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/m3 ). 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.
Background Chronic obstructive pulmonary disease (COPD) is a complex disease characterized by impaired lung function and airway obstruction resulting from interactions between multiple genes and ...multiple environmental exposures. Thus far, genome-wide association studies have largely disregarded environmental factors that might trigger the development of lung function impairment and COPD, such as occupational exposures, which are thought to contribute to 15% to 20% of the COPD prevalence. Objectives We performed a genome-wide interaction study to identify novel susceptibility loci for occupational exposure to biological dust, mineral dust, and gases and fumes in relation to FEV1 levels. Methods We performed an identification analysis in 12,400 subjects from the LifeLines cohort study and verified our findings in 1436 subjects from a second independent cohort, the Vlagtwedde-Vlaardingen cohort. Additionally, we assessed whether replicated single nucleotide polymorphisms (SNPs) were cis-acting expression (mRNA) quantitative trait loci in lung tissue. Results Of the 7 replicated SNPs that interacted with one of the occupational exposures, several identified loci were plausible candidates that might be involved in biological pathways leading to lung function impairment, such as PCDH9 and GALNT13 . Two of the 7 replicated SNPs were cis-acting expression quantitative trait loci associated with gene expression of PDE4D and TMEM176A in lung tissue. Conclusion This genome-wide interaction study on occupational exposures in relation to the level of lung function identified several novel genes. Further research should determine whether the identified genes are true susceptibility loci for occupational exposures and whether these SNP-by-exposure interactions consequently contribute to the development of COPD.
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 Although ambient air pollution has been linked to reduced lung function in healthy children, longitudinal analyses of pollution effects in asthmatic patients are lacking. Objective We ...sought to investigate pollution effects in a longitudinal asthma study and effect modification by controller medications. Methods We examined associations of lung function and methacholine responsiveness (PC20 ) with ozone, carbon monoxide (CO), nitrogen dioxide, and sulfur dioxide concentrations in 1003 asthmatic children participating in a 4-year clinical trial. We further investigated whether budesonide and nedocromil modified pollution effects. Daily pollutant concentrations were linked to ZIP/postal code of residence. Linear mixed models tested associations of within-subject pollutant concentrations with FEV1 and forced vital capacity (FVC) percent predicted, FEV1 /FVC ratio, and PC20 , adjusting for seasonality and confounders. Results Same-day and 1-week average CO concentrations were negatively associated with postbronchodilator percent predicted FEV1 (change per interquartile range, −0.33 95% CI, −0.49 to −0.16 and −0.41 95% CI, −0.62 to −0.21, respectively) and FVC (−0.19 95% CI, −0.25 to −0.07 and −0.25 95% CI, −0.43 to −0.07, respectively). Longer-term 4-month CO averages were negatively associated with prebronchodilator percent predicted FEV1 and FVC (−0.36 95% CI, −0.62 to −0.10 and −0.21 95% CI, −0.42 to −0.01, respectively). Four-month averaged CO and ozone concentrations were negatively associated with FEV1 /FVC ratio ( P < .05). Increased 4-month average nitrogen dioxide concentrations were associated with reduced postbronchodilator FEV1 and FVC percent predicted. Long-term exposures to sulfur dioxide were associated with reduced PC20 (percent change per interquartile range, −6% 95% CI, −11% to −1.5%). Treatment augmented the negative short-term CO effect on PC20. Conclusions Air pollution adversely influences lung function and PC20 in asthmatic children. Treatment with controller medications might not protect but rather worsens the effects of CO on PC20 . This clinical trial design evaluates modification of pollution effects by treatment without confounding by indication.
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 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.
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 The relationship between allergy and autoimmune disorders is complex and poorly understood. Objective We sought to investigate commonalities in genetic loci and pathways between allergy ...and autoimmune diseases to elucidate shared disease mechanisms. Methods We meta-analyzed 2 genome-wide association studies on self-reported allergy and sensitization comprising a total of 62,330 subjects. These results were used to calculate enrichment for single nucleotide polymorphisms (SNPs) previously associated with autoimmune diseases. Furthermore, we probed for enrichment within genetic pathways and of transcription factor binding sites and characterized commonalities in variant burden on tissue-specific regulatory sites by calculating the enrichment of allergy SNPs falling in gene regulatory regions in various cells using Encode Roadmap DNase-hypersensitive site data. Finally, we compared the allergy data with those of all known diseases. Results Among 290 loci previously associated with 16 autoimmune diseases, we found a significant enrichment of loci also associated with allergy ( P = 1.4e-17) encompassing 29 loci at a false discovery rate of less than 0.05. Such enrichment seemed to be a general characteristic for autoimmune diseases. Among the common loci, 48% had the same direction of effect for allergy and autoimmune diseases. Additionally, we observed an enrichment of allergy SNPs falling within immune pathways and regions of chromatin accessible in immune cells that was also represented in patients with autoimmune diseases but not those with other diseases. Conclusion We identified shared susceptibility loci and commonalities in pathways between allergy and autoimmune diseases, suggesting shared disease mechanisms. Further studies of these shared genetic mechanisms might help in understanding the complex relationship between these diseases, including the parallel increase in disease prevalence.
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.
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