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1.
Pharmacogenomics J ; 16(4): 326-35, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26503814

RESUMO

Short-acting ß2-agonist bronchodilators are the most common medications used in treating chronic obstructive pulmonary disease (COPD). Genetic variants determining bronchodilator responsiveness (BDR) in COPD have not been identified. We performed a genome-wide association study (GWAS) of BDR in 5789 current or former smokers with COPD in one African-American and four white populations. BDR was defined as the quantitative spirometric response to inhaled ß2-agonists. We combined results in a meta-analysis. In the meta-analysis, single-nucleotide polymorphisms (SNPs) in the genes KCNK1 (P=2.02 × 10(-7)) and KCNJ2 (P=1.79 × 10(-7)) were the top associations with BDR. Among African Americans, SNPs in CDH13 were significantly associated with BDR (P=5.1 × 10(-9)). A nominal association with CDH13 was identified in a gene-based analysis in all subjects. We identified suggestive association with BDR among COPD subjects for variants near two potassium channel genes (KCNK1 and KCNJ2). SNPs in CDH13 were significantly associated with BDR in African Americans.The Pharmacogenomics Journal advance online publication, 27 October 2015; doi:10.1038/tpj.2015.65.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Broncodilatadores/uso terapêutico , Pulmão/efeitos dos fármacos , Variantes Farmacogenômicos/genética , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/genética , Negro ou Afro-Americano/genética , Idoso , Caderinas/genética , Europa (Continente) , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Nova Zelândia , América do Norte , Testes Farmacogenômicos , Fenótipo , Canais de Potássio Corretores do Fluxo de Internalização/genética , Canais de Potássio de Domínios Poros em Tandem/genética , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Fatores de Risco , Sarcoglicanas/genética , Índice de Gravidade de Doença , Espirometria , Resultado do Tratamento , População Branca/genética
2.
Rev Mal Respir ; 31(10): 992-1002, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25442121

RESUMO

Alpha-1 antitrypsin (α1-AT) is the most abundant circulating protease inhibitor. The common severe Z allele of α1-AT (Glu342Lys) causes the protein to form ordered polymers that are retained within the endoplasmic reticulum of hepatocytes. These polymers form the periodic acid-Schiff positive inclusions that are associated with cirrhosis. The lack of circulating α1-AT predisposes the Z α1-AT homozygote to early onset emphysema. We review here the molecular basis of α1-AT deficiency and show how understanding the liver disease provides new insights in the pathobiology of the associated emphysema. The mechanism of α1-AT deficiency provides a paradigm for a wider group of conditions that we have termed the serpinopathies. We also examine the strategies that are being pursued to develop novel therapies for α1-AT deficiency. This review considers our understanding of the pathobiology of α1-AT deficiency and then illustrate the therapeutic possibilities that can ensue once we understand basic mechanisms of disease.


Assuntos
Deficiência de alfa 1-Antitripsina/genética , Animais , Humanos , Modelos Moleculares , Estrutura Terciária de Proteína , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/patologia , Doença Pulmonar Obstrutiva Crônica/terapia , alfa 1-Antitripsina/química , Deficiência de alfa 1-Antitripsina/patologia , Deficiência de alfa 1-Antitripsina/terapia
3.
Br J Cancer ; 108(6): 1340-7, 2013 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-23412101

RESUMO

BACKGROUND: Mesothelioma is an incurable cancer originating from the mesothelial cells that line the pleural, peritoneal and pericardial cavities. These cells synthesise large quantities of surface glycoproteins, rendering them dependent upon efficient endoplasmic reticulum (ER) function. When faced with elevated levels of secretory protein load, cells are said to experience ER stress, which has been implicated in the pathogenesis of many human diseases including cancer. METHOD: We set out to measure markers of ER stress in malignant mesothelioma and to determine whether ER stress signalling correlates with clinical parameters. RESULTS: We observed that expression of the ER stress-responsive transcription factor C/EBP homologous protein (CHOP) correlated with patient survival and remained an independent prognostic variable in pairwise comparisons with all clinical variables tested. The most parsimonious multivariate model in our study comprised only performance status and CHOP staining. In contrast, expression of the ER stress-responsive phosphatase growth arrest and DNA damage 34 (GADD34) correlated with the degree of mesothelial differentiation, being lost progressively in biphasic and sarcomatoid mesotheliomas. CONCLUSION: Our findings suggest that staining for CHOP provides prognostic information that may be useful in the stratification of patients with mesothelioma. Staining for GADD34 may prove useful in classification of mesothelioma histopathology.


Assuntos
Biomarcadores Tumorais/metabolismo , Estresse do Retículo Endoplasmático , Proteínas de Choque Térmico/metabolismo , Mesotelioma/mortalidade , Proteína Fosfatase 1/metabolismo , Fator de Transcrição CHOP/metabolismo , Diferenciação Celular , Chaperona BiP do Retículo Endoplasmático , Feminino , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Masculino , Mesotelioma/metabolismo , Mesotelioma/patologia , Estadiamento de Neoplasias , Prognóstico , Transdução de Sinais , Taxa de Sobrevida , Análise Serial de Tecidos
4.
Artigo em Inglês | MEDLINE | ID: mdl-23055718

RESUMO

BACKGROUND: The major concept behind augmentation therapy with human α(1)-antitrypsin (AAT) is to raise the levels of AAT in patients with protease inhibitor phenotype ZZ (Glu342Lys)-inherited AAT deficiency and to protect lung tissues from proteolysis and progression of emphysema. OBJECTIVE: To evaluate the short-term effects of augmentation therapy (Prolastin) on plasma levels of AAT, C-reactive protein, and chemokines/cytokines. MATERIALS AND METHODS: Serum and exhaled breath condensate were collected from individuals with protease inhibitor phenotype ZZ AAT deficiency-related emphysema (n = 12) on the first, third, and seventh day after the infusion of intravenous Prolastin. Concentrations of total and polymeric AAT, interleukin-8 (IL-8), monocyte chemotactic protein-1, IL-6, tumor necrosis factor-α, vascular endothelial growth factor, and C-reactive protein were determined. Blood neutrophils and primary epithelial cells were also exposed to Prolastin (1 mg/mL). RESULTS: There were significant fluctuations in serum (but not in exhaled breath condensate) levels of AAT polymers, IL-8, monocyte chemotactic protein-1, IL-6, tumor necrosis factor-α, and vascular endothelial growth factor within a week of augmentation therapy. In general, augmented individuals had higher AAT and lower serum levels of IL-8 than nonaugmented subjects. Prolastin added for 3 hours to neutrophils from protease inhibitor phenotype ZZ individuals in vitro reduced IL-8 release but showed no effect on cytokine/chemokine release from human bronchial epithelial cells. CONCLUSION: Within a week, augmentation with Prolastin induced fluctuations in serum levels of AAT polymers and cytokine/chemokines but specifically lowered IL-8 levels. It remains to be determined whether these effects are related to the Prolastin preparation per se or to the therapeutic efficacy of augmentation with AAT.


Assuntos
Terapia de Reposição de Enzimas , Deficiência de alfa 1-Antitripsina/tratamento farmacológico , alfa 1-Antitripsina/administração & dosagem , Adulto , Idoso , Biomarcadores/sangue , Testes Respiratórios , Proteína C-Reativa/metabolismo , Células Cultivadas , Quimiocinas/sangue , Citocinas/sangue , Esquema de Medicação , Feminino , Genótipo , Alemanha , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Fenótipo , Enfisema Pulmonar/sangue , Enfisema Pulmonar/tratamento farmacológico , Enfisema Pulmonar/enzimologia , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/metabolismo , Fatores de Tempo , Resultado do Tratamento , alfa 1-Antitripsina/sangue , alfa 1-Antitripsina/genética , Deficiência de alfa 1-Antitripsina/sangue , Deficiência de alfa 1-Antitripsina/diagnóstico , Deficiência de alfa 1-Antitripsina/enzimologia , Deficiência de alfa 1-Antitripsina/genética
5.
Hum Genet ; 131(7): 1105-14, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22200767

RESUMO

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.


Assuntos
Quitinases/genética , Volume Expiratório Forçado , Polimorfismo de Nucleotídeo Único , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Idoso , Líquido da Lavagem Broncoalveolar/química , Estudos de Casos e Controles , Quitinases/metabolismo , Feminino , Variação Genética , Genótipo , Humanos , Pulmão/metabolismo , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Doença Pulmonar Obstrutiva Crônica/enzimologia , Fenômenos Fisiológicos Respiratórios , Fumar
6.
Ann Rheum Dis ; 70(10): 1851-6, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21821620

RESUMO

BACKGROUND: Small studies have linked α1 antitrypsin (α1AT) deficiency to patients with antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). OBJECTIVE: To test the validity and the mechanism of this association between α1AT and AAV. METHODS: The distribution of α1AT deficiency alleles Z and S was compared between 856 White Europeans with AAV and 1505 geographic and ethnically matched healthy controls. Genotyping was performed by allelic discrimination assay. RESULTS: were compared between cases and controls using χ(2) tests. The serum and renal biopsies for α1AT polymers were compared using the polymer-specific 2C1 antibody. The role of α1AT polymers in promoting inflammation was investigated by examining their ability to prime neutrophils for ANCA activation as assessed by CD62L shedding, superoxide production and myeloperoxidase degranulation. Results The Z but not the S allele was over-represented in the patients compared with controls (HR=2.25, 95% CI 1.60 to 3.19). Higher concentrations of polymers of α1AT were detected in serum from patients carrying the Z allele than in those not carrying the Z allele (median (IQR) 1.40 (0.91-3.32) mg/dl vs 0.17 (0.06-0.28) mg/dl, p<0.001); polymers of α1AT were also seen in the renal biopsy of a patient with vasculitic glomerulonephritis. Polymers of α1AT primed neutrophils with CD62L shedding and increased superoxide production following ANCA activation. Carriage of the Z allele was not associated with disease severity, survival or relapse. CONCLUSIONS: The Z but not the S deficiency allele is associated with AAV. Polymers of α1AT are present in the serum and glomeruli of at least some patients with the Z allele, which may promote inflammation through priming of neutrophils.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/etiologia , Deficiência de alfa 1-Antitripsina/complicações , alfa 1-Antitripsina/genética , Adulto , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/genética , Biópsia , Estudos de Casos e Controles , Feminino , Frequência do Gene , Genótipo , Glomerulonefrite/etiologia , Glomerulonefrite/metabolismo , Glomerulonefrite/patologia , Heterozigoto , Humanos , Rim/metabolismo , Rim/patologia , Masculino , Pessoa de Meia-Idade , Ativação de Neutrófilo , alfa 1-Antitripsina/sangue , Deficiência de alfa 1-Antitripsina/genética
7.
Eur Respir J ; 37(2): 255-63, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20562129

RESUMO

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.


Assuntos
Polimorfismo Genético , Doença Pulmonar Obstrutiva Crônica/genética , Fator de Transcrição STAT1/genética , Sirtuína 2/genética , Proteína de Ligação a Vitamina D/genética , Idoso , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Noruega/epidemiologia , Polimorfismo de Nucleotídeo Único , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Testes de Função Respiratória/estatística & dados numéricos , Fumar/epidemiologia
8.
Thorax ; 66(10): 903-9, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21163806

RESUMO

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.


Assuntos
DNA/genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único , Doença Pulmonar Obstrutiva Crônica/genética , Fumar/genética , alfa 1-Antitripsina/genética , Feminino , Seguimentos , Volume Expiratório Forçado , Genótipo , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Noruega/epidemiologia , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Testes de Função Respiratória , Estudos Retrospectivos , Fatores de Risco , Fumar/efeitos adversos , Fumar/metabolismo , alfa 1-Antitripsina/metabolismo
9.
COPD ; 7(4): 262-8, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20673035

RESUMO

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.


Assuntos
Polimorfismo de Nucleotídeo Único , Doença Pulmonar Obstrutiva Crônica/genética , Enfisema Pulmonar/genética , Superóxido Dismutase/genética , Idoso , Feminino , Frequência do Gene , Genótipo , Humanos , Pulmão/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Fenótipo , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Enfisema Pulmonar/complicações , Fumar/genética , Tomografia Computadorizada por Raios X
10.
Eur Respir J ; 34(2): 475-88, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19648523

RESUMO

The severe, early onset emphysema that occurs in patients with circulating deficiency of alpha(1)-antitrypsin (alpha(1)-AT) attests to the importance of this protease inhibitor in maintaining lung parenchymal integrity. It has led to the powerful concept of protease:antiprotease balance being crucial to alveolar homeostasis. Pathogenic mutations cause alpha(1)-AT to self-associate into polymer chains that accumulate intracellularly rather than proceeding along the secretory pathway. Polymerisation of alpha(1)-AT abolishes antiprotease activity and confers toxic gain-of-function effects. Since alpha(1)-AT is predominantly synthesised in the liver, where it does not play a major homeostatic role, the directly toxic effects of polymerisation are clearest here. However, data from molecular, cellular, animal and ex vivo studies indicate that intrapulmonary polymerisation of alpha(1)-AT and inflammatory positive feedback loops may augment the destructive effects of decreased antiprotease levels in the lung. This review integrates the findings from these different approaches and highlights how multiple pathways may converge to give the severe, panacinar emphysema phenotype seen in alpha(1)-AT deficiency.


Assuntos
Enfisema/complicações , Enfisema/genética , Deficiência de alfa 1-Antitripsina/complicações , Deficiência de alfa 1-Antitripsina/genética , Animais , Homozigoto , Humanos , Inflamação , Pulmão/patologia , Modelos Biológicos , Elastase Pancreática/biossíntese , Polímeros/química , Serpinas/química , alfa 1-Antitripsina/genética , alfa 1-Antitripsina/metabolismo
11.
Proc Natl Acad Sci U S A ; 106(23): 9191-6, 2009 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-19458258

RESUMO

The amyloid-beta peptide (Abeta) can generate cytotoxic oligomers, and their accumulation is thought to underlie the neuropathologic changes found in Alzheimer's disease. Known inhibitors of Abeta polymerization bind to undefined structures and can work as nonspecific aggregators, and inhibitors that target conformations that also occur in larger Abeta assemblies may even increase oligomer-derived toxicity. Here we report on an alternative approach whereby ligands are designed to bind and stabilize the 13-26 region of Abeta in an alpha-helical conformation, inspired by the postulated Abeta native structure. This is achieved with 2 different classes of compounds that also reduce Abeta toxicity to cells in culture and to hippocampal slice preparations, and that do not show any nonspecific aggregatory properties. In addition, when these inhibitors are administered to Drosophila melanogaster expressing human Abeta(1-42) in the central nervous system, a prolonged lifespan, increased locomotor activity, and reduced neurodegeneration is observed. We conclude that stabilization of the central Abeta alpha-helix counteracts polymerization into toxic assemblies and provides a strategy for development of specific inhibitors of Abeta polymerization.


Assuntos
Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/química , Amiloide/metabolismo , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/química , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Animais Geneticamente Modificados , Drosophila melanogaster , Humanos , Modelos Moleculares , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Estrutura Secundária de Proteína
12.
Eur Respir J ; 34(3): 598-604, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19386687

RESUMO

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.


Assuntos
Antígenos CD/genética , Bronquite Crônica/genética , Polimorfismo de Nucleotídeo Único/genética , Idoso , Antígeno CTLA-4 , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Volume Expiratório Forçado , Estudos de Associação Genética , Humanos , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade , Fenótipo , Capacidade Vital
13.
Thorax ; 64(4): 359-64, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19329735

RESUMO

The airway and emphysema phenotypes of chronic obstructive pulmonary disease (COPD) cluster in susceptible families. Some of this clustering is likely to be the result of shared genetic factors. There are a number of relatively rare syndromes that predispose to COPD, and a growing number of association and linkage studies that have assessed the genetic factors that predispose smokers to airflow obstruction. A review of the literature was performed to determine what has been learnt about the factors and pathways that predispose some individuals to progressive airflow obstruction while others are relatively resistant. There is very strong evidence that the integrity of the extracellular matrix, and in particular the elastin fibres, are important in the pathogenesis of COPD. There is also support for the role of proteinase-antiproteinase imbalance and probably oxidative stress. However, many of the genetic studies have focused on pathways that have already been implicated in disease. It is now essential that future studies take advantage of multiple large cohorts that have been phenotyped for both airways disease and emphysema, and use modern technology to perform unbiased genome-wide analyses of genetic variation in COPD. Only then will we have new insights into the pathways that underlie this common condition.


Assuntos
Mutação/genética , Doença Pulmonar Obstrutiva Crônica/genética , Matriz Extracelular/genética , Humanos , Peptídeo Hidrolases/metabolismo , Inibidores de Proteases/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
14.
Eur Respir J ; 34(1): 95-102, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19164344

RESUMO

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.


Assuntos
Biomarcadores/metabolismo , Regulação da Expressão Gênica , Pneumopatias/sangue , Pneumopatias/imunologia , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Proteína D Associada a Surfactante Pulmonar/sangue , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Inflamação , Masculino , Pessoa de Meia-Idade , Risco , Fumar
15.
Thorax ; 63(12): 1058-63, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18757456

RESUMO

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.


Assuntos
Doença Pulmonar Obstrutiva Crônica/diagnóstico , Uteroglobina/sangue , Adulto , Idoso , Biomarcadores/sangue , Biomarcadores/metabolismo , Estudos de Coortes , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Sensibilidade e Especificidade , Fumar/efeitos adversos , Fumar/sangue , Uteroglobina/metabolismo
16.
Eur Respir J ; 31(4): 869-73, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18216052

RESUMO

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.


Assuntos
Nível de Saúde , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Índice de Gravidade de Doença , Adulto , Idoso , Biomarcadores/sangue , Biomarcadores/urina , Testes Respiratórios , Feminino , Volume Expiratório Forçado , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Fumar
17.
Neurology ; 69(16): 1569-79, 2007 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-17761554

RESUMO

OBJECTIVE: Serine protease inhibitors (serpins), the acute phase reactants and regulators of the proteolytic processing of proteins, have been recognized as potential contributors to the pathogenesis of Alzheimer disease (AD). We measured plasma and CSF levels of serpins in controls and patients with dementia. METHODS: Using rocket immunoelectrophoresis, ELISA, and Luminex xMAP technology, we analyzed plasma levels of alpha(1)-antichymotrypsin and alpha(1)-antitrypsin, and CSF levels of alpha(1)-antichymotrypsin, alpha(1)-antitrypsin, and neuroserpin along with three standard biomarkers (total tau, tau phosphorylated at threonine-181, and the A beta(1-42)) in patients with AD (n = 258), patients with dementia with Lewy bodies (DLB; n = 38), and age-matched controls (n = 37). RESULTS: The level of CSF neuroserpin was significantly higher in AD compared with controls and DLB, whereas CSF alpha(1)-antichymotrypsin and alpha(1)-antitrypsin were significantly higher in both AD and DLB groups than in controls. Results from logistic regression analyses demonstrate a relationship between higher CSF levels of alpha(1)-antichymotrypsin and neuroserpin and increased predicted probability and odds ratios (ORs) of AD (OR 5.3, 95% CI 1.3 to 20.8 and OR 3.3, CI 1.3 to 8.8). Furthermore, a logistic regression model based on CSF alpha(1)-antichymotrypsin, neuroserpin, and A beta(1-42) enabled us to discriminate between AD patients and controls with a sensitivity of 94.7% and a specificity of 77.8%. CONCLUSIONS: Higher CSF levels of neuroserpin and alpha(1)-antichymotrypsin were associated with the clinical diagnosis of Alzheimer disease (AD) and facilitated the diagnostic classification of AD vs controls. CSF serpin levels did not improve the diagnostic classification of AD vs dementia with Lewy bodies.


Assuntos
Doença de Alzheimer/sangue , Doença de Alzheimer/líquido cefalorraquidiano , Doença por Corpos de Lewy/sangue , Doença por Corpos de Lewy/líquido cefalorraquidiano , Serpinas/sangue , Serpinas/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Apolipoproteína E4/genética , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Diagnóstico Diferencial , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunoeletroforese , Doença por Corpos de Lewy/diagnóstico , Masculino , Neuropeptídeos/sangue , Neuropeptídeos/líquido cefalorraquidiano , Valor Preditivo dos Testes , Regulação para Cima/fisiologia , alfa 1-Antiquimotripsina/sangue , alfa 1-Antiquimotripsina/líquido cefalorraquidiano , alfa 1-Antitripsina/sangue , alfa 1-Antitripsina/líquido cefalorraquidiano , Neuroserpina
18.
Thorax ; 61(7): 568-571, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16774949

RESUMO

BACKGROUND: Cigarette smoking causes accelerated facial wrinkling and predisposes to chronic obstructive pulmonary disease (COPD). However, it has long been recognised that there is a subgroup of susceptible smokers who are at increased risk of developing airflow obstruction. We have tested the hypothesis that there is a common susceptibility for the development of COPD and facial wrinkling in cigarette smokers. METHODS: One hundred and forty nine current and ex-smokers were recruited from a family based study of COPD genetics, 68 (45.6%) of whom fulfilled the definition of COPD. 124 (83.2%) had no or minor facial wrinkling (Daniell /=IV). Generalised estimating equations were used to adjust for familial correlations between related individuals and the potential confounding effects of age and pack years smoked. RESULTS: Forced expiratory volume in 1 second (FEV(1)) was significantly lower in those with wrinkles than in those without (mean difference in FEV(1) % predicted -13.7%, 95% CI -27.5 to 0.0, p = 0.05) and facial wrinkling was associated with a substantially increased risk of COPD (adjusted OR 5.0, 95% CI 1.3 to 18.5, p<0.02). The Daniell score correlated with the extent of emphysema on the CT scan (p<0.05) and facial wrinkling was also associated with a greater risk of more extensive emphysema (adjusted OR 3.0, 95% CI 1.0 to 9.3, p = 0.05). CONCLUSION: Facial wrinkling is associated with COPD in smokers, and both disease processes may share a common susceptibility. Facial wrinkling in smokers may therefore be a biomarker of susceptibility to COPD.


Assuntos
Doença Pulmonar Obstrutiva Crônica/etiologia , Envelhecimento da Pele , Fumar/efeitos adversos , Suscetibilidade a Doenças , Face/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/patologia , Envelhecimento da Pele/patologia
19.
Thorax ; 61(5): 388-93, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16467075

RESUMO

BACKGROUND: Several antioxidant nutrients have been reported to be inversely associated with asthma. A study was undertaken to assess the independent associations of these nutrients with asthma in adults. METHODS: A nested case-control study was performed in 515 adults with physician diagnosed asthma and 515 matched controls using dietary data obtained from 7 day food diaries. The main outcome measures were physician diagnosed asthma and current symptomatic asthma (diagnosed asthma and self-reported wheeze within the previous 12 months). RESULTS: Cases were similar to controls in age, sex, social class, and daily energy intake but had a lower median intake of fruit (132.1 v 149.1 g/day, p< or =0.05). 51.5% of the population reported zero consumption of citrus fruit; relative to these individuals, people who consumed >46.3 g/day had a reduced risk of diagnosed and symptomatic asthma (OR adjusted for potential confounders 0.59 (95% CI 0.43 to 0.82) and 0.51 (95% CI 0.33 to 0.79), respectively). In nutrient analysis, dietary vitamin C and manganese were inversely and independently associated with symptomatic asthma (adjusted OR per quintile increase 0.88 (95% CI 0.77 to 1.00) for vitamin C and 0.85 (95% CI 0.74 to 0.98) for manganese), but only manganese was independently associated with diagnosed asthma (OR 0.86 (95% CI 0.77 to 0.95)). Adjusted plasma levels of vitamin C were significantly lower in symptomatic cases than in controls (54.3 v 58.2 micromol/l, p = 0.003). CONCLUSIONS: Symptomatic asthma in adults is associated with a low dietary intake of fruit, the antioxidant nutrients vitamin C and manganese, and low plasma vitamin C levels. These findings suggest that diet may be a potentially modifiable risk factor for the development of asthma.


Assuntos
Antioxidantes/administração & dosagem , Asma/etiologia , Dieta/normas , Idoso , Ácido Ascórbico/sangue , Asma/sangue , Estudos de Casos e Controles , Estudos de Coortes , Ingestão de Energia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
20.
Cell Mol Life Sci ; 63(6): 709-22, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16465451

RESUMO

Proteinases and their inhibitors play important roles in neural development, homeostasis and disease. Neuroserpin is a member of the serine proteinase inhibitor (serpin) superfamily that is secreted from the growth cones of neurons and inhibits the enzyme tissue-type plasminogen activator (tPA). The temporal and spatial pattern of neuroserpin expression suggests a role in synaptogenesis and is most prominent in areas of the brain that participate in learning, memory and behaviour. Neuroserpin also provides neuronal protection in pathologies such as cerebral ischaemia and epilepsy by preventing excessive activity of tPA. Point mutations in neuroserpin cause aberrant conformational transitions and the formation of loop-sheet polymers that are retained within the endoplasmic reticulum of neurons, forming inclusion bodies that underlie an autosomal dominant dementia that we have called familial encephalopathy with neuroserpin inclusion bodies or FENIB. We review here the role of neuroserpin and other proteinase inhibitors in brain development, function and disease.


Assuntos
Encéfalo/crescimento & desenvolvimento , Doenças do Sistema Nervoso/genética , Neuropeptídeos/fisiologia , Inibidores de Serina Proteinase/fisiologia , Serpinas/fisiologia , Animais , Encéfalo/patologia , Demência/genética , Humanos , Mutação , Neuropeptídeos/genética , Inibidores de Serina Proteinase/genética , Serpinas/genética , Neuroserpina
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