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1.
Thorax ; 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31484786

RESUMO

INTRODUCTION: Chronic non-invasive ventilation (NIV) has become evidence-based care for stable hypercapnic COPD patients. While the number of patients increases, home initiation of NIV would greatly alleviate the healthcare burden. We hypothesise that home initiation of NIV with the use of telemedicine in stable hypercapnic COPD is non-inferior to in-hospital NIV initiation. METHODS: Sixty-seven stable hypercapnic COPD patients were randomised to initiation of NIV in the hospital or at home using telemedicine. Primary outcome was daytime arterial carbon dioxide pressure (PaCO2) reduction after 6 months NIV, with a non-inferiority margin of 0.4 kPa. Secondary outcomes were health-related quality of life (HRQoL) and costs. RESULTS: Home NIV initiation was non-inferior to in-hospital initiation (adjusted mean difference in PaCO2 change home vs in-hospital: 0.04 kPa (95% CI -0.31 to 0.38 kPa), with both groups showing a PaCO2 reduction at 6 months compared with baseline (home: from 7.3±0.9 to 6.4±0.8 kPa (p<0.001) and in-hospital: from 7.4±1.0 to 6.4±0.6 kPa (p<0.001)). In both groups, HRQoL improved without a difference in change between groups (Clinical COPD Questionnaire total score-adjusted mean difference 0.0 (95% CI -0.4 to 0.5)). Furthermore, home NIV initiation was significantly cheaper (home: median €3768 (IQR €3546-€4163) vs in-hospital: median €8537 (IQR €7540-€9175); p<0.001). DISCUSSION: This is the first study showing that home initiation of chronic NIV in stable hypercapnic COPD patients, with the use of telemedicine, is non-inferior to in-hospital initiation, safe and reduces costs by over 50%. TRIAL REGISTRATION NUMBER: NCT02652559.

2.
Clin Exp Allergy ; 49(10): 1352-1361, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31336400

RESUMO

BACKGROUND: Pet and dampness or mould exposure are considered risk factors for asthma and sensitization. It is unclear whether timing of exposure to these factors is differentially associated with asthma risk and sensitization in adolescence. OBJECTIVE: We investigated the role of timing of pet and dampness or mould exposure in asthma and sensitization in adolescence. Understanding this role is essential to build targeted prevention strategies. METHODS: We used data from 1871 participants of the Dutch Prevention and Incidence of Asthma and Mite Allergy (PIAMA) cohort. Residential exposure to pets, dampness or mould was assessed by repeated parental questionnaires. We used asthma data from the 17-year questionnaire and sensitization data from the 16-year medical examination. We characterized timing using longitudinal exposure patterns from pregnancy till age 17 using longitudinal latent class growth modelling. We used logistic regression models to analyse associations of exposure patterns with asthma at age 17 and sensitization at age 16. RESULTS: For none of the time windows, exposure to pets and dampness or mould was associated with asthma at age 17, but a lower sensitization risk at age 16 was suggested, for example the odds ratio (95% confidence interval) for sensitization was 0.63 (0.35-1.11) and 0.69 (0.44-1.08) for early life and persistently high pet exposure, respectively, compared with very low exposure. An inverse association was also suggested for sensitization and moderate early childhood dampness or mould exposure (0.71 [0.42-1.19]). CONCLUSION AND CLINICAL RELEVANCE: Different timing of pet and dampness or mould exposure was not associated with asthma, but lower risk of sensitization in adolescence was suggested, which could be partly attributable to reversed causation. Current findings are not sufficient to recommend pet avoidance to prevent allergic disease. More prospective studies are needed to obtain insights that can be used in clinical practice.

3.
Hum Mol Genet ; 2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-31152171

RESUMO

Many workers are daily exposed to occupational agents like gases/fumes, mineral dust or biological dust, which could induce adverse health effects. Epigenetic mechanisms, such as DNA methylation, have been suggested to play a role. We therefore aimed to identify differentially methylated regions (DMRs) upon occupational exposures in never-smokers and investigated if these DMRs associated with gene expression levels. To determine the effects of occupational exposures independent of smoking, 903 never-smokers of the LifeLines cohort study were included. We performed three genome-wide methylation analyses (Illumina 450 K), one per occupational exposure being gases/fumes, mineral dust and biological dust, using robust linear regression adjusted for appropriate confounders. DMRs were identified using comb-p in Python. Results were validated in the Rotterdam Study (233 never-smokers) and methylation-expression associations were assessed using Biobank-based Integrative Omics Study data (n = 2802). Of the total 21 significant DMRs, 14 DMRs were associated with gases/fumes and 7 with mineral dust. Three of these DMRs were associated with both exposures (RPLP1 and LINC02169 (2×)) and 11 DMRs were located within transcript start sites of gene expression regulating genes. We replicated two DMRs with gases/fumes (VTRNA2-1 and GNAS) and one with mineral dust (CCDC144NL). In addition, nine gases/fumes DMRs and six mineral dust DMRs significantly associated with gene expression levels. Our data suggest that occupational exposures may induce differential methylation of gene expression regulating genes and thereby may induce adverse health effects. Given the millions of workers that are exposed daily to occupational exposures, further studies on this epigenetic mechanism and health outcomes are warranted.

6.
Environ Health ; 18(1): 39, 2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-31023382

RESUMO

BACKGROUND: Spirometric lung function measurements have been proven to be excellent objective markers of respiratory morbidity. The use of different types of spirometers in epidemiological and clinical studies may present systematically different results affecting interpretation and implication of results. We aimed to explore considerations in the use of different spirometers in epidemiological studies by comparing forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) measurements between the Masterscreen pneumotachograph and EasyOne spirometers. We also provide a correction equation for correcting systematic differences using regression calibration. METHODS: Forty-nine volunteers had lung function measured on two different spirometers in random order with at least three attempts on each spirometer. Data were analysed using correlation plots, Bland and Altman plots and formal paired t-tests. We used regression calibration to provide a correction equation. RESULTS: The mean (SD) FEV1 and FVC was 3.78 (0.63) L and 4.78 (0.63) L for the Masterscreen pneumotachograph and 3.54 (0.60) L and 4.41 (0.83) L for the EasyOne spirometer. The mean FEV1 difference of 0.24 L and mean FVC difference of 0.37 L between the spirometers (corresponding to 6.3 and 8.4% difference, respectively) were statistically significant and consistent between younger (< 30 years) and older volunteers (> 30 years) and between males and females. Regression calibration indicated that an increase of 1 L in the EasyOne measurements corresponded to an average increase of 1.032 L in FEV1 and 1.005 L in FVC in the Masterscreen measurements. CONCLUSION: Use of different types of spirometers may result in significant systematic differences in lung function values. Epidemiological researchers need to be aware of these potential systematic differences and correct for them in analyses using methods such as regression calibration.

7.
J Expo Sci Environ Epidemiol ; 29(4): 539-547, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31028280

RESUMO

OBJECTIVES: We aimed to investigate the role of genetics in the respiratory response of asthmatic children to air pollution, with a genome-wide level analysis of gene by nitrogen dioxide (NO2) and carbon monoxide (CO) interaction on lung function and to identify biological pathways involved. METHODS: We used a two-step method for fast linear mixed model computations for genome-wide association studies, exploring whether variants modify the longitudinal relationship between 4-month average pollution and post-bronchodilator FEV1 in 522 Caucasian and 88 African-American asthmatic children. Top hits were confirmed with classic linear mixed-effect models. We used the improved gene set enrichment analysis for GWAS (i-GSEA4GWAS) to identify plausible pathways. RESULTS: Two SNPs near the EPHA3 (rs13090972 and rs958144) and one in TXNDC8 (rs7041938) showed significant interactions with NO2 in Caucasians but we did not replicate this locus in African-Americans. SNP-CO interactions did not reach genome-wide significance. The i-GSEA4GWAS showed a pathway linked to the HO-1/CO system to be associated with CO-related FEV1 changes. For NO2-related FEV1 responses, we identified pathways involved in cellular adhesion, oxidative stress, inflammation, and metabolic responses. CONCLUSION: The host lung function response to long-term exposure to pollution is linked to genes involved in cellular adhesion, oxidative stress, inflammatory, and metabolic pathways.

8.
Am J Hum Genet ; 104(4): 665-684, 2019 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-30929738

RESUMO

The extent to which genetic risk factors are shared between childhood-onset (COA) and adult-onset (AOA) asthma has not been estimated. On the basis of data from the UK Biobank study (n = 447,628), we found that the variance in disease liability explained by common variants is higher for COA (onset at ages between 0 and 19 years; h2g = 25.6%) than for AOA (onset at ages between 20 and 60 years; h2g = 10.6%). The genetic correlation (rg) between COA and AOA was 0.67. Variation in age of onset among COA-affected individuals had a low heritability (h2g = 5%), which we confirmed in independent studies and also among AOA-affected individuals. To identify subtype-specific genetic associations, we performed a genome-wide association study (GWAS) in the UK Biobank for COA (13,962 affected individuals) and a separate GWAS for AOA (26,582 affected individuals) by using a common set of 300,671 controls for both studies. We identified 123 independent associations for COA and 56 for AOA (37 overlapped); of these, 98 and 34, respectively, were reproducible in an independent study (n = 262,767). Collectively, 28 associations were not previously reported. For 96 COA-associated variants, including five variants that represent COA-specific risk factors, the risk allele was more common in COA- than in AOA-affected individuals. Conversely, we identified three variants that are stronger risk factors for AOA. Variants associated with obesity and smoking had a stronger contribution to the risk of AOA than to the risk of COA. Lastly, we identified 109 likely target genes of the associated variants, primarily on the basis of correlated expression quantitative trait loci (up to n = 31,684). GWAS informed by age of onset can identify subtype-specific risk variants, which can help us understand differences in pathophysiology between COA and AOA and so can be informative for drug development.

9.
Environ Int ; 128: 63-69, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31029980

RESUMO

BACKGROUND: It has been suggested that adults who use cleaning agents in their homes have a higher risk of asthma and allergic symptoms. The associations of asthma and allergic symptoms with household use of cleaning agents in adolescents have not been investigated yet. OBJECTIVES: To examine the associations of household cleaning agents use with the prevalence of asthma, rhinitis and eczema in adolescents. METHODS: In this cross-sectional analysis, we included participants of the PIAMA birth cohort study with data on household use of 10 types of cleaning agents and information on asthma, rhinitis and/or eczema from parent-completed questionnaires at age 14 (N = 2333). For the cleaning agents, we developed a composite score ranging from 0 (no exposure) to 30 points (household use on 4-7 days per week for all 10 types of cleaning agents). Logistic regression was used to analyse associations between household cleaning agents use (composite score and specific cleaning agents) and outcomes, adjusting for potential confounders. RESULTS: Seven, 13 and 11% of the participants had asthma, rhinitis and eczema, respectively, at age 14. The composite score for household use of cleaning agents was not associated with asthma, rhinitis and eczema. For instance, adjusted odds ratios (95% confidence interval) for the prevalence of asthma, rhinitis and eczema comparing those with the highest use of cleaning agents (≥10 points) to those with never/seldom use (0-4 points) were 0.95 (0.56, 1.63), 1.23 (0.82, 1.82) and 0.95 (0.56, 1.63), respectively. For individual cleaning agents, we only found the use of ammonia to be significantly associated with a lower risk of rhinitis [0.60, (0.44, 0.82)]. CONCLUSIONS: There was no indication of an increased prevalence of asthma, rhinitis or eczema among adolescents living in households within the highest category of cleaning agents use.

10.
Sci Rep ; 9(1): 5735, 2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30952902

RESUMO

Short-term exposure to air pollution has been associated with cardiovascular and respiratory mortality and morbidity. Little is known about associations between air pollution caused by firework events and daily mortality. We investigated whether particulate matter from fireworks during New Year's celebrations was associated with daily mortality. We analyzed the celebrations of the years 1995-2012. PM10 concentrations increased dramatically during the firework events. Countrywide, the daily average PM10 concentrations from 27-30 December was 29 µg/m3 and increased during the first hour of the New Year by 277 µg/m3. In the more densely populated areas of the Netherlands the increase was even steeper, 598 µg/m3 in the first hour of the New Year. No consistent associations were found using linear regression models between PM10 concentrations during the first six hours of 1 January and daily mortality in the general population. Yet, using a case-crossover analysis firework-days and PM10 concentrations were associated with daily mortality. Therefore, in light of the contradictory results obtained with the different statistical analyses, we recommend further epidemiological research on the health effects of exposure to firework emissions.

11.
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
13.
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
14.
BMC Pulm Med ; 19(1): 23, 2019 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-30691429

RESUMO

BACKGROUND: Bronchial provocation is often used to confirm asthma. Dyspnea sensation, however, associates poorly with the evoked drop in FEV1. Provocation tests only use the large airways parameter FEV1, although dyspnea is associated with both large- and small airways dysfunction. Aim of this study was to explore if adenosine 5'-monophosphate (AMP) and adenosine evoke an equal dyspnea sensation and if dyspnea associates better with large or small airways dysfunction. METHODS: We targeted large airways with AMP and small airways with dry powder adenosine in 59 asthmatic (ex)-smokers with ≥5 packyears, 14 ± 7 days apart. All subjects performed spirometry, impulse oscillometry (IOS), and Borg dyspnea score. In 36 subjects multiple breath nitrogen washout (MBNW) was additionally performed. We analyzed the association of the change (Δ) in Borg score with the change in large and small airways parameters, using univariate and multivariate linear regression analyses. MBNW was analyzed separately. RESULTS: Provocation with AMP and adenosine evoked similar levels of dyspnea. ΔFEV1 was not significantly associated with ΔBorg after either AMP or adenosine provocation, in both univariate and multivariate analyses. In multivariate linear regression, a decrease in FEF25-75 during adenosine provocation was independently associated with an increase in Borg. In the multivariate analyses for AMP provocation, no significant associations were found between ΔBorg and any large or small airways parameters. CONCLUSION: AMP and adenosine induce equally severe dyspnea sensations. Our results suggest that dyspnea induced with dry powder adenosine is related to small airways involvement, while neither large nor small airways dysfunction was associated with AMP-induced dyspnea. TRAIL REGISTRATION: NCT01741285 at www.clinicaltrials.gov , first registered Dec 4th, 2012.


Assuntos
Asma/fisiopatologia , Brônquios/efeitos dos fármacos , Broncoconstritores , Dispneia/fisiopatologia , Adenosina , Monofosfato de Adenosina , Adulto , Testes de Provocação Brônquica , Dispneia/etiologia , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Espirometria
15.
Lancet Respir Med ; 7(4): 336-346, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30584054

RESUMO

BACKGROUND: Epigenetic mechanisms could alter the airway epithelial barrier and ultimately lead to atopic diseases such as asthma. We aimed to identify DNA methylation profiles that are associated with-and could accurately classify-atopy and atopic asthma in school-aged children. METHODS: We did a genome-wide study of DNA methylation in nasal epithelium and atopy or atopic asthma in 483 Puerto Rican children aged 9-20 years, recruited using multistage probability sampling. Atopy was defined as at least one positive IgE (≥0·35 IU/mL) to common aeroallergens, and asthma was defined as a physician's diagnosis plus wheeze in the previous year. Significant (false discovery rate p<0·01) methylation signals were correlated with gene expression, and top CpGs were validated by pyrosequencing. We then replicated our top methylation findings in a cohort of 72 predominantly African American children, and in 432 children from a European birth cohort. Next, we tested classification models based on nasal methylation for atopy or atopic asthma in all cohorts. FINDINGS: DNA methylation profiles were markedly different between children with (n=312) and without (n=171) atopy in the Puerto Rico discovery cohort, recruited from Feb 12, 2014, until May 8, 2017. After adjustment for covariates and multiple testing, we found 8664 differentially methylated CpGs by atopy, with false discovery rate-adjusted p values ranging from 9·58 × 10-17 to 2·18 × 10-22 for the top 30 CpGs. These CpGs were in or near genes relevant to epithelial barrier function, including CDHR3 and CDH26, and in other genes related to airway epithelial integrity and immune regulation, such as FBXL7, NTRK1, and SLC9A3. Moreover, 28 of the top 30 CpGs replicated in the same direction in both independent cohorts. Classification models of atopy based on nasal methylation performed well in the Puerto Rico cohort (area under the curve [AUC] 0·93-0·94 and accuracy 85-88%) and in both replication cohorts (AUC 0·74-0·92, accuracy 68-82%). The models also performed well for atopic asthma in the Puerto Rico cohort (AUC 0·95-1·00, accuracy 88%) and the replication cohorts (AUC 0·82-0·88, accuracy 86%). INTERPRETATION: We identified specific methylation profiles in airway epithelium that are associated with atopy and atopic asthma in children, and a nasal methylation panel that could classify children by atopy or atopic asthma. Our findings support the feasibility of using the nasal methylome for future clinical applications, such as predicting the development of asthma among wheezing infants. FUNDING: US National Institutes of Health.

16.
J Allergy Clin Immunol ; 143(6): 2062-2074, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30579849

RESUMO

BACKGROUND: Epigenetic mechanisms, including methylation, can contribute to childhood asthma. Identifying DNA methylation profiles in asthmatic patients can inform disease pathogenesis. OBJECTIVE: We sought to identify differential DNA methylation in newborns and children related to childhood asthma. METHODS: Within the Pregnancy And Childhood Epigenetics consortium, we performed epigenome-wide meta-analyses of school-age asthma in relation to CpG methylation (Illumina450K) in blood measured either in newborns, in prospective analyses, or cross-sectionally in school-aged children. We also identified differentially methylated regions. RESULTS: In newborns (8 cohorts, 668 cases), 9 CpGs (and 35 regions) were differentially methylated (epigenome-wide significance, false discovery rate < 0.05) in relation to asthma development. In a cross-sectional meta-analysis of asthma and methylation in children (9 cohorts, 631 cases), we identified 179 CpGs (false discovery rate < 0.05) and 36 differentially methylated regions. In replication studies of methylation in other tissues, most of the 179 CpGs discovered in blood replicated, despite smaller sample sizes, in studies of nasal respiratory epithelium or eosinophils. Pathway analyses highlighted enrichment for asthma-relevant immune processes and overlap in pathways enriched both in newborns and children. Gene expression correlated with methylation at most loci. Functional annotation supports a regulatory effect on gene expression at many asthma-associated CpGs. Several implicated genes are targets for approved or experimental drugs, including IL5RA and KCNH2. CONCLUSION: Novel loci differentially methylated in newborns represent potential biomarkers of risk of asthma by school age. Cross-sectional associations in children can reflect both risk for and effects of disease. Asthma-related differential methylation in blood in children was substantially replicated in eosinophils and respiratory epithelium.

17.
Respir Res ; 19(1): 256, 2018 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-30563522

RESUMO

We performed a post-hoc analysis of the OLiVIA-study investigating whether current and ex-smoking asthmatics with small airways dysfunction (SAD) show a better response in airway hyperresponsiveness (AHR) to small particle adenosine after treatment with extrafine compared to non-extrafine particle inhaled corticosteroids (ICS), and to investigate which clinical parameters predict a favorable response to both treatments. We show that smoking and ex-smoking asthmatics with and without SAD have a similar treatment response with either extrafine or non-extrafine particle ICS. We also found that lower blood neutrophils are associated with a smaller ICS-response in smokers and ex-smokers with asthma, independent from the level of blood eosinophils.


Assuntos
Corticosteroides/administração & dosagem , Antiasmáticos/administração & dosagem , Asma/tratamento farmacológico , Ex-Fumantes , Tamanho da Partícula , Fumantes , Fumar/tratamento farmacológico , Administração por Inalação , Adulto , Remodelação das Vias Aéreas/efeitos dos fármacos , Remodelação das Vias Aéreas/fisiologia , Asma/sangue , Asma/diagnóstico , Eosinófilos/efeitos dos fármacos , Eosinófilos/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Fumar/sangue , Resultado do Tratamento
18.
Environ Int ; 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30449631

RESUMO

Respiratory symptoms are important indicators of respiratory diseases. Both genetic and environmental factors contribute to respiratory symptoms development but less is known about gene-environment interactions. We aimed to assess interactions between single nucleotide polymorphisms (SNPs) and occupational exposures on respiratory symptoms cough, dyspnea and phlegm. As identification cohort LifeLines I (n = 7976 subjects) was used. Job-specific exposure was estimated using the ALOHA + job exposure matrix. SNP-by-occupational exposure interactions on respiratory symptoms were tested using logistic regression adjusted for gender, age, and current smoking. SNP-by-exposure interactions with a p-value <10-4 were tested for replication in two independent cohorts: LifeLines II (n = 5260) and the Vlagtwedde-Vlaardingen cohort (n = 1529). The interaction estimates of the replication cohorts were meta-analyzed using PLINK. Replication was achieved when the meta-analysis p-value was <0.05 and the interaction effect had the same direction as in the identification cohort. Additionally, we assessed whether replicated SNPs associated with gene expression by analyzing if they were cis-acting expression quantitative trait loci (eQTL) in lung tissue. In the replication meta-analysis, sixteen out of 477 identified SNP-by-occupational exposure interactions had a p-value <0.05 and 9 of these interactions had the same direction as in the identification cohort. Several identified loci were plausible candidates for respiratory symptoms, such as TMPRSS9, SERPINH1, TOX3, and ARHGAP18. Three replicated SNPs were cis-eQTLs for FCER1A, CHN1, and TIMM13 in lung tissue. Taken together, this genome-wide SNP-by-occupational exposure interaction study in relation to cough, dyspnea, and phlegm identified several suggestive susceptibility genes. Further research should determine if these genes are true susceptibility loci for respiratory symptoms in relation to occupational exposures.

19.
Respir Res ; 19(1): 212, 2018 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-30390659

RESUMO

BACKGROUND: Genetic and environmental factors play a role in the development of COPD. The epigenome, and more specifically DNA methylation, is recognized as important link between these factors. We postulate that DNA methylation is one of the routes by which cigarette smoke influences the development of COPD. In this study, we aim to identify CpG-sites that are associated with cigarette smoke exposure and lung function levels in whole blood and validate these CpG-sites in lung tissue. METHODS: The association between pack years and DNA methylation was studied genome-wide in 658 current smokers with >5 pack years using robust linear regression analysis. Using mediation analysis, we subsequently selected the CpG-sites that were also associated with lung function levels. Significant CpG-sites were validated in lung tissue with pyrosequencing and expression quantitative trait methylation (eQTM) analysis was performed to investigate the association between DNA methylation and gene expression. RESULTS: 15 CpG-sites were significantly associated with pack years and 10 of these were additionally associated with lung function levels. We validated 5 CpG-sites in lung tissue and found several associations between DNA methylation and gene expression. CONCLUSION: This study is the first to validate a panel of CpG-sites that are associated with cigarette smoking and lung function levels in whole blood in the tissue of interest: lung tissue.

20.
Int J Chron Obstruct Pulmon Dis ; 13: 3625-3634, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30464445

RESUMO

Purpose: It has recently been shown that chronic noninvasive ventilation (NIV) improves a number of outcomes including survival, in patients with stable hypercapnic COPD. However, the mechanisms responsible for these improved outcomes are still unknown. The aim of the present study was to identify parameters associated with: 1) an improved arterial partial pressure of carbon dioxide (PaCO2) and 2) survival, in a cohort of hypercapnic COPD patients treated with chronic NIV. Patients and methods: Data from 240 COPD patients treated with chronic NIV were analyzed. Predictors for the change in PaCO2 and survival were investigated using multivariate linear and Cox regression models, respectively. Results: A higher level of bicarbonate before NIV initiation, the use of higher inspiratory ventilator pressures, the presence of anxiety symptoms, and NIV initiated following an exacerbation compared to NIV initiated in stable disease were associated with a larger reduction in PaCO2. A higher body mass index, a higher FEV1, a lower bicarbonate before NIV initiation, and younger age and NIV initiation in stable condition were independently associated with better survival. The change in PaCO2 was not associated with survival, neither in a subgroup of patients with a PaCO2 >7.0 kPa before the initiation of NIV. Conclusion: Patients with anxiety symptoms and a high bicarbonate level at NIV initiation are potentially good responders in terms of an improvement in hypercapnia. Also, higher inspiratory ventilator pressures are associated with a larger reduction in PaCO2. However, the improvement in hypercapnia does not seem to be associated with an improved survival and emphasizes the need to look beyond PaCO2 when considering NIV initiation.

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