RESUMEN
BACKGROUND: Tracking longitudinal measurements of growth and decline in lung function in patients with persistent childhood asthma may reveal links between asthma and subsequent chronic airflow obstruction. METHODS: We classified children with asthma according to four characteristic patterns of lung-function growth and decline on the basis of graphs showing forced expiratory volume in 1 second (FEV1), representing spirometric measurements performed from childhood into adulthood. Risk factors associated with abnormal patterns were also examined. To define normal values, we used FEV1 values from participants in the National Health and Nutrition Examination Survey who did not have asthma. RESULTS: Of the 684 study participants, 170 (25%) had a normal pattern of lung-function growth without early decline, and 514 (75%) had abnormal patterns: 176 (26%) had reduced growth and an early decline, 160 (23%) had reduced growth only, and 178 (26%) had normal growth and an early decline. Lower baseline values for FEV1, smaller bronchodilator response, airway hyperresponsiveness at baseline, and male sex were associated with reduced growth (P<0.001 for all comparisons). At the last spirometric measurement (mean [±SD] age, 26.0±1.8 years), 73 participants (11%) met Global Initiative for Chronic Obstructive Lung Disease spirometric criteria for lung-function impairment that was consistent with chronic obstructive pulmonary disease (COPD); these participants were more likely to have a reduced pattern of growth than a normal pattern (18% vs. 3%, P<0.001). CONCLUSIONS: Childhood impairment of lung function and male sex were the most significant predictors of abnormal longitudinal patterns of lung-function growth and decline. Children with persistent asthma and reduced growth of lung function are at increased risk for fixed airflow obstruction and possibly COPD in early adulthood. (Funded by the Parker B. Francis Foundation and others; ClinicalTrials.gov number, NCT00000575.).
Asunto(s)
Antiinflamatorios/uso terapéutico , Asma/fisiopatología , Pulmón/fisiología , Administración por Inhalación , Adolescente , Asma/tratamiento farmacológico , Broncodilatadores/uso terapéutico , Budesonida/uso terapéutico , Niño , Preescolar , Femenino , Volumen Espiratorio Forzado , Humanos , Estimación de Kaplan-Meier , Estudios Longitudinales , Pulmón/crecimiento & desarrollo , Masculino , Nedocromil/uso terapéutico , Factores de Riesgo , Factores Sexuales , Espirometría , Adulto JovenRESUMEN
Two primary chitinases have been identified in humans--acid mammalian chitinase (AMCase) and chitotriosidase (CHIT1). Mammalian chitinases have been observed to affect the host's immune response. The aim of this study was to test for association between genetic variation in the chitinases and phenotypes related to chronic obstructive pulmonary disease (COPD). Polymorphisms in the chitinase genes were selected based on previous associations with respiratory diseases. Polymorphisms that were associated with lung function level or rate of decline in the Lung Health Study (LHS) cohort were analyzed for association with COPD affection status in four other COPD case-control populations. Chitinase activity and protein levels were also related to genotypes. In the caucasian LHS population, the baseline forced expiratory volume in one second (FEV(1)) was significantly different between the AA and GG genotypic groups of the AMCase rs3818822 polymorphism. Subjects with the GG genotype had higher AMCase protein and chitinase activity compared with AA homozygotes. For CHIT1 rs2494303, a significant association was observed between rate of decline in FEV(1) and the different genotypes. In the African American LHS population, CHIT1 rs2494303 and AMCase G339T genotypes were associated with rate of decline in FEV(1). Although a significant effect of chitinase gene alleles was found on lung function level and decline in the LHS, we were unable to replicate the associations with COPD affection status in the other COPD study groups.
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Quitinasas/genética , Volumen Espiratorio Forzado , Polimorfismo de Nucleótido Simple , Enfermedad Pulmonar Obstructiva Crónica/genética , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Anciano , Líquido del Lavado Bronquioalveolar/química , Estudios de Casos y Controles , Quitinasas/metabolismo , Femenino , Variación Genética , Genotipo , Humanos , Pulmón/metabolismo , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Fenotipo , Enfermedad Pulmonar Obstructiva Crónica/enzimología , Fenómenos Fisiológicos Respiratorios , FumarRESUMEN
BACKGROUND: Alpha-1 Antitrypsin (AAT) deficiency (AATD), the most common genetic cause of emphysema presents with unexplained phenotypic heterogeneity in affected subjects. Our objectives to identify unique and shared AATD plasma biomarkers with chronic obstructive pulmonary disease (COPD) may explain AATD phenotypic heterogeneity. METHODS: The plasma or serum of 5,924 subjects from four AATD and COPD cohorts were analyzed on SomaScan V4.0 platform. Using multivariable linear regression, inverse variance random-effects meta-analysis, and Least Absolute Shrinkage and Selection Operator (LASSO) regression we tested the association between 4,720 individual proteins or combined in a protein score with emphysema measured by 15th percentile lung density (PD15) or diffusion capacity (DLCO) in distinct AATD genotypes (Pi*ZZ, Pi*SZ, Pi*MZ) and non-AATD, PiMM COPD subjects. AAT SOMAmer accuracy for identifying AATD was tested using receiver operating characteristic curve analysis. FINDINGS: In PiZZ AATD subjects, 2 unique proteins were associated with PD15 and 98 proteins with DLCO. Of those, 68 were also associated with DLCO in COPD also and enriched for three cellular component pathways: insulin-like growth factor, lipid droplet, and myosin complex. PiMZ AATD subjects shared similar proteins associated with DLCO as COPD subjects. Our emphysema protein score included 262 SOMAmers and predicted emphysema in AATD and COPD subjects. SOMAmer AAT level <7.99 relative fluorescence unit (RFU) had 100% sensitivity and specificity for identifying Pi*ZZ, but it was lower for other AATD genotypes. INTERPRETATION: Using SomaScan, we identified unique and shared plasma biomarkers between AATD and COPD subjects and generated a protein score that strongly associates with emphysema in COPD and AATD. Furthermore, we discovered unique biomarkers associated with DLCO and emphysema in PiZZ AATD. FUNDING: This work was supported by a grant from the Alpha-1 Foundation to RPB. COPDGene was supported by Award U01 HL089897 and U01 HL089856 from the National Heart, Lung, and Blood Institute. Proteomics for COPDGene was supported by NIH 1R01HL137995. GRADS was supported by Award U01HL112707, U01 HL112695 from the National Heart, Lung, and Blood Institute, and UL1TRR002535 to CCTSI; QUANTUM-1 was supported by the National Heart Lung and Blood Institute, the Office of Rare Diseases through the Rare Lung Disease Clinical Research Network (1 U54 RR019498-01, Trapnell PI), and the Alpha-1 Foundation. COPDGene is also supported by the COPD Foundation through contributions made to an Industry Advisory Board that has included AstraZeneca, Bayer Pharmaceuticals, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, and Sunovion.
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Enfermedad Pulmonar Obstructiva Crónica , Enfisema Pulmonar , Somatomedinas , Deficiencia de alfa 1-Antitripsina , Biomarcadores , Humanos , Miosinas , Preparaciones Farmacéuticas , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/etiología , Enfisema Pulmonar/diagnóstico , Enfisema Pulmonar/etiología , Deficiencia de alfa 1-Antitripsina/complicaciones , Deficiencia de alfa 1-Antitripsina/diagnóstico , Deficiencia de alfa 1-Antitripsina/genéticaRESUMEN
BACKGROUND: The identification of gene-by-environment interactions is important for understanding the genetic basis of chronic obstructive pulmonary disease (COPD). Many COPD genetic association analyses assume a linear relationship between pack-years of smoking exposure and forced expiratory volume in 1 s (FEV(1)); however, this assumption has not been evaluated empirically in cohorts with a wide spectrum of COPD severity. METHODS: The relationship between FEV(1) and pack-years of smoking exposure was examined in four large cohorts assembled for the purpose of identifying genetic associations with COPD. Using data from the Alpha-1 Antitrypsin Genetic Modifiers Study, the accuracy and power of two different approaches to model smoking were compared by performing a simulation study of a genetic variant with a range of gene-by-smoking interaction effects. RESULTS: Non-linear relationships between smoking and FEV(1) were identified in the four cohorts. It was found that, in most situations where the relationship between pack-years and FEV(1) is non-linear, a piecewise linear approach to model smoking and gene-by-smoking interactions is preferable to the commonly used total pack-years approach. The piecewise linear approach was applied to a genetic association analysis of the PI*Z allele in the Norway Case-Control cohort and a potential PI*Z-by-smoking interaction was identified (p=0.03 for FEV(1) analysis, p=0.01 for COPD susceptibility analysis). CONCLUSION: In study samples of subjects with a wide range of COPD severity, a non-linear relationship between pack-years of smoking and FEV(1) is likely. In this setting, approaches that account for this non-linearity can be more powerful and less biased than the more common approach of using total pack-years to model the smoking effect.
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ADN/genética , Estudio de Asociación del Genoma Completo/métodos , Polimorfismo de Nucleótido Simple , Enfermedad Pulmonar Obstructiva Crónica/genética , Fumar/genética , alfa 1-Antitripsina/genética , Femenino , Estudios de Seguimiento , Volumen Espiratorio Forzado , Genotipo , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Noruega/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Pruebas de Función Respiratoria , Estudios Retrospectivos , Factores de Riesgo , Fumar/efectos adversos , Fumar/metabolismo , alfa 1-Antitripsina/metabolismoRESUMEN
The principal determining factors influencing the development of the airway disease and emphysema components of chronic obstructive pulmonary disease (COPD) have not been clearly defined. Genetic variability in COPD patients might influence the varying degrees of involvement of airway disease and emphysema. Therefore, we investigated the genetic association of single nucleotide polymorphisms (SNPs) in COPD candidate genes for association with emphysema severity and airway wall thickness phenotypes. Polymorphisms in six candidate genes were analysed in 379 subjects of the National Emphysema Treatment Trial (NETT) Genetics Ancillary Study with quantitative chest computed tomography (CT) data. Genetic association with per cent of lung area below -950 HU (LAA950), airway wall thickness, and derived square root wall area (SRWA) of 10-mm internal perimeter airways were investigated. Three SNPs in EPHX1, five SNPs in SERPINE2 and one SNP in GSTP1 were significantly associated with LAA950. Five SNPs in TGFB1, two SNPs in EPHX1, one SNP in SERPINE2 and two SNPs in ADRB2 were associated with airway wall phenotypes in NETT. In conclusion, several COPD candidate genes showed evidence for association with airway wall thickness and emphysema severity using CT in a severe COPD population. Further investigation will be required to replicate these genetic associations for emphysema and airway wall phenotypes.
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Enfisema/complicaciones , Enfisema/genética , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/genética , Anciano , Epóxido Hidrolasas/genética , Femenino , Volumen Espiratorio Forzado , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Fenotipo , Polimorfismo de Nucleótido Simple , Serpina E2/genética , Tomografía Computarizada por Rayos X/métodosRESUMEN
Lack of reproducibility of findings has been a criticism of genetic association studies on complex diseases, such as chronic obstructive pulmonary disease (COPD). We selected 257 polymorphisms of 16 genes with reported or potential relationships to COPD and genotyped these variants in a case-control study that included 953 COPD cases and 956 control subjects. We explored the association of these polymorphisms to three COPD phenotypes: a COPD binary phenotype and two quantitative traits (post-bronchodilator forced expiratory volume in 1 s (FEV1) % predicted and FEV1/forced vital capacity (FVC)). The polymorphisms significantly associated to these phenotypes in this first study were tested in a second, family-based study that included 635 pedigrees with 1,910 individuals. Significant associations to the binary COPD phenotype in both populations were seen for STAT1 (rs13010343) and NFKBIB/SIRT2 (rs2241704) (p<0.05). Single-nucleotide polymorphisms rs17467825 and rs1155563 of the GC gene were significantly associated with FEV1 % predicted and FEV1/FVC, respectively, in both populations (p<0.05). This study has replicated associations to COPD phenotypes in the STAT1, NFKBIB/SIRT2 and GC genes in two independent populations, the associations of the former two genes representing novel findings.
Asunto(s)
Polimorfismo Genético , Enfermedad Pulmonar Obstructiva Crónica/genética , Factor de Transcripción STAT1/genética , Sirtuina 2/genética , Proteína de Unión a Vitamina D/genética , Anciano , Estudios de Casos y Controles , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad/epidemiología , Predisposición Genética a la Enfermedad/genética , Humanos , Masculino , Persona de Mediana Edad , Noruega/epidemiología , Polimorfismo de Nucleótido Simple , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Pruebas de Función Respiratoria/estadística & datos numéricos , Fumar/epidemiologíaRESUMEN
Severe alpha-1 antitrypsin (AAT) deficiency is a proven genetic risk factor for COPD, but there is marked variation in the development of COPD among AAT deficient subjects. To investigate familial aggregation of lung function in subjects with AAT deficiency, we estimated heritability for forced expiratory volume in 1 s (FEV1) and FEV1/forced vital capacity (FVC) in 378 AAT deficient subjects from 167 families in the AAT Genetic Modifiers Study; all subjects were verified homozygous for the Z AAT deficiency allele. Heritability was evaluated for models that included and excluded an ascertainment correction, as well as for models that excluded, included and were stratified by a cigarette smoking covariate. In models without an ascertainment correction, and in all models without a covariate for smoking, no evidence for familial aggregation of lung function was observed. In models conditioned on the index proband with covariates for smoking, post-bronchodilator FEV1/FVC demonstrated significant heritability (0.26 +/- 0.14, p = 0.03). When we limited the analysis to subjects with a smoking history, post-bronchodilator FEV1 demonstrated significant heritability (0.47 +/- 0.21, p = 0.02). Severity rate phenotypes were also assessed as potential phenotypes for genetic modifier studies. Significant heritability was found with all age-of-onset threshold models that included smoking and ascertainment adjustments. Using the t-distribution, the heritability estimates ranged from 0.43 to 0.64, depending on the age-of-onset of FEV1 decline used for the severity rate calculation. Correction for ascertainment and consideration of gene-by-smoking interactions will be crucial for the identification of genes that may modify susceptibility for COPD in families with AAT deficiency.
Asunto(s)
Enfermedad Pulmonar Obstructiva Crónica/genética , Índice de Severidad de la Enfermedad , Deficiencia de alfa 1-Antitripsina/genética , alfa 1-Antitripsina/genética , Adulto , Edad de Inicio , Anciano , Estudios de Cohortes , Humanos , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Pruebas de Función Respiratoria , Fumar/efectos adversos , Fumar/genética , Fumar/fisiopatología , Espirometría , Adulto Joven , Deficiencia de alfa 1-Antitripsina/diagnósticoRESUMEN
Superoxide dismutase-3 (SOD3) is a major extracellular antioxidant enzyme, and previous studies have indicated a possible role of this gene in chronic obstructive pulmonary disease (COPD). We hypothesized that polymorphisms in the SOD3 gene would be associated with COPD and COPD-related phenotypes. We genotyped three SOD3 polymorphisms (rs8192287 (E1), rs8192288 (I1), and rs1799895 (R213G)) in a case-control cohort, with severe COPD cases from the National Emphysema Treatment Trial (NETT, n = 389) and smoking controls from the Normative Aging Study (NAS, n = 472). We examined whether the single nucleotide polymorphisms (SNPs) were associated with COPD status, lung function variables, and quantitative computed tomography (CT) measurements of emphysema and airway wall thickness. Furthermore, we tried to replicate our initial findings in two family-based studies, the International COPD Genetics Network (ICGN, n = 3061) and the Boston Early-Onset COPD Study (EOCOPD, n = 949). In NETT COPD cases, the minor alleles of SNPs E1 and I1 were associated with a higher percentage of emphysema (%LAA950) on chest CT scan (p = .029 and p = .0058). The association with E1 was replicated in the ICGN family study, where the minor allele was associated with more emphysema (p = .048). Airway wall thickness was positively associated with the E1 SNP in ICGN; however, this finding was not confirmed in NETT. Quantitative CT data were not available in EOCOPD. The SNPs were not associated with lung function variables or COPD status in any of the populations. In conclusion, polymorphisms in the SOD3 gene were associated with CT emphysema but not COPD susceptibility, highlighting the importance of phenotype definition in COPD genetics studies.
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Polimorfismo de Nucleótido Simple , Enfermedad Pulmonar Obstructiva Crónica/genética , Enfisema Pulmonar/genética , Superóxido Dismutasa/genética , Anciano , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Pulmón/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Fenotipo , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico por imagen , Enfisema Pulmonar/complicaciones , Fumar/genética , Tomografía Computarizada por Rayos XRESUMEN
Alpha-1-antitrypsin deficiency is a genetic condition associated with severe, early-onset chronic obstructive pulmonary disease (COPD). However, there is significant variability in lung function impairment among persons with the protease inhibitor ZZ genotype. Early identification of persons at highest risk of developing lung disease could be beneficial in guiding monitoring and treatment decisions. Using a multicenter, family-based study sample (2002-2005) of 372 persons with the protease inhibitor ZZ genotype, the authors developed prediction models for forced expiratory volume in 1 second (FEV(1)) and the presence of severe COPD using demographic, clinical, and genetic variables. Half of the data sample was used for model development, and the other half was used for model validation. In the training sample, variables found to be predictive of both FEV(1) and severe COPD were age, sex, pack-years of smoking, bronchodilator responsiveness, chronic bronchitis symptoms, and index case status. In the validation sample, the predictive model for FEV(1) explained 50% of the variance in FEV(1), and the model for severe COPD exhibited excellent discrimination (c statistic = 0.88).
Asunto(s)
Resistencia de las Vías Respiratorias , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Deficiencia de alfa 1-Antitripsina/fisiopatología , Femenino , Volumen Espiratorio Forzado , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Modelos Estadísticos , Enfermedad Pulmonar Obstructiva Crónica/etiología , Fumar , Deficiencia de alfa 1-Antitripsina/complicaciones , Deficiencia de alfa 1-Antitripsina/genéticaRESUMEN
BACKGROUND: Interleukin-6 (IL6) is a pleiotropic pro-inflammatory and immunomodulatory cytokine which probably plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). There is a functional single nucleotide polymorphism (SNP), -174G/C, in the promoter region of IL6. It was hypothesised that IL6 SNPs influence susceptibility for impaired lung function and COPD in smokers. METHODS: Seven and five SNPs in IL6 were genotyped in two nested case-control samples derived from the Lung Health Study (LHS) based on phenotypes of rate of decline of forced expiratory volume in 1 s (FEV(1)) over 5 years and baseline FEV(1) at the beginning of the LHS. Serum IL6 concentrations were measured for all subjects. A partially overlapping panel of nine IL6 SNPs was genotyped in 389 cases of COPD from the National Emphysema Treatment Trial (NETT) and 420 controls from the Normative Aging Study (NAS). RESULTS: In the LHS, three IL6 SNPs were associated with decline in FEV(1) (0.023< or =p< or =0.041 in additive models). Among them, the IL6_-174C allele was associated with a rapid decline in lung function. The association was more significant in a genotype-based analysis (p = 0.006). In the NETT-NAS study, IL6_-174G/C and four other IL6 SNPs, all of which are in linkage disequilibrium with IL6_-174G/C, were associated with susceptibility to COPD (0.01< or =p< or =0.04 in additive genetic models). CONCLUSION: The results suggest that the IL6_-174G/C SNP is associated with a rapid decline in FEV(1) and susceptibility to COPD in smokers.
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Interleucina-6/genética , Polimorfismo de Nucleótido Simple , Enfermedad Pulmonar Obstructiva Crónica/genética , Estudios de Casos y Controles , Femenino , Volumen Espiratorio Forzado , Haplotipos , Humanos , Interleucina-6/sangre , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Fenotipo , Enfermedad Pulmonar Obstructiva Crónica/fisiopatologíaRESUMEN
Chronic obstructive pulmonary disease (COPD) is characterised by chronic and progressive dyspnoea, cough and sputum production. T-lymphocytes may play a key role in the pathogenesis of COPD and chronic bronchitis. Cytotoxic T-lymphocyte antigen (CTLA) 4 is a potential candidate gene because it modulates T-cell activation. Genetic association between nine CTLA4 single nucleotide polymorphisms (SNPs) and chronic bronchitis was assessed in 606 pedigrees (1,896 individuals) from the International COPD Genetics Network (ICGN) population. We then replicated the associations in 342 COPD subjects with chronic bronchitis and 511 COPD subjects without chronic bronchitis from Bergen, Norway. Family-based association tests were used to analyse the ICGN cohort, and a logistic regression model was used for the Bergen cohort. Six CTLA4 SNPs were significantly associated with chronic bronchitis in the ICGN cohort (0.0079< or = p < or =0.0432), with three being replicated with the same directionality of association in the Bergen cohort (0.0325< or = p < or =0.0408). One of these replicated SNPs (rs231775) encodes the Thr to Ala substitution at amino acid position 17. Haplotype analyses supported the results of single SNP analyses. Thus, CTLA4 is likely to be a genetic determinant of chronic bronchitis among COPD cases.
Asunto(s)
Antígenos CD/genética , Bronquitis Crónica/genética , Polimorfismo de Nucleótido Simple/genética , Anciano , Antígeno CTLA-4 , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Volumen Espiratorio Forzado , Estudios de Asociación Genética , Humanos , Desequilibrio de Ligamiento/genética , Masculino , Persona de Mediana Edad , Fenotipo , Capacidad VitalRESUMEN
Surfactant protein (SP)-D is a lung-derived protein that has been proposed as a biomarker for inflammatory lung disease. Serum SP-D was evaluated as a biomarker for components of chronic obstructive pulmonary disease (COPD) in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) cohort and its response assessed to the administration of the anti-inflammatory agent prednisolone. The median level of serum SP-D was significantly elevated in 1,888 individuals with COPD compared to 296 current and former smokers without airflow obstruction (121.1 and 114.3 ng x mL(-1), respectively; p = 0.021) and 201 nonsmokers (82.2 ng x ml(-1); p<0.001). There was no correlation with the severity of COPD. Individuals with COPD who had a serum SP-D concentration that was greater than the 95th percentile of nonsmokers (175.4 ng x mL(-1)) showed an increased risk of exacerbations over the following 12 months (adjusted OR 1.30; 95% CI 1.03-1.63). Treatment with 20 mg x day(-1) prednisolone for 4 weeks resulted in a fall in serum SP-D levels (126.0 to 82.1 ng x mL(-1); p<0.001) but no significant change in post-bronchodilator forced expiratory volume in 1 s. Serum SP-D concentration is raised in smokers and may be useful in identifying individuals who are at increased risk of exacerbations of COPD. It may represent an intermediate measure for the development of novel anti-inflammatory agents.
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Biomarcadores/metabolismo , Regulación de la Expresión Génica , Enfermedades Pulmonares/sangre , Enfermedades Pulmonares/inmunología , Enfermedad Pulmonar Obstructiva Crónica/sangre , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Proteína D Asociada a Surfactante Pulmonar/sangre , Adulto , Anciano , Estudios de Cohortes , Femenino , Humanos , Inflamación , Masculino , Persona de Mediana Edad , Riesgo , FumarRESUMEN
BACKGROUND: Circulating levels of Clara cell secretory protein-16 (CC-16) have been linked to Clara cell toxicity. It has therefore been suggested that this protein may be a useful marker of chronic obstructive pulmonary disease (COPD). METHODS: Serum CC-16 levels were measured in 2083 individuals aged 40-75 years with COPD and a smoking history of >or=10 pack-years, 332 controls with a smoking history of >or=10 pack-years and normal lung function and 237 non-smoking controls. RESULTS: Serum CC-16 had a coefficient of repeatability of 2.90 over 3 months in a pilot study of 267 individuals. The median serum CC-16 level was significantly reduced in a replication group of 1888 current and former smokers with COPD compared with 296 current and former smokers without airflow obstruction (4.9 and 5.6 ng/ml, respectively; p<0.001) and 201 non-smokers (6.4 ng/ml; p<0.001). Serum levels of CC-16 were lower in current than in former smokers with GOLD stage II and III COPD but were not different in individuals with stage IV disease. Former, but not current smokers, with COPD had lower serum CC-16 levels with increasing severity of COPD (GOLD II vs GOLD IV COPD: 5.5 and 5.0 ng/ml, p = 0.006; r = 0.11 with forced expiratory volume in 1 s, p<0.001) and had significantly higher levels if they also had reversible airflow obstruction (p = 0.034). Serum CC-16 was affected by gender and age (r = 0.35; p<0.001) in subjects with COPD but not by body mass index or the presence of either chronic bronchitis or emphysema. CONCLUSIONS: Serum CC-16 levels are reduced in individuals with COPD and there is a weak correlation with disease severity in former smokers.
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Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Uteroglobina/sangre , Adulto , Anciano , Biomarcadores/sangre , Biomarcadores/metabolismo , Estudios de Cohortes , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Proyectos Piloto , Sensibilidad y Especificidad , Fumar/efectos adversos , Fumar/sangre , Uteroglobina/metabolismoRESUMEN
Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease and not well understood. The forced expiratory volume in one second is used for the diagnosis and staging of COPD, but there is wide acceptance that it is a crude measure and insensitive to change over shorter periods of time. Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) is a 3-yr longitudinal study with four specific aims: 1) definition of clinically relevant COPD subtypes; 2) identification of parameters that predict disease progression in these subtypes; 3) examination of biomarkers that correlate with COPD subtypes and may predict disease progression; and 4) identification of novel genetic factors and/or biomarkers that both correlate with clinically relevant COPD subtypes and predict disease progression. ECLIPSE plans to recruit 2,180 COPD subjects in Global Initiative for Chronic Obstructive Lung Disease categories II-IV and 343 smoking and 223 nonsmoking control subjects. Study procedures are to be performed at baseline, 3 months, 6 months and every 6 months thereafter. Assessments include pulmonary function measurements (spirometry, impulse oscillometry and plethysmography), chest computed tomography, biomarker measurement (in blood, sputum, urine and exhaled breath condensate), health outcomes, body impedance, resting oxygen saturation and 6-min walking distance. Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points is the largest study attempting to better describe the subtypes of chronic obstructive pulmonary disease, as well as defining predictive markers of its progression.
Asunto(s)
Estado de Salud , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Índice de Severidad de la Enfermedad , Adulto , Anciano , Biomarcadores/sangre , Biomarcadores/orina , Pruebas Respiratorias , Femenino , Volumen Espiratorio Forzado , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , FumarRESUMEN
Exacerbations of chronic obstructive pulmonary disease (COPD) reduce quality of life and increase mortality. Genetic variation might explain the substantial variability seen in exacerbation frequency among COPD subjects with similar lung function. Polymorphisms in five candidate genes, previously associated with COPD susceptibility, were analysed in order to determine whether they demonstrated association with COPD exacerbations. A total of 88 single nucleotide polymorphisms (SNPs) in the genes microsomal epoxide hydrolase (EPHX1), transforming growth factor, beta-1 (TGFB1), serpin peptidase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1), member 2 (SERPINE2), glutathione S-transferase pi (GSTP1) and surfactant protein B (SFTPB) were genotyped in 389 non-Hispanic white participants in the National Emphysema Treatment Trial. Exacerbations were defined as COPD-related emergency room visits or hospitalisations using the Centers for Medicare and Medicaid Services claims data. One or more exacerbations were experienced by 216 (56%) subjects during the study period. An SFTPB promoter polymorphism, rs3024791, was associated with COPD exacerbations. Logistic regression models, analysing a binary outcome of presence or absence of exacerbations, confirmed the association of rs3024791 with COPD exacerbations. Negative binomial regression models demonstrated association of multiple SFTPB SNPs (rs2118177, rs2304566, rs1130866 and rs3024791) with exacerbation rates. Polymorphisms in EPHX1, GSTP1, TGFB1 and SERPINE2 did not demonstrate association with COPD exacerbations. In conclusion, genetic variation in surfactant protein B is associated with chronic obstructive pulmonary disease susceptibility and exacerbation frequency.
Asunto(s)
Polimorfismo Genético , Enfermedad Pulmonar Obstructiva Crónica/genética , Proteína B Asociada a Surfactante Pulmonar/genética , Anciano , Alelos , Femenino , Predisposición Genética a la Enfermedad , Variación Genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Análisis de Regresión , FumarRESUMEN
There is indirect evidence that unopposed human neutrophil elastase (HNE) is responsible for emphysema in patients with alpha 1-proteinase inhibitor (Pi) deficiency. To directly explore this possibility, we developed an assay for fibrinopeptide A alpha 1-21 and its degradation products and used it to measure HNE activity in 128 subjects of known Pi phenotype. The mean elastase-specific fibrinopeptide (ESF) level in 49 deficient PiZ individuals is significantly higher than that in 56 PiMZ heterozygotes (4.5 and 1.5 nM, respectively; P less than 0.01), while the mean ESF value in heterozygotes is significantly elevated over that in 23 normal PiM subjects (1.5 and 0.6 nM, respectively; P less than 0.01), consistent with increased HNE activity in those deficient in the major regulator of the enzyme. These results are not due to differences in smoking history because after correction for pack-years of smoking, ESF values in PiZ subjects are fourfold higher than those in PiMZ individuals (P = 0.005), while the ESF levels in heterozygotes are threefold higher than those in PiM subjects (P = 0.02). In addition, this analysis suggests that cigarette smoking and alpha 1-proteinase inhibitor deficiency have additive effects on ESF levels thereby explaining why PiZ and some PiMZ individuals are at especially high risk for the development of lung disease if they smoke. Finally, the observation that ESF levels in nonsmoking PiZ subjects are inversely related to the percent of predicted forced expiratory volume in 1 s (FEV 1%) provides direct support for the concept that unregulated HNE activity causes alveolar septal destruction in patients with alpha 1-proteinase inhibitor deficiency.
Asunto(s)
Fibrinopéptido A/análisis , Elastasa Pancreática/sangre , Deficiencia de alfa 1-Antitripsina , Carboxipeptidasas/sangre , Carboxipeptidasas A , Cromatografía Líquida de Alta Presión , Humanos , Sueros Inmunes/inmunología , Elastasa de Leucocito , Fenotipo , Fumar/sangreRESUMEN
Five lipoxygenase (5-LO) is the first committed enzyme in the metabolic pathway leading to the synthesis of the leukotrienes. We examined genomic DNA isolated from 25 normal subjects and 31 patients with asthma (6 of whom had aspirin-sensitive asthma) for mutations in the known transcription factor binding regions and the protein encoding region of the 5-LO gene. A family of mutations in the G + C-rich transcription factor binding region was identified consisting of the deletion of one, deletion of two, or addition of one zinc finger (Sp1/Egr-1) binding sites in the region 176 to 147 bp upstream from the ATG translation start site where there are normally 5 Sp1 binding motifs in tandem. Reporter gene activity directed by any of the mutant forms of the transcription factor binding region was significantly (P < 0.05) less effective than the activity driven by the wild type transcription factor binding region. Electrophoretic mobility shift assays (EMSAs) demonstrated the capacity of wild type and mutant transcription factor binding regions to bind nuclear extracts from human umbilical vein endothelial cells (HUVECs). These data are consistent with a family of mutations in the 5-LO gene that can modify reporter gene transcription possibly through differences in Sp1 and Egr-1 transactivation.
Asunto(s)
Asma/genética , Genes Reporteros/genética , Proteínas Inmediatas-Precoces , Lipooxigenasa/genética , Regiones Promotoras Genéticas , Factores de Transcripción/genética , Transcripción Genética/genética , Alelos , Secuencia de Bases , Codón Iniciador , Cartilla de ADN , Proteínas de Unión al ADN/genética , Hipersensibilidad a las Drogas/genética , Proteína 1 de la Respuesta de Crecimiento Precoz , Exones , Femenino , Humanos , Masculino , Datos de Secuencia Molecular , Plásmidos , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , Polimorfismo Conformacional Retorcido-Simple , Recombinación Genética , Proteínas Oncogénicas de Retroviridae/genética , Análisis de Secuencia de ADN , Eliminación de SecuenciaRESUMEN
OBJECTIVE: Many genetic variations have been suggested as genetic risk factors for the development of chronic obstructive pulmonary disease (COPD), including single nucleotide polymorphisms in the transforming growth factor-beta1 (TGFB1) gene. We attempted to elucidate the association between TGFB1 genetic polymorphisms and COPD among Koreans. DESIGN: The genotypes of 102 male patients with COPD and 159 volunteers with similar distributions of age, sex and smoking intensity, as well as normal pulmonary function, were determined for three previously associated TGFB1 single nucleotide polymorphisms (SNPs), -10807G/A (rs2241712) and -509T/C (rs1800469), located in or near the promoter, and 29T/C (rs1982073), located in exon 1 of the TGFB1 gene. RESULTS: No significant associations between COPD and the three TGFB1 SNPs could be identified. In addition, the haplotypes composed of three TGFB1 SNPs were not associated with the presence of COPD. CONCLUSION: These results differ from previous reports involving Caucasians, and might reflect racial differences in the pathogenesis of COPD.
Asunto(s)
Polimorfismo Genético , Enfermedad Pulmonar Obstructiva Crónica/genética , Factor de Crecimiento Transformador beta/genética , Distribución de Chi-Cuadrado , Genotipo , Haplotipos , Humanos , Corea (Geográfico) , Modelos Logísticos , Masculino , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Factor de Crecimiento Transformador beta1RESUMEN
The marked variability in the development of chronic obstructive pulmonary disease (COPD) in response to cigarette smoking has been known for decades, but severe alpha 1-antitrypsin deficiency (PI Z) remains the only proven genetic risk factor for COPD. With cigarette smoking, PI Z subjects tend to develop more severe pulmonary impairment at an earlier age than non-smoking PI Z individuals. However, PI Z individuals exhibit wide variability in pulmonary function impairment, even among individuals with similar smoking histories. Therefore, other genes and environmental exposures are also likely involved. The role of heterozygosity for the Z allele as a risk factor for COPD remains controversial, but accumulating evidence suggests that at least some PI MZ individuals are at increased risk of developing airflow obstruction. In individuals without alpha 1-antitrypsin deficiency, familial aggregation of COPD has been reported in several studies. To study novel genetic determinants of COPD, our research group enrolled 44 severe, early-onset COPD probands (FEV1 < 40%, age < 53 yrs, non-PI Z) and 266 of their relatives. A marked female predominance was noted among the early-onset COPD probands. In addition, increased risk to current or ex-smoking first-degree relatives of early-onset COPD probands for reduced FEV1, chronic bronchitis and spirometric bronchodilator responsiveness has been demonstrated. These data strongly support the genetic basis for the development of COPD and the potential for gene-by-environment interaction. A variety of studies have examined candidate gene loci with association studies, comparing the distribution of variants in genes hypothesized to be involved in the development of COPD in COPD patients and control subjects. For most genetic loci which have been tested, there have been inconsistent results. Genetic heterogeneity could contribute to difficulty in replicating associations between studies. In addition, case-control association studies are susceptible to supporting associations based purely on population stratification, which can result from incomplete matching between cases and controls--including differences in ethnicity. No association studies in COPD have been reported which used family-based controls, a study design which is immune to such population stratification effects. More importantly, no linkage studies have been published in COPD to identify regions of the genome which are likely to contain COPD susceptibility genes--regions in which association studies are likely to be more productive.
Asunto(s)
Enfermedades Pulmonares Obstructivas/genética , Humanos , Relaciones Interpersonales , Factores de Riesgo , alfa 1-Antitripsina/genética , Deficiencia de alfa 1-AntitripsinaRESUMEN
BACKGROUND: Little is known about factors determining the pathogenesis and severity of asthma in Latin American countries. Costa Rica, one of the most prosperous Latin American nations, has a very high asthma prevalence. OBJECTIVE: To examine the relation between potential risk factors and childhood asthma in Costa Rica. METHODS: Cross-sectional study of 214 schoolchildren aged 10 to 13 years participating in phase II of the International Study of Asthma and Allergies in Childhood. RESULTS: After adjustment for age, gender, area of residence, maternal smoking during pregnancy, and airway responsiveness to hypertonic saline solution, sensitization to house dust mites was associated with asthma (odds ratio [OR], 2.2; 95% confidence interval [CI], 1.1 to 4.4; p = 0.02). In the multivariate analysis, parental education no higher than high school (OR, 3.0; 95% CI, 1.4 to 6.4; p < 0.01) and parental history of asthma (OR, 2.6; 95% CI, 1.3 to 5.2; p < 0.01) were also independent predictors of childhood asthma. CONCLUSIONS: Sensitization to house dust mites, low parental education, and parental history of asthma are associated with asthma in Costa Rica.