Association between COPD exacerbations and lung function decline during maintenance therapy.

BACKGROUND: Little is known about the impact of exacerbations on COPD progression or whether inhaled corticosteroid (ICS) use and blood eosinophil count (BEC) affect progression. We aimed to assess this in a prospective observational study. METHODS: The study population included patients with mild to moderate COPD, aged ≥35 years, with a smoking history, who were followed up for ≥3 years from first to last spirometry recording using two large UK electronic medical record databases: Clinical Practice Research Datalink (CPRD) and Optimum Patient Care Research Database (OPCRD). Multilevel mixed-effects linear regression models were used to determine the relationship between annual exacerbation rate following initiation of therapy (ICS vs non-ICS) and FEV1 decline. Effect modification by blood eosinophils was studied through interaction terms. RESULTS: Of 12178 patients included (mean age 66 years; 48% female), 8981 (74%) received ICS. In patients with BEC ≥350 cells/µL not on ICS, each exacerbation was associated with subsequent acceleration of FEV1 decline of 19.4 mL/year (95% CI 12.0 to 26.7, p<0.0001). This excess decline was reduced by 15.1 mL/year (6.6 to 23.6) to 4.3 mL/year (1.9 to 6.7, p<0.0001) in those with BEC ≥350 cells/µL treated with ICS. CONCLUSION: Exacerbations are associated with a more rapid loss of lung function among COPD patients with elevated blood eosinophils, defined as ≥350 cells/µL, not treated with ICS. More aggressive prevention of exacerbations using ICS in such patients may prevent excess loss of lung function.

DNA Methylation in Newborns and Maternal Smoking in Pregnancy: Genome-wide Consortium Meta-analysis.

Epigenetic modifications, including DNA methylation, represent a potential mechanism for environmental impacts on human disease. Maternal smoking in pregnancy remains an important public health problem that impacts child health in a myriad of ways and has potential lifelong consequences. The mechanisms are largely unknown, but epigenetics most likely plays a role. We formed the Pregnancy And Childhood Epigenetics (PACE) consortium and meta-analyzed, across 13 cohorts (n = 6,685), the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) by using the Illumina 450K BeadChip. Over 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation in either newborns or adults. Several genes are relevant to diseases that can be caused by maternal smoking (e.g., orofacial clefts and asthma) or adult smoking (e.g., certain cancers). A number of differentially methylated CpGs were associated with gene expression. We observed enrichment in pathways and processes critical to development. In older children (5 cohorts, n = 3,187), 100% of CpGs gave at least nominal levels of significance, far more than expected by chance (p value < 2.2 × 10(-16)). Results were robust to different normalization methods used across studies and cell type adjustment. In this large scale meta-analysis of methylation data, we identified numerous loci involved in response to maternal smoking in pregnancy with persistence into later childhood and provide insights into mechanisms underlying effects of this important exposure.

Healthcare resource utilization and costs associated with incremental systemic corticosteroid exposure in asthma.

BACKGROUND: Although systemic corticosteroid (SCS) treatment, irrespective of duration or dosage, is associated with adverse outcomes for patients with asthma, the longitudinal effects of this treatment on adverse outcomes, healthcare resource utilization (HCRU), and healthcare costs are unknown. METHODS: We identified patients initiating intermittent or long-term SCS who were diagnosed with active asthma from UK general practice with linked secondary care data. Control (non-SCS) patients were matched by sex and index date with those initiating SCS. Minimum baseline period was 1 year prior to index date; minimum follow-up duration was 2 years post-index date. Cumulative incidence of SCS-associated adverse outcomes and associated HCRU and costs were compared between SCS and non-SCS patient groups and among average SCS daily exposure categories. Associations between exposure and annualized HCRU and costs were assessed, adjusted for confounders. RESULTS: Analyses included 9413 matched pairs. Median (interquartile range) follow up was as follows: SCS group: 7.1 (4.1-11.8) years; control group: 6.4 (3.8-10.0) years. Greater SCS dosages were correlated with greater cumulative incidence. For example, patients with type 2 diabetes receiving an average daily dosage of ≥7.5 mg had a 15-year cumulative incidence (37.5%) that was 1.5-5 times greater than those receiving lower dosages. HCRU and costs increased annually for SCS patients but not for non-SCS patients. Increases in all-cause adverse outcome (excluding asthma)-associated HCRU and costs were dose-dependent. CONCLUSIONS: Over the long term, adverse outcomes associated with SCS initiation were relatively frequent and costly, with a positive dosage-response relationship with SCS exposure.

Healthcare resource use and costs of severe, uncontrolled eosinophilic asthma in the UK general population.

BACKGROUND: Little is known about the prevalence of severe, uncontrolled eosinophilic asthma (SUEA) and associated costs. AIMS: We sought to determine the prevalence of SUEA and compare asthma-related healthcare resource use (HCRU) and associated costs with overall means for a general asthma population. METHODS: This cohort study evaluated anonymised medical record data (December 1989 through June 2015) from the Clinical Practice Research Datalink and the Optimum Patient Care Research Database to study UK patients with active asthma (diagnostic code and one or more drug prescriptions in the baseline year), aged 5 years and older, without concomitant COPD, and with recorded eosinophil count. SUEA was defined as two or more asthma attacks during 1 baseline year preceding a high blood eosinophil count (≥0.3×109/L) for patients prescribed long-acting ß2-agonist (LABA) and high-dosage inhaled corticosteroids (ICS) during baseline plus 1 follow-up year. We compared asthma-related HCRU and associated direct costs (2015 pounds sterling, £) during the follow-up year for SUEA versus the general asthma population. RESULTS: Of 363 558 patients with active asthma and recorded eosinophil count, 64% were women, mean (SD) age was 49 (21) years; 43% had high eosinophil counts, 7% had two or more attacks in the baseline year and 10% were prescribed high-dosage ICS/LABA for 2 study years. Overall, 2940 (0.81%; 95% CI 0.78% to 0.84%) patients had SUEA. Total mean per-patient HCRU and associated costs were four times greater for SUEA versus all patients (HCRU and cost ratios 3.9; 95% CI 3.7 to 4.1). CONCLUSIONS: Less than 1% of patients in a general asthma population had SUEA. These patients accounted for substantially greater asthma-related HCRU and costs than average patients with asthma.

Atopic dermatitis: Interaction between genetic variants of GSTP1, TNF, TLR2, and TLR4 and air pollution in early life.

BACKGROUND: Associations between traffic-related air pollution (TRAP) and childhood atopic dermatitis (AD) remain inconsistent, possibly due to unexplored gene-environment interactions. The aim of this study was to examine whether a potential effect of TRAP on AD prevalence in children is modified by selected single nucleotide polymorphisms (SNPs) related to oxidative stress and inflammation. METHODS: Doctor-diagnosed AD up to age 2 years and at 7-8 years, as well as AD symptoms up to age 2 years, was assessed using parental-reported questionnaires in six birth cohorts (N = 5685). Associations of nitrogen dioxide (NO2 ) estimated at the home address of each child at birth and nine SNPs within the GSTP1, TNF, TLR2, or TLR4 genes with AD were examined. Weighted genetic risk scores (GRS) were calculated from the above SNPs and used to estimate combined marginal genetic effects of oxidative stress and inflammation on AD and its interaction with TRAP. RESULTS: GRS was associated with childhood AD and modified the association between NO2 and doctor-diagnosed AD up to the age of 2 years (P(interaction) = .029). This interaction was mainly driven by a higher susceptibility to air pollution in TNF rs1800629 minor allele (A) carriers. TRAP was not associated with the prevalence of AD in the general population. CONCLUSIONS: The marginal genetic association of a weighted GRS from GSTP1, TNF, TLR2, and TLR4SNPs and its interaction with air pollution supports the role of oxidative stress and inflammation in AD.

A novel common variant in DCST2 is associated with length in early life and height in adulthood.

Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 × 10(-6)) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; ß = 0.046, SE = 0.008, P = 2.46 × 10(-8), explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 × 10(-4)) and adult height (N = 127 513; P = 1.45 × 10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.

Eligibility of real-life patients with COPD for inclusion in trials of inhaled long-acting bronchodilator therapy.

BACKGROUND: Management guidelines of chronic obstructive pulmonary disease (COPD) are mainly based on results of randomised controlled trials (RCTs), but some authors have suggested limited representativeness of patients included in these trials. No previous studies have applied the full range of selection criteria to a broad COPD patient population in a real-life setting. METHODS: We identified all RCTs of inhaled long-acting bronchodilator therapy, during 1999-2013, at ClinicalTrials.gov and translated trial selection criteria into definitions compatible with electronic medical records. Eligibility was calculated for each RCT by applying these criteria to a uniquely representative, well-characterised population of patients with COPD from the Optimum Patient Care Research Database (OPCRD). RESULTS: Median eligibility of 36 893 patients with COPD for participation in 31 RCTs was 23 % (interquartile range 12-38). Two studies of olodaterol showed the highest eligibility of 55 and 58 %. Conversely, the lowest eligibility was observed in two studies that required a history of exacerbations in the past year (3.5 and 3.9 %). For the patient subgroup with modified Medical Research Council score ≥2, the overall median eligibility was 27 %. CONCLUSIONS: By applying an extensive range of RCT selection criteria to a large, representative COPD patient population, this study highlights that the interpretation of results from RCTs must take into account that RCT participants are variably, but generally more representative of patients in the community than previously believed.

Genome-wide association and longitudinal analyses reveal genetic loci linking pubertal height growth, pubertal timing and childhood adiposity.

The pubertal height growth spurt is a distinctive feature of childhood growth reflecting both the central onset of puberty and local growth factors. Although little is known about the underlying genetics, growth variability during puberty correlates with adult risks for hormone-dependent cancer and adverse cardiometabolic health. The only gene so far associated with pubertal height growth, LIN28B, pleiotropically influences childhood growth, puberty and cancer progression, pointing to shared underlying mechanisms. To discover genetic loci influencing pubertal height and growth and to place them in context of overall growth and maturation, we performed genome-wide association meta-analyses in 18 737 European samples utilizing longitudinally collected height measurements. We found significant associations (P < 1.67 × 10(-8)) at 10 loci, including LIN28B. Five loci associated with pubertal timing, all impacting multiple aspects of growth. In particular, a novel variant correlated with expression of MAPK3, and associated both with increased prepubertal growth and earlier menarche. Another variant near ADCY3-POMC associated with increased body mass index, reduced pubertal growth and earlier puberty. Whereas epidemiological correlations suggest that early puberty marks a pathway from rapid prepubertal growth to reduced final height and adult obesity, our study shows that individual loci associating with pubertal growth have variable longitudinal growth patterns that may differ from epidemiological observations. Overall, this study uncovers part of the complex genetic architecture linking pubertal height growth, the timing of puberty and childhood obesity and provides new information to pinpoint processes linking these traits.

Early exposure to bio-contaminants and asthma up to 10 years of age: results of the HITEA study.

Inverse associations have been found between exposure to bio-contaminants and asthma and allergies. The aim of this study was to prospectively assess whether early exposure to bio-contaminants in dust is associated with asthma and allergy later in childhood among children from (sub)-urban areas. In subsets of three European birth cohorts (PIAMA: n=553; INMA: n=481; and LISAplus: n=395), endotoxin, (1,3,)-ß-d-glucan and extracellular polysaccharide were measured in dust from living rooms shortly after birth. Current asthma at 6 years and 10 years of age and ever asthma up to 10 years of age were assessed by parental questionnaires. Specific IgE levels at 8 years (PIAMA) and 10 years (LISAplus) were available. Adjusted, cohort-specific logistic regression analyses were performed. Higher endotoxin concentrations were positively associated with current asthma at 6 years of age in PIAMA (adjusted OR 1.96, 95% CI 1.07-3.58), but were inversely related with ever asthma up to 10 years of age in INMA (adjusted OR 0.39, 95% CI 0.16-0.94). No associations with asthma were found for LISAplus. No associations were observed with atopic sensitisation in all cohorts. All associations with (1,3)-ß-d-glucan and extracellular polysaccharide were statistically nonsignificant. The suggested immunological mechanisms of early exposure to bio-contaminants with regards to asthma and allergy might be different for children growing up in (sub)-urban environments.

Serum Visfatin and Leptin in Relation to Childhood Adiposity and Body Fat Distribution: The PIAMA Birth Cohort Study.

BACKGROUND/AIMS: Visfatin has been suggested as a marker of visceral adiposity. We hypothesized that visfatin, but not leptin, would be specifically associated with visceral adiposity. We investigated the relation of serum visfatin and leptin with measures of adiposity and body fat distribution in children. METHODS: Serum leptin and visfatin levels were measured in 1,022 12-year-old children participating in the PIAMA birth cohort. BMI, waist, hip and upper arm circumference were available for all children. Multiple linear regression analyses were conducted to study associations between different anthropometric indices and log serum visfatin and leptin levels. RESULTS: All anthropometric indices showed positive and strong dose-response relationships with serum leptin. Visfatin was increased only in children with a high waist-to-hip ratio. The effect size was small compared to those observed for leptin and the association was present in overweight children (n = 133) but not in normal weight children. CONCLUSION: Serum leptin levels strongly increased with increasing adiposity, but were not related to a specific type of fat distribution. In contrast, serum visfatin was associated only with high waist-to-hip ratio in overweight children. Based on our study we would currently not recommend visfatin as a marker of visceral adiposity in the general population of children.

Association of IL33-IL-1 receptor-like 1 (IL1RL1) pathway polymorphisms with wheezing phenotypes and asthma in childhood.

BACKGROUND: Genome-wide association studies identified IL33 and IL-1 receptor-like 1 (IL1RL1)/IL18R1 as asthma susceptibility loci. IL33 and IL1RL1 constitute a single ligand-receptor pathway. OBJECTIVE: In 2 birth cohorts, the Prevalence and Incidence of Asthma and Mite Allergy (PIAMA) study and Avon Longitudinal Study of Parents and Children (ALSPAC), we analyzed associations of longitudinal wheezing phenotypes and asthma with single nucleotide polymorphisms (SNPs) of 8 genes encoding IL-33, IL1RL1, its coreceptor IL1RAcP, its adaptors myeloid differentiation primary response gene 88 (MyD88) and Toll-IL-11 receptor domain containing adaptor protein (TIRAP), and the downstream IL-1 receptor-associated kinase 1, IL-1 receptor-associated kinase 4, and TNF receptor-associated factor 6 (TRAF6). Furthermore, we investigated whether SNPs in this pathway show replicable evidence of gene-gene interaction. METHODS: Ninety-four SNPs were investigated in 2007 children in the PIAMA study and 7247 children in ALSPAC. Associations with wheezing phenotypes and asthma at 8 years of age were analyzed in each cohort and subsequently meta-analyzed. Gene-gene interactions were assessed through model-based multifactor dimensionality reduction in the PIAMA study, and gene-gene interactions of 10 SNP pairs were further evaluated. RESULTS: Intermediate-onset wheeze was associated with SNPs in several genes in the IL33-IL1RL1 pathway after applying multiple testing correction in the meta-analysis: 2 IL33 SNPs (rs4742170 and rs7037276), 1 IL-1 receptor accessory protein (IL1RAP) SNP (rs10513854), and 1 TRAF6 SNP (rs5030411). Late-onset wheeze was associated with 2 IL1RL1 SNPs (rs10208293 and rs13424006), and persistent wheeze was associated with 1 IL33 SNP (rs1342326) and 1 IL1RAP SNP (rs9290936). IL33 and IL1RL1 SNPs were nominally associated with asthma. Three SNP pairs showed interaction for asthma in the PIAMA study but not in ALSPAC. CONCLUSIONS: IL33-IL1RL1 pathway polymorphisms are associated with asthma and specific wheezing phenotypes; that is, most SNPs are associated with intermediate-onset wheeze, a phenotype closely associated with sensitization. We speculate that IL33-IL1RL1 pathway polymorphisms affect development of wheeze and subsequent asthma through sensitization in early childhood.

Transient early wheeze and lung function in early childhood associated with chronic obstructive pulmonary disease genes.

BACKGROUND: It has been hypothesized that a disturbed early lung development underlies the susceptibility to chronic obstructive pulmonary disease (COPD). Little is known about whether subjects genetically predisposed to COPD show their first symptoms or reduced lung function in childhood. OBJECTIVE: We investigated whether replicated genes for COPD associate with transient early wheeze (TEW) and lung function levels in 6- to 8-year-old children and whether cigarette smoke exposure in utero and after birth (environmental tobacco smoke [ETS]) modifies these effects. METHODS: The association of COPD-related genotypes of 20 single nucleotide polymorphisms in 15 genes with TEW, FEV1, forced vital capacity (FVC), and FEV1/FVC ratio was studied in the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort (n = 1996) and replicated in the Child, parents and health: lifestyle and genetic constitution (KOALA) and Avon Longitudinal Study of Parents and Children (ALSPAC) cohorts. RESULTS: AGER showed replicated association with FEV1/FVC ratio. TNS1 associated with more TEW in PIAMA and lower FEV1 in ALSPAC. TNS1 interacted with ETS in PIAMA, showing lower FEV1 in exposed children. HHIP rs1828591 interacted with cigarette smoke exposure in utero in PIAMA and with ETS in ALSPAC, with lower lung function in nonexposed children. SERPINE2, FAM13A, and MMP12 associated with higher FEV1 and FVC, and SERPINE2, HHIP, and TGFB1 interacted with cigarette smoke exposure in utero in PIAMA only, showing adverse effects of exposure on FEV1 being limited to children with genotypes conferring the lowest risk of COPD. CONCLUSION: Our findings indicate relevant involvement of at least 3 COPD genes in lung development and lung growth by demonstrating associations pointing toward reduced airway caliber in early childhood. Furthermore, our results suggest that COPD genes are involved in the infant's lung response to smoke exposure in utero and in early life.

Time in bed, sleep quality and associations with cardiometabolic markers in children: the Prevention and Incidence of Asthma and Mite Allergy birth cohort study.

We investigated associations of time in bed and multiple sleep quality characteristics with cardiometabolic markers in children. Data from the prevention and incidence of asthma and mite allergy study, a population-based prospective birth-cohort study started in 1996-1997 in the Netherlands, were analysed. In total 1481 children aged 11-12 years completed a questionnaire (including questions on sleep) and underwent a medical examination. We measured body mass index, waist circumference, total- and high-density lipoprotein cholesterol, blood pressure and glycated haemoglobin. Results showed that in girls, some sleep characteristics were related to anthropometrics (body mass index, waist circumference) and cholesterol. Girls who had a long time in bed (11-12.5 h) had 0.16 lower body mass index z-score (95% confidence interval -0.31; -0.01) and 0.99 cm smaller waist circumference (95% confidence interval -2.01; -0.13) compared with girls who spent 10-10.5 h in bed. Girls who went to bed late and rose early had 0.16 mm higher total cholesterol (95% confidence interval 0.01; 0.31) and 0.08 mm higher high-density lipoprotein cholesterol (95% confidence interval 0.01; 0.14) than 'early to bed/early rise' girls. Girls with night-time awakenings had 0.14 mm higher total cholesterol (95% confidence interval 0.03; 0.25) than girls without night-time awakenings. Girls who felt sleepy/tired ≥1 day per week had 0.10 mm lower high-density lipoprotein cholesterol (95% confidence interval -0.16; -0.04) and 0.17 mm higher total cholesterol/high-density lipoprotein cholesterol ratio (95% confidence interval 0.02; 0.32) than girls who did not feel sleepy. No associations were found for boys. Sleep characteristics were not related to blood pressure and glycated haemoglobin, and effect sizes of the associations in girls were small. Therefore, we consider it premature to propose that improved sleep could reduce cardiovascular risk during childhood.

Guideline-recommended use of asthma medication by children is associated with parental information and knowledge: the PIAMA birth cohort.

PURPOSE: We investigated the use of asthma medication by children and the association of use as recommended by guidelines with modifiable risk factors: parental attitudes, knowledge of asthma medication and information provided by health care providers. METHODS: Questionnaire data were obtained from parents of 229 8-year-old children participating in the prevention and incidence of asthma and mite allergy birth cohort who used asthma medication in the past 12 months. They reported on their child's medication use, their own knowledge and attitudes towards the medication and their satisfaction with the information they received from health care providers. RESULTS: Irregular use of inhaled corticosteroids (ICS) was common: 40% of the parents only gave their child ICS when the child felt breathless and 52% only 'when the child needed it'; 15% of the parents tried to avoid giving medication, and about 25% of the parents sometimes discontinued medication. Parental knowledge of how asthma medication should be given was a major determinant of guideline-recommended use: Of the parents who knew that anti-inflammatory drugs should be taken everyday (53% of all parents), 84% reported that they actually gave their child the medicines everyday as compared with 25% of the parents who did not know this. Guideline-recommended use was also significantly associated with parental satisfaction with the amount of information received from health care providers. These associations were independent of maternal school education. CONCLUSIONS: Our findings suggest that substantial improvements in the use of asthma medication are feasible, and this could considerably improve the effectiveness of current asthma treatment.

Overweight in infancy: which pre- and perinatal factors determine overweight persistence or reduction? A birth cohort followed for 11 years.

BACKGROUND: A considerable proportion of children with early-life overweight attain a normal weight. To recognize infants at risk of persistent overweight, we compared early-life factors of children with a longitudinal pattern of persistent overweight to children with a pattern of overweight in early but not in later childhood. METHODS: In 3,550 children participating in a birth cohort that started in 1996/1997 in the Netherlands, body mass index was repeatedly assessed until age 11 and dichotomized into with/without overweight. Latent class growth modeling was used to distinguish trajectories. Our analysis was focused on the comparison of early-life factors in children in a persistent overweight pattern with those in an overweight reduction pattern using multivariable log-binomial regression analyses. RESULTS: Children (n = 133) in the persistent overweight pattern were more likely to have overweight parents [relative risk (RR)mother: 1.85, 95% CI: 1.37-2.49: RRfather: 1.75, 95% CI: 1.21-2.55] than children in the overweight reduction pattern (n = 303). Maternal education, child's gender, ethnicity, birth weight, breast-feeding and maternal smoking during pregnancy did not differ between the trajectories. CONCLUSION: Health care practitioners should focus on high-weight infants with overweight parents, as these children are less likely to resolve their overweight.

Childhood allergic rhinitis, traffic-related air pollution, and variability in the GSTP1, TNF, TLR2, and TLR4 genes: results from the TAG Study.

BACKGROUND: Associations between traffic-related air pollution (TRAP) and allergic rhinitis remain inconsistent, possibly because of unexplored gene-environment interactions. OBJECTIVE: In a pooled analysis of 6 birth cohorts (Ntotal = 15,299), we examined whether TRAP and genetic polymorphisms related to inflammation and oxidative stress predict allergic rhinitis and sensitization. METHODS: Allergic rhinitis was defined with a doctor diagnosis or reported symptoms at age 7 or 8 years. Associations between nitrogen dioxide, particulate matter 2.5 (PM2.5) mass, PM2.5 absorbance, and ozone, estimated for each child at the year of birth, and single nucleotide polymorphisms within the GSTP1, TNF, TLR2, or TLR4 genes with allergic rhinitis and aeroallergen sensitization were examined with logistic regression. Models were stratified by genotype and interaction terms tested for gene-environment associations. RESULTS: Point estimates for associations between nitrogen dioxide, PM2.5 mass, and PM2.5 absorbance with allergic rhinitis were elevated, but only that for PM2.5 mass was statistically significant (1.37 [1.01, 1.86] per 5 µg/m(3)). This result was not robust to single-cohort exclusions. Carriers of at least 1 minor rs1800629 (TNF) or rs1927911 (TLR4) allele were consistently at an increased risk of developing allergic rhinitis (1.19 [1.00, 1.41] and 1.24 [1.01, 1.53], respectively), regardless of TRAP exposure. No evidence of gene-environment interactions was observed. CONCLUSION: The generally null effect of TRAP on allergic rhinitis and aeroallergen sensitization was not modified by the studied variants in the GSTP1, TNF, TLR2, or TLR4 genes. Children carrying a minor rs1800629 (TNF) or rs1927911 (TLR4) allele may be at a higher risk of allergic rhinitis.

Predicting asthma in preschool children with asthma-like symptoms: validating and updating the PIAMA risk score.

BACKGROUND: The Prevention and Incidence of Asthma and Mite Allergy (PIAMA) risk score predicts the probability of having asthma at school age among preschool children with suggestive symptoms. OBJECTIVE: We sought to externally validate the PIAMA risk score at different ages and in ethnic and socioeconomic subgroups of children in addition to updating it. METHODS: We studied 2877 children with preschool asthma-like symptoms participating in the multiethnic, prospective, population-based cohort study Generation R. The PIAMA risk score was assessed at preschool age, and asthma was predicted at age 6 years. Discrimination (concordance index [C-index]) and calibration were calculated. The PIAMA risk score was updated, and its performance was similarly analyzed. RESULTS: At age 6 years, 6% (168/2877) of the children had asthma. The discriminative ability of the original PIAMA risk score to predict asthma in Generation R was similar compared with that in the PIAMA cohort (C-index = 0.74 vs 0.71). The predicted risks by using the original PIAMA risk score for having asthma at the age of 6 years tended to be slightly higher than the observed risks (8% vs 6%). No differences in discriminative ability were found at different ages or in ethnic and socioeconomic subgroups (P > .05). The updated PIAMA risk score had a C-index of 0.75. CONCLUSIONS: The PIAMA risk score showed good external validity. The discriminative ability was similar at different ages and in ethnic and socioeconomic subgroups of preschool children, which suggests good generalizability. Further studies are needed to reproduce the predictive performance of the updated PIAMA risk score in other populations and settings and to assess its clinical relevance.

Traffic-related air pollution is related to interrupter resistance in 4-year-old children.

Outdoor air pollution has been associated with decrements in lung function and growth of lung function in school-age children. Lung function effects have not been examined in preschoolers, with the exception of one study on minute ventilation in newborns. Our goal was to assess the relationship between long- and short-term exposure to traffic-related air pollution and interrupter resistance in 4-year-old children. Lung function was measured using the interrupter resistance method in children participating in a Dutch birth cohort study. Long-term average air pollution concentrations of fine particulate matter, nitrogen dioxide and soot at the residential address at birth were assessed using land-use regression models. Daily average air pollution concentrations on the day of clinical examination were obtained from the Dutch National Air Quality Monitoring Network. Significant associations were found between long-term average air pollution concentrations and interrupter resistance. Interrupter resistance increased by 0.04 kPa·s·L(-1) (95% CI 0.01-0.07) per interquartile range increase (3.3 µg·m(-3)) in fine particle concentration. Short-term exposure was not associated with interrupter resistance. Long-term exposure to traffic-related air pollution was associated with increased interrupter resistance in 4-year-old children, supporting previous birth cohort studies reporting effects of air pollution on subjectively reported respiratory symptoms in preschool children.

Traffic, asthma and genetics: combining international birth cohort data to examine genetics as a mediator of traffic-related air pollution's impact on childhood asthma.

Associations between traffic-related air pollution and incident childhood asthma can be strengthened by analysis of gene-environment interactions, but studies have typically been limited by lack of study power. We combined data from six birth cohorts on: asthma, eczema and allergic rhinitis to 7/8 years, and candidate genes. Individual-level assessment of traffic-related air pollution exposure was estimated using land use regression or dispersion modeling. A total of 11,760 children were included in the Traffic, Asthma and Genetics (TAG) Study; 6.3 % reported physician-diagnosed asthma at school-age, 16.0 % had asthma at anytime during childhood, 14.1 % had allergic rhinitis at school-age, 10.0 % had eczema at school-age and 33.1 % were sensitized to any allergen. For GSTP1 rs1138272, the prevalence of heterozygosity was 16 % (range amongst individual cohorts, 11-17 %) and homozygosity for the minor allele was 1 % (0-2 %). For GSTP1 rs1695, the prevalence of heterozygosity was 45 % (40-48 %) and homozygosity for the minor allele, 12 % (10-12 %). For TNF rs1800629, the prevalence of heterozygosity was 29 % (25-32 %) and homozygosity for the minor allele, 3 % (1-3 %). TAG comprises a rich database, the largest of its kind, for investigating the effect of genotype on the association between air pollution and childhood allergic disease.

Gas cooking, respiratory and allergic outcomes in the PIAMA birth cohort study.

OBJECTIVES: Evidence for a relationship between gas cooking and childhood respiratory health is inconsistent and few longitudinal studies have been reported. Our aim was to examine the association between gas cooking and the development of respiratory and allergic outcomes longitudinally in a prospective birth cohort study. METHODS: The Prevention and Incidence of Asthma and Mite Allergy birth cohort study followed children from birth (1996/1997) until age 8. Annual questionnaires were used to document respiratory and allergic symptoms. Allergic sensitisation and bronchial hyper-responsiveness (BHR) were measured at age 8 in subpopulations. A total of 3590 children were included in the present analysis. We used generalised estimating equations and discrete-time hazard models to study the overall and age-specific associations between exposure to gas cooking and the risk of developing respiratory illnesses. Sensitivity analyses of intermittent, always, current and early exposure to gas cooking were conducted. RESULTS: Ever gas cooking exposure was associated with nasal symptoms (sneezing, runny/blocked nose without a cold) during the first 8 years of life (OR=1.32, 95% CI 1.09 to 1.59), but not with lower respiratory tract infections, eczema, allergic sensitisation and BHR. Associations with nasal symptoms were similar among children with intermittent, always, current and early exposure. Among girls only, prevalent asthma was associated with ever gas cooking (OR=1.97, 95% CI 1.05 to 3.72). CONCLUSIONS: Overall, our findings provide little evidence for an adverse effect of exposure to gas cooking on the development of asthma and allergies.