Rationale

Asthma is a complex heterogeneous disease that has increased in prevalence in many industrialised countries. However, the causes of asthma inception remain elusive. Consideration of sub-phenotypes of wheezing may reveal important clues to aetiological risk factors.

Methods

Longitudinal phenotypes capturing population heterogeneity in wheezing reports from birth to 7 years were derived using latent class analysis in the Avon Longitudinal Study of Parents and Children (ALSPAC). Probability of class membership was used to examine the association between five wheezing phenotypes (transient early, prolonged early, intermediate-onset, late-onset, persistent) and early life risk factors for asthma.

Results

Phenotypes had similar patterns and strengths of associations with early environmental factors. Comparing transient early with prolonged early wheezing showed a similar pattern of association with most exposure variables considered in terms of the direction of the effect estimates but with prolonged early wheezing tending to have stronger associations than transient early wheezing except for parity and day care attendance.

Conclusions

Associations with early life risk factors suggested that prolonged early wheeze might be a severe form of transient early wheezing. Although differences were found in the associations of early life risk factors with individual phenotypes, these did not point to novel aetiological pathways. Persistent wheezing phenotype has features suggesting overlap of early and late-onset phenotypes.

Earlier menarche and irregular periods, among other markers of sex-hormone levels, have been associated with a higher risk of asthma and allergic diseases. This has suggested an etiologic role of sex hormones in the development of these conditions. The authors investigated the association of age at menarche, irregular periods, duration of menstruation, and acne with reported medical history of asthma and/or atopy (hay fever and/or eczema/urticaria) in a historical cohort of students born before the rise in asthma prevalence in the United Kingdom and attending university in 1948–1968. Finding consistent associations in a cohort that has experienced different life-course exposures and has different confounding structure can help to identify causal associations. In the Glasgow Alumni Cohort, irregular periods were associated with atopic asthma (multinomial odds ratio (MOR) = 2.79, 95% confidence interval (CI): 1.33, 5.83) and atopy alone (MOR = 1.40, 95% CI: 1.06, 1.84) but not with nonatopic asthma (MOR = 1.02, 95% CI: 0.45, 2.30), compared with students reporting no asthma and no atopy. The authors found no association with acne, a marker of high testosterone levels, that they hypothesized could point to polycystic ovary syndrome underpinning these associations. In summary, the authors found evidence for a potentially etiologic role of irregular menstruations with some specific asthma phenotypes, namely, atopic asthma and atopy, but not with nonatopic asthma.

Understanding the association between asthma and socioeconomic position (SEP) is key to identify preventable exposures to prevent inequalities and lessen overall disease burden. We aim to assess the variation in asthma across SEP groups in a historical cohort before the rise in asthma prevalence. Male students participating in a health survey at Glasgow University from 1948 to 1968 (n = 11,274) completed medical history of bronchitis, asthma, hay fever, eczema/urticaria, and reported father’s occupation. A subsample responded to postal follow-up in adulthood (n = 4,101) that collected data on respiratory diseases, early life and adult SEP. Lower father’s occupational class was associated with higher odds of asthma only (asthma without eczema/urticaria or hay fever) (trend adjusted multinomial odds ratio (aMOR) = 1.23, 95 % CI 1.03–1.47) but with lower odds of asthma with atopy (asthma with eczema/urticaria or hay fever) (trend aMOR = 0.66, 95 % CI 0.52–0.83) and atopy alone (trend aMOR = 0.84, 95 % CI 0.75–0.93). Household amenities (<3), in early life was associated with higher odds of adult-onset asthma (onset > 30 years) (OR = 1.48, 95 % CI 1.07–2.05) though this association attenuated after adjusting for age. Adult SEP (household crowding, occupation, income and car ownership) was not associated with adult-onset asthma. Lower father’s occupational class in early life was associated with higher odds of asthma alone but lower odds of asthma with atopy in a cohort that preceded the 1960s rise in asthma prevalence. Different environmental exposures and/or disease awareness may explain this opposed socioeconomic patterning, but it is important to highlight that such patterning was already present before rises in the prevalence of asthma and atopy.

The Avon Longitudinal Study of Parents and Children (ALSPAC) is a transgenerational prospective observational study investigating influences on health and development across the life course. It considers multiple genetic, epigenetic, biological, psychological, social and other environmental exposures in relation to a similarly diverse range of health, social and developmental outcomes. Recruitment sought to enrol pregnant women in the Bristol area of the UK during 1990–92; this was extended to include additional children eligible using the original enrolment definition up to the age of 18 years. The children from 14 541 pregnancies were recruited in 1990–92, increasing to 15 247 pregnancies by the age of 18 years. This cohort profile describes the index children of these pregnancies. Follow-up includes 59 questionnaires (4 weeks–18 years of age) and 9 clinical assessment visits (7–17 years of age). The resource comprises a wide range of phenotypic and environmental measures in addition to biological samples, genetic (DNA on 11 343 children, genome-wide data on 8365 children, complete genome sequencing on 2000 children) and epigenetic (methylation sampling on 1000 children) information and linkage to health and administrative records. Data access is described in this article and is currently set up as a supported access resource. To date, over 700 peer-reviewed articles have been published using ALSPAC data.

Summary The Avon Longitudinal Study of Children and Parents (ALSPAC) was established to understand how genetic and environmental characteristics influence health and development in parents and children. All pregnant women resident in a defined area in the South West of England, with an expected date of delivery between 1st April 1991 and 31st December 1992, were eligible and 13 761 women (contributing 13 867 pregnancies) were recruited. These women have been followed over the last 19–22 years and have completed up to 20 questionnaires, have had detailed data abstracted from their medical records and have information on any cancer diagnoses and deaths through record linkage. A follow-up assessment was completed 17–18 years postnatal at which anthropometry, blood pressure, fat, lean and bone mass and carotid intima media thickness were assessed, and a fasting blood sample taken. The second follow-up clinic, which additionally measures cognitive function, physical capability, physical activity (with accelerometer) and wrist bone architecture, is underway and two further assessments with similar measurements will take place over the next 5 years. There is a detailed biobank that includes DNA, with genome-wide data available on >10 000, stored serum and plasma taken repeatedly since pregnancy and other samples; a wide range of data on completed biospecimen assays are available. Details of how to access these data are provided in this cohort profile.

An important research question is whether Attention Deficit Hyperactivity Disorder (ADHD) is related to early or late stage attentional control mechanisms and whether this differentiates a non-hyperactive subtype (“ADD”). This question was addressed in a sample of 145 ADD/ADHD and typically developing comparison adolescents (aged 13-17). Attentional blink and antisaccade tasks were used to assay early and late stage control, respectively. ADD was defined using normative cutoffs to assure low activity level in children who otherwise met full criteria for ADHD. The ADD group had an attenuated attentional blink versus controls and ADHD-combined (ADHD-C). The effect was not produced using DSM-IV definition of ADHD-primarily inattentive type nor DSM symptom counts. ADHD-C showed greater weakness in response inhibition, as manifest in the antisaccade task. Combining tasks yielded an interaction differentiating group performance on the two tasks.

Background

Evidence suggests that higher levels of vitamin D and calcium are associated with greater lung function and that vitamin D is inversely associated with atopic sensitisation. It is unknown whether the associations of vitamin D and calcium with lung function are independent of each other or mediated by atopic sensitisation.

Objective

To study the associations of 25-hydroxyvitamin D [25(OH)D] and ionised calcium levels with lung function and specific allergen sensitisation in adolescents (12-19 years) and adults (20-59 years) and to assess whether the associations with lung function are due to altered atopic sensitisation.

Methods

Cross-sectional analysis of the data from the third National Health and Nutrition Examination Survey.

Results

25(OH)D levels were positively associated with forced vital capacity in adolescents [0.035(95 %CI: 0.007-0.064) standard deviations;SD in model adjusted for multiple confounders]. This association and the previously reported association between higher serum levels of 25(OH)D and better lung function in adults were independent of serum calcium levels, which were not associated with lung function. In adults, calcium was associated with sensitisation to grass allergens [OR per SD,1.17(1.03-1.32), 1.15(1.01-1.31) and 1.18 (1.06-1.32) for white oak, Bermuda grass and short ragweed, respectively] and peanut OR 1.21 (95%CI 1.02-1.43) after adjusting for age, gender and race/ethnicity, but these associations attenuated towards the null after adjusting for additional confounders. The associations were independent of 25(OH)D levels, which were not associated with allergen sensitisation.

Conclusions

Circulating levels of 25(OH)D are positively associated with lung function and this does not appear to be driven by allergen sensitisation or influenced by calcium levels.

Rationale: Cross-sectional studies have reported inconsistent findings for the association between recreational swimming pool attendance and asthma and allergic diseases in childhood.

Objectives: To examine whether swimming in infancy and childhood was associated with asthma and allergic symptoms at age 7 and 10 years in a UK longitudinal population-based birth cohort, the Avon Longitudinal Study of Parents and Children.

Methods: Data on swimming were collected by questionnaire at 6, 18, 38, 42, 57, 65, and 81 months. Data on rhinitis, wheezing, asthma, eczema, hay fever, asthma medication, and potential confounders were collected through questionnaires at 7 and 10 years. Spirometry and skin prick testing were performed at 7 to 8 years. Data for analysis were available for 5,738 children.

Measurements and Main Results: At age 7 years, more than 50% of the children swam once per week or more. Swimming frequency did not increase the risk of any evaluated symptom, either overall or in atopic children. Children with a high versus low cumulative swimming pool attendance from birth to 7 years had an odds ratio of 0.88 (95% confidence interval, 0.56–1.38) and 0.50 (0.28–0.87), respectively, for ever and current asthma at 7 years, and a 0.20 (0.02–0.39) standard deviation increase in the forced midexpiratory flow. Children with asthma with a high versus low cumulative swimming had an odds ratio for current asthma at 10 years of 0.34 (0.14–0.80).

Conclusions: This first prospective longitudinal study suggests that swimming did not increase the risk of asthma or allergic symptoms in British children. Swimming was associated with increased lung function and lower risk of asthma symptoms, especially among children with preexisting respiratory conditions.

Rationale

Lung function measures are heritable traits that predict population morbidity and mortality and are essential for the diagnosis of chronic obstructive pulmonary disease (COPD). Variations in many genes have been reported to affect these traits, but attempts at replication have provided conflicting results. Recently, we undertook a meta-analysis of Genome Wide Association Study (GWAS) results for lung function measures in 20,288 individuals from the general population (the SpiroMeta consortium).

Objectives

To comprehensively analyse previously reported genetic associations with lung function measures, and to investigate whether single nucleotide polymorphisms (SNPs) in these genomic regions are associated with lung function in a large population sample.

Methods

We analysed association for SNPs tagging 130 genes and 48 intergenic regions (+/−10 kb), after conducting a systematic review of the literature in the PubMed database for genetic association studies reporting lung function associations.

Results

The analysis included 16,936 genotyped and imputed SNPs. No loci showed overall significant association for FEV1 or FEV1/FVC traits using a carefully defined significance threshold of 1.3×10−5. The most significant loci associated with FEV1 include SNPs tagging MACROD2 (P = 6.81×10−5), CNTN5 (P = 4.37×10−4), and TRPV4 (P = 1.58×10−3). Among ever-smokers, SERPINA1 showed the most significant association with FEV1 (P = 8.41×10−5), followed by PDE4D (P = 1.22×10−4). The strongest association with FEV1/FVC ratio was observed with ABCC1 (P = 4.38×10−4), and ESR1 (P = 5.42×10−4) among ever-smokers.

Conclusions

Polymorphisms spanning previously associated lung function genes did not show strong evidence for association with lung function measures in the SpiroMeta consortium population. Common SERPINA1 polymorphisms may affect FEV1 among smokers in the general population.

Background

IgE-mediated peanut allergy is a complex trait with strong heritability, but its genetic basis is currently unknown. Loss-of-function mutations within the filaggrin gene are associated with atopic dermatitis and other atopic diseases; therefore, filaggrin is a candidate gene in the etiology of peanut allergy.

Objective

To investigate the association between filaggrin loss-of-function mutations and peanut allergy.

Methods

Case-control study of 71 English, Dutch, and Irish oral food challenge–positive patients with peanut allergy and 1000 non peanut-sensitized English population controls. Replication was tested in 390 white Canadian patients with peanut allergy (defined by food challenge, or clinical history and skin prick test wheal to peanut ≥8 mm and/or peanut-specific IgE ≥15 kUL−1) and 891 white Canadian population controls. The most prevalent filaggrin loss-of-function mutations were assayed in each population: R501X and 2282del4 in the Europeans, and R501X, 2282del4, R2447X, and S3247X in the Canadians. The Fisher exact test and logistic regression were used to test for association; covariate analysis controlled for coexistent atopic dermatitis.

Results

Filaggrin loss-of-function mutations showed a strong and significant association with peanut allergy in the food challenge–positive patients (P = 3.0 × 10−6; odds ratio, 5.3; 95% CI, 2.8-10.2), and this association was replicated in the Canadian study (P = 5.4 × 10−5; odds ratio, 1.9; 95% CI, 1.4-2.6). The association of filaggrin mutations with peanut allergy remains significant (P = .0008) after controlling for coexistent atopic dermatitis.

Conclusion

Filaggrin mutations represent a significant risk factor for IgE-mediated peanut allergy, indicating a role for epithelial barrier dysfunction in the pathogenesis of this disease.

Rationale: Few studies have investigated childhood respiratory outcomes of intrauterine growth retardation (IUGR), and it is unclear if catch-up growth in these children influences lung function.

Objectives: We determined if lung function differed in 8- to 9-year-old children born at term with or without growth retardation, and, in the growth-retarded group, if lung function differed between those who did and those who did not show weight catch up.

Methods: Caucasian singleton births of 37 weeks or longer gestation from the Avon Longitudinal Study of Parents and Children (n = 14,062) who had lung spirometry at 8–9 years of age were included (n = 5,770).

Measurements and Main Results: Infants with gestation-appropriate birthweight (n = 3,462) had significantly better lung function at 8–9 years of age than those with IUGR (i.e., birthweight <10th centile [n = 576] [SD differences and confidence intervals adjusted for sex, gestation, maternal smoking during pregnancy, and social class: FEV1, −0.198 (−0.294 to −0.102), FVC, −0.131 (−0.227 to −0.036), forced midexpiratory flow between 25 and 75% of vital capacity −0.149 (−0.246 to −0.053)]). Both groups had similar respiratory symptoms. All spirometry measurements were higher in children with IUGR who had weight catch-up growth (n = 430) than in those without (n = 146), although the differences were not statistically significant. Both groups remained significantly lower than control subjects. Growth-retarded asymmetric and symmetric children had similar lung function.

Conclusions: IUGR is associated with poorer lung function at 8–9 years of age compared with control children. Although the differences were not statistically significant, spirometry was higher in children who showed weight catch-up growth, but remained significantly lower than the control children.

Pulmonary function measures are heritable traits that predict morbidity and mortality and define chronic obstructive pulmonary disease (COPD). We tested genome-wide association with forced expiratory volume in 1 s (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) in the SpiroMeta consortium (n = 20,288 individuals of European ancestry). We conducted a meta-analysis of top signals with data from direct genotyping (n ≤ 32,184 additional individuals) and in silico summary association data from the CHARGE Consortium (n = 21,209) and the Health 2000 survey (n ≤ 883). We confirmed the reported locus at 4q31 and identified associations with FEV1 or FEV1/FVC and common variants at five additional loci: 2q35 in TNS1 (P = 1.11 × 10−12), 4q24 in GSTCD (2.18 × 10−23), 5q33 in HTR4 (P = 4.29 × 10−9), 6p21 in AGER (P = 3.07 × 10−15) and 15q23 in THSD4 (P = 7.24 × 10−15). mRNA analyses showed expression of TNS1, GSTCD, AGER, HTR4 and THSD4 in human lung tissue. These associations offer mechanistic insight into pulmonary function regulation and indicate potential targets for interventions to alleviate respiratory disease.

Background Oxidative stress is thought to be involved in the pathogenesis of asthma. Glutathione-S-transferase (GST) enzymes, which play an important role in antioxidant defences, may therefore influence asthma risk. Two common deletion polymorphisms of GSTM1 and GSTT1 genes and the GSTP1 Ile105Val polymorphism have been associated with asthma in children and adults, but results are inconsistent across studies.

Methods Systematic review and meta-analysis of the effects of GST genes on asthma, wheezing and bronchial hyper-responsiveness (BHR), with inclusion of unpublished data from three studies, including the large Avon Longitudinal Study of Parents and Children (ALSPAC). Random effect or fixed effect models were used as appropriate, and sensitivity analyses were performed to assess the impact of study characteristics and quality on pooled results.

Results The meta-analyses of GSTM1 (n = 22 studies) and GSTT1 (n = 19) showed increased asthma risk associated with the null genotype, but there was extreme between-study heterogeneity and publication bias and the association disappeared when meta-analysis was restricted to the largest studies. Meta-analysis of GSTP1 Ile105Val (n = 17) and asthma suggested a possible protective effect of the Val allele, but heterogeneity was extreme. Few studies evaluated wheezing and BHR and most reported no associations, although weak evidence was found for positive associations of GSTM1 null and GSTP1 Val allele with wheezing and a negative association of GSTP1 Val allele with BHR.

Conclusions Our findings do not support a substantial role of GST genes alone in the development of asthma. Future studies of large size should focus on interactions of GST genes with environmental oxidative exposures and with other genes involved in antioxidant pathways. Quality of study conduct and reporting needs to be improved to increase credibility of the evidence accumulating over time.

Background

People with mental disorders have a higher prevalence of physical illnesses and reduced life expectancy as compared with the general population. However, there is a lack of knowledge across Europe concerning interventions that aim at reducing somatic morbidity and excess mortality by promoting behaviour-based and/or environment-based interventions.

Methods and design

HELPS is an interdisciplinary European network that aims at (i) gathering relevant knowledge on physical illness in people with mental illness, (ii) identifying health promotion initiatives in European countries that meet country-specific needs, and (iii) at identifying best practice across Europe. Criteria for best practice will include evidence on the efficacy of physical health interventions and of their effectiveness in routine care, cost implications and feasibility for adaptation and implementation of interventions across different settings in Europe. HELPS will develop and implement a "physical health promotion toolkit". The toolkit will provide information to empower residents and staff to identify the most relevant risk factors in their specific context and to select the most appropriate action out of a range of defined health promoting interventions. The key methods are (a) stakeholder analysis, (b) international literature reviews, (c) Delphi rounds with experts from participating centres, and (d) focus groups with staff and residents of mental health care facilities.

Meanwhile a multi-disciplinary network consisting of 15 European countries has been established and took up the work. As one main result of the project they expect that a widespread use of the HELPS toolkit could have a significant positive effect on the physical health status of residents of mental health and social care facilities, as well as to hold resonance for community dwelling people with mental health problems.

Discussion

A general strategy on health promotion for people with mental disorders must take into account behavioural, environmental and iatrogenic health risks. A European health promotion toolkit needs to consider heterogeneity of mental disorders, the multitude of physical health problems, health-relevant behaviour, health-related attitudes, health-relevant living conditions, and resource levels in mental health and social care facilities.

Court-ordered monitoring of blood cholinesterases (ChEs) from orchard workers in Washington State is underway. In 2008, the mean red blood cell acetylcholinesterase (AChE, EC 3.1.1.7) activity was 9.65 ± 1.11 μmoles/min/ml (n = 1,793) and the mean serum (BChE, 3.1.1.6) activity was 5.19 ± 0.90 μmoles/min/ml (n = 1,811). Determinations were made using the Ellman assay and automated equipment of Pathology Associates Medical Laboratories (PAML), Spokane, Washington.

Background

Filaggrin is a major protein in the epidermis. Several mutations in the filaggrin gene (FLG) have been associated with a number of conditions. Filaggrin is expressed in the tympanic membrane and could alter its mechanical properties, but the relationship between genetic variation in FLG and hearing has not yet been tested.

Methodology/Principal Findings

We examined whether loss-of function mutations R501X and 2282del4 in the FLG gene affected hearing in children. Twenty eight hearing variables representing five different aspects of hearing at age nine years in 5,377 children from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort were tested for association with these mutations. No evidence of association was found between R501X or 2282del4 (or overall FLG mutation carrier status) and any of the hearing phenotypes analysed.

Conclusions/Significance

In conclusion, carrier status for common filaggrin mutations does not affect hearing in children.

The amount of time viewers could process a scene during eye fixations was varied by a mask that appeared at a certain point in each eye fixation. The scene did not reappear until the viewer made an eye movement. The main finding in the studies was that in order to normally process a scene, viewers needed to see the scene for at least 150 ms during each eye fixation. This result is surprising because viewers can extract the gist of a scene from a brief 40- to 100-ms exposure. It also stands in marked contrast to reading, as readers need only to view the words in the text for 50 to 60 ms to read normally. Thus, although the same neural mechanisms control eye movements in scene perception and reading, the cognitive processes associated with each task drive processing in different ways.

Background

Maternal stress in early life has been associated with the development of asthma in children, although it is unclear whether there are any critical periods of exposure. The association of asthma with prenatal exposure to maternal stress has not been reported.

Objective

We tested whether prenatal and postnatal anxiety and/or depression in pregnant women predicted the risk of their offspring developing asthma in childhood.

Methods

The Avon Longitudinal Study of Parents and Children is a population-based birth cohort recruited during pregnancy. Data were available on maternal anxiety scores and asthma at age 7½ years in 5810 children. Anxiety was assessed at 18 and 32 weeks of gestation by using the validated Crown-Crisp Experiential Index. Asthma was defined at age 7½ years as doctor-diagnosed asthma with current symptoms or treatment in the previous 12 months. Multivariable logistic regression was used to determine the association of prenatal anxiety with asthma (odds ratio; 95% CI).

Results

Independent of postnatal anxiety and adjusted for a number of likely confounders, there was a higher likelihood of asthma at age 7½ years (odds ratio, 1.64; 95% CI, 1.25-2.17) in children of mothers in the highest compared with lowest quartile of anxiety scores at 32 weeks of gestation, with evidence for a dose-response (P value for trend <0.001).

Conclusions

Maternal anxiety symptoms as an indicator of stress during fetal life may program the development of asthma during childhood.

Background

Breastfeeding clearly protects against early wheezing, but recent data suggest that it may increase later risk of atopic disease and asthma.

Objective

To examine the relationship between breastfeeding and later asthma and allergy outcomes using data from the Avon Longitudinal Study of Parents and Children, a large birth cohort in the United Kingdom.

Methods

We used adjusted logistic regression models to evaluate the association between breastfeeding and atopy at age 7 years, bronchial responsiveness to methacholine at age 8 years, and wheeze at ages 3 and 7½ years. Bayesian methods were used to assess the possibility of bias due to an influence of early wheezing on duration of breastfeeding as well as selection bias.

Results

Breastfeeding was protective for wheeze in the first 3 years of life (OR =0.80, 95% CI 0.70-0.90 for 6+ months relative to never) but not wheeze (OR=0.98, 95% CI 0.79-1.22), atopy (OR=1.12, 95% CI 0.92-1.35) or BHR (1.07, 95% CI 0.82-1.40) at ages 7-8 years. Bayesian models adjusting for the longer duration of breastfeeding among children with wheezing in early infancy gave virtually identical results.

Conclusions

We did not find consistent evidence for either a deleterious effect or a protective effect of breastfeeding on later risk of allergic disease in a large prospective birth cohort of children with objective outcome measures and extensive data on potential confounders and effect modifiers. Neither reverse causation nor loss to follow-up appears to have materially biased our results.

Clinical implications

Breastfeeding does not increase the risk of asthma or atopy in children, even when their mothers are asthmatic.

Capsule Summary

This study supports the evidence that breastfeeding does not adversely affect children with regard to asthma and other allergic outcomes. Breastfeeding’s protective role against early wheezing is a benefit for respiratory health.

We explored incidental retention of visual details of encountered objects during search. Participants searched for conjunction targets in 32 arrays of 12 pictures of real-world objects and then performed a token discrimination task that examined their memory for visual details of the targets and distractors from the search task. The results indicate that even though participants had not been instructed to memorize the objects, the visual details of search targets and distractor objects related to the targets were retained after the search. Distractor objects unrelated to the search target were remembered more poorly. Eye-movement measures indicated that the objects that were remembered were looked at more frequently during search than those that were not remembered. These results provide support that detailed visual information is included incidentally in the visual representation of an object after the object is no longer in view.