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1.
Artigo em Inglês | MEDLINE | ID: mdl-31707051

RESUMO

BACKGROUND: 15% of atopic dermatitis liability-scale heritability could be attributed to 31 susceptibility loci identified by genome-wide association studies, with only three of them (IL13, IL6R, and FLG) resolved to protein-coding variants. OBJECTIVE: We examined whether a significant portion of unexplained atopic dermatitis heritability is further explained by low-frequency and rare variants in gene coding sequence. METHODS: We evaluated common, low-frequency and rare protein-coding variants using exome chip and replication genotype data of 15,574 patients and 377,839 controls, combined with whole transcriptome data on lesional, non-lesional and healthy skin samples of 27 patients and 38 controls. RESULTS: Additional 12.56% (s.e. 0.74%) of atopic dermatitis heritability is explained by rare protein-coding variation. We identified Docking protein 2 (DOK2) and CD200 Receptor 1 (CD200R1) as novel genome-wide significant susceptibility genes. Rare coding variants associated with atopic dermatitis are further enriched in five genes (IL4R, IL13, JAK1, JAK2, TYK2) of the IL13 pathway, all of which are targets for novel systemic atopic dermatitis therapeutics. Multiomics-based network and RNA-Sequencing analysis revealed DOK2 as a central hub interacting, among others, with CD200R1, IL6R and STAT3. Multi-tissue gene expression profile analysis for 53 tissue types from GTEx showed that disease-associated protein-coding variants exert their greatest effect in skin tissues. CONCLUSION: Our discoveries highlight a major role of rare coding variants in atopic dermatitis acting independently of common variants. Further extensive functional studies are required to detect all potential causal variants and to specify the contribution of novel susceptibility genes DOK2 and CD200R1 to overall disease susceptibility.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31707066

RESUMO

BACKGROUND: Children with asthma may have a disease course with or without exacerbations, but the relationship between exacerbations and lung function development is poorly understood. OBJECTIVE: To compare lung function trajectories from birth till adolescence in asthmatic children with and without exacerbations. METHODS: Children with asthma from the Copenhagen Prospective Studies on Asthma in Childhood2000 (COPSAC2000) birth cohort had lung function and bronchial reactivity assessed repeatedly from 1 month to 13 years. Exacerbations were diagnosed at the COPSAC clinic defined as symptoms requiring hospitalization, oral or high-dose inhaled corticosteroid treatment. Mixed models were applied to analyze lung function trajectories. RESULTS: Children with asthma with exacerbations (N = 50) had a trajectory of increased, fixed airway obstruction compared with children without exacerbations (N = 47): z-score difference in airway resistance (sRawz) (95% confidence interval [CI]): +0.34 (+0.03; +0.66), P = .03, and maximal mid-expiratory flow (MMEFz): -0.41 (-0.69; -0.13), P = .004, but no differences in forced expiratory volume (FEVz): -0.14 (-0.41; +0.13), P = .29, or bronchial reactivity to methacholine (PDz): +0.08 (-0.26; +0.42), P = .65. This did not change comparing lung function trajectories before and after exacerbations: z-score difference (95% CI) sRawz: -0.04 (-0.35; 0.27), P = .80; MMEFz: 0.01 (-0.02; 0.04), P = .55; FEVz: 0.02 (-0.02; 0.05), P = .42; and PDz: -0.01 (-0.06; 0.05), P = .88. CONCLUSION: Children with asthma with exacerbations compared with children with asthma without exacerbations are characterized by increased airway obstruction since infancy through childhood. The airway obstruction is a fixed trajectory without progression due to exacerbations, suggesting that exacerbations are a consequence rather than a cause of diminished airway caliber in childhood.

3.
Nat Commun ; 10(1): 5001, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31676759

RESUMO

Asthma is believed to arise through early life aberrant immune development in response to environmental exposures that may influence the airway microbiota. Here, we examine the airway microbiota during the first three months of life by 16S rRNA gene amplicon sequencing in the population-based Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010) cohort consisting of 700 children monitored for the development of asthma since birth. Microbial diversity and the relative abundances of Veillonella and Prevotella in the airways at age one month are associated with asthma by age 6 years, both individually and with additional taxa in a multivariable model. Higher relative abundance of these bacteria is furthermore associated with an airway immune profile dominated by reduced TNF-α and IL-1ß and increased CCL2 and CCL17, which itself is an independent predictor for asthma. These findings suggest a mechanism of microbiota-immune interactions in early infancy that predisposes to childhood asthma.

4.
Chest ; 2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31557467

RESUMO

BACKGROUND: Asthma is a common respiratory disorder with a highly heterogeneous nature that remains poorly understood. The objective was to use whole genome sequencing (WGS) data to identify regions of common genetic variation contributing to lung function in individuals with a diagnosis of asthma. METHODS: WGS data were generated for 1,053 individuals from trios and extended pedigrees participating in the family-based Genetic Epidemiology of Asthma in Costa Rica study. The degree to which participants were affected by asthma was defined through a physician's diagnosis of asthma, and most participants with asthma also had airway hyperresponsiveness (AHR) to methacholine. Family-based association tests for single variants were performed to assess the associations with lung function phenotypes. RESULTS: A plausible association was identified between baseline FEV1/FVC ratio and a single-nucleotide polymorphism in the top hit cysteine-rich secretory protein LCCL domain-containing 2 (CRISPLD2) (rs12051168; P = 3.6 × 10-8 in the unadjusted model) that retained suggestive significance in the covariate-adjusted model (P = 5.6 × 10-6). Rs12051168 was also nominally associated with other related phenotypes: baseline FEV1 (P = 3.3 × 10-3), postbronchodilator (PB) FEV1 (7.3 × 10-3), and PB FEV1/FVC ratio (P = 2.7 × 10-3). The identified baseline FEV1/FVC ratio and rs12051168 association was meta-analyzed and replicated in three independent cohorts in which most participants with asthma also had confirmed AHR (combined weighted z-score P = .015) but not in cohorts without information about AHR. CONCLUSIONS: These findings suggest that using specific asthma characteristics, such as AHR, can help identify more genetically homogeneous asthma subgroups with genotype-phenotype associations that may not be observed in all children with asthma. CRISPLD2 also may be important for baseline lung function in individuals with asthma who also may have AHR.

5.
JAMA Pediatr ; 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31381020

RESUMO

Importance: Enamel defects of developmental origin affect up to 38% of schoolchildren and is recognized as a global public health challenge. The impaired enamel formation results in pain owing to hypersensitivity, posteruptive breakdowns, rapid caries progression, and extractions in some cases. The etiology is unknown; therefore, prevention is currently not possible. Objective: To assess the association of a high-dose vitamin D supplementation in pregnant women with enamel defects and caries in their offspring. Design, Setting, and Participants: Post hoc analysis of a double-blind, single-center, randomized clinical trial, the Copenhagen Prospective Studies on Asthma in Childhood 2010 cohort (COPSAC2010). Enrollment began March 2009 and included 623 women recruited at 24 weeks of pregnancy and 588 of their children. A dental examination was completed at age 6 years in 496 of 588 children (84%). Data were analyzed in 2018. Intervention: High-dose vitamin D3 (2400 IU/d; N = 315) or matching placebo tablets (N = 308) from pregnancy week 24 to 1 week post partum. In addition, all women received 400 IU/d of vitamin D3 as part of standard care. Main Outcomes and Measures: Enamel defect was defined as having at least 1 molar affected by demarcated opacity, enamel breakdown, and/or atypical restoration. Caries was defined as decayed, missing, or filled surfaces in both the deciduous and permanent dentitions (World Health Organization standard). Results: The risk of enamel defects in the permanent dentition was lower in the offspring of mothers who received high-dose vitamin D supplementation during pregnancy compared with standard dose (15.1% [n = 26 of 172] vs 27.5% [n = 44 of 160]; odds ratio, 0.47; 95% CI, 0.27-0.81). A similar association was observed for the deciduous dentition (8.6% [n = 21 of 244] vs 15.9% [n = 40 of 252]; odds ratio, 0.50; 95% CI, 0.28-0.87). There was no association between supplementation and caries. Conclusions and Relevance: High-dose vitamin D supplementation during pregnancy was associated with approximately 50% reduced odds of enamel defects in the offspring. This suggests prenatal vitamin D supplementation as a preventive intervention for enamel defects, with a clinically important association with dental health. Trial Registration: ClinicalTrials.gov identifier: NCT00856947.

6.
EBioMedicine ; 46: 399-410, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31399385

RESUMO

BACKGROUND: We recently demonstrated that maternal dietary supplementation with fish oil-derived n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFAs) during pregnancy reduces the risk of asthma in the offspring but the mechanisms involved are unknown. METHODS: Here we investigated potential metabolic mechanisms using untargeted liquid chromatography-mass spectrometry-based metabolomics on 577 plasma samples collected at age 6 months in the offspring of mothers participating in the n-3 LCPUFA randomized controlled trial. First, associations between the n-3 LCPUFA supplementation groups and child metabolite levels were investigated using univariate regression models and data-driven partial least square discriminant analyses (PLS-DA). Second, we analyzed the association between the n-3 LCPUFA metabolomic profile and asthma development using Cox-regression. Third, we conducted mediation analyses to investigate whether the protective effect of n-3 LCPUFA on asthma was mediated via the metabolome. FINDINGS: The univariate analyses and the PLS-DA showed that maternal fish oil supplementation affected the child's metabolome, especially with lower levels of the n-6 LCPUFA pathway-related metabolites and saturated and monounsaturated long-chain fatty acids-containing compounds, lower levels of metabolites of the tryptophan pathway, and higher levels of metabolites in the tyrosine and glutamic acid pathway. This fish oil-related metabolic profile at age 6 months was significantly associated with a reduced risk of asthma by age 5 and the metabolic profile explained 24% of the observed asthma-protective effect in the mediation analysis. INTERPRETATION: Several of the observed pathways may be involved in the asthma-protective effect of maternal n-3 LCPUFA supplementation and act as mediators between the intervention and disease development. FUNDING: COPSAC is funded by private and public research funds all listed on www.copsac.com.

7.
Eur Respir J ; 54(4)2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31439681

RESUMO

Evidence suggests vitamin D has preventive potential in asthma; however, not all children benefit from this intervention. This study aimed to investigate whether variation in the functional 17q21 single nucleotide polymorphism rs12936231 affects the preventive potential of vitamin D against asthma.A combined secondary analysis of two randomised controlled trials of prenatal vitamin D supplementation for the prevention of asthma in offspring (Vitamin D Antenatal Asthma Reduction Trial (VDAART) and Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010)) was performed, stratifying by genotype and integrating metabolite data to explore underlying mechanisms.The protective effect of vitamin D on asthma/wheeze was evident among children with the low-risk rs12936231 GG genotype (hazard ratio (HR) 0.49, 95% CI 0.26-0.94, p=0.032) but not the high-risk CC genotype (HR 1.08, 95% CI 0.69-1.69, p=0.751). In VDAART, in the GG genotype vitamin D supplementation was associated with increased plasma levels of sphingolipids, including sphingosine-1-phosphate (ß 0.022, 95% CI 0.001-0.044, p=0.038), but this was not evident with the CC genotype, known to be associated with increased expression of ORMDL3 in bronchial epithelial cells. Sphingolipid levels were associated with decreased risk of asthma/wheeze, and there was evidence of interactions between sphingolipid levels, vitamin D and genotype (p-interactionvitaminD*genotype*sphingosine-1-phosphate=0.035). In a cellular model, there was a significant difference in the induction of sphingosine-1-phosphate by vitamin D between a control human bronchial epithelial cell line and a cell line overexpressing ORMDL3 (p=0.002).Results suggest prenatal vitamin D supplementation may reduce the risk of early childhood asthma/wheeze via alterations of sphingolipid metabolism dependent on the 17q21 genotype.

8.
Pediatr Allergy Immunol ; 30(7): 716-723, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31299117

RESUMO

BACKGROUND: The relationship between allergic sensitization during childhood and risk of developing asthma remains unclear. OBJECTIVE: To analyze single time-point and temporal patterns of sensitization in childhood in relation to asthma at age 13. METHODS: Specific IgE (sIgE) level and skin prick test (SPT) toward 22 food allergens and aeroallergens were assessed at 6, 18 months, 4, 6, and 13 years in children from the high-risk Copenhagen Prospective Studies on Asthma in Childhood2000 (COPSAC2000 ) mother-child cohort. We analyzed the association between single time-point monosensitization, polysensitization, and quantitative assessment of sensitization, that is, sum of all sIgE levels and SPT wheal sizes, against asthma at age 13. In addition, we analyzed the association between three temporal patterns of sensitization: (a) early-transient, (b) late-onset, and (c) persistent sensitization and asthma. RESULTS: Polysensitization status measured by SPT or sIgE was at all single time-points associated with increased risk of asthma at age 13: OR range, SPT = 3.0-15.7, and sIgE = 2.6-15.7, respectively, whereas monosensitization status was inconsistently associated with asthma. Quantitative assessment of both sIgE and SPT results was associated with asthma at all single time-points: OR range, SPT = 1.3-3.6, and sIgE = 1.1-1.7. Persistent sensitization, but not early-transient or late-onset sensitization was associated with asthma by age 13: OR [95% CI], SPT = 8.9 [2.8-28.23], and sIgE = 2.9 [1.1-7.6], respectively. CONCLUSION: Sensitization to multiple allergens at single time-points, increasing sIgE levels and SPT wheal sizes, and persistent sensitization during childhood were associated with increased risk of asthma at age 13, suggesting the use of quantitative and repetitive sensitization measurements when assessing risk of developing asthma.

9.
EBioMedicine ; 43: 587-593, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31056472

RESUMO

BACKGROUND: Autoimmunity and allergy have been associated with decreased number and function of regulatory T-cells (Tregs) and low interleukin-2 (IL-2) levels. We aimed to investigate if the release of IL-2 from peripheral blood mononuclear cells (PBMCs) stimulated with pathogenic airway bacteria was associated with development of allergy-outcomes in early childhood. METHODS: PBMCs were isolated at age 6 months in 331 infants from the Copenhagen Prospective Studies on Asthma in Childhood 2000 (COPSAC2000) mother-child cohort, and subsequently stimulated with H. influenzae, M. catarrhalis and S. pneumoniae in in vitro cultures. Levels of cytokines (IL-2, IL-10, IFN-γ, TNF-α, IL-5, IL-13 and IL-17A) were determined in the supernatant by electrochemiluminescence immunoassays. The immune profiles were analyzed for association with development of total-IgE, allergic sensitization and rhinitis during the first 7 years of life using regression models and principal component analysis (PCA). FINDINGS: An attenuated IL-2 response to stimulation with H. influenzae (p = 0∙011) and M. catarrhalis (p = 0∙027) was associated with elevated total-IgE at age 7, which was confirmed in a multivariate PCA model including all cytokine measurements (PC2, p = 0∙032). An immune profile with both reduced IL-2 and elevated IL-5 was associated with increased risk of allergic rhinitis (PC3, p = 0∙038). We found no associations with development of allergic sensitization. INTERPRETATION: A reduced IL-2 response from PBMCs exposed to common pathogenic airway bacteria at age 6 months was associated with elevated total-IgE and allergic rhinitis during the first 7 years of life. These findings suggest that suppressed Treg activity in early life may herald onset of allergy in early childhood, which could be a target for low-dose IL-2 trials in the future. FUND: COPSAC is funded by private and public research funds all listed on www.copsac.com.


Assuntos
Bactérias/imunologia , Imunoglobulina E/imunologia , Interleucina-2/metabolismo , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Rinite Alérgica/etiologia , Rinite Alérgica/metabolismo , Fatores Etários , Alérgenos/imunologia , Infecções Bacterianas/complicações , Infecções Bacterianas/imunologia , Infecções Bacterianas/microbiologia , Estudos de Coortes , Citocinas/metabolismo , Suscetibilidade a Doenças , Feminino , Humanos , Imunização , Imunoglobulina E/sangue , Imunofenotipagem , Lactente , Recém-Nascido , Masculino , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
10.
Sci Rep ; 9(1): 3043, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30816254

RESUMO

High sensitivity C-reactive protein (hs-CRP) is a marker of systemic low-grade inflammation and associated with chronic inflammatory diseases. It is unknown whether maternal and infant hs-CRP levels are correlated and little is known about risk factors in early childhood. Hs-CRP were measured in mothers during pregnancy week 24 (N = 690), and one-week postpartum (N = 675) and in their children age 6 mo (N = 640) enrolled in the Copenhagen Prospective Studies on Asthma in Childhood2010 (COPSAC2010) cohort. The risk factor analysis included anthropometrics, environmental exposures and CRP-Genetic Risk Score (GRS). Mother's body mass index (BMI), use of antibiotics, smoking, cesarean delivery and season were associated with higher maternal hs-CRP level, whereas higher social circumstances were associated with lower hs-CRP level (p < 0.05). Child's BMI, siblings, bacterial airway colonization, current infection, CRP-genetic risk score and season were associated with higher hs-CRP at age 6 mo (all p < 0.05). Mother's hs-CRP level in pregnancy week 24 was associated with hs-CRP level in the child at 6 mo: ß-coefficient = 0.11 [95% CI: 0.01-0.20], R2 = 0.22, p = 0.03. The association was unchanged adjusted for all significant risk factors. Systemic low-grade inflammation in pregnant mothers and their offspring is correlated independently of BMI, environmental exposures and genetic risk factors.

12.
Acta Paediatr ; 108(9): 1632-1641, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30748036

RESUMO

AIM: The objective of this study was to identify possible pre- and postnatal factors influencing neurodevelopment of the young child. METHODS: We used data from the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010 ) mother-child cohort, but excluded those with a neurological diagnosis, born <37 weeks of gestation and birthweights <2500 g, resulting in 650 children analysed. Neurodevelopment was assessed as age of achievement of early milestones, language scores at 1 and 2 years and cognitive score at 2 ½ years of age. RESULTS: Neurodevelopmental scores were not associated with breastfeeding, persistent wheeze, eczema and number of sick days (p > 0.05 in all tests). Early age at milestone achievement was associated with male sex (p = 0.05), lower maternal age (p = 0.02), higher gestational age (p < 0.001) and paternity leave (p = 0.01). A higher 1-year language score was associated with female sex (p = 0.02) and maternal smoking during pregnancy (p = 0.01) and a higher 2-year language score with female sex (p < 0.001) and being first born (p = 0.01). A higher cognitive score was associated with female sex (p = 0.02). CONCLUSION: Neurodevelopmental scores were unrelated to breastfeeding, persistent wheeze, eczema and number of sick days. Neurodevelopment in early childhood was mostly associated with gender.

14.
PLoS Med ; 16(1): e1002722, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30620743

RESUMO

BACKGROUND: Studies have shown that airway obstruction and increased bronchial reactivity are present in early life in children developing asthma, which challenges the dogma that airway inflammation leads to low lung function. Further studies are needed to explore whether low lung function and bronchial hyperreactivity are inherent traits increasing the risk of developing airway inflammation and asthmatic symptoms in order to establish timely primary preventive initiatives. METHODS AND FINDINGS: We investigated 367 (89%) of the 411 children from the at-risk Copenhagen Prospective Studies on Asthma in Childhood 2000 (COPSAC2000) birth cohort born to mothers with asthma, who were assessed by spirometry and bronchial reactivity to methacholine from age 1 month, plethysmography and bronchial reversibility from age 3 years, cold dry air hyperventilation from age 4 years, and exercise challenge at age 7 years. The COPSAC pediatricians diagnosed and treated asthma based on symptom load, response to inhaled corticosteroid, and relapse after treatment withdrawal according to a standardized algorithm. Repeated measures mixed models were applied to analyze lung function trajectories in children with asthma ever or never at age 1 month to 13 years. The number of children ever versus never developing asthma in their first 13 years of life was 97 (27%) versus 270 (73%), respectively. Median age at diagnosis was 2.0 years (IQR 1.2-5.7), and median remission age was 6.2 years (IQR 4.2-7.8). Children with versus without asthma had reduced lung function (z-score difference, forced expiratory volume, -0.31 [95% CI -0.47; -0.15], p < 0.001), increased airway resistance (z-score difference, specific airway resistance, +0.40 [95% CI +0.24; +0.56], p < 0.001), increased bronchial reversibility (difference in change in forced expiratory volume in the first second [ΔFEV1], +3% [95% CI +2%; +4%], p < 0.001), increased reactivity to methacholine (z-score difference for provocative dose, -0.40 [95% CI -0.58; -0.22], p < 0.001), decreased forced expiratory volume at cold dry air challenge (ΔFEV1, -4% [95% CI -7%; -1%], p < 0.01), and decreased forced expiratory volume after exercise (ΔFEV1, -4% [95% CI -7%; -1%], p = 0.02). Both airway obstruction and bronchial hyperreactivity were present before symptom debut, independent of disease duration, and did not improve with symptom remission. The generalizability of these findings may be limited by the high-risk nature of the cohort (all mothers had a diagnosis of asthma), the modest study size, and limited ethnic variation. CONCLUSIONS: Children with asthma at some point at age 1 month to 13 years had airway obstruction and bronchial hyperreactivity before symptom debut, which did not worsen with increased asthma symptom duration or attenuate with remission. This suggests that airway obstruction and bronchial hyperreactivity are stable traits of childhood asthma since neonatal life, implying that symptomatic disease may in part be a consequence of these traits but not their cause.


Assuntos
Obstrução das Vias Respiratórias/epidemiologia , Asma/epidemiologia , Hiper-Reatividade Brônquica/epidemiologia , Adolescente , Fatores Etários , Obstrução das Vias Respiratórias/complicações , Asma/etiologia , Hiper-Reatividade Brônquica/complicações , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Prospectivos , Testes de Função Respiratória , Espirometria
15.
Nat Commun ; 10(1): 357, 2019 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-30664637

RESUMO

Cranial growth and development is a complex process which affects the closely related traits of head circumference (HC) and intracranial volume (ICV). The underlying genetic influences shaping these traits during the transition from childhood to adulthood are little understood, but might include both age-specific genetic factors and low-frequency genetic variation. Here, we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV + HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for low-frequency variants within TP53, with 0.5 cm wider heads in increaser-allele carriers versus non-carriers during mid-childhood, suggesting a previously unrecognized role of TP53 transcripts in human cranial development.


Assuntos
Alelos , Loci Gênicos , Variação Genética , RNA Mensageiro/genética , Crânio/metabolismo , Proteína Supressora de Tumor p53/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Cefalometria , Criança , Grupo com Ancestrais do Continente Europeu , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Frequência do Gene , Genoma Humano , Humanos , Masculino , Pessoa de Meia-Idade , Crânio/anatomia & histologia
16.
Ann Am Thorac Soc ; 16(5): 599-605, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30580555

RESUMO

Rationale: There is an unmet need for sensitive lung function tests for young children to aid in the diagnosis of asthma and wheezy disorders. We hypothesized that multiple breath washout (MBW) could be a valuable tool for such a purpose. Objectives: To compare the ability of MBW lung clearance index with traditional lung function measurements to discriminate between preschool children with well-controlled asthma/persistent wheeze and healthy children. Methods: We investigated 646 children from the COPSAC2010 (Copenhagen Prospective Studies on Asthma in Childhood 2010) mother-child cohort, who completed MBW testing with nitrogen, spirometry, and plethysmography before age 6 years. Asthma/persistent wheeze was prospectively diagnosed according to a validated symptom-based algorithm at the COPSAC clinic. Student's t tests and receiver operating characteristic curves were applied to analyze the discriminative ability of the lung function indices. Results: A total of 144 (22.3%) children were diagnosed with asthma/persistent wheeze during their first 6 years of life. Lung clearance index from MBW was not significantly different in children with versus those without asthma/persistent wheeze (mean standard deviation [SD] = 6.96 [1.14] vs. 6.95 [0.93], mean difference [95% confidence interval] = 0.02 [-0.18 to 0.22], P = 0.86, area under the curve [AUC] = 0.48), whereas significant differences were observed for specific airway resistance from plethysmography (1.21 kPa/s [0.31] vs. 1.14 kPa/s [0.25]; +0.07 kPa/s [0.02-0.13]; P < 0.01; AUC = 0.56) and spirometry forced expiratory volume in 1 second (FEV1) % predicted (99.4% [12.0] vs. 102.6% [12.5]; -3.2% [-5.6 to -0.9]; P < 0.01; AUC = 0.56) and forced expiratory flow at 25-75% (1.55 L/s [0.44] vs. 1.68 L/s [0.46]; -0.14 L/s [-0.22 to -0.05]; P < 0.01; AUC = 0.58). FEV1 (L/s) and FEV1/forced vital capacity ratio were not significantly different (P > 0.4). Conclusions: MBW, spirometry, and plethysmography are not sensitive tools for diagnosing mild asthmatic disease in young children.

17.
Int J Epidemiol ; 48(1): 45-57, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30541029

RESUMO

BACKGROUND: Accumulating evidence suggests that breastfeeding benefits children's intelligence, possibly due to long-chain polyunsaturated fatty acids (LC-PUFAs) present in breast milk. Under a nutritional adequacy hypothesis, an interaction between breastfeeding and genetic variants associated with endogenous LC-PUFAs synthesis might be expected. However, the literature on this topic is controversial. METHODS: We investigated this gene × environment interaction through a collaborative effort. The primary analysis involved >12 000 individuals and used ever breastfeeding, FADS2 polymorphisms rs174575 and rs1535 coded assuming a recessive effect of the G allele, and intelligence quotient (IQ) in Z scores. RESULTS: There was no strong evidence of interaction, with pooled covariate-adjusted interaction coefficients (i.e. difference between genetic groups of the difference in IQ Z scores comparing ever with never breastfed individuals) of 0.12[(95% confidence interval (CI): -0.19; 0.43] and 0.06 (95% CI: -0.16; 0.27) for the rs174575 and rs1535 variants, respectively. Secondary analyses corroborated these results. In studies with ≥5.85 and <5.85 months of breastfeeding duration, pooled estimates for the rs174575 variant were 0.50 (95% CI: -0.06; 1.06) and 0.14 (95% CI: -0.10; 0.38), respectively, and 0.27 (95% CI: -0.28; 0.82) and -0.01 (95% CI: -0.19; 0.16) for the rs1535 variant. CONCLUSIONS: Our findings did not support an interaction between ever breastfeeding and FADS2 polymorphisms. However, subgroup analysis suggested that breastfeeding may supply LC-PUFAs requirements for cognitive development if breastfeeding lasts for some (currently unknown) time. Future studies in large individual-level datasets would allow properly powered subgroup analyses and further improve our understanding on the breastfeeding × FADS2 interaction.

18.
J Nutr ; 2018 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-30418579

RESUMO

Background: Randomized trials have reported that supplementation with n-3 long-chain polyunsaturated fatty acids (LCPUFAs) in pregnancy can prolong pregnancy and thereby increase birth weight. Objective: We aimed to examine the relations of n-3 LCPUFA supplementation in pregnancy with duration of pregnancy, birth weight, and size for gestational age (GA). Methods: This was a double-blind randomized controlled trial conducted in 736 pregnant women and their offspring, from the Copenhagen Prospective Studies on Asthma in Childhood2010cohort. They were recruited between weeks 22 and 26 in pregnancy and randomly assigned to either of 2.4 g n-3 LCPUFA or control (olive oil) daily until 1 wk after birth. Exclusion criteria were endocrine, cardiovascular, or nephrologic disorders and vitamin D supplementation intake >600 IU/d. In this study we analyzed secondary outcomes, and further excluded twin pregnancies and extrauterine death. The primary outcome for the trial was persistent wheeze or asthma. Results: The random assignment ran between 2008 and 2010. Six hundred and ninety-nine mother-infant pairs were included in the analysis. n-3 LCPUFA compared with control was associated with a 2-d prolongation of pregnancy [median (IQR): 282 (275-288) d compared with 280 (273-286) d, P = 0.02], a 97-g higher birth weight (mean ± SD: 3601 ± 534 g compared with 3504 ± 528 g, P = 0.02), and an increased size for GA according to the Norwegian population-based growth curves-Skjærven (mean ± SD: 49.9 ± 28.3 percentiles compared with 44.5 ± 27.6 percentiles, P = 0.01). Conclusion: Supplementing pregnant women with n-3 LCPUFAs during the third trimester is associated with prolonged gestation and increased size for GA, leading to a higher birth weight in this randomized controlled trial. This trial was registered at clinicaltrials.gov as NCT00798226.

19.
JAMA Dermatol ; 2018 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-30427975

RESUMO

Importance: Knowledge about factors associated with persistence of atopic dermatitis (AD) during childhood is sparse. Objective: To explore heritable, environmental, and clinical factors associated with persistent AD based on 13 years' follow-up of an at-risk birth cohort. Design, Setting, and Participants: In the Copenhagen Prospective Study on Asthma in Childhood 2000 (COPSAC2000) clinical birth cohort study, 411 children born to mothers with asthma were followed up until the age of 13 years at a clinical research unit in Copenhagen, Denmark, from August 1998 to June 2015. Atopic dermatitis was diagnosed prospectively during close clinical follow-up according to the criteria of Hanifin and Rajka. Data were gathered on parental history, social circumstances, and environmental factors through parent interviews. The cohort was followed up with biannual visits to the clinic until the age of 7 years and were seen again at age 13 years. Data were analyzed from August 2015 to January 2018. Main Outcomes and Measures: Atopic dermatitis was diagnosed using Hanifin and Rajka major and minor criteria, and severity was determined by Scoring Atopic Dermatitis (SCORAD) index, with possible scores from 0 to 83, with higher scores indicating more severe AD. Results: Of the 411 children in the cohort, 203 (49.4%) were male and 186 (45.3%) were diagnosed with AD before the age of 13 years; 40 of 166 children (24.1%) had persistent AD at the age of 13 years, and 126 (76.0%) experienced remission. Factors associated with persistent AD to age 13 years included heritability, environmental exposures, asthma and allergic sensitization, clinical presentation at the time of diagnosis, the composition of Hanifin and Rajka diagnostic minor criteria, and AD severity according to SCORAD. A higher AD genetic risk score was associated with an increased the risk for persistent AD (multivariable odds ratio [OR], 1.8; 95% CI, 1.1-2.9; P = .02), together with paternal asthma (multivariable OR, 3.7; 95% CI, 1.2-11.5; P = .02); paternal AD (multivariable OR, 6.2; 95% CI, 1.17-23.2; P = .007), and higher social circumstances (multivariable OR, 1.6; 95% CI, 1.0-2.5; P = .05). Particular clinical presentations at time of diagnosis were also associated with specific minor criteria of Hanifin and Rajka (Dennie-Morgan and anterior neck folds, white dermographism, intolerance to wool, itching when sweating, tendency to skin infection, food intolerance, and food allergy) (OR, 2.6; 95% CI, 1.1-6.2; P = .03) as well as increased severity at diagnosis (OR, 1.1; 95% CI, 1.0-1.1; P = .007). Conclusions and Relevance: In a birth cohort of children at risk for asthma who received close clinical follow-up to age 13 years, known genetic AD risk variants, paternal asthma and AD, high social circumstances, diagnostic minor criteria, and disease severity at onset were associated with persistent AD at age 13 years. These findings may be applied in clinical practice to evaluate the likely disease course for individual patients.

20.
ERJ Open Res ; 4(4)2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30443556

RESUMO

Exhaled volatile organic compound measurements do not aid the clinician diagnosing asthma in children http://ow.ly/Z2d930lpZ60.

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