Background Both gastrointestinal microbiota composition and cesarean section have been linked to atopic manifestations. However, results are inconsistent, and the hypothesized intermediate role of ...the microbiota in the association between birth mode and atopic manifestations has not been studied yet. Objectives We sought to investigate the relationship between microbiota composition, mode and place of delivery, and atopic manifestations. Methods The Child, Parent and Health: Lifestyle and Genetic Constitution Birth Cohort Study included data on birth characteristics, lifestyle factors, and atopic manifestations collected through repeated questionnaires from birth until age 7 years. Fecal samples were collected at age 1 month (n = 1176) to determine microbiota composition, and blood samples were collected at ages 1 (n = 921), 2 (n = 822), and 6 to 7 (n = 384) years to determine specific IgE levels. Results Colonization by Clostridium difficile at age 1 month was associated with wheeze and eczema throughout the first 6 to 7 years of life and with asthma at age 6 to 7 years. Vaginal home delivery compared with vaginal hospital delivery was associated with a decreased risk of eczema, sensitization to food allergens, and asthma. After stratification for parental history of atopy, the decreased risk of sensitization to food allergens (adjusted odds ratio, 0.52; 95% CI, 0.35-0.77) and asthma (adjusted odds ratio, 0.47; 95% CI, 0.29-0.77) among vaginally home-born infants was only found for children with atopic parents. Mediation analysis showed that the effects of mode and place of delivery on atopic outcomes were mediated by C difficile colonization. Conclusion Mode and place of delivery affect the gastrointestinal microbiota composition, which subsequently influences the risk of atopic manifestations.
Background Asthma has its origins in early childhood, but different patterns of childhood wheezing vary in their associations with subsequent asthma, atopy, and bronchial hyperresponsiveness (BHR). ...Novel wheezing phenotypes have been identified on the basis of analyses of longitudinal data from the Avon Longitudinal Study of Parents And Children (ALSPAC). It is unclear whether these phenotypes can be replicated in other birth cohorts. Objective To compare wheezing phenotypes identified in the first 8 years of life in the ALSPAC study and the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) study. Methods We used longitudinal latent class analysis to identify phenotypes on the basis of repeated reports of wheezing from 0 to 8 years in 5760 children from the ALSPAC study and 2810 children from the PIAMA study. Phenotypes were compared between cohorts. Associations with asthma, atopy, BHR, and lung function were analyzed by using weighted regression analyses. Results The model with the best fit to PIAMA data in the first 8 years of life was a 5-class model. Phenotypes identified in the PIAMA study had wheezing patterns that were similar to those previously reported in ALSPAC, adding further evidence to the existence of an intermediate-onset phenotype with onset of wheeze after 2 years of age. Associations with asthma, atopy, BHR, and lung function were remarkably similar in the 2 cohorts. Conclusion Wheezing phenotypes identified by using longitudinal latent class analysis were comparable in 2 large birth cohorts. Study of genetic and environmental factors associated with different phenotypes may help elucidate the origins of asthma.
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.
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.
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.
It is difficult to distinguish at preschool age whether a wheezing child will or will not have asthma at school age. A prediction rule for asthma in preschool children might help to determine a ...prognosis and to study improvements in treatment and prevention. This review discusses (1) the development and use of clinical prediction rules, (2) the European Respiratory Society Task Force classification of wheeze at preschool age, (3) published prediction rules developed to identify preschool children who will have asthma at school age, and (4) recommendations to improve asthma prediction. Prediction rules are currently created more frequently, yet their clinical use remains low. The classification of episodic wheeze and multiple-trigger wheeze in preschool children shows conflicting results as to whether episodic wheeze and multiple-trigger wheeze differ in clinical features and has limited value in predicting asthma at school age. Clearly, more studies are needed to confirm this. Currently available prediction rules aiming to identify preschool children having asthma at school age are of modest clinical value. Prediction can be improved by more precise definitions and measures and, ultimately, by more knowledge of pathophysiologic mechanisms. In the future, biomarkers and genomic risk profiles to develop personalized medicine might further improve asthma prediction, treatment, and prevention.
Background Currently, the longitudinal validity (validity over time) and responsiveness (ability to measure change over time) of the Food Allergy Quality of Life Questionnaire–Adult Form (FAQLQ-AF), ...the Food Allergy Quality of Life Questionnaire–Teenager Form (FAQLQ-TF), and the Food Allergy Quality of Life Questionnaire–Child Form (FAQLQ-CF) are unknown. Additionally, the self-reported impact of a double-blind, placebo-controlled food challenge (DBPCFC) on health-related quality of life (HRQL) in adults (≥18 years of age), adolescents (13-17 years of age), and children (8-12 years of age) is unknown. Objective The aims of this study were to assess the longitudinal validity and responsiveness of the FAQLQ-AF, FAQLQ-TF, and FAQLQ-CF and to assess the impact of a DBPCFC on HRQL. Methods Two hundred twenty-one participants suspected of food allergy were included from Dutch allergy centers. Participants undergoing a DBPCFC (experimental group) completed the FAQLQ and Food Allergy Independent Measure (FAIM) 1 month before (baseline) and 6 months after (follow-up) a DBPCFC. Participants not undergoing a DBPCFC (control group) completed the questionnaire package twice with a 7-month interval. Results HRQL scores improved after a DBPCFC, with greater improvements in HRQL scores after a negative outcome (food allergy ruled out) than a positive outcome (food allergy confirmed), demonstrating responsiveness of the FAQLQs. Significant correlations were shown between the change (follow-up minus baseline) in FAQLQ and FAIM scores supporting longitudinal validity of these questionnaires: FAQLQ-AF (Pearson correlation coefficient = 0.71, P < .001), FAQLQ-TF (Pearson correlation coefficient = 0.35, P = .018), and FAQLQ-CF (Pearson correlation coefficient = 0.51, P < .001). Conclusions Our findings demonstrate the longitudinal validity and responsiveness of the FAQLQs. Greater improvements in HRQL scores were shown after a negative outcome than after a positive outcome.
Because the mechanisms underlying the observed sex differences in childhood asthma are not yet fully understood,3 we also evaluated the role of atopy and perinatal exposures. In these analyses, atopy ...was included in the definition of asthma at age 8 years. ...wheeze at ages 1 to 7 years was only considered to be asthmatic in children with atopic asthma at age 8 years.
Background IL-1 receptor–like 1 (IL1RL1) is a membrane receptor involved in TH 2 inflammatory responses and eosinophilia. Single nucleotide polymorphisms (SNPs) in IL1RL1 have been associated with ...blood eosinophil counts in a genome-wide association study and with asthma in family-based and case-control studies. Objective We assessed in the prospective birth cohort Prevention and Incidence of Asthma and Mite Allergy (PIAMA) whether IL1RL1 SNPs associate with levels of its soluble transcript IL1RL1 (IL1RL1-a) in serum, blood eosinophil counts, and asthma prevalence from birth to age 8 years, and whether IL1RL1-a serum levels associate with blood eosinophil counts. Methods Fifteen IL1RL1 SNPs were genotyped. Serum IL1RL1-a levels were measured in 2 independent subsets within PIAMA, at 4 and 8 years. Blood eosinophil counts were measured in 4-year-old children. Results In 2 independent subsets of children, 13 of 15 SNPs were associated with serum IL1RL1-a levels at ages 4 and 8 years with a consistent direction of effect for each allele. Rs11685480 allele A and rs1420102 allele A were significantly associated with lower numbers of blood eosinophils. In the total cohort, rs1041973 allele A was associated with a decreased risk of developing asthma (odds ratio, 0.70; 95% CI, 0.54-0.90). Rs1420101, recently identified in a genome-wide association study in the Icelandic population, was not associated with asthma in this study. IL1RL1-a levels were not associated with eosinophil counts. Conclusion We demonstrate that IL1RL1 polymorphisms are associated with serum IL1RL1-a, blood eosinophils, and asthma in childhood.
Background Regulatory T–cell dysfunction is associated with development of the complex genetic conditions atopy and asthma. Therefore, we hypothesized that single nucleotide polymorphisms in genes ...involved in the development and function of regulatory T cells are associated with atopy and asthma development. Objective To evaluate main effects and gene-gene interactions of haplotype tagging single nucleotide polymorphisms of genes involved in regulatory T–cell function— IL6 , IL6R , IL10 , heme-oxygenase 1 (HMOX1) , IL2 , Toll-like receptor 2 (TLR2) , TGFB1 , TGF-β receptor (TGFBR)–1 , TGFBR2 , IL2RA , and forkhead box protein 3 (FOXP3) —in relation to atopy and asthma. Methods Single-locus and multilocus associations with total IgE (3rd vs 1st tertile); specific IgE to egg, milk, and indoor allergens; and asthma were evaluated by χ2 tests and the multifactor dimensionality-reduction method in 3 birth cohorts (Allergenic study). Results Multiple statistically significant multilocus associations existed. IL2RA rs4749926 and TLR2 rs4696480 associated with IgE in both age groups tested (1-2 and 6-8 years). TGFBR2 polymorphisms associated with total and specific IgE in both age groups and with asthma. TGFBR2 rs9831477 associated with specific IgE for milk at age 1 to 2 years and indoor allergens at age 6 to 8 years. For milk-specific IgE, interaction between TGFBR2 and FOXP3 polymorphisms was confirmed by logistic regression and consistent in 2 birth cohorts and when stratified for sex, supplying internal replications. Conclusion Genes involved in the development and function of regulatory T cells, specifically IL2RA , TLR2 , TGFBR2 , and FOXP3 , associate with atopy and asthma by gene-gene interaction. Modeling of multiple gene-gene interactions is important to unravel further the genetic susceptibility to atopy and asthma.
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