predictors of carotid IMT measurements in uninfected controls were body mass index and homocysteine, but only the duration of ARV therapy was predictive of IMT in the HIV infected group. CONCLUSION: Higher levels of carotid IMT and some cardiac markers were found in ART treated HIV infected children when compared to matched uninfected controls. These results suggest that HIV infected children receiving ART may be at increased risk of cardiovascular disease.
Subject(s)
Cardiovascular Diseases/etiology , Carotid Arteries/pathology , HIV Infections/pathology , Tunica Intima/pathology , Tunica Media/pathology , Adolescent , Adult , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/adverse effects , Antiretroviral Therapy, Highly Active/adverse effects , Biomarkers/blood , Body Composition , C-Reactive Protein/metabolism , Cardiovascular Diseases/blood , Cardiovascular Diseases/pathology , Carotid Arteries/diagnostic imaging , Carotid Artery, Common/pathology , Carotid Artery, Internal/pathology , Child , Child, Preschool , Cross-Sectional Studies , Drug Administration Schedule , Female , HIV Infections/blood , HIV Infections/complications , HIV Infections/drug therapy , Homocysteine/blood , Humans , Lipids/blood , Male , Peroxidase/blood , Tunica Intima/diagnostic imaging , Tunica Media/diagnostic imaging , UltrasonographyABSTRACT
In recent studies we demonstrated that systemic levels of protein-bound nitrotyrosine (NO(2)Tyr) and myeloperoxidase (MPO), a protein that catalyzes generation of nitrating oxidants, serve as independent predictors of atherosclerotic risk, burden, and incident cardiac events. We now show both that apolipoprotein A-I (apoA-I), the primary protein constituent of HDL, is a selective target for MPO-catalyzed nitration and chlorination in vivo and that MPO-catalyzed oxidation of HDL and apoA-I results in selective inhibition in ABCA1-dependent cholesterol efflux from macrophages. Dramatic selective enrichment in NO(2)Tyr and chlorotyrosine (ClTyr) content within apoA-I recovered from serum and human atherosclerotic lesions is noted, and analysis of serum from sequential subjects demonstrates that the NO(2)Tyr and ClTyr contents of apoA-I are markedly higher in individuals with cardiovascular disease (CVD). Analysis of circulating HDL further reveals that higher NO(2)Tyr and ClTyr contents of the lipoprotein are each significantly associated with diminished ABCA1-dependent cholesterol efflux capacity of the lipoprotein. MPO as a likely mechanism for oxidative modification of apoA-I in vivo is apparently facilitated by MPO binding to apoA-I, as revealed by cross-immunoprecipitation studies in plasma, recovery of MPO within HDL-like particles isolated from human atheroma, and identification of a probable contact site between the apoA-I moiety of HDL and MPO. To our knowledge, the present results provide the first direct evidence for apoA-I as a selective target for MPO-catalyzed oxidative modification in human atheroma. They also suggest a potential mechanism for MPO-dependent generation of a proatherogenic dysfunctional form of HDL in vivo.
Subject(s)
Apolipoprotein A-I/metabolism , Cardiovascular Diseases/metabolism , Cardiovascular Diseases/physiopathology , Peroxidase/metabolism , Tyrosine/analogs & derivatives , ATP Binding Cassette Transporter 1 , ATP-Binding Cassette Transporters/metabolism , Aged , Animals , Aorta/chemistry , Aorta/pathology , Apolipoprotein A-I/blood , Arteriosclerosis/physiopathology , Blotting, Western , Catalysis , Cell Line , Cholesterol/metabolism , Cohort Studies , Female , Femoral Artery/chemistry , Femoral Artery/pathology , Humans , Lipoproteins, HDL/chemistry , Lipoproteins, HDL/metabolism , Macrophages/metabolism , Male , Mice , Middle Aged , Nitro Compounds/metabolism , Oxidation-Reduction , Peroxidase/blood , Tyrosine/metabolismABSTRACT
BACKGROUND: Inflammation is linked to adverse outcomes in acute coronary syndromes. Myeloperoxidase, an abundant leukocyte enzyme, is elevated in culprit lesions that have fissured or ruptured in patients with sudden death from cardiac causes. Numerous lines of evidence suggest mechanistic links between myeloperoxidase and both inflammation and cardiovascular disease. METHODS: We assessed the value of plasma levels of myeloperoxidase as a predictor of the risk of cardiovascular events in 604 sequential patients presenting to the emergency department with chest pain. RESULTS: Initial plasma myeloperoxidase levels predicted the risk of myocardial infarction, even in patients who are negative for troponin T (<0.1 ng per milliliter) at base line (P<0.001). Myeloperoxidase levels at presentation also predicted the risk of major adverse cardiac events (myocardial infarction, the need for revascularization, or death) within 30 days and 6 months after presentation (P<0.001). In patients without evidence of myocardial necrosis (defined as those who were negative for troponin T), the base-line myeloperoxidase levels independently predicted the risk of major adverse coronary events at 30 days (unadjusted 2nd, 3rd, and 4th quartile odds ratios, 2.2 [95 percent confidence interval, 1.1 to 4.6], 4.2 [95 percent confidence interval, 2.1 to 8.4], and 4.1 [95 percent confidence interval, 2.0 to 8.4], respectively) and at 6 months. CONCLUSIONS: A single initial measurement of plasma myeloperoxidase independently predicts the early risk of myocardial infarction, as well as the risk of major adverse cardiac events in the ensuing 30-day and 6-month periods. Myeloperoxidase levels, in contrast to troponin T, creatine kinase MB isoform, and C-reactive protein levels, identified patients at risk for cardiac events in the absence of myocardial necrosis, highlighting its potential usefulness for risk stratification among patients who present with chest pain.
Subject(s)
Chest Pain/enzymology , Coronary Artery Disease/enzymology , Myocardial Infarction , Peroxidase/blood , Aged , Biomarkers/blood , C-Reactive Protein/analysis , Coronary Artery Disease/blood , Coronary Artery Disease/diagnosis , Coronary Thrombosis/blood , Coronary Thrombosis/diagnosis , Coronary Thrombosis/enzymology , Creatine Kinase/blood , Creatine Kinase, MB Form , Female , Humans , Isoenzymes/blood , Male , Middle Aged , Myocardial Revascularization , Prognosis , Risk , Troponin T/bloodABSTRACT
Asbestos fibers are carcinogens causing oxidative stress and inflammation, but the sources and ramifications of oxidant production by asbestos are poorly understood. Here, we show that inhaled chrysotile asbestos fibers cause increased myeloperoxidase activity in bronchoalveolar lavage fluids (BALF) and myeloperoxidase immunoreactivity in epithelial cells lining distal bronchioles and alveolar ducts, sites of initial lung deposition of asbestos fibers. In comparison with sham mice, asbestos-exposed myeloperoxidase-null (MPO-/-) and normal (MPO+/+) mice exhibited comparable increases in polymorphonuclear leukocytes, predominately neutrophils, in BALF after 9 days of asbestos inhalation. Differential cell counts on BALF revealed decreased proportions of macrophages and increased lymphocytes in all mice exposed to asbestos, but numbers were decreased overall in asbestos-exposed myeloperoxidase-null versus normal mice. Asbestos-associated lung inflammation in myeloperoxidase-null mice was reduced (P < or = 0.05) in comparison with normal asbestos-exposed mice at 9 days. Decreased lung inflammation in asbestos-exposed myeloperoxidase-null mice at 9 days was accompanied by increases (P < or = 0.05) in Ki-67- and cyclin D1-positive immunoreactive cells, markers of cell cycle reentry, in the distal bronchiolar epithelium. Asbestos-induced epithelial cell proliferation in myeloperoxidase-null mice at 30 days was comparable to that found at 9 days. In contrast, inflammation and epithelial cell proliferation in asbestos-exposed normal mice increased over time. These results support the hypothesis that myeloperoxidase status modulates early asbestos-induced oxidative stress, epithelial cell proliferation, and inflammation.
Subject(s)
Asbestos/toxicity , Peroxidase/deficiency , Pneumonia/chemically induced , Pneumonia/enzymology , Animals , Bronchoalveolar Lavage Fluid , Cell Growth Processes/drug effects , Cell Growth Processes/physiology , Cyclin D1/metabolism , Epithelial Cells/cytology , Epithelial Cells/drug effects , Epithelial Cells/enzymology , Inhalation Exposure , Male , Mice , Mice, Inbred C57BL , Peroxidase/metabolismABSTRACT
BACKGROUND: Inflammation after myocardial infarction (MI) heralds worse left ventricular (LV) function and clinical outcomes. However, whether inflammation affects LV function by extending myonecrosis and/or altering LV remodeling remains unknown. We hypothesized that cytotoxic aldehydes generated during oxidative stress may adversely affect remodeling and infarct size. One theoretical source of reactive aldehydes is oxidation of common alpha-amino acids by myeloperoxidase (MPO) released by leukocytes. However, a role for MPO in formation of aldehydes in vivo and the functional consequences of MPO-generated oxidants in ischemia/reperfusion models of MI have not been established. METHODS AND RESULTS: In studies with cell types found in vascular tissue, MPO-oxidation products of glycine (formaldehyde) and threonine (acrolein) were the most cytotoxic. Mass spectrometry studies of myocardial tissue from murine models of acute MI (both chronic left anterior descending coronary artery ligation and ischemia/reperfusion injury) confirmed that MPO serves as a major enzymatic source in the generation of these cytotoxic aldehydes. Interestingly, although MPO-null mice experienced 35.1% (P<0.001) less LV dilation and a 52.2% (P<0.0001) improvement in LV function compared with wild-type mice 24 days after ischemia/reperfusion injury, no difference in infarct size between wild-type and MPO-null mice was noted. CONCLUSIONS: The present data separate inflammatory effects on infarct size and LV remodeling and demonstrate that MPO-generated oxidants do not significantly affect tissue necrosis after MI but rather have a profound adverse effect on LV remodeling and function.
Subject(s)
Acrolein/toxicity , Formaldehyde/toxicity , Muscle, Smooth, Vascular/physiology , Myocardial Infarction/pathology , Peroxidase/metabolism , Pulmonary Artery/physiology , Ventricular Remodeling/physiology , Aldehydes/pharmacology , Animals , Aorta , Cattle , Cell Line , Cell Survival/drug effects , Cells, Cultured , Glutathione/metabolism , Glutathione Disulfide/metabolism , Humans , Hydrogen Peroxide/pharmacology , Muscle, Smooth, Vascular/drug effects , Neutrophils/physiology , Pulmonary Artery/drug effects , Ventricular Remodeling/drug effectsABSTRACT
Oxidant stress is widely believed to participate in cardiovascular disease pathogenesis. However, progress in defining appropriate systemic antioxidant targeted therapies has been hindered by uncertainty in defining clinically relevant systemic oxidant stress measures. In a case control study, 50 subjects with CAD (>50% stenosis in one or more major coronary vessels) and 54 without CAD (<30% stenosis in all major coronary vessels) were tested. Plasma was isolated and stored under conditions designed to prevent artificial lipid peroxidation. Systemic levels of multiple (n=9) specific fatty acid oxidation products including individual hydroxyoctadecadienoic acids (HODEs), hydroxyeicosatetraenoic acids (HETEs), and F(2)-isoprostanes were simultaneously measured by high-performance liquid chromatography (HPLC) with on-line tandem mass spectrometry, along with traditional risk factors and C-reactive protein (CRP) levels. Of the markers monitored, only 9-HETE and F(2)-isoprostanes, both products of free radical-mediated arachidonic acid oxidation, were significantly elevated in patients with angiographically defined CAD (9-HETE, 8.7 +/- 4 vs 6.8 +/- 4 micromol/mol arachidonate, P = 0.011; and F(2)-isoprostanes, 9.4 +/- 5 vs 6.2 +/- 3 micromol/mol arachidonate, P < 0.001). In multivariable analyses with simultaneous adjustment for Framingham risk score and C-reactive protein, 9-HETE (4th quartile OR = 4.8, 95% CI=1.3 to 17.1; P = 0.016) and F(2)-isoprostanes (4th quartile OR=9.7, 95% CI=2.56 to 36.9; P < 0.001) remained strong and independent predictors of CAD risk. Systemic levels of 9-HETE and F(2)-isoprostanes are independently associated with angiographic evidence of CAD and appear superior to other specific oxidation products of arachidonic and linoleic acids as predictors of the presence of angiographically evident coronary artery disease.
Subject(s)
Arachidonic Acid/chemistry , Coronary Artery Disease/metabolism , Fatty Acids/metabolism , Free Radicals/metabolism , C-Reactive Protein/metabolism , Case-Control Studies , Coronary Angiography , Coronary Artery Disease/pathology , F2-Isoprostanes/metabolism , Female , Humans , Hydroxyeicosatetraenoic Acids/metabolism , Lipid Peroxidation , Male , Middle Aged , Oxidation-Reduction , PrognosisABSTRACT
Increased oxidative stress and endothelial dysfunction are commonly observed in patients with chronic heart failure (HF). The relation between myeloperoxidase (MPO), an inflammatory marker with mechanistic links to plaque vulnerability and abnormal ventricular remodeling, and degrees of severity in chronic HF has not been reported. Plasma MPO levels were measured in 105 normal controls (no history of HF or left ventricular dysfunction) and 102 patients with chronic systolic HF (left ventricular ejection fraction <50%), and the relations among plasma MPO levels, plasma B-type natriuretic peptide levels, and the left ventricular ejection fraction were examined. Plasma MPO levels in patients with chronic systolic HF were significantly elevated compared with those of healthy controls (1,158 +/- 2,965 vs 204 +/- 139 pM, p <0.0001). Plasma MPO levels increased in parallel with increasing New York Heart Association class (p <0.0001) and were correlated with plasma B-type natriuretic peptide levels (Spearman's r = 0.39, p <0.0001). Levels of MPO were strongly associated with the prevalence of HF (unadjusted odds ratio 30.3, 95% confidence interval 11.1 to 94.5) and remained significant when adjusted for age and B-type natriuretic peptide (odds ratio 27.7, 95% confidence interval 3.6 to 371.1). In conclusion, in a cohort of patients with chronic HF, plasma MPO levels were elevated compared with those of normal controls and were associated with worsening functional class.
Subject(s)
Heart Failure/blood , Peroxidase/blood , Adult , Aged , Biomarkers/blood , Female , Heart Failure/physiopathology , Humans , Male , Middle Aged , Natriuretic Peptide, Brain/blood , Sensitivity and Specificity , Stroke VolumeABSTRACT
BACKGROUND: During inflammation, myeloperoxidase (MPO) is released, for which its measurement in systemic circulation may be used as an index of leukocyte activation and oxidant stress. MPO levels correlate with angiographic evidence of coronary atherosclerosis and cardiovascular events in subjects with chest pain within the general population. We hypothesized that serum MPO levels are associated with adverse clinical outcomes in maintenance hemodialysis (MHD) patients. METHODS: MPO levels were determined in serum samples from 356 MHD patients at the start of a 3-year cohort. RESULTS: Patients (46% women, 28% blacks, 54% with diabetes) were 54.6 +/- 14.6 (SD) years old and had undergone MHD for a median period of 26 months. Measured serum MPO level was 2,005 +/- 1,877 pmol/L (median, 1,444 pmol/L; interquartile range, 861 to 2,490 pmol/L). MHD patients with greater total body fat had greater MPO levels. MPO level had statistically significant (P < 0.01) and positive correlations with values for serum C-reactive protein (CRP; r = +0.15), interleukin 6 (IL-6; r = +0.23), tumor necrosis factor alpha (TNF-alpha; r = +0.21), and white blood cell count (r = +0.21). A death hazard ratio for each 1,000-pmol/L increase in serum MPO level was 1.14 (95% confidence interval [CI], 1.03 to 1.26; P = 0.01) after controlling for age, race (black), diabetes mellitus, dialysis vintage, Charlson comorbidity score, history of previous cardiovascular disease, blood hemoglobin level, and serum concentrations of albumin, CRP, IL-6, and TNF-alpha. After dividing MPO values into 3 equal groups (tertiles), the death hazard ratio of the highest tertile (versus the middle tertile) was 1.82 (95% CI, 1.07 to 3.10; P = 0.03). CONCLUSION: Serum MPO levels correlate with levels of markers of inflammation and prospective mortality risk in MHD patients.
Subject(s)
Kidney Diseases/mortality , Peroxidase/blood , Renal Dialysis , Adult , Aged , Biomarkers/blood , Chronic Disease , Cohort Studies , Cytokines/blood , Female , Humans , Inflammation , Kidney Diseases/pathology , Kidney Diseases/therapy , Male , Malnutrition , Middle Aged , Oxidative Stress , Prognosis , Survival Analysis , SyndromeABSTRACT
Chronic inflammation is known to promote cancer, suggesting that negative regulation of inflammation is likely to be tumor suppressive. We found that p53 is a general inhibitor of inflammation that acts as an antagonist of nuclear factor kappaB (NFkappaB). We first observed striking similarities in global gene expression profiles in human prostate cancer cells LNCaP transduced with p53 inhibitory genetic element or treated with TNF, suggesting that p53 inhibits transcription of TNF-inducible genes that are largely regulated by NFkappaB. Consistently, ectopically expressed p53 acts as an inhibitor of transcription of NFkappaB-dependent promoters. Furthermore, suppression of inflammatory response by p53 was observed in vivo in mice by comparing wild-type and p53 null animals at molecular (inhibition of transcription of genes encoding cytokines and chemokines, reducing accumulation of reactive oxygen species and protein oxidation products), cellular (activation of macrophages and neutrophil clearance) and organismal (high levels of metabolic markers of inflammation in tissues of p53-deficient mice and their hypersensitivity to LPS) levels. These observations indicate that p53, acting through suppression of NFkappaB, plays the role of a general "buffer" of innate immune response in vivo that is well consistent with its tumor suppressor function and frequent constitutive activation of NFkappaB in tumors.
Subject(s)
Inflammation/prevention & control , NF-kappa B/antagonists & inhibitors , Tumor Suppressor Protein p53/physiology , Animals , Cecum/surgery , Chemokines/genetics , Cytokines/genetics , DNA/metabolism , Humans , Inflammation/chemically induced , Ligation , Lipopolysaccharides/pharmacology , Macrophage Activation/physiology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , NF-kappa B/analysis , NF-kappa B/physiology , Neutrophils/physiology , Oligonucleotide Array Sequence Analysis , Oxidation-Reduction , Peritonitis/etiology , Peroxidase/blood , Phagocytosis , Promoter Regions, Genetic/genetics , Punctures , Reactive Oxygen Species/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Shock, Septic/mortality , Thioglycolates , Transcription, Genetic/drug effects , Transcriptional Activation/physiology , Transfection , Tumor Suppressor Protein p53/deficiency , Tumor Suppressor Protein p53/geneticsABSTRACT
Cystic fibrosis (CF) is an autosomal recessive disease with significant associated morbidity and mortality. It is now appreciated that the broad phenotypic CF spectrum is not explained by obvious genotype-phenotype correlations, suggesting that CF transmembrane conductance regulator (CFTR)-related disease may occur because of multiple additive effects. These contributing effects include complex CFTR alleles, modifier genes, mutations in alternative genes that produce CF-like phenotypes, epigenetic factors, and environmental influences. Most patients in the United States are now diagnosed through newborn screening and use of molecular testing methods. We review the molecular testing approaches and laboratory guidelines for carrier screening, prenatal testing, newborn screening, and clinical diagnostic testing, as well as recent developments in CF treatment, and reasons for the lack of a molecular diagnosis in some patients.