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1.
Clin Exp Allergy ; 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31441980

RESUMO

BACKGROUND: Allergic diseases (eczema, wheeze and rhinitis) in children often present as heterogeneous phenotypes. Understanding genetic associations of specific patterns of symptoms might facilitate understanding of the underlying biological mechanisms. OBJECTIVE: To examine associations between allergic disease-related variants identified in a recent genome-wide association study and latent classes of allergic diseases (LCADs) in two population-based birth cohorts. METHODS: Eight previously defined LCADs between birth and 11 years: "No disease," "Atopic march," "Persistent eczema and wheeze," "Persistent eczema with later-onset rhinitis," "Persistent wheeze with later-onset rhinitis," "Transient wheeze," "Eczema only" and "Rhinitis only" were used as the study outcome. Weighted multinomial logistic regression was used to estimate associations between 135 SNPs (and a polygenic risk score, PRS) and LCADs among 6345 individuals from The Avon Longitudinal Study of Parents and Children (ALSPAC). Heterogeneity across LCADs was assessed before and after Bonferroni correction. Results were replicated in Manchester Asthma and Allergy Study (MAAS) (n = 896) and pooled in a meta-analysis. RESULTS: We found strong evidence for differential genetic associations across the LCADs; pooled PRS heterogeneity P-value = 3.3 × 10-14 , excluding "no disease" class. The associations between the PRS and LCADs in MAAS were remarkably similar to ALSPAC. Two SNPs (a protein-truncating variant in FLG and a SNP within an intron of GSDMB) had evidence for differential association (pooled P-values ≤ 0.006). The FLG locus was differentially associated across LCADs that included eczema, with stronger associations for LCADs with comorbid wheeze and rhinitis. The GSDMB locus in contrast was equally associated across LCADs that included wheeze. CONCLUSIONS AND CLINICAL RELEVANCE: We have shown complex, but distinct patterns of genetic associations with LCADs, suggesting that heterogeneous mechanisms underlie individual disease trajectories. Establishing the combination of allergic diseases with which each genetic variant is associated may inform therapeutic development and/or predictive modelling.

2.
Clin Exp Allergy ; 49(10): 1342-1351, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31379025

RESUMO

BACKGROUND: Asthma, a heterogeneous disease with variable age of onset, results from the interplay between genetic and environmental factors. Early-life tobacco smoke (ELTS) exposure is a major asthma risk factor. Only a few genetic loci have been reported to interact with ELTS exposure in asthma. OBJECTIVE: Our aim was to identify new loci interacting with ELTS exposure on time-to-asthma onset (TAO) in childhood. METHODS: We conducted genome-wide interaction analyses of ELTS exposure on time-to-asthma onset in childhood in five European-ancestry studies (totalling 8273 subjects) using Cox proportional-hazard model. The results of all five genome-wide analyses were meta-analysed. RESULTS: The 13q21 locus showed genome-wide significant interaction with ELTS exposure (P = 4.3 × 10-8 for rs7334050 within KLHL1 with consistent results across the five studies). Suggestive interactions (P < 5 × 10-6 ) were found at three other loci: 20p12 (rs13037508 within MACROD2; P = 4.9 × 10-7 ), 14q22 (rs7493885 near NIN; P = 2.9 × 10-6 ) and 2p22 (rs232542 near CYP1B1; P = 4.1 × 10-6 ). Functional annotations and the literature showed that the lead SNPs at these four loci influence DNA methylation in the blood and are located nearby CpG sites reported to be associated with exposure to tobacco smoke components, which strongly support our findings. CONCLUSIONS AND CLINICAL RELEVANCE: We identified novel candidate genes interacting with ELTS exposure on time-to-asthma onset in childhood. These genes have plausible biological relevance related to tobacco smoke exposure. Further epigenetic and functional studies are needed to confirm these findings and to shed light on the underlying mechanisms.

3.
Eur Respir J ; 53(4)2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30765504

RESUMO

RATIONALE: We aimed to identify differentially methylated regions (DMRs) in cord blood DNA associated with childhood lung function, asthma and chronic obstructive pulmonary disease (COPD) across the life course. METHODS: We meta-analysed epigenome-wide data of 1688 children from five cohorts to identify cord blood DMRs and their annotated genes, in relation to forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity (FVC) ratio and forced expiratory flow at 75% of FVC at ages 7-13 years. Identified DMRs were explored for associations with childhood asthma, adult lung function and COPD, gene expression and involvement in biological processes. RESULTS: We identified 59 DMRs associated with childhood lung function, of which 18 were associated with childhood asthma and nine with COPD in adulthood. Genes annotated to the top 10 identified DMRs were HOXA5, PAOX, LINC00602, ABCA7, PER3, CLCA1, VENTX, NUDT12, PTPRN2 and TCL1A. Differential gene expression in blood was observed for 32 DMRs in childhood and 18 in adulthood. Genes related with 16 identified DMRs were associated with respiratory developmental or pathogenic pathways. INTERPRETATION: Our findings suggest that the epigenetic status of the newborn affects respiratory health and disease across the life course.

4.
Am J Epidemiol ; 188(3): 527-536, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30668648

RESUMO

Although respiratory symptoms, including wheezing, are common in preterm-born subjects, the natural history of the wheezing phenotypes and the influence of early-life factors and characteristics on phenotypes are unclear. Participants from the Millennium Cohort Study who were born between 2000 and 2002 were studied at 9 months and at 3, 5, 7, and 11 years. We used data-driven methods to define wheezing phenotypes in preterm-born children and investigated whether the association of early-life factors and characteristics with wheezing phenotypes was similar between preterm- and term-born children. A total of 1,049/1,502 (70%) preterm-born children and 12,307/17,063 (72%) term-born children had recent wheeze data for 3 or 4 time points. Recent wheeze was more common at all time points in the preterm-born group than in term-born group. Four wheezing phenotypes were defined for both groups: no/infrequent, early, persistent, and late. Early-life factors and characteristics, especially antenatal maternal smoking, atopy, and male sex, were associated with increased rates for all phenotypes in both groups, and breastfeeding was protective in both groups, except late wheeze in the preterm group. Preterm-born children had similar phenotypes to term-born children. Although early-life factors and characteristics were similarly associated with the wheezing phenotypes in both groups, the preterm-born group had higher rates of early and persistent wheeze. However, a large proportion of preterm-born children had early wheeze that resolved with time.

5.
BMJ Open ; 9(1): e024858, 2019 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-30662005

RESUMO

OBJECTIVES: To compare the physical activity of adolescents with three common long-term conditions (asthma, eczema and obesity) with adolescents without these conditions. DESIGN: Cross-sectional and longitudinal analyses of adolescents at ages 12, 14 and 16 in a large UK cohort study. SETTING: The Avon Longitudinal Study of Parents and Children. PARTICIPANTS: 6473 adolescents with complete accelerometer data at at least one time point. METHODS: Mean minutes of moderate to vigorous intensity physical activity (MVPA) and sedentary time per day were derived from accelerometer-based measurements at ages 12, 14 and 16. Obesity was defined at each time point from height and weight measurements. Parents reported doctor-assessed asthma or eczema. Cross-sectional and longitudinal regression models examined any differences in MVPA or sedentary time for adolescents with asthma, eczema or obesity compared with those without. RESULTS: In longitudinal models, boys engaged in an average of 69.7 (95% CI 67.6 to 71.7) min MVPA at age 12, declining by 3.1 (95% CI 2.6 to 3.6) min/year while girls' average MVPA was 47.5 (95% CI 46.1 to 48.9) min at age 12, declining by 1.8 (95% CI 1.5 to 2.1) min/year. There was no strong evidence of differences in physical activity patterns of those with and without asthma or eczema. Obese boys engaged in 11.1 (95% CI 8.7 to 13.6) fewer minutes of MVPA, and obese girls in 5.0 (95% CI 3.3 to 6.8) fewer minutes than their non-obese counterparts. Cross-sectional models showed comparable findings. CONCLUSIONS: Mean minutes of MVPA per day did not differ between adolescents with asthma or eczema and those without, but obese adolescents engaged in fewer minutes of MVPA. Findings reinforce the need for strategies to help obese adolescents be more active but suggest no need to develop bespoke physical activity strategies for adolescents with mild asthma or eczema.

6.
J Allergy Clin Immunol ; 143(5): 1783-1790.e11, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30528616

RESUMO

BACKGROUND: Latent class analysis (LCA) has been used extensively to identify (latent) phenotypes of childhood wheezing. However, the number and trajectory of discovered phenotypes differed substantially between studies. OBJECTIVE: We sought to investigate sources of variability affecting the classification of phenotypes, identify key time points for data collection to understand wheeze heterogeneity, and ascertain the association of childhood wheeze phenotypes with asthma and lung function in adulthood. METHODS: We used LCA to derive wheeze phenotypes among 3167 participants in the ALSPAC cohort who had complete information on current wheeze recorded at 14 time points from birth to age 16½ years. We examined the effects of sample size and data collection age and intervals on the results and identified time points. We examined the associations of derived phenotypes with asthma and lung function at age 23 to 24 years. RESULTS: A relatively large sample size (>2000) underestimated the number of phenotypes under some conditions (eg, number of time points <11). Increasing the number of data points resulted in an increase in the optimal number of phenotypes, but an identical number of randomly selected follow-up points led to different solutions. A variable selection algorithm identified 8 informative time points (months 18, 42, 57, 81, 91, 140, 157, and 166). The proportion of asthmatic patients at age 23 to 24 years differed between phenotypes, whereas lung function was lower among persistent wheezers. CONCLUSIONS: Sample size, frequency, and timing of data collection have a major influence on the number and type of wheeze phenotypes identified by using LCA in longitudinal data.

7.
Artigo em Inglês | MEDLINE | ID: mdl-30312804

RESUMO

BACKGROUND: External validation of prediction models is important to assess generalizability to other populations than the one used for model development. The Predicting Asthma Risk in Children (PARC) tool, developed in the Leicestershire Respiratory Cohort (LRC), uses information on preschool respiratory symptoms to predict asthma at school age. OBJECTIVE: We performed an external validation of PARC using the Avon Longitudinal Study of Parents and Children (ALSPAC). METHODS: We defined inclusion criteria, prediction score items at baseline and asthma at follow-up in ALSPAC to match those used in LRC using information from parent-reported questionnaires. We assessed performance of PARC by calculating sensitivity, specificity, predictive values, likelihood ratios, area under the curve (AUC), Brier score and Nagelkerke's R2. Sensitivity analyses varied inclusion criteria, scoring items, and outcomes. RESULTS: The validation population included 2690 children with preschool respiratory symptoms of whom 373 (14%) had asthma at school age. Discriminative performance of PARC was similar in ALSPAC (AUC = 0.77, Brier score 0.13) as in LRC (0.78, 0.22). The score cutoff of 4 showed the highest sum of sensitivity (69%) and specificity (76%) and positive and negative likelihood ratios of 2.87 and 0.41, respectively. Changes to inclusion criteria, scoring items, or outcome definitions barely altered the prediction performance. CONCLUSIONS: Performing equally well in the validation cohort as in the development cohort, PARC is a valid tool for predicting asthma in population-based cohorts. Its use in clinical practice is ready to be tested.

8.
Eur Respir J ; 52(2)2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30093569

RESUMO

Evidence for a possible protective effect of maternal dietary antioxidant intake during pregnancy on childhood asthma and other atopic outcomes is conflicting, and associations with childhood lung function have been little studied.In the Avon Longitudinal Study of Parents and Children, we analysed associations between maternal intake of fruits, vegetables, vitamins C and E, carotene, zinc, and selenium in pregnancy and current doctor-diagnosed asthma, atopy and lung function in 8915 children at age 7-9 years. Potential modification of associations by maternal smoking and common maternal antioxidant gene polymorphisms was explored to strengthen causal inference.After controlling for confounders, positive associations were observed between maternal intake of zinc and childhood forced expiratory volume in 1 s and forced vital capacity (difference in age-, height- and sex-adjusted sd units per quartile increase in maternal dietary zinc intake ß 0.05 (95% CI 0.01-0.08); ptrend=0.01 and 0.05 (95% CI 0.02-0.09); ptrend=0.005, respectively). Weak evidence was found for an interaction between maternal zinc intake and maternal glutathione S-transferase GSTM1 genotype on childhood forced vital capacity (pinteraction=0.05); association among the GSTM1 null group ß 0.11 (95% CI 0.05-0.17); ptrend=0.001.Our results suggest that a higher maternal intake of zinc during pregnancy may be associated with better lung function in the offspring.

9.
Lancet Respir Med ; 6(7): 526-534, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29628377

RESUMO

BACKGROUND: Maximal lung function in early adulthood is an important determinant of mortality and COPD. We investigated whether distinct trajectories of lung function are present during childhood and whether these extend to adulthood and infancy. METHODS: To ascertain trajectories of FEV1, we studied two population-based birth cohorts (MAAS and ALSPAC) with repeat spirometry from childhood into early adulthood (1046 participants from 5-16 years and 1390 participants from 8-24 years). We used a third cohort (PIAF) with repeat lung function measures in infancy (V'maxFRC) and childhood (FEV1; 196 participants from 1 month to 18 years of age) to investigate whether these childhood trajectories extend from early life. We identified trajectories using latent profile modelling. We created an allele score to investigate genetic associations of trajectories, and constructed a multivariable model to identify their early-life predictors. FINDINGS: We identified four childhood FEV1 trajectories: persistently high, normal, below average, and persistently low. The persistently low trajectory (129 [5%] of 2436 participants) was associated with persistent wheezing and asthma throughout follow-up. In genetic analysis, compared with the normal trajectory, the pooled relative risk ratio per allele was 0·96 (95% CI 0·92-1·01; p=0·13) for persistently high, 1·01 (0·99-1·02; p=0·49) for below average, and 1·05 (0·98-1·13; p=0·13) for persistently low. Most children in the low V'maxFRC trajectory in infancy did not progress to the low FEV1 trajectory in childhood. Early-life factors associated with the persistently low trajectory included recurrent wheeze with severe wheezing exacerbations, early allergic sensitisation, and tobacco smoke exposure. INTERPRETATION: Reduction of childhood smoke exposure and minimisation of the risk of early-life sensitisation and wheezing exacerbations might reduce the risk of diminished lung function in early adulthood. FUNDING: None.

10.
BMJ Open Respir Res ; 5(1): e000275, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29636978

RESUMO

Introduction: Limited evidence from birth cohort studies suggests that lower prenatal iron status may be a risk factor for childhood respiratory and atopic outcomes, but these observational findings may be confounded. Mendelian randomisation (MR) can potentially provide unconfounded estimates of causal effects by using common genetic variants as instrumental variables. We aimed to study the relationship between prenatal iron status and respiratory and atopic outcomes in the offspring using MR. Methods: In the Avon Longitudinal Study of Parents and Children birth cohort, we constructed four maternal genotypic risk scores by summing the total number of risk alleles (associated with lower iron status) across single nucleotide polymorphisms known to be associated with at least one of four iron biomarkers (serum iron, ferritin, transferrin and transferrin saturation). We used MR to study their associations with respiratory and atopic outcomes in children aged 7-9 years (n=6002). Results: When analyses were restricted to mothers without iron supplementation during late pregnancy, negative associations were found between the maternal transferrin saturation score and childhood forced expiratory volume in 1 s and forced vital capacity (difference in age, height and gender-adjusted SD units per SD increase in genotypic score: -0.05 (-0.09, -0.01) p=0.03, and -0.04 (-0.08, 0.00) p=0.04, respectively). Conclusion: Using MR we have found weak evidence suggesting that low maternal iron status during pregnancy may cause impaired childhood lung function.

11.
J Allergy Clin Immunol ; 141(3): 964-971, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29129583

RESUMO

BACKGROUND: Atopic dermatitis (AD) is a prevalent disease with variable natural history. Longitudinal birth cohort studies provide an opportunity to define subgroups on the basis of disease trajectories, which may represent different genetic and environmental pathomechanisms. OBJECTIVES: We sought to investigate the existence of distinct longitudinal phenotypes of AD and test whether these findings are reproducible in 2 independent cohorts. METHODS: The presence of AD was examined in 2 birth cohort studies including 9894 children from the United Kingdom (ALSPAC) and 3652 from the Netherlands (PIAMA). AD was defined by parental report of a typical itchy and/or flexural rash. Longitudinal latent class analysis was used to investigate patterns of AD from birth to the age of 11 to 16 years. We investigated associations with known AD risk factors, including FLG null mutations, 23 other established AD-genetic risk variants, and atopic comorbidity. RESULTS: Six latent classes were identified, representing subphenotypes of AD, with remarkable consistency between the 2 cohorts. The most prevalent class was early-onset-early-resolving AD, which was associated with male sex. Two classes of persistent disease were identified (early-onset-persistent and early-onset-late-resolving); these were most strongly associated with the AD-genetic risk score as well as personal and parental history of atopic disease. A yet unrecognized class of mid-onset-resolving AD, not associated with FLG mutations, but strongly associated with asthma, was identified. CONCLUSIONS: Six classes based on temporal trajectories of rash were consistently identified in 2 population-based cohorts. The differing risk factor profiles and diverse prognoses demonstrate the potential importance of a stratified medicine approach for AD.

12.
JAMA Pediatr ; 172(1): e174064, 2018 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-29131887

RESUMO

Importance: Atopic diseases, including asthma and atopic eczema, are the most common chronic conditions of childhood. Objective: To investigate whether an intervention to promote prolonged and exclusive breastfeeding protects against asthma, atopic eczema, and low lung function in adolescence. Design, Setting, and Participants: Follow-up of the Promotion of Breastfeeding Intervention Trial (PROBIT), a cluster randomized trial in 30 Belarusian maternity hospitals and affiliated polyclinics; recruitment of 17 046 healthy term infants took place from June 15, 1996, to December 31, 1997. Data analysis was conducted from May 9, 2016, to April 21, 2017. The primary analytic approach was by modified intention-to-treat analysis. Interventions: Randomization to receive a breastfeeding promotion intervention vs usual care. Main Outcomes and Measures: Spirometry and flexural eczema on standardized skin examination by study pediatricians were the primary outcomes; secondary outcomes were self-reported asthma diagnosis ever, and wheezing and flexural eczema symptoms in the previous year. Results: A total of 13 557 (79.5%) participants were followed up from September 15, 2012 to July 15, 2015. The intervention (7064 [79.7%]) and control (6493 [79.4%]) groups were similar at follow-up (3590 [50.8%] and 3391 [52.2%] male; mean [SD] age, 16.2 [0.6] and 16.1 [0.5] years, respectively). In the intervention group, 0.3% (21 of 7064) had flexural eczema on skin examination and mean (SD) forced expiratory volume in the first second of expiration/forced vital capacity (FEV1/FVC) ratio z score was -0.10 (1.82), compared with 0.7% (43 of 6493) and 0.35 (1.34), respectively, in the control group. In modified intention-to-treat analysis, accounting for clustering by polyclinic, a 54% lower risk of flexural eczema on skin examination was observed in the intervention compared with the control group (odds ratio [OR], 0.46; 95% CI, 0.25 to 0.86). Self-reported flexural eczema symptoms in the past year (OR, 0.57; 95% CI, 0.27 to 1.18), asthma (OR, 0.76; 95% CI, 0.47 to 1.23), and wheezing in the past year (OR, 0.66; 95% CI, 0.37 to 1.18) were less frequently reported in the intervention compared with the control group, but 95% CIs were wide and included the null. There was no significant difference in the FEV1/FVC ratio z score (ß -0.15; 95% CI, -0.76 to 0.45). All results were similar with additional adjustment for baseline characteristics, on instrumental variable analysis, and with multiple imputation among all 17 046 randomized participants. Conclusions and Relevance: A breastfeeding promotion intervention reduced flexural dermatitis risk but had no detectable effect on lung function or questionnaire-derived measures of atopic eczema or asthma in adolescence in a setting where atopic eczema and allergies are rare. Trial Registration: clinicaltrials.gov Identifier: NCT01561612.

13.
Acta Paediatr ; 106(12): 2011-2016, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28833606

RESUMO

AIM: Epidemiological studies of deoxyribonucleic acid (DNA) methylation in airway disease have largely been conducted using blood or buccal samples. However, given tissue specificity of DNA methylation, these surrogate tissues may not allow reliable inferences about methylation in the lung. We sought to compare the pattern of DNA methylation in blood, buccal and nasal epithelial cells to that in airway epithelial cells from children. METHODS: Samples of blood, and buccal, nasal and airway epithelium were obtained from six children undergoing elective anaesthesia for adenotonsillectomy. DNA methylation was assessed at 450 000 5'-C-phosphate-G-3' (CpG) sites using the Illumina HumanMethylation450 array. RESULTS: Eighteen samples from all sites were suitable for analysis. Hierarchical clustering demonstrated that the methylation profile in nasal epithelium was most representative of that in airway epithelium; the profile in buccal cells was moderately similar and that in blood was least similar. CONCLUSION: DNA methylation in blood poorly reflects methylation in airway epithelium. Future epidemiological studies of DNA methylation and airway diseases should consider measurement of methylation either in buccal cells or, preferably, in nasal epithelial cells.


Assuntos
Células Sanguíneas , Metilação de DNA , Células Epiteliais , Mucosa Bucal/citologia , Mucosa Nasal/citologia , Mucosa Respiratória/citologia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino
14.
Eur Respir J ; 50(1)2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28679610

RESUMO

The possible role of maternal consumption of free sugar during pregnancy in the inception of respiratory and atopic diseases has not been studied. We aimed to study the relationship between maternal intake of free sugar during pregnancy and respiratory and atopic outcomes in the offspring in a population-based birth cohort, the Avon Longitudinal Study of Parents and Children.We analysed associations between maternal intake of free sugar in pregnancy (estimated by a food frequency questionnaire), and current doctor-diagnosed asthma, wheezing, hay fever, eczema, atopy, serum total IgE and lung function in children aged 7-9 years (n=8956 with information on maternal diet in pregnancy and at least one outcome of interest).After controlling for potential confounders, maternal intake of free sugar was positively associated with atopy (OR for highest versus lowest quintile of sugar intake 1.38, 95% CI 1.06-1.78; per quintile p-trend=0.006) and atopic asthma (OR 2.01, 95% CI 1.23-3.29; per quintile p-trend=0.004). These associations were not confounded by intake of sugar in early childhood, which was unrelated to these outcomes.Our results suggest that a higher maternal intake of free sugar during pregnancy is associated with an increased risk of atopy and atopic asthma in the offspring, independently of sugar intake in early childhood.


Assuntos
Asma/epidemiologia , Dermatite Atópica/epidemiologia , Sacarose na Dieta/efeitos adversos , Fenômenos Fisiológicos da Nutrição Pré-Natal , Rinite Alérgica Sazonal/epidemiologia , Adolescente , Adulto , Criança , Sacarose na Dieta/administração & dosagem , Feminino , Humanos , Imunoglobulina E/sangue , Modelos Lineares , Modelos Logísticos , Estudos Longitudinais , Masculino , Mães , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Sons Respiratórios , Reino Unido/epidemiologia
15.
BMJ Open ; 7(3): e014020, 2017 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-28341689

RESUMO

OBJECTIVES: Qualitative methods were used to examine: (1) the attitudes of health professionals to promoting physical activity for children with asthma; (2) reasons why children with asthma are less active and (3) how a physical activity programme for children with asthma could be designed. DESIGN: Semistructured interviews were conducted with health professionals, children with asthma and their parents between October 2015 and March 2016. Interviews were transcribed verbatim and thematically analysed. SETTING: Primary and secondary care in Bristol (UK). PARTICIPANTS: Interviews were held with 8 primary care practitioners (5 general practitioners, 2 nurse practitioners and 1 practice nurse), 9 parent-child dyads (2 fathers, 7 mothers, 6 sons, 3 daughters) of children aged 6-7 who had asthma and 4 secondary care professionals (2 respiratory consultants, 2 specialist nurses). RESULTS: Health professionals reported that physical activity was beneficial for children with asthma and if managed appropriately, children with asthma could be as active as children without asthma. Current promotion of physical activity for children with asthma was limited and restricted by NHS staff time, access to inhalers at school and a lack of parental knowledge. Potentially important components of a new programme include parental education on the possibilities of activity for children with asthma and the difference between exercise-induced breathlessness and asthma symptoms. Other important elements include how to use inhalers as a preventive measure, coping with exacerbations and practical solutions (such as clearing sputum), managing transitions from warm to cold climates and general symptom control. CONCLUSIONS: There is a need to build on current asthma programmes to increase the support for children with asthma to be physically active. Future programmes could consider working more closely with schools, increasing parental knowledge and providing children with practical support to help be physically active.


Assuntos
Asma/terapia , Atitude do Pessoal de Saúde , Atitude Frente a Saúde , Exercício/fisiologia , Promoção da Saúde/métodos , Pais/psicologia , Asma/psicologia , Criança , Feminino , Humanos , Entrevistas como Assunto , Masculino , Pesquisa Qualitativa , Reino Unido
16.
Pediatr Allergy Immunol ; 28(2): 191-198, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27779810

RESUMO

BACKGROUND: Animal data have suggested that the transient receptor potential ankyrin-1 (TRPA1) ion channel plays a key role in promoting airway inflammation in asthma and may mediate effects of paracetamol on asthma, yet confirmatory human data are lacking. To study associations of TRPA1 gene variants with childhood asthma and total IgE concentration, and interactions between TRPA1 and prenatal paracetamol exposure on these outcomes. METHODS: We analysed associations between 31 TRPA1 single nucleotide polymorphisms (SNPs) and current doctor-diagnosed asthma and total IgE concentration at 7.5 years in the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. We sought to confirm the most significant associations with comparable outcomes in the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) and Generation R birth cohorts. In ALSPAC, we explored interactions with prenatal paracetamol exposure. RESULTS: In ALSPAC, there was strong evidence for association between six SNPs and asthma: rs959974 and rs1384001 (per-allele odds ratio for both: 1.30 (95% CI: 1.15-1.47), p = 0.00001), rs7010969 (OR 1.28 (1.13-1.46), p = 0.00004), rs3735945 (OR 1.30 (1.09-1.55), p = 0.003), rs920829 (OR 1.30 (1.09-1.54), p = 0.004) and rs4738202 (OR 1.22 (1.07-1.39), p = 0.004). In a meta-analysis across the three cohorts, the pooled effect estimates confirmed that all six SNPs were significantly associated with asthma. In ALSPAC, TRPA1 associations with asthma were not modified by prenatal paracetamol, although associations with IgE concentration were. CONCLUSION: This study suggests that TRPA1 may play a role in the development of childhood asthma. (249 words).


Assuntos
Asma/genética , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Canal de Cátion TRPA1/genética , Acetaminofen/administração & dosagem , Acetaminofen/efeitos adversos , Asma/epidemiologia , Pré-Escolar , Estudos de Coortes , Feminino , Seguimentos , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Imunoglobulina E/sangue , Exposição Materna/efeitos adversos , Países Baixos/epidemiologia , Polimorfismo de Nucleotídeo Único , Gravidez
17.
J Allergy Clin Immunol ; 138(4): 1071-1080, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27130862

RESUMO

BACKGROUND: Asthma is a heterogeneous disease in which age of onset plays an important role. OBJECTIVE: We sought to identify the genetic variants associated with time to asthma onset (TAO). METHODS: We conducted a large-scale meta-analysis of 9 genome-wide association studies of TAO (total of 5462 asthmatic patients with a broad range of age of asthma onset and 8424 control subjects of European ancestry) performed by using survival analysis techniques. RESULTS: We detected 5 regions associated with TAO at the genome-wide significant level (P < 5 × 10-8). We evidenced a new locus in the 16q12 region (near cylindromatosis turban tumor syndrome gene [CYLD]) and confirmed 4 asthma risk regions: 2q12 (IL-1 receptor-like 1 [IL1RL1]), 6p21 (HLA-DQA1), 9p24 (IL33), and 17q12-q21 (zona pellucida binding protein 2 [ZPBP2]-gasdermin A [GSDMA]). Conditional analyses identified 2 distinct signals at 9p24 (both upstream of IL33) and 17q12-q21 (near ZPBP2 and within GSDMA). Together, these 7 distinct loci explained 6.0% of the variance in TAO. In addition, we showed that genetic variants at 9p24 and 17q12-q21 were strongly associated with an earlier onset of childhood asthma (P ≤ .002), whereas the 16q12 single nucleotide polymorphism was associated with later asthma onset (P = .04). A high burden of disease risk alleles at these loci was associated with earlier age of asthma onset (4 vs 9-12 years, P = 10-4). CONCLUSION: The new susceptibility region for TAO at 16q12 harbors variants that correlate with the expression of CYLD and nucleotide-binding oligomerization domain 2 (NOD2), 2 strong candidates for asthma. This study demonstrates that incorporating the variability of age of asthma onset in asthma modeling is a helpful approach in the search for disease susceptibility genes.


Assuntos
Asma/genética , Cromossomos Humanos Par 16/genética , Variação Genética , Adolescente , Idade de Início , Criança , Enzima Desubiquitinante CYLD , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Proteína Adaptadora de Sinalização NOD2/genética , Proteínas Supressoras de Tumor/genética
18.
Pediatr Pulmonol ; 51(11): 1212-1221, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27124554

RESUMO

BACKGROUND: Early-term-born subjects, (37-38 weeks' gestation), form a large part of the population and have an increased risk of neonatal respiratory morbidity and childhood respiratory symptoms; there is a paucity of data on their later lung function. We sought to (1) compare lung function at 8-9 and 14-17 years in early-term-born children with full-term-born children (39-43 weeks' gestation); (2) assess the role of caesarean section delivery; and (3) compare respiratory symptoms and diagnosis of asthma. METHODS: Caucasian, singleton, term births from the Avon Longitudinal Study of Parents and Children (n = 14,062) who had lung spirometry at 8-9 (n = 5,465) and/or 14-17 (n = 3,666) years were classified as early or full term. RESULTS: At 8-9 years, standardized spirometry measures, although within the normal range, were lower in the early-term-born group, (n = 911), compared to full-term controls (n = 4,554). Delivery by caesarean section did not influence later spirometry, and the effect of early-term birth was not modified by delivery by caesarean section. At 14-17 years, the spirometry measures in the early-term group, (n = 602), were similar to the full-term group (3,064), and the rates of asthma and respiratory symptoms were also similar between the two gestation groups. CONCLUSIONS: Early-term-born children had lower lung function values at 8-9 years compared to the full-term group, but were similar by 14-17 years of age. Delivery at early term should be avoided due to early and late morbidity. Pediatr Pulmonol. 2016;51:1212-1221. © 2016 Wiley Periodicals, Inc.


Assuntos
Asma/fisiopatologia , Idade Gestacional , Pulmão/fisiopatologia , Nascimento Prematuro/fisiopatologia , Sons Respiratórios/fisiopatologia , Adolescente , Cesárea , Criança , Pré-Escolar , Feminino , Humanos , Estudos Longitudinais , Masculino , Gravidez , Testes de Função Respiratória , Espirometria
19.
J Allergy Clin Immunol ; 138(4): 1060-1070.e11, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27106203

RESUMO

BACKGROUND: Variable patterns of childhood wheezing might indicate differences in the cause and prognosis of respiratory illnesses. Better understanding of these patterns could facilitate identification of modifiable factors related to development of asthma. OBJECTIVES: We characterized childhood wheezing phenotypes from infancy to adolescence and their associations with asthma outcomes. METHODS: Latent class analysis was used to derive phenotypes based on patterns of wheezing recorded at up to 14 time points from birth to 16½ years among 12,303 participants from the Avon Longitudinal Study of Parents and Children. Measures of lung function (FEV1, forced vital capacity [FVC], and forced expiratory flow between 25% and 75% [FEF25-75]) and fraction of exhaled nitric oxide (Feno) were made at 14 to 15 years of age. RESULTS: Six wheezing phenotypes were identified: never/infrequent, preschool-onset remitting, midchildhood-onset remitting, school age-onset persisting, late childhood-onset persisting, and continuous wheeze. The 3 persistent phenotypes were associated with bronchodilator reversibility of 12% or greater (BDR) from baseline (odds ratio [OR] range, 2.14-3.34), a Feno value of 35 ppb or greater (OR range, 3.82-6.24), and lung function decrements (mean range of differences: -0.22 to -0.27 SD units (SDU) for FEV1/FVC ratio and -0.21 to -0.33 SDU for FEF25-75) compared with never/infrequent wheeze. Midchildhood-onset (4½ years) remitting wheeze was associated with BDR (OR, 1.77; 95% CI, 1.11-2.82), a Feno value of 35 ppb or greater (OR, 1.72; 95% CI, 1.14-2.59), FEV1/FVC ratio decrements (OR, -0.22 SDU; 95% CI, -0.36 to -0.08 SDU), and FEF25-75 decrements (OR, -0.16 SDU; 95% CI, -0.30 to -0.01 SDU). Preschool-onset (18 months) remitting wheeze was only associated with FEV1/FVC ratio decrements (OR, -0.15 SDU; 95% CI, -0.25 to -0.05 SDU) and FEF25-75 decrements (OR, -0.14 SDU; 95% CI, -0.24 to -0.04 SDU). The persisting phenotypes showed evidence of sex stratification during adolescence. CONCLUSIONS: Early childhood-onset wheezing that persists into adolescence represents the clearest target group for interventions to maximize lung function outcomes.


Assuntos
Asma/patologia , Sons Respiratórios/classificação , Adolescente , Idade de Início , Asma/complicações , Asma/epidemiologia , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Estudos Longitudinais , Masculino , Fenótipo , Sons Respiratórios/etiologia , Sons Respiratórios/fisiopatologia , Inquéritos e Questionários , Fatores de Tempo
20.
Eur Respir J ; 47(1): 156-65, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26541530

RESUMO

Few epidemiological studies have investigated the role of hypertensive disorders of pregnancy in the aetiology of childhood respiratory and atopic outcomes.In the Avon Longitudinal Study of Parents and Children we examined associations of maternal gestational hypertension, hypertension before pregnancy and pre-eclampsia with wheezing at 18 months, wheezing and asthma at 7 years and lung function at 8-9 years, after controlling for potential confounders (n=5322-8734, depending on outcome).Gestational hypertension was not associated with any of the outcomes. There was weak evidence for a positive association between pre-eclampsia and early wheezing (adjusted OR 1.31, 95% CI 0.94-1.82, compared to normotensive pregnancies) and for negative associations between pre-eclampsia and forced expiratory volume in 1 s (adjusted mean difference in sd score -0.14, 95% CI -0.33-0.06) and maximal mid-expiratory flow (-0.15, 95% CI -0.34-0.04). Hypertension before pregnancy was positively associated with wheezing (OR 1.63, 95% CI 1.16-2.31) and asthma (OR 1.34, 95% CI 1.00-1.79).Gestational hypertension is unlikely to be a risk factor for childhood respiratory disorders; hypertension before pregnancy may be a risk factor for childhood wheezing and asthma, but this finding needs replication. Larger studies are needed to confirm whether pre-eclampsia is associated with impaired childhood lung function.


Assuntos
Asma/epidemiologia , Hipersensibilidade Imediata/epidemiologia , Hipertensão Induzida pela Gravidez/epidemiologia , Hipertensão/epidemiologia , Pré-Eclâmpsia/epidemiologia , Complicações Cardiovasculares na Gravidez/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Asma/fisiopatologia , Criança , Feminino , Volume Expiratório Forçado , Humanos , Lactente , Estudos Longitudinais , Masculino , Gravidez , Sons Respiratórios/fisiopatologia , Fatores de Risco , Reino Unido/epidemiologia
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