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1.
Eur Respir J ; 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33795317

RESUMO

Longitudinal epidemiological data are scarce on the relation between dietary intake of vitamin A and respiratory outcomes in childhood. We investigated whether a higher intake of preformed vitamin A or provitamin ß-carotene in mid-childhood is associated with higher lung function and with asthma risk in adolescence.In the Avon Longitudinal Study of Parents and Children, dietary intakes of preformed vitamin A and ß-carotene equivalents were estimated by food frequency questionnaire at 7 years of age. Post- bronchodilator forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and forced expiratory flow at 25-75% of FVC (FEF25-75) were measured at 15.5 years and transformed to z scores. Incident asthma was defined by new cases of doctor-diagnosed asthma at age 11 or 14 years.In multivariable adjusted models, a higher intake of preformed vitamin A was associated with higher lung function and a lower risk of incident asthma: comparing top versus bottom quartiles of intake, regression coefficients (95% confidence intervals) for FEV1 and FEF25-75 were, respectively, 0.21 (0.05-0.38; P-trend 0.008) and 0.18 (0.03-0.32; P-trend 0.02); odds ratios (95% confidence intervals) for FEV1/FVC ratio below the lower limit of normal and incident asthma were, respectively, 0.49 (0.27-0.90, P-trend 0.04) and 0.68 (0.47, 0.99; P-trend 0.07). In contrast, there was no evidence for association with ß-carotene. We also found some evidence for modification of the associations between preformed vitamin A intake and lung function by BCMO1, NCOR2 and CC16 gene polymorphisms.A higher intake of preformed vitamin A, but not ß-carotene, in mid-childhood is associated with higher subsequent lung function and lower risk of fixed airflow limitation and incident asthma.

3.
Eur Respir J ; 2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33574079

RESUMO

BACKGROUND: Observational studies suggest an association between reduced lung function and risk of coronary artery disease and ischaemic stroke, independent of shared cardiovascular risk factors such as cigarette smoking. We use the latest genetic epidemiological methods to determine if impaired lung function is causally associated with an increased risk of cardiovascular disease. METHODS AND FINDINGS: Mendelian Randomisation uses genetic variants as instrumental variables to investigate causation. Preliminary analysis used two sample Mendelian Randomisation with lung function single nucleotide polymorphisms. To avoid collider bias the main analysis used single nucleotide polymorphisms for lung function identified from UKBiobank in a Multivariable Mendelian Randomisation model conditioning for height, body mass index and smoking.Multivariable Mendelian Randomisation shows strong evidence that reduced FVC causes increased risk of coronary artery disease, Odds Ratio:1·32 (1·19-1·46) per Standard Deviation. Reduced FEV1 is unlikely to be cause increased risk of coronary artery disease as evidence of its effect becomes weak after conditioning for height 1·08 (0·89, 1·30). There is weak evidence that reduced lung function increases risk of ischaemic stroke. CONCLUSION: There is strong evidence that reduced FVC is independently and causally associated with coronary artery disease. Although the mechanism remains unclear, FVC could be taken into consideration when assessing cardiovascular risk and considered a potential target for reducing cardiovascular events. FEV1 and airflow obstruction do not appear to cause increased cardiovascular events, confounding and collider bias may explain previous findings of a causal association.

4.
Environ Health ; 20(1): 4, 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33413476

RESUMO

BACKGROUND: Evidence suggests that exposure to particulate matter with aerodynamic diameter less than 10 µm (PM10) is associated with reduced birth weight, but information is limited on the sources of PM10 and exposure misclassification from assigning exposures to place of residence at birth. METHODS: Trimester and source-specific PM10 exposures (PM10 from road source, local non-road source, and total source) in pregnancy were estimated using dispersion models and a full maternal residential history for 12,020 births from the Avon longitudinal study of parents and children (ALSPAC) cohort in 1990-1992 in the Bristol area. Information on birth outcomes were obtained from birth records. Maternal sociodemographic and lifestyle factors were obtained from questionnaires. We used linear regression models for continuous outcomes (birth weight, head circumference (HC), and birth length (BL) and logistic regression models for binary outcomes (preterm birth (PTB), term low birth weight (TLBW) and small for gestational age (SGA)). Sensitivity analysis was performed using multiple imputation for missing covariate data. RESULTS: After adjustment, interquartile range increases in source specific PM10 from traffic were associated with 17 to 18% increased odds of TLBW in all pregnancy periods. We also found odds of TLBW increased by 40% (OR: 1.40, 95%CI: 1.12, 1.75) and odds of SGA increased by 18% (OR: 1.18, 95%CI: 1.05, 1.32) per IQR (6.54 µg/m3) increase of total PM10 exposure in the third trimester. CONCLUSION: This study adds to evidence that maternal PM10 exposures affect birth weight, with particular concern in relation to exposures to PM10 from road transport sources; results for total PM10 suggest greatest effect in the third trimester. Effect size estimates relate to exposures in the 1990s and are higher than those for recent studies - this may relate to reduced exposure misclassification through use of full residential history information, changes in air pollution toxicity over time and/or residual confounding.

5.
Eur Respir J ; 2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33509958

RESUMO

Longitudinal evidence on the relation between dietary intake of n-3 (omega-3) very long-chain polyunsaturated fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), in mid-childhood and asthma risk is scarce. We aimed to investigate whether a higher intake of EPA and DHA from fish in childhood is associated with a lower risk of incident asthma.In the Avon Longitudinal Study of Parents and Children, dietary intakes of EPA and DHA from fish were estimated by food frequency questionnaire at 7 years of age. We used logistic regression, controlling for confounders, to analyse associations between intake of EPA and DHA (quartiles) and incidence of doctor-diagnosed asthma at age 11 or 14 years, and explored potential effect modification by a fatty acid desaturase (FADS) polymorphism (rs1535). Replication was sought in the Swedish BAMSE birth cohort.There was no evidence of association between intake of EPA plus DHA from fish and incident asthma overall (n=4543). However, when stratified by FADS genotype, the odds ratio (95% confidence interval) comparing top versus bottom quartile amongst the 2025 minor G allele carriers was 0.49 (0.31-0.79) (p-trend 0.006), but no inverse association was observed in the homozygous major A allele group (odds ratio 1.43, 95% confidence interval 0.83-2.46, p-trend 0.19) (p-interaction 0.006). This gene-nutrient interaction on incident asthma was replicated in BAMSE.In children with a common FADS variant, higher intake of EPA and DHA from fish in childhood was strongly associated with a lower risk of incident asthma up to mid-adolescence.

6.
Eur Respir J ; 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33303529

RESUMO

RATIONALE: Substantial variability in response to asthma treatment with inhaled corticosteroids (ICS) has been described among individuals and populations, suggesting the contribution of genetic factors. Nonetheless, only a few genes have been identified to date. We aimed to identify genetic variants associated with asthma exacerbations despite ICS use in European children and young adults and to validate the findings in non-Europeans. Moreover, we explored whether a gene-set enrichment analysis could suggest potential novel asthma therapies. METHODS: A genome-wide association study (GWAS) of asthma exacerbations was tested in 2681 European-descent children treated with ICS from eight studies. Suggestive association signals were followed up for replication in 538 European asthma patients. Further evaluation was performed in 1773 non-Europeans. Variants revealed by published GWAS were assessed for replication. Additionally, gene-set enrichment analysis focused on drugs was performed. RESULTS: Ten independent variants were associated with asthma exacerbations despite ICS treatment in the discovery phase (p≤5×10-6). Of those, one variant at the CACNA2D3-WNT5A locus was nominally replicated in Europeans (rs67026078, p=0.010), but this was not validated in non-European populations. Five other genes associated with ICS response in previous studies were replicated. Additionally, an enrichment of associations in genes regulated by trichostatin A treatment was found. CONCLUSIONS: The intergenic region of CACNA2D3 and WNT5A was revealed as a novel locus for asthma exacerbations despite ICS treatment in European populations. Genes associated were related to trichostatin A, suggesting that this drug could regulate the molecular mechanisms involved in treatment response.

7.
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.
Environ Int ; 140: 105749, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32380303

RESUMO

BACKGROUND: Residing in greener areas is increasingly linked to beneficial health outcomes, but little is known about its effect on respiratory health. OBJECTIVE: We examined associations between residential greenness and nearby green spaces with lung function up to 24 years in the UK Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. METHODS: Lung function was measured by spirometry at eight, 15 and 24 years of age. Greenness levels within circular buffers (100-1000 m) around the birth, eight-, 15- and 24-year home addresses were calculated using the satellite-derived Normalized Difference Vegetation Index and averaged (lifetime greenness). The presence and proportion of green spaces (urban green spaces, forests and agricultural land) within a 300 m buffer was determined. First, associations between repeated greenness and green space variables and repeated lung function parameters were assessed using generalized estimation equations (N = 7094, 47.9% male). Second, associations between lifetime average greenness and lifetime average proportion of green spaces with lung function at 24-years were assessed using linear regression models (N = 1763, 39.6% male). All models were adjusted for individual and environmental covariates. RESULTS: Using repeated greenspace and lung function data at eight, 15 and 24 years, greenness in a 100 m buffer was associated with higher FEV1 and FVC (11.4 ml [2.6, 20.3] and 12.2 ml [1.8, 22.7], respectively, per interquartile range increase), as was the presence of urban green spaces in a 300 m buffer (20.3 ml [-0.1, 40.7] and 23.1 ml [-0.3, 46.5] for FEV1 and FVC, respectively). These associations were independent of air pollution, urbanicity and socio-economic status. Lifetime average greenness within a 100 m buffer and proportion of agricultural land within a 300 m buffer were associated with better lung function at 24 years but adjusting for asthma attenuated these associations. DISCUSSION: This study provides suggestive evidence that children whose homes are in more vegetated places or are in close proximity of green spaces have better lung function up to 24 years of age.

10.
Am J Respir Crit Care Med ; 202(1): 112-123, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32142356

RESUMO

Rationale: Exposure to air pollution during intrauterine development and through childhood may have lasting effects on respiratory health.Objectives: To investigate lung function at ages 8 and 15 years in relation to air pollution exposures during pregnancy, infancy, and childhood in a UK population-based birth cohort.Methods: Individual exposures to source-specific particulate matter ≤10 µm in aerodynamic diameter (PM10) during each trimester, 0-6 months, 7-12 months (1990-1993), and up to age 15 years (1991-2008) were examined in relation to FEV1% predicted and FVC% predicted at ages 8 (n = 5,276) and 15 (n = 3,446) years using linear regression models adjusted for potential confounders. A profile regression model was used to identify sensitive time periods.Measurements and Main Results: We did not find clear evidence of a sensitive exposure period for PM10 from road traffic. At age 8 years, 1 µg/m3 higher exposure during the first trimester was associated with lower FEV1% predicted (-0.826; 95% confidence interval [CI], -1.357 to -0.296) and FVC% predicted (-0.817; 95% CI, -1.357 to -0.276), but similar associations were seen for exposures for other trimesters, 0-6 months, 7-12 months, and 0-7 years. Associations were stronger among boys, as well as children whose mother had a lower education level or smoked during pregnancy. For PM10 from all sources, the third trimester was associated with lower FVC% predicted (-1.312; 95% CI, -2.100 to -0.525). At age 15 years, no adverse associations with lung function were seen.Conclusions: Exposure to road-traffic PM10 during pregnancy may result in small but significant reductions in lung function at age 8 years.


Assuntos
Poluentes Atmosféricos/toxicidade , Poluição do Ar/efeitos adversos , Exposição Ambiental/efeitos adversos , Pulmão/efeitos dos fármacos , Pulmão/fisiopatologia , Material Particulado/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Adolescente , Poluição do Ar/análise , Poluição do Ar/estatística & dados numéricos , Criança , Saúde da Criança , Pré-Escolar , Exposição Ambiental/análise , Exposição Ambiental/estatística & dados numéricos , Feminino , Volume Expiratório Forçado , Nível de Saúde , Humanos , Lactente , Recém-Nascido , Modelos Lineares , Estudos Longitudinais , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/diagnóstico , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Reino Unido/epidemiologia , Emissões de Veículos/análise , Emissões de Veículos/toxicidade , Capacidade Vital
12.
Int J Epidemiol ; 49(1): 131-141, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31270549

RESUMO

BACKGROUND: Although physical activity has many known health benefits, its association with lung function in childhood/adolescence remains unclear. We examined the association of physical-activity trajectories between 11 and 15 years with lung function at 15 years in 2266 adolescents. METHODS: A population-based cohort of 14 305 singleton births alive at 1 year was recruited in the UK population-based Avon Longitudinal Study of Parents and Children cohort. Physical activity (counts/minute and moderate-to-vigorous physical activity) was assessed for 7 days using an accelerometer at 11, 13 and 15 years. We identified sex-specific physical-activity trajectories applying K-means for longitudinal data in children with at least two accelerometer measurements (n = 3584). We then estimated the sex-specific associations of these trajectories with post-bronchodilation lung-function parameters using multivariable linear-regression models (n = 2266, 45% boys). RESULTS: Fewer than 7% of participants met the WHO physical-activity recommendations (i.e. daily average of at least 60 minutes of moderate-to-vigorous physical activity). Boys were substantially more active than girls. In both sexes, we identified three distinct physical-activity trajectories ('low': 39.8% boys, 45.8% girls; 'moderate': 42.9% boys, 41.4% girls; and 'high' physical activity: 17.3% boys, 12.8% girls). Girls in the moderate and high physical-activity trajectories had 0.11 L [95% confidence interval (CI): 0.04-0.19] and 0.15 L (95% CI: 0.03-0.26) higher forced vital capacity than their less-active peers. No association was observed in boys. CONCLUSIONS: Higher childhood physical activity relates to higher lung-function levels in adolescent girls. A better understanding of the mechanisms underlying this association should be pursued.


Assuntos
Exercício Físico , Pulmão/fisiologia , Vigilância da População/métodos , Adolescente , Índice de Massa Corporal , Criança , Estudos de Coortes , Feminino , Humanos , Estudos Longitudinais , Masculino , Capacidade Vital
13.
Clin Exp Allergy ; 49(10): 1342-1351, 2019 10.
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.


Assuntos
Asma/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Poluição por Fumaça de Tabaco/efeitos adversos , Criança , Citocromo P-450 CYP1B1/genética , Proteínas do Citoesqueleto/genética , Enzimas Reparadoras do DNA/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Hidrolases/genética , Masculino , Proteínas dos Microfilamentos/genética , Proteínas Nucleares/genética
14.
Clin Exp Allergy ; 49(11): 1475-1486, 2019 11.
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.


Assuntos
Eczema/genética , Hipersensibilidade/genética , Polimorfismo de Nucleotídeo Único , Sons Respiratórios/genética , Rinite/genética , Criança , Feminino , Estudo de Associação Genômica Ampla , Humanos , Estudos Longitudinais , Masculino
15.
Thorax ; 74(7): 633-642, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30936389

RESUMO

INTRODUCTION: Males have a higher prevalence of asthma in childhood, whereas females have a higher prevalence in adolescence and adulthood. The 'adolescent switch' observed between sexes during puberty has been hypothesised to be due to fluctuating sex hormones. Robust evidence of the involvement of sex hormones in asthma could lead to development of therapeutic interventions. METHODS: We combine observational evidence using longitudinal data on sex hormone-binding globulin (SHBG), total and bioavailable testosterone and asthma from a subset of males (n=512) in the Avon Longitudinal Study of Parents and Children, and genetic evidence of SHBG and asthma using two-sample Mendelian randomisation (MR), a method of causal inference. We meta-analysed two-sample MR results across two large data sets, the Trans-National Asthma Genetics Consortium genome-wide association study of asthma and UK Biobank (over 460 000 individuals combined). RESULTS: Observational evidence indicated weak evidence of a protective effect of increased circulating testosterone on asthma in males in adolescence, but no strong pattern of association with SHBG. Genetic evidence using two-sample MR indicated a protective effect of increased SHBG, with an OR for asthma of 0.86 (95% CI 0.74 to 1.00) for the inverse-variance weighted approach and an OR of 0.83 (95% CI 0.72 to 0.96) for the weighted median estimator, per unit increase in natural log SHBG. A sex-stratified sensitivity analysis suggested the protective effect of SHBG was mostly evident in females. CONCLUSION: We report the first suggestive evidence of a protective effect of genetically elevated SHBG on asthma, which may provide a biological explanation behind the observed asthma sex discordance. Further work is required to disentangle the downstream effects of SHBG on asthma and the molecular pathways involved.


Assuntos
Asma/genética , Hormônios Esteroides Gonadais/fisiologia , Asma/sangue , Asma/fisiopatologia , Medicina Baseada em Evidências/métodos , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise da Randomização Mendeliana , Estudos Observacionais como Assunto , Fatores Sexuais , Globulina de Ligação a Hormônio Sexual/metabolismo , Testosterona/sangue , Testosterona/fisiologia , Bancos de Tecidos
16.
Am J Hum Genet ; 104(4): 665-684, 2019 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-30929738

RESUMO

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


Assuntos
Asma/genética , Predisposição Genética para Doença , Adolescente , Adulto , Idade de Início , Alelos , Criança , Pré-Escolar , Feminino , Estudo de Associação Genômica Ampla , Humanos , Hipersensibilidade , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Fatores de Risco , Reino Unido , Adulto Jovem
17.
Ann Am Thorac Soc ; 16(7): 868-876, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30888842

RESUMO

Rationale: Pooling data from multiple cohorts and extending the time frame across childhood should minimize study-specific effects, enabling better characterization of childhood wheezing. Objectives: To analyze wheezing patterns from early childhood to adolescence using combined data from five birth cohorts. Methods: We used latent class analysis to derive wheeze phenotypes among 7,719 participants from five birth cohorts with complete report of wheeze at five time periods. We tested the associations of derived phenotypes with late asthma outcomes and lung function, and investigated the uncertainty in phenotype assignment. Results: We identified five phenotypes: never/infrequent wheeze (52.1%), early onset preschool remitting (23.9%), early onset midchildhood remitting (9%), persistent (7.9%), and late-onset wheeze (7.1%). Compared with the never/infrequent wheeze, all phenotypes had higher odds of asthma and lower forced expiratory volume in 1 second and forced expiratory volume in 1 second/forced vital capacity in adolescence. The association with asthma was strongest for persistent wheeze (adjusted odds ratio, 56.54; 95% confidence interval, 43.75-73.06). We observed considerable within-class heterogeneity at the individual level, with 913 (12%) children having low membership probability (<0.60) of any phenotype. Class membership certainty was highest in persistent and never/infrequent, and lowest in late-onset wheeze (with 51% of participants having membership probabilities <0.80). Individual wheezing patterns were particularly heterogeneous in late-onset wheeze, whereas many children assigned to early onset preschool remitting class reported wheezing at later time points. Conclusions: All wheeze phenotypes had significantly diminished lung function in school-age children, suggesting that the notion that early life episodic wheeze has a benign prognosis may not be true for a proportion of transient wheezers. We observed considerable within-phenotype heterogeneity in individual wheezing patterns.


Assuntos
Asma/diagnóstico , Asma/patologia , Sons Respiratórios/classificação , Adolescente , Idade de Início , Asma/complicações , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Volume Expiratório Forçado , Humanos , Lactente , Modelos Logísticos , Masculino , Fenótipo , Sons Respiratórios/etiologia , Capacidade Vital
18.
Am J Respir Crit Care Med ; 200(1): 75-83, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30630337

RESUMO

Rationale: Body composition changes throughout life may explain the inconsistent associations reported between body mass index and lung function in children. Objectives: To assess the associations of body weight and composition trajectories from 7 to 15 years with lung function at 15 years and lung function growth between 8 and 15 years. Methods: Sex-specific body mass index, lean body mass index, and fat mass index trajectories were developed using Group-Based Trajectory Modeling on data collected at least twice between 7 and 15 years from 6,964 children (49% boys) in the UK Avon Longitudinal Study of Parents and Children birth cohort. Associations of these trajectories with post-bronchodilation lung function parameters at 15 years and with lung function growth rates from 8 to 15 years were assessed using multivariable linear regression models, stratified by sex, in a subgroup with lung function data (n = 3,575). Measurements and Main Results: For all body mass measures we identified parallel trajectories that increased with age. There was no consistent evidence of an association between the body mass index trajectories and lung function measures. Higher lean body mass index trajectories were associated with higher levels and growth rates of FVC, FEV1, and forced expiratory flow, midexpiratory phase in both sexes (e.g., boys in the highest lean body mass index trajectory had on average a 0.62 L [95% confidence interval, 0.44-0.79; P trend < 0.0001] higher FVC at 15 yr than boys in the lowest trajectory). Increasing fat mass index trajectories were associated with lower levels and growth rates of FEV1 and forced expiratory flow, midexpiratory phase only in boys and lower levels of FEV1/FVC in both sexes. Conclusions: Higher lean body mass during childhood and adolescence is consistently associated with higher lung function at 15 years in both sexes, whereas higher fat mass is associated with lower levels of only some lung function parameters.


Assuntos
Composição Corporal , Trajetória do Peso do Corpo , Pulmão/fisiologia , Tecido Adiposo , Adolescente , Índice de Massa Corporal , Criança , Feminino , Volume Expiratório Forçado , Humanos , Modelos Lineares , Estudos Longitudinais , Pulmão/fisiopatologia , Masculino , Fluxo Máximo Médio Expiratório , Análise Multivariada , Reino Unido , Capacidade Vital
19.
Am J Epidemiol ; 188(3): 527-536, 2019 03 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.


Assuntos
Exposição Materna/efeitos adversos , Nascimento Prematuro/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Sons Respiratórios/fisiopatologia , Nascimento a Termo/fisiologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Fenótipo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Fatores de Risco
20.
J Allergy Clin Immunol ; 143(5): 1783-1790.e11, 2019 05.
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.


Assuntos
Asma/diagnóstico , Coleta de Dados/estatística & dados numéricos , Sons Respiratórios/diagnóstico , Adulto , Idade de Início , Asma/epidemiologia , Viés , Criança , Estudos de Coortes , Feminino , Humanos , Análise de Classes Latentes , Masculino , Modelos Estatísticos , Fenótipo , Prevalência , Fatores de Risco , Tamanho da Amostra , Adulto Jovem
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