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1.
Clin Exp Allergy ; 49(11): 1475-1486, 2019 Nov.
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.
Int J Epidemiol ; 2019 Jul 03.
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.

4.
Thorax ; 74(7): 633-642, 2019 Jul.
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.

5.
Am J Hum Genet ; 104(4): 665-684, 2019 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-30929738

RESUMO

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

6.
Ann Am Thorac Soc ; 16(7): 868-876, 2019 Jul.
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.

7.
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.

8.
Am J Respir Crit Care Med ; 200(1): 75-83, 2019 Jul 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.

9.
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.

10.
BMC Genet ; 19(1): 113, 2018 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-30547757

RESUMO

BACKGROUND: Levels of sex hormone-binding globulin (SHBG) and the androgen testosterone have been associated with risk of diseases throughout the lifecourse. Although both SHBG and testosterone have been shown to be highly heritable, only a fraction of that heritability has been explained by genetic studies. Epigenetic modifications such as DNA methylation may explain some of the missing heritability and could potentially inform biological knowledge of endocrine disease mechanisms involved in development of later life disease. Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC), we explored cross-sectional associations of SHBG, total testosterone and bioavailable testosterone in childhood (males only) and adolescence (both males and females) with genome-wide DNA methylation. We also report associations of a SHBG polymorphism (rs12150660) with DNA methylation, which leads to differential levels of SHBG in carriers, as a genetic proxy of circulating SHBG levels. RESULTS: We identified several novel sites and genomic regions where levels of SHBG, total testosterone, and bioavailable testosterone were associated with DNA methylation, including one region associated with total testosterone in males (annotated to the KLHL31 gene) in both childhood and adolescence and a second region associated with bioavailable testosterone (annotated to the CMYA5 gene) at both time-points. We also identified one region where both SHBG and bioavailable testosterone in males in childhood (annotated to the ZNF718 gene) was associated with DNA methylation. CONCLUSION: Our findings have important implications in the understanding of the biological processes of SHBG and testosterone, with the potential for future work to determine the molecular mechanisms that could underpin these associations.


Assuntos
Metilação de DNA , Globulina de Ligação a Hormônio Sexual/metabolismo , Testosterona/metabolismo , Adolescente , Criança , Epigenômica , Feminino , Genótipo , Humanos , Modelos Lineares , Estudos Longitudinais , Masculino , Polimorfismo de Nucleotídeo Único , Globulina de Ligação a Hormônio Sexual/análise , Globulina de Ligação a Hormônio Sexual/genética , Testosterona/análise
11.
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.

13.
PLoS Med ; 15(8): e1002634, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30086135

RESUMO

BACKGROUND: Observational studies on pubertal timing and asthma, mainly performed in females, have provided conflicting results about a possible association of early puberty with higher risk of adult asthma, possibly due to residual confounding. To overcome issues of confounding, we used Mendelian randomisation (MR), i.e., genetic variants were used as instrumental variables to estimate causal effects of early puberty on post-pubertal asthma in both females and males. METHODS AND FINDINGS: MR analyses were performed in UK Biobank on 243,316 women using 254 genetic variants for age at menarche, and on 192,067 men using 46 variants for age at voice breaking. Age at menarche, recorded in years, was categorised as early (<12), normal (12-14), or late (>14); age at voice breaking was recorded and analysed as early (younger than average), normal (about average age), or late (older than average). In females, we found evidence for a causal effect of pubertal timing on asthma, with an 8% increase in asthma risk for early menarche (odds ratio [OR] 1.08; 95% CI 1.04 to 1.12; p = 8.7 × 10-5) and an 8% decrease for late menarche (OR 0.92; 95% CI 0.89 to 0.97; p = 3.4 × 10-4), suggesting a continuous protective effect of increasing age at puberty. In males, we found very similar estimates of causal effects, although with wider confidence intervals (early voice breaking: OR 1.07; 95% CI 1.00 to 1.16; p = 0.06; late voice breaking: OR 0.93; 95% CI 0.87 to 0.99; p = 0.03). We detected only modest pleiotropy, and our findings showed robustness when different methods to account for pleiotropy were applied. BMI may either introduce pleiotropy or lie on the causal pathway; secondary analyses excluding variants associated with BMI yielded similar results to those of the main analyses. Our study relies on self-reported exposures and outcomes, which may have particularly affected the power of the analyses on age at voice breaking. CONCLUSIONS: This large MR study provides evidence for a causal detrimental effect of early puberty on asthma, and does not support previous observational findings of a U-shaped relationship between pubertal timing and asthma. Common biological or psychological mechanisms associated with early puberty might explain the similarity of our results in females and males, but further research is needed to investigate this. Taken together with evidence for other detrimental effects of early puberty on health, our study emphasises the need to further investigate and address the causes of the secular shift towards earlier puberty observed worldwide.

15.
Nat Genet ; 50(8): 1072-1080, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30013184

RESUMO

Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries1,2. To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis.

16.
Artigo em Inglês | MEDLINE | ID: mdl-29995435

RESUMO

RATIONALE: Puberty may influence lung function, but the precise role of pubertal height growth in lung development is unclear. OBJECTIVES: To examine associations of timing of puberty and peak velocity of pubertal height growth with lung function in adolescence and early-adulthood. METHODS: Longitudinal analyses of repeat height measurements from age 5-20 years for a British birth cohort with 4,772 males and 4,849 females were conducted to characterise height growth trajectories, and derive pubertal age and peak height velocity using the validated SuperImposition by Translation and Rotation (SITAR) model. Association of these estimates with pre-bronchodilator and post-bronchodilator spirometry measures: FEV1; FVC; FEV1/FVC; FEF25-75 at age 15 and 24 years were investigated using multivariable regression models adjusted for lung function at age 8 years, height and age at time of outcome measurements, and potential confounders. MEASUREMENTS AND MAIN RESULTS: Later pubertal age and greater peak velocity were associated with higher FEV1 and FVC at 24 years in both sexes. A 1-year advanced pubertal age was associated with a 263 ml higher FVC (95% confidence interval: 167, 360) for males (n=567), 100 ml (50, 150) for females (n=990). A 1-cm/year increase in peak velocity was associated with 145 ml (56, 234) and 50 ml (2, 99) increase in FVC for males and females respectively. No associations were found with FEV1/FVC. CONCLUSIONS: Later onset and greater peak velocity of height growth in puberty are associated with increased FEV1 and FVC in young adults but there was no evidence of dysanapsis of pubertal lung growth.

17.
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.

18.
Nat Genet ; 50(1): 42-53, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29273806

RESUMO

We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms.

19.
Eur Respir J ; 50(5)2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29097430

RESUMO

The distinction between episodic viral wheeze (EVW) and multitrigger wheeze (MTW) is used to guide management of preschool wheeze. It has been questioned whether these phenotypes are stable over time. We examined the temporal stability of MTW and EVW in two large population-based cohorts.We classified children from the Avon Longitudinal Study of Parents and Children (n=10 970) and the Leicester Respiratory Cohorts ((LRCs), n=3263) into EVW, MTW and no wheeze at ages 2, 4 and 6 years based on parent-reported symptoms. Using multinomial regression, we estimated relative risk ratios for EVW and MTW at follow-up (no wheeze as reference category) with and without adjusting for wheeze severity.Although large proportions of children with EVW and MTW became asymptomatic, those that continued to wheeze showed a tendency to remain in the same phenotype: among children with MTW at 4 years in the LRCs, the adjusted relative risk ratio was 15.6 (95% CI 8.3-29.2) for MTW (stable phenotype) compared to 7.0 (95% CI 2.6-18.9) for EVW (phenotype switching) at 6 years. The tendency to persist was weaker for EVW and from 2-4 years. Results were similar across cohorts.This suggests that MTW, and to a lesser extent EVW, tend to persist regardless of wheeze severity.


Assuntos
Sons Respiratórios/classificação , Sons Respiratórios/diagnóstico , Viroses/diagnóstico , Asma/diagnóstico , Criança , Pré-Escolar , Feminino , Humanos , Modelos Logísticos , Estudos Longitudinais , Masculino , Fenótipo , Testes de Função Respiratória , Sons Respiratórios/fisiopatologia , Fatores de Risco , Fatores de Tempo , Reino Unido , Viroses/fisiopatologia
20.
Clin Epigenetics ; 9: 112, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29046734

RESUMO

BACKGROUND: Asthma heritability has only been partially explained by genetic variants and is known to be sensitive to environmental factors, implicating epigenetic modifications such as DNA methylation in its pathogenesis. METHODS: Using data collected in the Avon Longitudinal Study of Parents and Children (ALSPAC), we assessed associations of asthma and wheeze with DNA methylation at 7.5 and 16.5 years, at over 450,000 CpG sites in DNA from the peripheral blood of approx. 1000 participants. We used Mendelian randomization (MR), a method of causal inference that uses genetic variants as instrumental variables, to infer the direction of association between DNA methylation and asthma. RESULTS: We identified 302 CpGs associated with current asthma status (FDR-adjusted P value < 0.05) and 445 with current wheeze status at 7.5 years, with substantial overlap between the two. Genes annotated to the 302 associated CpGs were enriched for pathways related to movement of cellular/subcellular components, locomotion, interleukin-4 production and eosinophil migration. All associations attenuated when adjusted for eosinophil and neutrophil cell count estimates. At 16.5 years, two sites were associated with current asthma after adjustment for cell counts. The CpGs mapped to the AP2A2 and IL5RA genes, with a - 2.32 [95% CI - 1.47, - 3.18] and - 2.49 [95% CI - 1.56, - 3.43] difference in percentage methylation in asthma cases respectively. Two-sample bi-directional MR indicated a causal effect of asthma on DNA methylation at several CpG sites at 7.5 years. However, associations did not persist after adjustment for multiple testing. There was no evidence of a causal effect of asthma on DNA methylation at either of the two CpG sites at 16.5 years. CONCLUSION: The majority of observed associations are driven by higher eosinophil cell counts in asthma cases, acting as an intermediate phenotype, with important implications for future studies of DNA methylation in atopic diseases.


Assuntos
Asma/genética , Metilação de DNA , Epigenômica/métodos , Estudo de Associação Genômica Ampla/métodos , Sons Respiratórios/genética , Complexo 2 de Proteínas Adaptadoras/genética , Subunidades alfa do Complexo de Proteínas Adaptadoras/genética , Adolescente , Asma/imunologia , Contagem de Células Sanguíneas , Criança , Ilhas de CpG , Eosinófilos/citologia , Feminino , Predisposição Genética para Doença , Humanos , Subunidade alfa de Receptor de Interleucina-5/genética , Estudos Longitudinais , Masculino , Neutrófilos/citologia , Sons Respiratórios/imunologia
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