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1.
Zhonghua Jie He He Hu Xi Za Zhi ; 42(10): 760-764, 2019 Oct 12.
Artigo em Chinês | MEDLINE | ID: mdl-31594110

RESUMO

Objective: To explore the difference of mRNA, protein expression levels and the indexes of peripheral blood antioxidant capacity in peripheral blood lymphocytes of different EPHX1 genotypes in chronic obstructive pulmonary disease(COPD). Methods: A case-control study was conducted to collect peripheral blood samples of 220 stable chronic COPD patients with smoking history and 230 healthy smokers (control group) from October 2016 to February 2018 in the First Affiliated Hospital of Kunming Medical University, and the genetic testing was carried out according to the operation instructions of BigDye Terminator v1.1 DNA Sequencing Kit. Based on their EPHX1 exon 3 and exon 4 polymorphism status, the EPHX1 was classified into 4 groups, i. e., normal activity, slow activity, extremely slow activity and fast activity. Then COPD patients were allocated to either a slow activity group (slow and very slow activity) or a fast activity group (normal and fast activity) according to EPHX1 genotype and gene activity. The expression of EPHX1 mRNA and protein in peripheral blood lymphocytes were detected by qRT-PCR and Western blot, and indexes of serum antioxidant capacity was detected by corresponding kits. Results: (1)The 2(-ΔΔCt) of the control group was 1.000, and the 2(-ΔΔCt) of the COPD group was 1.052±0.023. There was no significant difference in the level of EPHX1 mRNA expression between the two groups (t=1.992 P=0.865). The level of EPHX1 mRNA expression in the slow activity group was not different significantly compared to that in the fast-active group (1.053±0.023 vs 1.048±0.021, t=1.133, P=0.260). (2)The level of EPHX1 protein expression by Western blot analysis showed that the EHPX1/GAPDH gray ratio was not different significantly between the COPD group and the control group (0.613±0.089 vs 0.602±0.075, t=0.805, P=0.422). The level of EPHX1 protein expression in the slow activity group was not significantly different compared to that in the fast activity group (0.606±0.088 vs 0.622±0.092, t=-0.786 P=0.434). (3)There were significant differences in indexes of antioxidant capacity between the control group and the COPD group (P<0.05). There were significant differences in indexes of antioxidant capacity between the slow activity group and the fast activity group of COPD patients (P<0.05). Conclusions: The different antioxidant capacity of COPD patients with different EPHX1 genotypes may be related to the polymorphism of EPHX1 gene affecting the activity of microsomal epoxidase, but not to the level of EPHX1 mRNA and protein expression.


Assuntos
Antioxidantes/metabolismo , Grupo com Ancestrais do Continente Asiático/genética , Epóxido Hidrolases/genética , Doença Pulmonar Obstrutiva Crônica/genética , Fumar/efeitos adversos , Adulto , Western Blotting , Estudos de Casos e Controles , China/epidemiologia , Epóxido Hidrolases/metabolismo , Predisposição Genética para Doença/genética , Genótipo , Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora)/metabolismo , Humanos , Pessoa de Meia-Idade , Polimorfismo Genético , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Reação em Cadeia da Polimerase em Tempo Real , Fumar/epidemiologia
3.
Gene ; 714: 143968, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31323308

RESUMO

Sulfur mustard (SM) is a destructive and harmful chemical agent for the eyes, skin and lungs that causes short-term and long-term lesions and was widely used in Iraq war against Iran (1980-1988). SM causes DNA damages, oxidative stress, and Inflammation. Considering the similarities between SM and COPD (Chronic Obstructive Pulmonary Disease) pathogens and limited available treatments, a novel therapeutic approach is not developed. Gene therapy is a novel therapeutic approach that uses genetic engineering science in treatment of most diseases including chronic obstructive pulmonary disease. In this review, attempts to presenting a comprehensive study of mustard lung and introducing the genes therapy involved in chronic obstructive pulmonary disease and emphasizing the pathways and genes involved in the pathology and pathogenesis of sulfur Mustard. It seems that, given the high potential of gene therapy and the fact that this experimental technique is a candidate for the treatment of pulmonary diseases, further study of genes, vectors and gene transfer systems can draw a very positive perspective of gene therapy in near future.


Assuntos
Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/genética , Gás de Mostarda/efeitos adversos , Transdução de Sinais/genética , Animais , Terapia Genética/métodos , Humanos , Pulmão/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/genética
4.
Gene ; 719: 144009, 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31357020

RESUMO

BACKGROUND: The F+1 (rs511898 G>A) polymorphism in a disintegrin and metalloprotease 33 (ADAM33) gene has been implicated in susceptibility of chronic obstruction pulmonary disease (COPD). However, a series of studies have reported inconclusive. The aim of this study is to explore the association between the F+1 (rs511898) of ADAM33 gene and COPD susceptibility by using the method of meta-analysis. METHOD: PubMed, Embase, Cochrane Library, Chinese National Knowledge Infrastructure database (CNKI), Chongqing VIP database, Wanfang and China Biology Medicine (CBM) were searched comprehensively to obtain the related cohort studies and case-control studies. The included studies were selected according to inclusion criteria. The pooled odds ratios were performed respectively for allele comparison, additive model, dominant genetic model and recessive genetic model. The association between the F+1 polymorphism of ADAM33 gene and COPD susceptibility was measured by OR and 95%CI by STATA 12.0. The subgroup analysis was distinguished according to the ethnicity. The publication bias was tested by funnel plots and Egger's linear regression method. RESULTS: Twelve case-control studies were included in the meta-analysis, which study is comprised of 6935 participants (2454 patients with COPD and 4481 controls). The meta results showed significant association between ADAM33 F+1 polymorphism and COPD susceptibility in allele model OR total = 1.16(95% CI 1.04-1.30, P = 0.007), OR Asian = 1.14(95% CI 1.02-1.27, P = 0.022), additive model OR total = 1.27 (95% CI 1.13-1.43, P = 0.000), OR Asian = 1.25 (95% CI 1.08-1.45, P = 0.003), recessive model OR total = 1.49 (95% CI 1.16-1.91, P = 0.002), OR Asian = 1.56(95% CI 1.09-2.22, P = 0.014), but not significant in Caucasians. CONCLUSION: The ADAM33 F+1 mutant gene A may increase the risk of COPD among the Asian population, while it may not associate with the European population.


Assuntos
Proteínas ADAM/genética , Medicina Baseada em Evidências , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Doença Pulmonar Obstrutiva Crônica/genética , Proteínas ADAM/química , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Humanos
5.
Life Sci ; 231: 116485, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31116959

RESUMO

Airway mucin overproduction is the hallmark risk factor of asthma, which is associated with the reduction of lung function. An aberrant mucin expression is responsible for airway obstruction due to its high viscous characteristics. Among the mucins discovered, MUC5AC is the prime mucin of airway epithelia. Nowadays, mucins induced asthma and chronic obstructive pulmonary disease (COPD) are a great concern all over the world. This review focuses on the effects of natural compounds that can be beneficial to explore new drugs to halt MUC5AC secretion and production in airway epithelial, and also their underlying molecular mechanisms based on recent studies. Several researchers are seeking natural sources to identify a new potent MUC5AC inhibitory agent for clinical applications, because of countable limitations of existing synthetic drugs. Currently, flavonoids, glycoside and steroids like natural compounds have acquired great attention due to their anti-inflammatory and mucoregulatory effects. Most importantly, many natural compounds have shown their potential effects as the modulator of mucin expression, secretion, and production. Therefore, targeting airway MUC5AC expression and production represents an auspicious area of research for the development of drugs against various respiratory diseases.


Assuntos
Mucina-5AC/antagonistas & inibidores , Mucina-5AC/biossíntese , Animais , Asma/tratamento farmacológico , Asma/genética , Asma/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Regulação da Expressão Gênica , Humanos , Mucina-5AC/genética , Mucina-5AC/metabolismo , Mucina-1/genética , Mucina-1/metabolismo , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/metabolismo , Mucosa Respiratória/citologia , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/metabolismo , Sistema Respiratório/efeitos dos fármacos
6.
Mol Cells ; 42(4): 333-344, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31085807

RESUMO

Various genetic and environmental factors are known to be associated with chronic obstructive pulmonary disease (COPD). We identified COPD-related differentially expressed genes (DEGs) using 189 samples accompanying either adenocarcinoma (AC) or squamous cell carcinoma (SC), comprising 91 normal and 98 COPD samples. DEGs were obtained from the intersection of two DEG sets separately identified for AC and SC to exclude the influence of different cancer backgrounds co-occurring with COPD. We also measured patient samples named group 'I', which were unable to be determined as normal or COPD based on alterations in gene expression. The Gene Ontology (GO) analysis revealed significant alterations in the expression of genes categorized with the 'cell adhesion', 'inflammatory response', and 'mitochondrial functions', i.e., well-known functions related to COPD, in samples from patients with COPD. Multi-omics data were subsequently integrated to decipher the upstream regulatory changes linked to the gene expression alterations in COPD. COPD-associated expression quantitative trait loci (eQTLs) were located at the upstream regulatory regions of 96 DEGs. Additionally, 45 previously identified COPD-related miRNAs were predicted to target 66 of the DEGs. The eQTLs and miRNAs might affect the expression of 'respiratory electron transport chain' genes and 'cell proliferation' genes, respectively, while both eQTLs and miRNAs might affect the expression of 'apoptosis' genes. We think that our present study will contribute to our understanding of the molecular etiology of COPD accompanying lung cancer.


Assuntos
Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes , MicroRNAs/genética , Doença Pulmonar Obstrutiva Crônica/genética , Adenocarcinoma/genética , Carcinoma de Células Escamosas/genética , Comorbidade , Regulação da Expressão Gênica , Ontologia Genética , Predisposição Genética para Doença , Humanos , Neoplasias Pulmonares/genética , Masculino , Mapas de Interação de Proteínas , Análise de Sequência de RNA
7.
Respir Res ; 20(1): 70, 2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30971245

RESUMO

Cigarette smoking is one of the major risk factors for the development of chronic obstructive pulmonary disease (COPD). Evidence is accumulating that Receptor for Advanced Glycation-End products (RAGE)-signaling is a key pathway in the pathophysiology of COPD. To date, it is unknown how smoking affects RAGE expression. In the current study, we investigated the effect of smoking on AGER, the gene encoding RAGE, expression and on alternative splicing of AGER. To this end, we conducted RNA-Seq on bronchial biopsies for asymptomatic smokers (n = 36) and never smokers (n = 40). Total AGER gene expression was accessed using DESeq2, while alternative splicing was investigated by measuring the number of specific split reads spanning exon-exon junctions and the total split reads. One of the major isoforms of RAGE is endogenous soluble (es) RAGE, an anti-inflammatory decoy receptor, making up for approximately 10% of the total amount of soluble (s)RAGE. We found that smokers show decreased total gene expression of AGER in bronchial biopsies, while the relative abundance of the esRAGE isoform is increased. Furthermore, no difference in the serum levels of total sRAGE were observed between smokers and non-smokers. Our data indicates that smoking initiates a protective anti-inflammatory mechanism with decreased expression of the pro-inflammatory gene AGER and increased relative abundance of the anti-inflammatory isoform esRAGE.


Assuntos
Processamento Alternativo/fisiologia , Fumar Cigarros/metabolismo , Pulmão/metabolismo , Receptor para Produtos Finais de Glicação Avançada/biossíntese , Fumantes , Adulto , Biópsia , Fumar Cigarros/genética , Fumar Cigarros/patologia , Feminino , Expressão Gênica , Humanos , Pulmão/patologia , Masculino , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/metabolismo , Receptor para Produtos Finais de Glicação Avançada/genética
8.
Int J Mol Sci ; 20(8)2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-31022961

RESUMO

Background: Chronic obstructive pulmonary disease (COPD) is a common, preventable, and manageable lung disease characterized by large heterogeneity in disease presentation and grades impairment. Inhaled corticosteroids (ICS) are commonly used to manage COPD/COPD-exacerbation. The patient's response is characterized by interindividual variability without disease progression/survival modification. Objectives: We hypothesize that a therapeutic intervention may be more effective if single nucleotide polymorphisms (SNPs) are investigated. Methods: In 71 COPD patients under pulmonary rehabilitation, a small number of powerful SNPs, selected according to current literature, were analyzed; namely the glucocorticoid receptor gene NR3C1 (rs6190/rs6189/rs41423247), the glucocorticoid-induced transcript 1 gene (GLCCI1 rs37972), and the related co-chaperone FKBP5 gene (rs4713916). MDR1 rs2032582 was also evaluated. Lung function outcomes were assessed. Results: A significant association with functional outcomes, namely FEV1 (forced expiration volume/one second) and 6MWD (six-minutes walking distance), was found for rs4713916 and weakly for rs37972. The genotype rs4713916(GA) and, in a lesser extent, the genotype rs37972(TT), were more favorable than the wild-type. Conclusions: Our study supports a possible picture of pharmacogenomic control for COPD intervention. rs4713916 and, possibly, rs37972 may be useful predictors of clinical outcome. These results may help to tailor an optimal dose for individual COPD patients based on their genetic makeup.


Assuntos
Corticosteroides/uso terapêutico , Polimorfismo de Nucleotídeo Único , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/genética , Proteínas de Ligação a Tacrolimo/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Administração por Inalação , Corticosteroides/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptores de Glucocorticoides/genética , Resultado do Tratamento
9.
Yakugaku Zasshi ; 139(6): 955-961, 2019 Jun 01.
Artigo em Japonês | MEDLINE | ID: mdl-30944262

RESUMO

Reduction of corticosteroid responsiveness is one of the important clinical problems in chronic obstructive pulmonary disease (COPD). In this study, we determined the effects of neutralization of tumor necrosis factor-α (TNF-α) on corticosteroid insensitivity in mice models of airway inflammation induced by poly(I:C) and tobacco smoke (TS) exposure. Mice (male A/J strain, 5 weeks old) were exposed to TS for 10 d, or TS for 11 d and poly(I:C) for 3 d. Anti-TNF-α antibody was intranasally treated once every other day 2 h before the TS exposure, and dexamethasone 21-phosphate (DEX) was treated 30 min before the TS or poly(I:C) exposure. On the next day of the last stimulation, mice were sacrificed. The combination treatment of DEX and TNF-α neutralization was significantly attenuated the increase of the numbers of inflammatory cells in BALF and the TNF-α mRNA expression levels induced by TS and poly(I:C) exposure, even though TNF-α neutralization alone had little effect. These data indicated that neutralization of TNF-α restores corticosteroid responsiveness. Therefore, our study suggests that targeting TNF-α signaling pathway provides a new therapeutic approach to corticosteroid refractory airway diseases.


Assuntos
Dexametasona/análogos & derivados , Exposição Ambiental/efeitos adversos , Glucocorticoides/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/etiologia , RNA de Cadeia Dupla/efeitos adversos , Transdução de Sinais , Fumar/efeitos adversos , Tabaco/efeitos adversos , Fator de Necrose Tumoral alfa , Administração Intranasal , Animais , Anticorpos/administração & dosagem , Dexametasona/administração & dosagem , Modelos Animais de Doenças , Resistência a Medicamentos , Inflamação , Masculino , Camundongos Endogâmicos A , Terapia de Alvo Molecular , Doença Pulmonar Obstrutiva Crônica/genética , Fator de Necrose Tumoral alfa/imunologia
10.
Respir Res ; 20(1): 64, 2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30940143

RESUMO

BACKGROUND: A growing number of studies clearly demonstrate a substantial association between chronic obstructive pulmonary disease (COPD) and cardiovascular diseases (CVD), although little is known about the shared genetics that contribute to this association. METHODS: We conducted a large-scale cross-trait genome-wide association study to investigate genetic overlap between COPD (Ncase = 12,550, Ncontrol = 46,368) from the International COPD Genetics Consortium and four primary cardiac traits: resting heart rate (RHR) (N = 458,969), high blood pressure (HBP) (Ncase = 144,793, Ncontrol = 313,761), coronary artery disease (CAD)(Ncase = 60,801, Ncontrol = 123,504), and stroke (Ncase = 40,585, Ncontrol = 406,111) from UK Biobank, CARDIoGRAMplusC4D Consortium, and International Stroke Genetics Consortium data. RESULTS: RHR and HBP had modest genetic correlation, and CAD had borderline evidence with COPD at a genome-wide level. We found evidence of local genetic correlation with particular regions of the genome. Cross-trait meta-analysis of COPD identified 21 loci jointly associated with RHR, 22 loci with HBP, and 3 loci with CAD. Functional analysis revealed that shared genes were enriched in smoking-related pathways and in cardiovascular, nervous, and immune system tissues. An examination of smoking-related genetic variants identified SNPs located in 15q25.1 region associated with cigarettes per day, with effects on RHR and CAD. A Mendelian randomization analysis showed a significant positive causal effect of COPD on RHR (causal estimate = 0.1374, P = 0.008). CONCLUSION: In a set of large-scale GWAS, we identify evidence of shared genetics between COPD and cardiac traits.


Assuntos
Doenças Cardiovasculares/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único/genética , Doença Pulmonar Obstrutiva Crônica/genética , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Bases de Dados Genéticas/tendências , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Humanos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Característica Quantitativa Herdável
12.
Respir Res ; 20(1): 65, 2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30940135

RESUMO

BACKGROUND: Multiple gene expression studies have been performed separately in peripheral blood, lung, and airway tissues to study COPD. We performed RNA-sequencing gene expression profiling of large-airway epithelium, alveolar macrophage and peripheral blood samples from the same subset of COPD cases and controls from the COPDGene study who underwent bronchoscopy at a single center. Using statistical and gene set enrichment approaches, we sought to improve the understanding of COPD by studying gene sets and pathways across these tissues, beyond the individual genomic determinants. METHODS: We performed differential expression analysis using RNA-seq data obtained from 63 samples from 21 COPD cases and controls (includes four non-smokers) via the R package DESeq2. We tested associations between gene expression and variables related to lung function, smoking history, and CT scan measures of emphysema and airway disease. We examined the correlation of differential gene expression across the tissues and phenotypes, hypothesizing that this would reveal preserved and private gene expression signatures. We performed gene set enrichment analyses using curated databases and findings from prior COPD studies to provide biological and disease relevance. RESULTS: The known smoking-related genes CYP1B1 and AHRR were among the top differential expression results for smoking status in the large-airway epithelium data. We observed a significant overlap of genes primarily across large-airway and macrophage results for smoking and airway disease phenotypes. We did not observe specific genes differentially expressed in all three tissues for any of the phenotypes. However, we did observe hemostasis and immune signaling pathways in the overlaps across all three tissues for emphysema, and amyloid and telomere-related pathways for smoking. In peripheral blood, the emphysema results were enriched for B cell related genes previously identified in lung tissue studies. CONCLUSIONS: Our integrative analyses across COPD-relevant tissues and prior studies revealed shared and tissue-specific disease biology. These replicated and novel findings in the airway and peripheral blood have highlighted candidate genes and pathways for COPD pathogenesis.


Assuntos
Perfilação da Expressão Gênica/métodos , Macrófagos Alveolares/metabolismo , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/metabolismo , Mucosa Respiratória/metabolismo , Análise de Sequência de RNA/métodos , Estudos de Coortes , Seguimentos , Humanos , Estudos Longitudinais , Macrófagos Alveolares/patologia , Doença Pulmonar Obstrutiva Crônica/patologia , Mucosa Respiratória/patologia
13.
Clin Epigenetics ; 11(1): 37, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30819252

RESUMO

BACKGROUND: Ambient air pollution is associated with numerous adverse health outcomes, but the underlying mechanisms are not well understood; epigenetic effects including altered DNA methylation could play a role. To evaluate associations of long-term air pollution exposure with DNA methylation in blood, we conducted an epigenome-wide association study in a Korean chronic obstructive pulmonary disease cohort (N = 100 including 60 cases) using Illumina's Infinium HumanMethylation450K Beadchip. Annual average concentrations of particulate matter ≤ 10 µm in diameter (PM10) and nitrogen dioxide (NO2) were estimated at participants' residential addresses using exposure prediction models. We used robust linear regression to identify differentially methylated probes (DMPs) and two different approaches, DMRcate and comb-p, to identify differentially methylated regions (DMRs). RESULTS: After multiple testing correction (false discovery rate < 0.05), there were 12 DMPs and 27 DMRs associated with PM10 and 45 DMPs and 57 DMRs related to NO2. DMP cg06992688 (OTUB2) and several DMRs were associated with both exposures. Eleven DMPs in relation to NO2 confirmed previous findings in Europeans; the remainder were novel. Methylation levels of 39 DMPs were associated with expression levels of nearby genes in a separate dataset of 3075 individuals. Enriched networks were related to outcomes associated with air pollution including cardiovascular and respiratory diseases as well as inflammatory and immune responses. CONCLUSIONS: This study provides evidence that long-term ambient air pollution exposure impacts DNA methylation. The differential methylation signals can serve as potential air pollution biomarkers. These results may help better understand the influences of ambient air pollution on human health.


Assuntos
Poluição do Ar/análise , Metilação de DNA , Doença Pulmonar Obstrutiva Crônica/genética , Sequenciamento Completo do Genoma/métodos , Idoso , Idoso de 80 Anos ou mais , Poluição do Ar/efeitos adversos , Estudos de Coortes , Metilação de DNA/efeitos dos fármacos , Epigênese Genética , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Dióxido de Nitrogênio/efeitos adversos , Dióxido de Nitrogênio/análise , Material Particulado/análise , Doença Pulmonar Obstrutiva Crônica/induzido quimicamente , República da Coreia
14.
Int J Mol Sci ; 20(5)2019 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-30836679

RESUMO

In clinical practice, there are patients with a combination of metabolic syndrome (MS) and chronic obstructive pulmonary disease (COPD). The pathological mechanisms linking MS and COPD are largely unknown. It remains unclear whether the effect of MS (possible obesity) has a major impact on the progression of COPD. This complicates the development of effective approaches for the treatment of patients with a diagnosis of MS and COPD. Experiments were performed on female C57BL/6 mice. Introduction of monosodium glutamate and extract of cigarette smoke was modeled to simulate the combined pathology of lipid disorders and emphysema. Biological effects of glucagon-like peptide 1 (GLP-1) and GLP-1 on endothelial progenitor cells (EPC) in vitro and in vivo were evaluated. Histological, immunohistochemical methods, biochemical methods, cytometric analysis of markers identifying EPC were used in the study. The CD31⁺ endothelial cells in vitro evaluation was produced by Flow Cytometry and Image Processing of each well with a Cytation™ 3. GLP-1 reduces the area of emphysema and increases the number of CD31⁺ endothelial cells in the lungs of mice in conditions of dyslipidemia and damage to alveolar tissue of cigarette smoke extract. The regenerative effects of GLP-1 are caused by a decrease in inflammation, a positive effect on lipid metabolism and glucose metabolism. EPC are proposed as pathogenetic and diagnostic markers of endothelial disorders in combination of MS with COPD. Based on GLP-1, it is proposed to create a drug to stimulate the regeneration of endothelium damaged in MS and COPD.


Assuntos
Peptídeo 1 Semelhante ao Glucagon/genética , Síndrome Metabólica/genética , Doença Pulmonar Obstrutiva Crônica/genética , Enfisema Pulmonar/genética , Animais , Fumar Cigarros/efeitos adversos , Modelos Animais de Doenças , Progressão da Doença , Células Progenitoras Endoteliais/metabolismo , Citometria de Fluxo , Glucose/metabolismo , Humanos , Metabolismo dos Lipídeos/genética , Pulmão/efeitos dos fármacos , Pulmão/patologia , Síndrome Metabólica/induzido quimicamente , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/tratamento farmacológico , Camundongos , Molécula-1 de Adesão Celular Endotelial a Plaquetas/genética , Doença Pulmonar Obstrutiva Crônica/induzido quimicamente , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Enfisema Pulmonar/diagnóstico , Enfisema Pulmonar/tratamento farmacológico , Enfisema Pulmonar/patologia , Glutamato de Sódio/toxicidade
15.
BMC Pulm Med ; 19(1): 58, 2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30845926

RESUMO

BACKGROUND: Airflow obstruction is a hallmark of chronic obstructive pulmonary disease (COPD), and is defined as either the ratio between forced expiratory volume in one second and forced vital capacity (FEV1/FVC) < 70% or < lower limit of normal (LLN). This study aimed to assess the overlap between genome-wide association studies (GWAS) on airflow obstruction using these two definitions in the same population stratified by smoking. METHODS: GWASes were performed in the LifeLines Cohort Study for both airflow obstruction definitions in never-smokers (NS = 5071) and ever-smokers (ES = 4855). The FEV1/FVC < 70% models were adjusted for sex, age, and height; FEV1/FVC < LLN models were not adjusted. Ever-smokers models were additionally adjusted for pack-years and current-smoking. The overlap in significantly associated SNPs between the two definitions and never/ever-smokers was assessed using several p-value thresholds. To quantify the agreement, the Pearson correlation coefficient was calculated between the p-values and ORs. Replication was performed in the Vlagtwedde-Vlaardingen study (NS = 432, ES = 823). The overlapping SNPs with p < 10- 4 were validated in the Vlagtwedde-Vlaardingen and Rotterdam Study cohorts (NS = 1966, ES = 3134) and analysed for expression quantitative trait loci (eQTL) in lung tissue (n = 1087). RESULTS: In the LifeLines cohort, 96% and 93% of the never- and ever-smokers were classified concordantly based on the two definitions. 26 and 29% of the investigated SNPs were overlapping at p < 0.05 in never- and ever-smokers, respectively. At p < 10- 4 the overlap was 4% and 6% respectively, which could be change findings as shown by simulation studies. The effect estimates of the SNPs of the two definitions correlated strongly, but the p-values showed more variation and correlated only moderately. Similar observations were made in the Vlagtwedde-Vlaardingen study. Two overlapping SNPs in never-smokers (NFYC and FABP7) had the same direction of effect in the validation cohorts and the NFYC SNP was an eQTL for NFYC-AS1. NFYC is a transcription factor that binds to several known COPD genes, and FABP7 may be involved in abnormal pulmonary development. CONCLUSIONS: The definition of airflow obstruction and the population under study may be important determinants of which SNPs are associated with airflow obstruction. The genes FABP7 and NFYC(-AS1) could play a role in airflow obstruction in never-smokers specifically.


Assuntos
Fator de Ligação a CCAAT/genética , Proteína 7 de Ligação a Ácidos Graxos/genética , Estudo de Associação Genômica Ampla , Doença Pulmonar Obstrutiva Crônica/genética , Fumar/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Volume Expiratório Forçado , Homologia de Genes/genética , Predisposição Genética para Doença , Humanos , Modelos Lineares , Modelos Logísticos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética , Fumar/efeitos adversos , Espirometria , Capacidade Vital , Adulto Jovem
16.
Nat Genet ; 51(3): 481-493, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30804560

RESUMO

Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function-associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.


Assuntos
Predisposição Genética para Doença/genética , Pulmão/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Fumar/genética
17.
Nat Genet ; 51(3): 494-505, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30804561

RESUMO

Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide new insights into disease pathogenesis. We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci associated with P < 5 × 10-8; 47 of these were previously described in association with either COPD or population-based measures of lung function. Of the remaining 35 new loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified functional enrichment of COPD risk loci in lung tissue, smooth muscle, and several lung cell types. We found 14 COPD loci shared with either asthma or pulmonary fibrosis. COPD genetic risk loci clustered into groups based on associations with quantitative imaging features and comorbidities. Our analyses provide further support for the genetic susceptibility and heterogeneity of COPD.


Assuntos
Predisposição Genética para Doença/genética , Doença Pulmonar Obstrutiva Crônica/genética , Adulto , Idoso , Asma/genética , Estudos de Casos e Controles , Feminino , Expressão Gênica/genética , Loci Gênicos/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Fibrose Pulmonar/genética , Fumar/genética
18.
Genet Epidemiol ; 43(3): 318-329, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30740764

RESUMO

Genetic association studies have increasingly recognized variant effects on multiple phenotypes. Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease with environmental and genetic causes. Multiple genetic variants have been associated with COPD, many of which show significant associations to additional phenotypes. However, it is unknown if these associations represent biological pleiotropy or if they exist through correlation of related phenotypes ("mediated pleiotropy"). Using 6,670 subjects from the COPDGene study, we describe the association of known COPD susceptibility loci with other COPD-related phenotypes and distinguish if these act directly on the phenotypes (i.e., biological pleiotropy) or if the association is due to correlation (i.e., mediated pleiotropy). We identified additional associated phenotypes for 13 of 25 known COPD loci. Tests for pleiotropy between genotype and associated outcomes were significant for all loci. In cases of significant pleiotropy, we performed mediation analysis to test if SNPs had a direct association to phenotype. Most loci showed a mediated effect through the hypothesized causal pathway. However, many loci also had direct associations, suggesting causal explanations (i.e., emphysema leading to reduced lung function) are incomplete. Our results highlight the high degree of pleiotropy in complex disease-associated loci and provide novel insights into the mechanisms underlying COPD.


Assuntos
Loci Gênicos , Pleiotropia Genética , Predisposição Genética para Doença , Doença Pulmonar Obstrutiva Crônica/genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Estudo de Associação Genômica Ampla , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único/genética
19.
BMC Med Genet ; 20(1): 33, 2019 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-30777021

RESUMO

BACKGROUND: Genome-wide association studies (GWASs) of a large cohort of subjects with chronic obstructive pulmonary disease (COPD) have successfully identified multiple risk genes, including fibroblast growth factor 7 (FGF7). However, the underlying molecular mechanism influencing function of FGF7 and risk of COPD remains further study. METHODS: In this study, we replicated the genetic association of variants near the FGF7 gene in 258 Chinese Han patients with COPD and 311 healthy controls. Additionally, we functionally evaluated a candidate causal variant upstream of the FGF7 gene. RESULTS: The most significant association was observed at rs12905203 (P = 5.9 × 10- 3, odd ratio, OR = 1.516) that explains associations of previously reported variants at the FGF7 locus. Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-qPCR) assays showed that the risk allele of the variant was bound to activator protein 1 transcription factors (c-Fos and c-Jun) with a significantly reduced affinity and associated with decreased mRNA expression of FGF7 in fibroblast cells at both resting and PMA/Ionomycin-stimulated conditions. Overexpression of c-Fos and c-Jun proteins or stimulation with PMA/Ionomycin significantly increases mRNA expression of FGF7 in fibroblast cells. Bioinformatic analysis showed that the variant overlaps with multiple genetic regulatory marks, suggesting the regulatory DNA element might function as an enhancer for the FGF7 gene. Luciferase enhancer activity assays demonstrated that the DNA sequences carrying the variant produce enhancer activity while the risk allele of the variant reduces its activity. CONCLUSIONS: In this study, we demonstrated a consistent association of the FGF7 gene with COPD and mechanistically characterized a candidate functional variant upstream of the FGF7 gene. These data highlighted the important role of the risk variant and the FGF7 gene in influencing risk for COPD.


Assuntos
Fator 7 de Crescimento de Fibroblastos/genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único , Doença Pulmonar Obstrutiva Crônica/genética , Fator de Transcrição AP-1/metabolismo , Idoso , Estudos de Casos e Controles , China/etnologia , Feminino , Fator 7 de Crescimento de Fibroblastos/metabolismo , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Ligação Proteica , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Doença Pulmonar Obstrutiva Crônica/etnologia , Doença Pulmonar Obstrutiva Crônica/metabolismo
20.
Rev Invest Clin ; 71(1): 36-54, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30810540

RESUMO

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality in developed countries. Although cigarette smoking is the major risk factor, only 10-20% of smokers develop COPD. The extent of cigarette smoking (pack-years and smoking duration) accounts for only 15% of the variation in lung function, indicating that differences in susceptibility to COPD must exist. We provide an overview of the complexity of nicotine addiction and COPD, with special attention to the involvement of genetic factors. The following aspects are discussed in the present article: (1) epidemiology in Mexico and (2) a review of the published literature on genetic association studies using the National Center for Biotechnology Information database of the United States as a search tool. COPD is unique among complex genetic diseases where an environmental risk factor is known and the level of exposure can be documented with some precision. The high morbidity and mortality associated with COPD and its chronic and progressive nature has prompted the use of molecular genetic studies to identify susceptibility factors for the disease. Biomedical research has a remarkable set of tools to aid in the discovery of genes and polymorphisms. We present a review of the most relevant genetic associations in nicotine addiction and COPD.


Assuntos
Predisposição Genética para Doença , Doença Pulmonar Obstrutiva Crônica/genética , Tabagismo/genética , Progressão da Doença , Humanos , México/epidemiologia , Nicotina/administração & dosagem , Nicotina/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/etiologia , Fatores de Risco , Fumar/efeitos adversos , Fumar/epidemiologia , Fumar/genética , Tabagismo/complicações , Tabagismo/epidemiologia
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