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1.
PLoS Genet ; 16(10): e1008718, 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33045005

RESUMO

The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood.

2.
Respir Med ; 171: 106064, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32917359

RESUMO

INTRODUCTION: Most guidelines recommend long-acting bronchodilators over short-acting bronchodilators for patients with chronic obstructive pulmonary disease (COPD). The available evidence for the guidelines was based on dry powder or pressurized metered dose inhalers, but not nebulizations. Nevertheless, there is considerable, poorly evidenced based, use of short acting nebulized bronchodilators. METHODS: This was an investigator initiated, randomized, active controlled, cross-over, double-blind and double-dummy single centre study in patients with stable COPD. The active comparators were indacaterol/glycopyrronium 110/50 µg as Ultibro® via Breezhaler® (IND/GLY) and salbutamol/ipratropium 2,5/0,5 mg via air driven nebulization (SAL/IPR), both given as a single dose on separate days. The primary end point was the area under the FEV1 curve from baseline till 6 h. Secondary end points included change in Borg dyspnoea score, adverse events and change in hyperinflation measured by the inspiratory capacity. RESULTS: A total of 33 COPD patients completed the trial and were evaluable, most of them were ex-smokers. The difference between the tested regimens for the primary endpoint, FEV1 AUC 0-6 h, 2965 ± 1544 mL (mean ± SD) for IND/GLY versus 3513 ± 1762 mL for SAL/IPR, was not significant (P = 0.08). The peak in FEV1 was higher and was reached faster with SAL/IPR compared to IND/GLY. No other significant differences were detected for the secondary endpoints including the Borg score, or adverse events. CONCLUSION: Among patients with stable COPD, dry powder long-acting single inhalation of a LABA and a LAMA (IND/GLY) was not superior compared to nebulized short-acting salbutamol plus ipratropium (SAL/IPR) in its bronchodilating effects over 6 h.The effects of the nebulization kicked in faster and peaked higher. The observed differences may be caused by the difference in dosing between the two regimens. The improvement in Borg dyspnoea score did not favour the nebulization. Long-term outcomes were not assessed in this study.

3.
Artigo em Inglês | MEDLINE | ID: mdl-32926877

RESUMO

BACKGROUND: Whether long-term exposure air to pollution has effects on allergic sensitization is controversial. OBJECTIVE: Our aim was to investigate associations of air pollution exposure at birth and at the time of later biosampling with IgE sensitization against common food and inhalant allergens, or specific allergen molecules, in children aged up to 16 years. METHODS: A total of 6163 children from 4 European birth cohorts participating in the Mechanisms of the Development of ALLergy [MeDALL] consortium were included in this meta-analysis of the following studies: Children, Allergy, Milieu, Stockholm, Epidemiology (BAMSE) (Sweden), Influences of Lifestyle-Related Factors on the Human Immune System and Development of Allergies in Childhood (LISA)/German Infant Study on the Influence of Nutrition Intervention PLUS Environmental and Genetic Influences on Allergy Development (GINIplus) (Germany), and Prevention and Incidence of Asthma and Mite Allergy (PIAMA) (The Netherlands). The following indicators were modeled by land use regression: individual residential outdoor levels of particulate matter with aerodynamic diameters less than 2.5 µm, less than 10 µm, and between 2.5 and 10 µm; PM2.5 absorbance (a measurement of the blackness of PM2.5 filters); and nitrogen oxides levels. Blood samples drawn at ages 4 to 6 (n = 5989), 8 to 10 (n = 6603), and 15 to 16 (n = 5825) years were analyzed for IgE sensitization to allergen extracts by ImmunoCAP. Additionally, IgE against 132 allergen molecules was measured by using the MedALL microarray chip (n = 1021). RESULTS: Air pollution was not consistently associated with IgE sensitization to any common allergen extract up to age 16 years. However, allergen-specific analyses suggested increased risks of sensitization to birch (odds ratio [OR] = 1.12 [95% CI = 1.01-1.25] per 10-µg/m3 increase in NO2 exposure). In a subpopulation with microarray data, IgE to the major timothy grass allergen Phleum pratense 1 (Phl p 1) and the cat allergen Felis domesticus 1 (Fel d 1) greater than 3.5 Immuno Solid-phase Allergen Chip standardized units for detection of IgE antibodies were related to PM2.5 exposure at birth (OR = 3.33 [95% CI = 1.40-7.94] and OR = 4.98 [95% CI = 1.59-15.60], respectively, per 5-µg/m3 increase in exposure). CONCLUSION: Air pollution exposure does not seem to increase the overall risk of allergic sensitization; however, sensitization to birch as well as grass pollen Phl p 1 and cat Fel d 1 allergen molecules may be related to specific pollutants.

4.
Ann Am Thorac Soc ; 2020 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32795190

RESUMO

RATIONALE: The association between airborne occupational exposures and lung function level is inconsistent in the general population. Moreover, little is known about the association between occupational exposures and annual lung function decline. OBJECTIVES: We investigated the association between occupational exposures and lung function level and annual lung function decline in the population-based Lifelines cohort study. METHODS: We included 55,631 adults with baseline spirometry and reliable job code-13,759 of these subjects were aged ≥ 30 years and underwent spirometry again after 4.5 years of follow-up. Occupational exposures in the current or last-held job at baseline were estimated with the ALOHA+ job-exposure matrix. Linear regression analyses adjusted for covariates were used to test the association between each occupational exposure-biological dust, mineral dust, gases/fumes, pesticides, solvents, and metals- and lung function level and annual lung function decline. Interactions were used to test effect-modification by sex or smoking. RESULTS: Exposures to biological dust, mineral dust, gases/fumes, insecticides, fungicides, and aromatic solvents were associated with a lower lung function level at baseline. The effects were larger in males and smokers compared to females and non-smokers, respectively. However, no association between occupational exposures and the rate of annual lung function decline was found between baseline and follow-up. CONCLUSIONS: In this study, airborne occupational exposures are associated with lower lung function level but not with a faster lung function decline. These negative effects are more pronounced among males and smokers.

5.
Sci Rep ; 10(1): 12963, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737337

RESUMO

In this cross-sectional study, we investigated the association between occupational exposures and sickness absence (SA), the mediating role of respiratory symptoms, and whether genetic susceptibility to SA upon occupational exposures exists. Logistic regression was used to examine associations and structural equation modelling was used for mediation analyses. Genetic susceptibility was investigated by including interactions between occupational exposures and 11 candidate single nucleotide polymorphisms (SNPs). Biological dust, mineral dust, and pesticides exposure were associated with a lower prevalence of any SA (OR (95% CI) = 0.72 (0.58-0.89), 0.88 (0.78-0.99), and 0.70 (0.55-0.89), respectively) while gases/fumes exposure was associated with a higher prevalence of long-term SA (1.46 (1.11-1.91)). Subjects exposed to solvents and metals had a higher prevalence of any (1.14 (1.03-1.26) and 1.68 (1.26-2.24)) and long-term SA (1.26 (1.08-1.46) and 1.75 (1.15-2.67)). Chronic cough and chronic phlegm mediated the association between high gases/fumes exposure and long-term SA. Two of 11 SNPs investigated had a positive interaction with exposure on SA and one SNP negatively interacted with exposure on SA. Exposure to metals and gases/fumes showed a clear dose-response relationship with a higher prevalence of long-term SA; contrary, exposure to pesticides and biological/mineral dust showed a protective effect on any SA. Respiratory symptoms mediated the association between occupational exposures and SA. Moreover, gene-by-exposure interactions exist.

6.
Occup Environ Med ; 2020 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-32769140

RESUMO

INTRODUCTION: Inflammatory biomarkers are associated with negative health outcomes. In this study, we investigated the associations between airborne occupational exposures and levels and changes in inflammatory biomarkers. METHODS: We included 79 604 adults at baseline from the Lifelines cohort of which 48 403 (60.8%) subjects were followed for a median of 4.5 years. Airborne occupational exposures at the current or last-held job at baseline were estimated with the occupational asthma-specific job-exposure matrix. Both in cross-sectional and longitudinal analyses, we used linear regression models (adjusted for age, sex, education, monthly income, body mass index, smoking, pack-years, asthma and anti-inflammatory medication) to investigate the associations between airborne occupational exposures (allergens, reactive chemicals, pesticides and micro-organisms) and inflammatory biomarkers (C reactive protein (CRP), eosinophils and neutrophils). RESULTS: In the cross-sectional analyses, exposure to allergens, reactive chemicals and micro-organisms was associated with a lower (Log) CRP level (B(95% CI)=-0.05 (-0.08 to -0.02),-0.05(-0.08 to -0.02) and -0.09(-0.16 to -0.02), respectively). Likewise, exposure to allergens, reactive chemicals, pesticides and micro-organisms was associated with a lower (log) neutrophils count (-0.01 (-0.02 to -0.01), -0.01 (-0.02 to -0.01),-0.02 (-0.04 to -0.01) and -0.02(-0.03 to -0.01), respectively). No association between airborne occupational exposures and eosinophils count was found. In the longitudinal analyses, no association between airborne occupational exposures and changes in inflammatory biomarkers was found. CONCLUSIONS: At baseline, airborne occupational exposures are inversely associated with inflammation; no effect of occupational exposures on inflammation was found at follow-up. In the future studies, details of occupational exposures, such as duration of exposures and cumulative exposures, need to be included to investigate the airborne occupational exposures and inflammatory biomarkers.

7.
BMC Pulm Med ; 20(1): 193, 2020 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-32677943

RESUMO

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common lung disorder characterized by persistent and progressive airflow limitation as well as systemic changes. Metabolic changes in blood may help detect COPD in an earlier stage and predict prognosis. METHODS: We conducted a comprehensive study of circulating metabolites, measured by proton Nuclear Magnetic Resonance Spectroscopy, in relation with COPD and lung function. The discovery sample consisted of 5557 individuals from two large population-based studies in the Netherlands, the Rotterdam Study and the Erasmus Rucphen Family study. Significant findings were replicated in 12,205 individuals from the Lifelines-DEEP study, FINRISK and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) studies. For replicated metabolites further investigation of causality was performed, utilizing genetics in the Mendelian randomization approach. RESULTS: There were 602 cases of COPD and 4955 controls used in the discovery meta-analysis. Our logistic regression results showed that higher levels of plasma Glycoprotein acetyls (GlycA) are significantly associated with COPD (OR = 1.16, P = 5.6 × 10- 4 in the discovery and OR = 1.30, P = 1.8 × 10- 6 in the replication sample). A bi-directional two-sample Mendelian randomization analysis suggested that circulating blood GlycA is not causally related to COPD, but that COPD causally increases GlycA levels. Using the prospective data of the same sample of Rotterdam Study in Cox-regression, we show that the circulating GlycA level is a predictive biomarker of COPD incidence (HR = 1.99, 95%CI 1.52-2.60, comparing those in the highest and lowest quartile of GlycA) but is not significantly associated with mortality in COPD patients (HR = 1.07, 95%CI 0.94-1.20). CONCLUSIONS: Our study shows that circulating blood GlycA is a biomarker of early COPD pathology.

8.
PLoS Genet ; 16(6): e1008725, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32603359

RESUMO

Risk factors that contribute to inter-individual differences in the age-of-onset of allergic diseases are poorly understood. The aim of this study was to identify genetic risk variants associated with the age at which symptoms of allergic disease first develop, considering information from asthma, hay fever and eczema. Self-reported age-of-onset information was available for 117,130 genotyped individuals of European ancestry from the UK Biobank study. For each individual, we identified the earliest age at which asthma, hay fever and/or eczema was first diagnosed and performed a genome-wide association study (GWAS) of this combined age-of-onset phenotype. We identified 50 variants with a significant independent association (P<3x10-8) with age-of-onset. Forty-five variants had comparable effects on the onset of the three individual diseases and 38 were also associated with allergic disease case-control status in an independent study (n = 222,484). We observed a strong negative genetic correlation between age-of-onset and case-control status of allergic disease (rg = -0.63, P = 4.5x10-61), indicating that cases with early disease onset have a greater burden of allergy risk alleles than those with late disease onset. Subsequently, a multivariate GWAS of age-of-onset and case-control status identified a further 26 associations that were missed by the univariate analyses of age-of-onset or case-control status only. Collectively, of the 76 variants identified, 18 represent novel associations for allergic disease. We identified 81 likely target genes of the 76 associated variants based on information from expression quantitative trait loci (eQTL) and non-synonymous variants, of which we highlight ADAM15, FOSL2, TRIM8, BMPR2, CD200R1, PRKCQ, NOD2, SMAD4, ABCA7 and UBE2L3. Our results support the notion that early and late onset allergic disease have partly distinct genetic architectures, potentially explaining known differences in pathophysiology between individuals.


Assuntos
Asma/genética , Eczema/genética , Polimorfismo de Nucleotídeo Único , Rinite Alérgica Sazonal/genética , Adolescente , Adulto , Idade de Início , Idoso , Asma/patologia , Criança , Eczema/patologia , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Rinite Alérgica Sazonal/patologia
9.
Clin Exp Allergy ; 50(9): 1055-1064, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32640057

RESUMO

BACKGROUND: House dust endotoxin may have beneficial effects on allergic sensitization and asthma in children. Evidence is scarce for adolescents and most studies so far have been cross-sectional and limited to a single exposure measurement. OBJECTIVE: We assessed associations of house dust endotoxin with asthma and allergic sensitization from birth to age 17 years longitudinally taking into account exposure early in life and at primary school age. METHODS: We used data of 854 participants of the prospective Dutch PIAMA birth cohort study with house dust endotoxin measurements at 3 months and/or 5-6 years and data on asthma and/or allergic sensitization from at least one of 11 follow-ups until age 17. We assessed overall and age-specific associations of the prevalence of asthma and sensitization with mattress and living room floor dust concentrations (per gram of dust) and loads (per m2 of sampling surface). RESULTS: Higher living room floor dust endotoxin concentrations at 3 months were associated with lower odds of asthma until age 4 [odds ratio (95% confidence interval) ranging from 0.70 (0.51-0.97) at age 1 to 0.76 (0.57-1.00) at age 3 per interquartile range increase], but not thereafter in children of allergic mothers. Higher living room floor dust endotoxin at 5-6 years was associated with higher odds of sensitization at 8-16 years [eg odds ratio (95% confidence interval) 1.70 (1.17-2.47) per interquartile range increase in endotoxin load]. CONCLUSIONS AND CLINICAL RELEVANCE: House dust endotoxin may have beneficial effects on asthma in preschool children of allergic mothers, which do not persist into adolescence. Beneficial associations with allergic sensitization could not be confirmed.

10.
PLoS One ; 15(5): e0231818, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32401757

RESUMO

BACKGROUND: It is challenging to define likely food allergy (FA) in large populations which limited the number of large studies regarding risk factors for FA. OBJECTIVE: We studied the prevalence and characteristics of self-reported FA (s-rFA) in the large, population-based Dutch Lifelines cohort and identified associated risk factors. METHODS: Likely food allergic cases (LikelyFA) were classified based on questionnaire reported characteristics consistent with FA. Subjects with atypical characteristics were classified as Indeterminate. We investigated 13 potential risk factors for LikelyFA such as birth mode and living on a farm and addressed health-related quality of life (H-RQOL). RESULTS: Of the 78, 890 subjects, 12.1% had s-rFA of which 4.0% and 8.1% were classified as LikelyFA and Indeterminate, respectively. Younger age, female sex, asthma, eczema and nasal allergy increased the risk of LikelyFA (p-value range <1.00*10-250-1.29*10-7). Living in a small city/large village or suburb during childhood was associated with a higher risk of LikelyFA than living on a farm (p-value = 7.81*10-4 and p = 4.84*10-4, respectively). Subjects classified as Indeterminate more often reported depression and burn-out compared to those without FA (p-value = 1.46*10-4 and p = 8.39*10-13, respectively). No association was found with ethnicity, (duration of) breastfeeding, birth mode and reported eating disorder. Mental and physical component scores measuring H-RQOL were lower in both those classified as LikelyFA and Indeterminate compared to those without FA. CONCLUSION: The prevalence of s-rFA among adults is considerable and one-third reports characteristics consistent with LikelyFA. Living on a farm decreased the risk of LikelyFA. The association of poorer H-RQOL as well as depression and burn-out with questionable self-perceived FA is striking and a priority for future study.


Assuntos
Hipersensibilidade Alimentar/epidemiologia , Adulto , Alérgenos , Asma/epidemiologia , Estudos de Coortes , Eczema/epidemiologia , Feminino , Alimentos , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Prevalência , Qualidade de Vida , Rinite Alérgica Sazonal/epidemiologia , Fatores de Risco , Inquéritos e Questionários
11.
Artigo em Inglês | MEDLINE | ID: mdl-32442646

RESUMO

BACKGROUND: Asthma is a complex disease with multiple phenotypes that may differ in disease pathobiology and treatment response. IL33 single nucleotide polymorphisms (SNPs) have been reproducibly associated with asthma. IL33 levels are elevated in sputum and bronchial biopsies of patients with asthma. The functional consequences of IL33 asthma SNPs remain unknown. OBJECTIVE: This study sought to determine whether IL33 SNPs associate with asthma-related phenotypes and with IL33 expression in lung or bronchial epithelium. This study investigated the effect of increased IL33 expression on human bronchial epithelial cell (HBEC) function. METHODS: Association between IL33 SNPs (Chr9: 5,815,786-6,657,983) and asthma phenotypes (Lifelines/DAG [Dutch Asthma GWAS]/GASP [Genetics of Asthma Severity & Phenotypes] cohorts) and between SNPs and expression (lung tissue, bronchial brushes, HBECs) was done using regression modeling. Lentiviral overexpression was used to study IL33 effects on HBECs. RESULTS: We found that 161 SNPs spanning the IL33 region associated with 1 or more asthma phenotypes after correction for multiple testing. We report a main independent signal tagged by rs992969 associating with blood eosinophil levels, asthma, and eosinophilic asthma. A second, independent signal tagged by rs4008366 presented modest association with eosinophilic asthma. Neither signal associated with FEV1, FEV1/forced vital capacity, atopy, and age of asthma onset. The 2 IL33 signals are expression quantitative loci in bronchial brushes and cultured HBECs, but not in lung tissue. IL33 overexpression in vitro resulted in reduced viability and reactive oxygen species-capturing of HBECs, without influencing epithelial cell count, metabolic activity, or barrier function. CONCLUSIONS: We identify IL33 as an epithelial susceptibility gene for eosinophilia and asthma, provide mechanistic insight, and implicate targeting of the IL33 pathway specifically in eosinophilic asthma.

12.
Eur Respir J ; 56(1)2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32299858

RESUMO

BACKGROUND: Air pollution is associated with asthma development in children and adults, but the impact on asthma development during the transition from adolescence to adulthood is unclear. Adult studies lack historical exposures and consequently cannot assess the relevance of exposure during different periods of life. We assessed the relevance of early-life and more recent air pollution exposure for asthma development from birth until early adulthood. METHODS: We used data of 3687 participants of the prospective Dutch PIAMA (Prevention and Incidence of Asthma and Mite Allergy) birth cohort and linked asthma incidence until age 20 years to estimated concentrations of nitrogen dioxide (NO2), particulate matter with a diameter <2.5 µm (PM2.5), <10 µm (PM10), and 2.5-10 µm, and PM2.5 absorbance ("soot") at the residential address. We assessed overall and age-specific associations with air pollution exposure with discrete time-hazard models, adjusting for potential confounders. RESULTS: Overall, we found higher incidence of asthma until the age of 20 years with higher exposure to all pollutants at the birth address (adjusted odds ratio (95% CI) ranging from 1.09 (1.01-1.18) for PM10 to 1.20 (1.10-1.32) for NO2) per interquartile range increase) that were rather persistent with age. Similar associations were observed with more recent exposure defined as exposure at the current home address. In two-pollutant models with particulate matter, associations with NO2 persisted. CONCLUSIONS: Exposure to air pollution, especially from motorised traffic, early in life may have long-term consequences for asthma development, as it is associated with an increased risk of developing asthma through childhood and adolescence into early adulthood.

13.
FASEB J ; 34(6): 7703-7717, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32277855

RESUMO

Parasympathetic neurons in the airways control bronchomotor tone. Increased activity of cholinergic neurons are mediators of airway hyperresponsiveness (AHR) in asthma, however, mechanisms are not elucidated. We describe remodeling of the cholinergic neuronal network in asthmatic airways driven by brain-derived neurotrophic factor (BDNF) and Tropomyosin receptor kinase B (TrkB). Human bronchial biopsies were stained for cholinergic marker vesicular acetylcholine transporter (VAChT). Human lung gene expression and single nucleotide polymorphisms (SNP) in neuroplasticity-related genes were compared between asthma and healthy patients. Wild-type (WT) and mutated TrkB knock-in mice (Ntrk2tm1Ddg/J) with impaired BDNF signaling were chronically exposed to ovalbumin (OVA). Neuronal VAChT staining and airway narrowing in response to electrical field stimulation in precision cut lung slices (PCLS) were assessed. Increased cholinergic fibers in asthmatic airway biopsies was found, paralleled by increased TrkB gene expression in human lung tissue, and SNPs in the NTRK2 [TrkB] and BDNF genes linked to asthma. Chronic allergen exposure in mice resulted in increased density of cholinergic nerves, which was prevented by inhibiting TrkB. Increased nerve density resulted in AHR in vivo and in increased nerve-dependent airway reactivity in lung slices mediated via TrkB. These findings show cholinergic neuroplasticity in asthma driven by TrkB signaling and suggest that the BDNF-TrkB pathway may be a potential target.

14.
JCI Insight ; 5(8)2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32324168

RESUMO

The IL1RL1 (ST2) gene locus is robustly associated with asthma; however, the contribution of single nucleotide polymorphisms (SNPs) in this locus to specific asthma subtypes and the functional mechanisms underlying these associations remain to be defined. We tested for association between IL1RL1 region SNPs and characteristics of asthma as defined by clinical and immunological measures and addressed functional effects of these genetic variants in lung tissue and airway epithelium. Utilizing 4 independent cohorts (Lifelines, Dutch Asthma GWAS [DAG], Genetics of Asthma Severity and Phenotypes [GASP], and Manchester Asthma and Allergy Study [MAAS]) and resequencing data, we identified 3 key signals associated with asthma features. Investigations in lung tissue and primary bronchial epithelial cells identified context-dependent relationships between the signals and IL1RL1 mRNA and soluble protein expression. This was also observed for asthma-associated IL1RL1 nonsynonymous coding TIR domain SNPs. Bronchial epithelial cell cultures from asthma patients, exposed to exacerbation-relevant stimulations, revealed modulatory effects for all 4 signals on IL1RL1 mRNA and/or protein expression, suggesting SNP-environment interactions. The IL1RL1 TIR signaling domain haplotype affected IL-33-driven NF-κB signaling, while not interfering with TLR signaling. In summary, we identify that IL1RL1 genetic signals potentially contribute to severe and eosinophilic phenotypes in asthma, as well as provide initial mechanistic insight, including genetic regulation of IL1RL1 isoform expression and receptor signaling.

15.
BMC Pregnancy Childbirth ; 20(1): 132, 2020 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-32106826

RESUMO

BACKGROUND: It is well known that maternal smoking during pregnancy and maternal pre-pregnancy overweight have opposite effects on the infants' birth weight. We report on the association of the combination between both risk factors and the infants' birth weight. METHODS: We studied 3241 infants born at term in the PIAMA birth cohort. Maternal smoking during pregnancy and pre-pregnancy height and weight were self-reported. Multivariable regression analysis was performed to assess the associations between infants of mothers who only smoked during pregnancy, who only had pre-pregnancy overweight and who had both risk factors simultaneously, on term birth weight and the risk of being SGA or LGA. RESULTS: Of 3241 infants, 421 infants (13%) were born to smoking, non-overweight mothers, 514 (15.8%) to non-smoking, overweight mothers, 129 (4%) to smoking and overweight mothers and 2177 (67%) to non-smoking, non-overweight mothers (reference group). Infants of mothers who smoked and also had pre-pregnancy overweight had similar term birth weight (- 26.6 g, 95%CI: - 113.0, 59.8), SGA risk (OR = 1.06, 95%CI: 0.56, 2.04), and LGA risk (OR = 1.09, 95%CI: 0.61, 1.96) as the reference group. CONCLUSIONS: Our findings suggested that the effects of maternal smoking during pregnancy and maternal pre-pregnancy overweight on infants' birth weight cancel each other out. Therefore, birth weight may not be a good indicator of an infant's health status in perinatal practice because it may mask potential health risks due to these maternal risk factors when both present together.

16.
J Allergy Clin Immunol ; 145(6): 1655-1663, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31953105

RESUMO

BACKGROUND: Epigenetic signatures in the nasal epithelium, which is a primary interface with the environment and an accessible proxy for the bronchial epithelium, might provide insights into mechanisms of allergic disease. OBJECTIVE: We aimed to identify and interpret methylation signatures in nasal epithelial brushes associated with rhinitis and asthma. METHODS: Nasal epithelial brushes were obtained from 455 children at the 16-year follow-up of the Dutch Prevention and Incidence of Asthma and Mite Allergy birth cohort study. Epigenome-wide association studies were performed on children with asthma, rhinitis, and asthma and/or rhinitis (AsRh) by using logistic regression, and the top results were replicated in 2 independent cohorts of African American and Puerto Rican children. Significant CpG sites were related to environmental exposures (pets, active and passive smoking, and molds) during secondary school and were correlated with gene expression by RNA-sequencing (n = 244). RESULTS: The epigenome-wide association studies identified CpG sites significantly associated with rhinitis (n = 81) and AsRh (n = 75), but not with asthma. We significantly replicated 62 of 81 CpG sites with rhinitis and 60 of 75 with AsRh, as well as 1 CpG site with asthma. Methylation of cg03565274 was negatively associated with AsRh and positively associated with exposure to pets during secondary school. DNA methylation signals associated with AsRh were mainly driven by specific IgE-positive subjects. DNA methylation related to gene transcripts that were enriched for immune pathways and expressed in immune and epithelial cells. Nasal CpG sites performed well in predicting AsRh. CONCLUSIONS: We identified replicable DNA methylation profiles of asthma and rhinitis in nasal brushes. Exposure to pets may affect nasal epithelial methylation in relation to asthma and rhinitis.

17.
J Cancer Surviv ; 14(3): 377-385, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31933151

RESUMO

PURPOSE: To compare the differences in lifestyle behaviours between cancer survivors (CSs) and cancer-free participants in a large and representative population-based cohort. METHODS: We included 115,257 adults from the Lifelines cohort. Cancer status was self-reported, and health behaviours were measured (e.g. body mass index [BMI]) or assessed by questionnaire (e.g. physical activity, smoking, alcohol consumption, sedentary behaviour and diet). The data were then categorised for logistic regression analysis, stratified and adjusted by sex and age (< 55 vs ≥ 55 years). RESULTS: CSs (5473; 4.7%) were diagnosed 9 ± 8.5 years before data collection, were older (mean age 55.4 vs 44.4 years) and more often female (66.6% vs 33.4%) than the cancer-free participants. They were also more likely to be physically active and to have a better diet, and also less likely to be alcohol drinkers; but, were more likely to have a higher BMI, be former smokers and to be sedentary. After adjustment for sex and age, however, BMI was more likely to be normal, physical activity was more likely to be higher and smoking to be prevalent in CSs. Current smoking was also significantly higher among females and those aged < 55 years who were CSs than for those with no history of cancer. CONCLUSIONS: In this population-based cohort, CSs have health behaviour comparable to those without a cancer diagnosis. IMPLICATIONS FOR CANCER SURVIVORS: Smoking cessation strategies should target all CSs, but efforts could yield greatest benefit if they target females and those younger than 55 years.

18.
Thorax ; 75(3): 244-252, 2020 Mar.
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.

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