PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (70)
 

Clipboard (0)
None

Select a Filter Below

Journals
more »
Year of Publication
more »
1.  Effects of BMI, Fat Mass, and Lean Mass on Asthma in Childhood: A Mendelian Randomization Study 
PLoS Medicine  2014;11(7):e1001669.
In this study, Granell and colleagues used Mendelian randomization to investigate causal effects of BMI, fat mass, and lean mass on current asthma at age 7½ years in the Avon Longitudinal Study of Parents and Children (ALSPAC) and found that higher BMI increases the risk of asthma in mid-childhood.
Please see later in the article for the Editors' Summary
Background
Observational studies have reported associations between body mass index (BMI) and asthma, but confounding and reverse causality remain plausible explanations. We aim to investigate evidence for a causal effect of BMI on asthma using a Mendelian randomization approach.
Methods and Findings
We used Mendelian randomization to investigate causal effects of BMI, fat mass, and lean mass on current asthma at age 7½ y in the Avon Longitudinal Study of Parents and Children (ALSPAC). A weighted allele score based on 32 independent BMI-related single nucleotide polymorphisms (SNPs) was derived from external data, and associations with BMI, fat mass, lean mass, and asthma were estimated. We derived instrumental variable (IV) estimates of causal risk ratios (RRs). 4,835 children had available data on BMI-associated SNPs, asthma, and BMI. The weighted allele score was strongly associated with BMI, fat mass, and lean mass (all p-values<0.001) and with childhood asthma (RR 2.56, 95% CI 1.38–4.76 per unit score, p = 0.003). The estimated causal RR for the effect of BMI on asthma was 1.55 (95% CI 1.16–2.07) per kg/m2, p = 0.003. This effect appeared stronger for non-atopic (1.90, 95% CI 1.19–3.03) than for atopic asthma (1.37, 95% CI 0.89–2.11) though there was little evidence of heterogeneity (p = 0.31). The estimated causal RRs for the effects of fat mass and lean mass on asthma were 1.41 (95% CI 1.11–1.79) per 0.5 kg and 2.25 (95% CI 1.23–4.11) per kg, respectively. The possibility of genetic pleiotropy could not be discounted completely; however, additional IV analyses using FTO variant rs1558902 and the other BMI-related SNPs separately provided similar causal effects with wider confidence intervals. Loss of follow-up was unlikely to bias the estimated effects.
Conclusions
Higher BMI increases the risk of asthma in mid-childhood. Higher BMI may have contributed to the increase in asthma risk toward the end of the 20th century.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The global burden of asthma, a chronic (long-term) condition caused by inflammation of the airways (the tubes that carry air in and out of the lungs), has been rising steadily over the past few decades. It is estimated that, nowadays, 200–300 million adults and children worldwide are affected by asthma. Although asthma can develop at any age, it is often diagnosed in childhood—asthma is the most common chronic disease in children. In people with asthma, the airways can react very strongly to allergens such as animal fur or to irritants such as cigarette smoke, becoming narrower so that less air can enter the lungs. Exercise, cold air, and infections can also trigger asthma attacks, which can be fatal. The symptoms of asthma include wheezing, coughing, chest tightness, and shortness of breath. Asthma cannot be cured, but drugs can relieve its symptoms and prevent acute asthma attacks.
Why Was This Study Done?
We cannot halt the ongoing rise in global asthma rates without understanding the causes of asthma. Some experts think obesity may be one cause of asthma. Obesity, like asthma, is increasingly common, and observational studies (investigations that ask whether individuals exposed to a suspected risk factor for a condition develop that condition more often than unexposed individuals) in children have reported that body mass index (BMI, an indicator of body fat calculated by dividing a person's weight in kilograms by their height in meters squared) is positively associated with asthma. Observational studies cannot prove that obesity causes asthma because of “confounding.” Overweight children with asthma may share another unknown characteristic (confounder) that actually causes both obesity and asthma. Moreover, children with asthma may be less active than unaffected children, so they become overweight (reverse causality). Here, the researchers use “Mendelian randomization” to assess whether BMI has a causal effect on asthma. In Mendelian randomization, causality is inferred from associations between genetic variants that mimic the effect of a modifiable risk factor and the outcome of interest. Because gene variants are inherited randomly, they are not prone to confounding and are free from reverse causation. So, if a higher BMI leads to asthma, genetic variants associated with increased BMI should be associated with an increased risk of asthma.
What Did the Researchers Do and Find?
The researchers investigated causal effects of BMI, fat mass, and lean mass on current asthma at age 7½ years in 4,835 children enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC, a long-term health project that started in 1991). They calculated an allele score for each child based on 32 BMI-related genetic variants, and estimated associations between this score and BMI, fat mass and lean mass (both measured using a special type of X-ray scanner; in children BMI is not a good indicator of “fatness”), and asthma. They report that the allele score was strongly associated with BMI, fat mass, and lean mass, and with childhood asthma. The estimated causal relative risk (risk ratio) for the effect of BMI on asthma was 1.55 per kg/m2. That is, the relative risk of asthma increased by 55% for every extra unit of BMI. The estimated causal relative risks for the effects of fat mass and lean mass on asthma were 1.41 per 0.5 kg and 2.25 per kg, respectively.
What Do These Findings Mean?
These findings suggest that a higher BMI increases the risk of asthma in mid-childhood and that global increases in BMI toward the end of the 20th century may have contributed to the global increase in asthma that occurred at the same time. It is possible that the observed association between BMI and asthma reported in this study is underpinned by “genetic pleiotropy” (a potential limitation of all Mendelian randomization analyses). That is, some of the genetic variants included in the BMI allele score could conceivably also increase the risk of asthma. Nevertheless, these findings suggest that public health interventions designed to reduce obesity may also help to limit the global rise in asthma.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001669.
The US Centers for Disease Control and Prevention provides information on asthma and on all aspects of overweight and obesity (in English and Spanish)
The World Health Organization provides information on asthma and on obesity (in several languages)
The UK National Health Service Choices website provides information about asthma, about asthma in children, and about obesity (including real stories)
The Global Asthma Report 2011 is available
The Global Initiative for Asthma released its updated Global Strategy for Asthma Management and Prevention on World Asthma Day 2014
Information about the Avon Longitudinal Study of Parents and Children is available
MedlinePlus provides links to further information on obesity in children, on asthma, and on asthma in children (in English and Spanish
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001669
PMCID: PMC4077660  PMID: 24983943
2.  Preterm birth, infant weight gain, and childhood asthma risk: A meta-analysis of 147,000 European children 
Background
Preterm birth, low birth weight, and infant catch-up growth seem associated with an increased risk of respiratory diseases in later life, but individual studies showed conflicting results.
Objectives
We performed an individual participant data meta-analysis for 147,252 children of 31 birth cohort studies to determine the associations of birth and infant growth characteristics with the risks of preschool wheezing (1-4 years) and school-age asthma (5-10 years).
Methods
First, we performed an adjusted 1-stage random-effect meta-analysis to assess the combined associations of gestational age, birth weight, and infant weight gain with childhood asthma. Second, we performed an adjusted 2-stage random-effect meta-analysis to assess the associations of preterm birth (gestational age <37 weeks) and low birth weight (<2500 g) with childhood asthma outcomes.
Results
Younger gestational age at birth and higher infant weight gain were independently associated with higher risks of preschool wheezing and school-age asthma (P < .05). The inverse associations of birth weight with childhood asthma were explained by gestational age at birth. Compared with term-born children with normal infant weight gain, we observed the highest risks of school-age asthma in children born preterm with high infant weight gain (odds ratio [OR], 4.47; 95% CI, 2.58-7.76). Preterm birth was positively associated with an increased risk of preschool wheezing (pooled odds ratio [pOR], 1.34; 95% CI, 1.25-1.43) and school-age asthma (pOR, 1.40; 95% CI, 1.18-1.67) independent of birth weight. Weaker effect estimates were observed for the associations of low birth weight adjusted for gestational age at birth with preschool wheezing (pOR, 1.10; 95% CI, 1.00-1.21) and school-age asthma (pOR, 1.13; 95% CI, 1.01-1.27).
Conclusion
Younger gestational age at birth and higher infant weight gain were associated with childhood asthma outcomes. The associations of lower birth weight with childhood asthma were largely explained by gestational age at birth.
doi:10.1016/j.jaci.2013.12.1082
PMCID: PMC4024198  PMID: 24529685
Gestational age; low birth weight; infant growth; wheezing; asthma; children; cohort studies; epidemiology; BMI, Body mass index; ISAAC, International Study on Asthma and Allergy in Childhood; OR, Odds ratio; pOR, Pooled odds ratio; SDS, Standard deviation scores
3.  Validating childhood asthma in an epidemiological study using linked electronic patient records 
BMJ Open  2014;4(4):e005345.
Objective
To investigate the performance of parent-reported data in identifying physician-confirmed asthma.
Design and setting
Validation study using linkage between the Avon Longitudinal Study of Parents and Children (ALSPAC) and electronic patient records held within the General Practice Research Database (GPRD).
Participants
Participants were those eligible to participate in ALSPAC who also had a record in the GPRD; this included 765 individuals, just under 4% of ALSPAC-eligible participants. The analysis was based on 141 participants with complete parent-reported asthma data.
Primary and secondary outcome measures
The main GPRD outcome measure was whether a child had a diagnosis of asthma before they were nine. Parent-reported measures were doctor diagnosis of asthma (before mean age 7.5 years), various outcomes based on wheezing and breathlessness recorded longitudinally between 6 months and 8.5 years. Secondary outcomes were bronchial hyper-responsiveness (BHR), forced expiratory volume in 1 s/forced vital capacity ratio and skin prick test responses.
Results
Among the 141 participants with complete parent-reported data, 26 (18%) had an asthma diagnosis before age nine. Using general practitioner (GP)-recorded asthma as the gold standard, the question ‘Has a doctor ever diagnosed your child with asthma?’ was both sensitive (88.5%) and specific (95.7%). ‘Ever wheezed’ had the highest sensitivity (100%) but low specificity (60%). More specific definitions were obtained by restricting to those who had wheezed on more than one occasion, experienced frequent wheeze and/or wheezed after the age of 3, but these measures had low sensitivities. BHR only identified 50% of those with a GP-recorded diagnosis.
Conclusions
Parental reports of a doctor's diagnosis agree well with a GP-recorded diagnosis. High specificity for asthma can be achieved by using detailed wheezing questions, although these definitions are likely to exclude mild cases of asthma. Our study shows that linkage between observational studies and electronic patient records has the potential to enhance epidemiological research.
doi:10.1136/bmjopen-2014-005345
PMCID: PMC4010849  PMID: 24760357
Epidemiology; Primary Care
4.  Genome-wide association study of body mass index in 23,000 individuals with and without asthma 
Background
Both asthma and obesity are complex disorders that are influenced by environmental and genetic factors. Shared genetic factors between asthma and obesity have been proposed to partly explain epidemiological findings of co-morbidity between these conditions.
Objective
To identify genetic variants that are associated with body mass index (BMI) in asthmatic children and adults, and to evaluate if there are differences between the genetics of BMI in asthmatics and healthy individuals.
Methods
In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23,000 individuals with predominantly European descent, of whom 8,165 are asthmatics.
Results
We report associations between several DENND1B variants (p=2.2×10−7 for rs4915551) on chromosome 1q31 and BMI from a meta-analysis of GWAS data using 2,691 asthmatic children (screening data). The top DENND1B SNPs were next evaluated in seven independent replication data sets comprising 2,014 asthmatics, and rs4915551 was nominally replicated (p<0.05) in two of the seven studies and of borderline significance in one (p=0.059). However, strong evidence of effect heterogeneity was observed and overall, the association between rs4915551 and BMI was not significant in the total replication data set, p=0.71. Using a random effects model, BMI was overall estimated to increase by 0.30 kg/m2 (p=0.01 for combined screening and replication data sets, N=4,705) per additional G allele of this DENND1B SNP. FTO was confirmed as an important gene for adult and childhood BMI regardless of asthma status.
Conclusions and Clinical Relevance
DENND1B was recently identified as an asthma susceptibility gene in a GWAS on children, and here we find evidence that DENND1B variants may also be associated with BMI in asthmatic children. However, the association was overall not replicated in the independent data sets and the heterogeneous effect of DENND1B points to complex associations with the studied diseases that deserve further study.
doi:10.1111/cea.12054
PMCID: PMC3608930  PMID: 23517042
Association; Asthma; BMI; Genetics; Genome-wide; Obesity
6.  Prenatal alcohol exposure and childhood atopic disease: A Mendelian randomization approach☆ 
Background
Alcohol consumption in western pregnant women is not uncommon and could be a risk factor for childhood atopic disease. However, reported alcohol intake may be unreliable, and associations are likely to be confounded.
Objective
We aimed to study the relation between prenatal alcohol exposure and atopic phenotypes in a large population-based birth cohort with the use of a Mendelian randomization approach to minimize bias and confounding.
Methods
In white mothers and children in the Avon Longitudinal Study of Parents and Children (ALSPAC) we first analyzed associations between reported maternal alcohol consumption during pregnancy and atopic outcomes in the offspring measured at 7 years of age (asthma, wheezing, hay fever, eczema, atopy, and total IgE). We then analyzed the relation of maternal alcohol dehydrogenase (ADH)1B genotype (rs1229984) with these outcomes (the A allele is associated with faster metabolism and reduced alcohol consumption and, among drinkers, would be expected to reduce fetal exposure to ethanol).
Results
After controlling for confounders, reported maternal drinking in late pregnancy was negatively associated with childhood asthma and hay fever (adjusted odds ratio [OR] per category increase in intake: 0.91 [95% CI, 0.82-1.01] and 0.87 [95% CI, 0.78-0.98], respectively). However, maternal ADH1B genotype was not associated with asthma comparing carriers of A allele with persons homozygous for G allele (OR, 0.98 [95% CI, 0.66-1.47]) or hay fever (OR, 1.11 [95% CI, 0.71-1.72]), nor with any other atopic outcome.
Conclusion
We have found no evidence to suggest that prenatal alcohol exposure increases the risk of asthma or atopy in childhood.
doi:10.1016/j.jaci.2013.04.051
PMCID: PMC3884122  PMID: 23806636
Alcohol; ADH1B; Mendelian randomization; prenatal exposure; ALSPAC; pregnancy; birth cohort; asthma; atopy; ADH, Alcohol dehydrogenase; ALSPAC, Avon Longitudinal Study of Parents and Children (ALSPAC); GWAS, Genome Wide Association Study; PCA, Principal Components Analysis
7.  Do Grandmaternal Smoking Patterns Influence the Etiology of Childhood Asthma? 
Chest  2013;145(6):1213-1218.
Background:
Animal data suggest that tobacco smoke exposure of a mother when she is in utero influences DNA methylation patterns in her offspring and that there is an effect on the respiratory system, particularly airway responsiveness. The only study, to our knowledge, in humans suggests that there is a similar effect on asthma. The present study tests whether an association with respiratory problems can be confirmed in a large population study and aims to determine whether in utero exposure of the father has similar effects on his offspring.
Methods:
Information from the Avon Longitudinal Study of Parents and Children was used to compare the offspring of women and of men who had themselves been exposed to cigarette smoke in utero; separate analyses were performed for children of women smokers and nonsmokers. The outcome measures were trajectories of history of early wheezing, doctor-diagnosed asthma by age 7 years, and results of lung function and methacholine challenge tests at 8 years. A variety of social and environmental factors were taken into account; offspring sexes were examined separately.
Results:
There was no association with any outcome in relation to maternal prenatal exposure. There was some evidence of an increase in asthma risk with paternal prenatal exposure when the study mother was a nonsmoker (adjusted OR, 1.17; 95% CI, 0.97-1.41). This was particularly strong for girls (adjusted OR, 1.39; 95% CI, 1.04-1.86).
Conclusions:
We did not find that maternal prenatal exposure to her mother’s smoking had any effect on her children’s respiratory outcomes. There was suggestive evidence of paternal prenatal exposure being associated with asthma and persistent wheezing in the granddaughters.
doi:10.1378/chest.13-1371
PMCID: PMC4042509  PMID: 24158349
8.  Temporal oculomotor inhibition of return and spatial facilitation of return in a visual encoding task 
Oculomotor inhibition of return (O-IOR) is an increase in saccade latency prior to an eye movement to a recently fixated location compared to other locations. It has been proposed that this temporal O-IOR may have spatial consequences, facilitating foraging by inhibiting return to previously attended regions. In order to test this possibility, participants viewed arrays of objects and of words while their eye movements were recorded. Temporal O-IOR was observed, with equivalent effects for object and word arrays, indicating that temporal O-IOR is an oculomotor phenomenon independent of array content. There was no evidence for spatial inhibition of return (IOR). Instead, spatial facilitation of return was observed: participants were significantly more likely than chance to make return saccades and to re-fixate just-visited locations. Further, the likelihood of making a return saccade to an object or word was contingent on the amount of time spent viewing that object or word before leaving it. This suggests that, unlike temporal O-IOR, return probability is influenced by cognitive processing. Taken together, these results are inconsistent with the hypothesis that IOR functions as a foraging facilitator. The results also provide strong evidence for a different oculomotor bias that could serve as a foraging facilitator: saccadic momentum, a tendency to repeat the most recently executed saccade program. We suggest that models of visual attention could incorporate saccadic momentum in place of IOR.
doi:10.3389/fpsyg.2013.00400
PMCID: PMC3698447  PMID: 23847574
inhibition of return; facilitation of return; eye movement control; saccadic momentum; foraging facilitator
10.  Predicting Cognitive State from Eye Movements 
PLoS ONE  2013;8(5):e64937.
In human vision, acuity and color sensitivity are greatest at the center of fixation and fall off rapidly as visual eccentricity increases. Humans exploit the high resolution of central vision by actively moving their eyes three to four times each second. Here we demonstrate that it is possible to classify the task that a person is engaged in from their eye movements using multivariate pattern classification. The results have important theoretical implications for computational and neural models of eye movement control. They also have important practical implications for using passively recorded eye movements to infer the cognitive state of a viewer, information that can be used as input for intelligent human-computer interfaces and related applications.
doi:10.1371/journal.pone.0064937
PMCID: PMC3666973  PMID: 23734228
11.  Co-registration of eye movements and event-related potentials in connected-text paragraph reading 
Eyetracking during reading has provided a critical source of on-line behavioral data informing basic theory in language processing. Similarly, event-related potentials (ERPs) have provided an important on-line measure of the neural correlates of language processing. Recently there has been strong interest in co-registering eyetracking and ERPs from simultaneous recording to capitalize on the strengths of both techniques, but a challenge has been devising approaches for controlling artifacts produced by eye movements in the EEG waveform. In this paper we describe our approach to correcting for eye movements in EEG and demonstrate its applicability to reading. The method is based on independent components analysis, and uses three criteria for identifying components tied to saccades: (1) component loadings on the surface of the head are consistent with eye movements; (2) source analysis localizes component activity to the eyes, and (3) the temporal activation of the component occurred at the time of the eye movement and differed for right and left eye movements. We demonstrate this method's applicability to reading by comparing ERPs time-locked to fixation onset in two reading conditions. In the text-reading condition, participants read paragraphs of text. In the pseudo-reading control condition, participants moved their eyes through spatially similar pseudo-text that preserved word locations, word shapes, and paragraph spatial structure, but eliminated meaning. The corrected EEG, time-locked to fixation onsets, showed effects of reading condition in early ERP components. The results indicate that co-registration of eyetracking and EEG in connected-text paragraph reading is possible, and has the potential to become an important tool for investigating the cognitive and neural bases of on-line language processing in reading.
doi:10.3389/fnsys.2013.00028
PMCID: PMC3706749  PMID: 23847477
eyetracking; event-related potentials (ERPs); reading; eye movements; coregistration; pseudo-reading
12.  Associations of Different Phenotypes of Wheezing Illness in Early Childhood with Environmental Variables Implicated in the Aetiology of Asthma 
PLoS ONE  2012;7(10):e48359.
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.
doi:10.1371/journal.pone.0048359
PMCID: PMC3485223  PMID: 23118993
13.  The Association Between Irregular Menstruations and Acne With Asthma and Atopy Phenotypes 
American Journal of Epidemiology  2012;176(8):733-737.
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.
doi:10.1093/aje/kws161
PMCID: PMC3472614  PMID: 23028012
acne; age at menarche; asthma; atopy; irregular menstruation
14.  Associations between socioeconomic position and asthma: findings from a historical cohort 
European Journal of Epidemiology  2012;27(8):623-631.
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.
doi:10.1007/s10654-012-9703-9
PMCID: PMC3444704  PMID: 22696048
Asthma; Socioeconomic position; Early life; Atopy
15.  Cohort Profile: The ‘Children of the 90s’—the index offspring of the Avon Longitudinal Study of Parents and Children 
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.
doi:10.1093/ije/dys064
PMCID: PMC3600618  PMID: 22507743
16.  Cohort Profile: The Avon Longitudinal Study of Parents and Children: ALSPAC mothers cohort 
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.
doi:10.1093/ije/dys066
PMCID: PMC3600619  PMID: 22507742
17.  Cognitive Control and Attentional Selection in Adolescents with ADHD versus ADD 
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.
doi:10.1080/15374416.2010.517168
PMCID: PMC3059559  PMID: 21058121
ADHD; ADD; ADHD subtypes; response inhibition; attentional blink; antisaccade; adolescence
18.  Serum 25-hydroxy-vitamin D and ionised calcium in relation to lung function and allergen skin tests 
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.
doi:10.1038/ejcn.2011.6
PMCID: PMC3072311  PMID: 21326268
vitamin D; calcium; allergy; spirometry; the third National Health and Nutrition Examination Survey
19.  Swimming Pool Attendance, Asthma, Allergies, and Lung Function in the Avon Longitudinal Study of Parents and Children Cohort 
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.
doi:10.1164/rccm.201005-0761OC
PMCID: PMC3081279  PMID: 20889905
Avon Longitudinal Study of Parents and Children; pediatric; epidemiology, prospective; irritants
20.  A Comprehensive Evaluation of Potential Lung Function Associated Genes in the SpiroMeta General Population Sample 
PLoS ONE  2011;6(5):e19382.
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.
doi:10.1371/journal.pone.0019382
PMCID: PMC3098839  PMID: 21625484
21.  Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut allergy 
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.
doi:10.1016/j.jaci.2011.01.031
PMCID: PMC3081065  PMID: 21377035
Atopic dermatitis; filaggrin; IgE; peanut allergy; risk factor; AD, Atopic dermatitis; ALSPAC, Avon Longitudinal Study of Parents and Children; FLG, Filaggrin; OR, Odds ratio; SPT, Skin prick test; UK, United Kingdom
22.  Spirometric Lung Function in School-Age Children 
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.
doi:10.1164/rccm.200906-0897OC
PMCID: PMC2862306  PMID: 20093643
nutrition; somatic growth; somatic catch-up growth; Avon Longitudinal Study of Parents and Children; fetal development
23.  Genome-wide association study identifies five loci associated with lung function 
Repapi, Emmanouela | Sayers, Ian | Wain, Louise V | Burton, Paul R | Johnson, Toby | Obeidat, Ma’en | Zhao, Jing Hua | Ramasamy, Adaikalavan | Zhai, Guangju | Vitart, Veronique | Huffman, Jennifer E | Igl, Wilmar | Albrecht, Eva | Deloukas, Panos | Henderson, John | Granell, Raquel | McArdle, Wendy L | Rudnicka, Alicja R | Barroso, Inês | Loos, Ruth J F | Wareham, Nicholas J | Mustelin, Linda | Rantanen, Taina | Surakka, Ida | Imboden, Medea | Wichmann, H Erich | Grkovic, Ivica | Jankovic, Stipan | Zgaga, Lina | Hartikainen, Anna-Liisa | Peltonen, Leena | Gyllensten, Ulf | Johansson, Åsa | Zaboli, Ghazal | Campbell, Harry | Wild, Sarah H | Wilson, James F | Gläser, Sven | Homuth, Georg | Völzke, Henry | Mangino, Massimo | Soranzo, Nicole | Spector, Tim D | Polašek, Ozren | Rudan, Igor | Wright, Alan F | Heliövaara, Markku | Ripatti, Samuli | Pouta, Anneli | Naluai, Åsa Torinsson | Olin, Anna-Carin | Torén, Kjell | Cooper, Matthew N | James, Alan L | Palmer, Lyle J | Hingorani, Aroon D | Wannamethee, S Goya | Whincup, Peter H | Smith, George Davey | Ebrahim, Shah | McKeever, Tricia M | Pavord, Ian D | MacLeod, Andrew K | Morris, Andrew D | Porteous, David J | Cooper, Cyrus | Dennison, Elaine | Shaheen, Seif | Karrasch, Stefan | Schnabel, Eva | Schulz, Holger | Grallert, Harald | Bouatia-Naji, Nabila | Delplanque, Jérôme | Froguel, Philippe | Blakey, John D | Britton, John R | Morris, Richard W | Holloway, John W | Lawlor, Debbie A | Hui, Jennie | Nyberg, Fredrik | Jarvelin, Marjo-Riitta | Jackson, Cathy | Kähönen, Mika | Kaprio, Jaakko | Probst-Hensch, Nicole M | Koch, Beate | Hayward, Caroline | Evans, David M | Elliott, Paul | Strachan, David P | Hall, Ian P | Tobin, Martin D
Nature genetics  2009;42(1):36-44.
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.
doi:10.1038/ng.501
PMCID: PMC2862965  PMID: 20010834
24.  Glutathione-S-transferase genes and asthma phenotypes: a Human Genome Epidemiology (HuGE) systematic review and meta-analysis including unpublished data 
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.
doi:10.1093/ije/dyp337
PMCID: PMC2846443  PMID: 20032267
Meta-analysis; systematic review; glutathione-S-transferase genes; GSTM1 gene; GSTT1 gene; GSTP1 gene; asthma; wheezing; bronchial responsiveness; The Avon Longitudinal Study of Parents and Children (ALSPAC)
25.  European network for promoting the physical health of residents in psychiatric and social care facilities (HELPS): background, aims and methods 
BMC Public Health  2009;9:315.
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.
doi:10.1186/1471-2458-9-315
PMCID: PMC2741451  PMID: 19715560

Results 1-25 (70)