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Single-nucleotide polymorphisms (SNPs) in GSDMB (Gasdermin B) and ORMDL3 (ORMDL sphingolipid biosynthesis regulator 3) are strongly associated with childhood asthma, but the molecular alterations contributing to disease remain unknown. We investigated the effects of asthma-associated SNPs on DNA methylation and mRNA levels of GSDMB and ORMDL3. Genetic association between GSDMB/ORMDL3 and physician-diagnosed childhood asthma was confirmed in the Swedish birth-cohort BAMSE. CpG-site SNPs (rs7216389 and rs4065275) showed differences in DNA methylation depending on carrier status of the risk alleles, and were significantly associated with methylation levels in two CpG sites in the 5′ UTR (untranslated region) of ORMDL3. In the Swedish Search study, we found significant differences in DNA methylation between asthmatics and controls in five CpG sites; after adjusting for lymphocyte and neutrophil cell counts, three remained significant: one in IKZF3 [IKAROS family zinc finger 3 (Aiolos); cg16293631] and two in the CpG island (CGI) of ORMDL3 (cg02305874 and cg16638648). Also, cg16293631 and cg02305874 correlated with mRNA levels of ORMDL3. The association between methylation and asthma was independent of the genotype in rs7216389, rs4065275 and rs12603332. Both SNPs and CpG sites showed significant associations with ORMDL3 mRNA levels. SNPs influenced expression independently of methylation, and the residual association between methylation and expression was not mediated by these SNPs. We found a differentially methylated region in the CGI shore of ORMDL3 with six CpG sites less methylated in CD8+ T-cells. In summary, this study supports that there are differences in DNA methylation at this locus between asthmatics and controls; and both SNPs and CpG sites are independently associated with ORMDL3 expression.

Background: Genetics may partially explain observed heterogeneity in associations between traffic-related air pollution and incident asthma.Objective: Our aim was to investigate the impact of gene variants associated with oxidative stress and inflammation on associations between air pollution and incident childhood asthma.Methods: Traffic-related air pollution, asthma, wheeze, gene variant, and potential confounder data were pooled across six birth cohorts. Parents reported physician-diagnosed asthma and wheeze from birth to 7–8 years of age (confirmed by pediatric allergist in two cohorts). Individual estimates of annual average air pollution [nitrogen dioxide (NO2), particulate matter ≤ 2.5 μm (PM2.5), PM2.5 absorbance, ozone] were assigned to each child’s birth address using land use regression, atmospheric modeling, and ambient monitoring data. Effect modification by variants in GSTP1 (rs1138272/Ala114Val and rs1695/IIe105Val) and TNF (rs1800629/G-308A) was investigated.Results: Data on asthma, wheeze, potential confounders, at least one SNP of interest, and NO2 were available for 5,115 children. GSTP1 rs1138272 and TNF rs1800629 SNPs were associated with asthma and wheeze, respectively. In relation to air pollution exposure, children with one or more GSTP1 rs1138272 minor allele were at increased risk of current asthma [odds ratio (OR) = 2.59; 95% CI: 1.43, 4.68 per 10 μg/m3 NO2] and ever asthma (OR = 1.64; 95% CI: 1.06, 2.53) compared with homozygous major allele carriers (OR = 0.95; 95% CI: 0.68, 1.32 for current and OR = 1.20; 95% CI: 0.98, 1.48 for ever asthma; Bonferroni-corrected interaction p = 0.04 and 0.01, respectively). Similarly, for GSTP1 rs1695, associations between NO2 and current and ever asthma had ORs of 1.43 (95% CI: 1.03, 1.98) and 1.36 (95% CI: 1.08, 1.70), respectively, for minor allele carriers compared with ORs of 0.82 (95% CI: 0.52, 1.32) and 1.12 (95% CI: 0.84, 1.49) for homozygous major allele carriers (Bonferroni-corrected interaction p-values 0.48 and 0.09). There were no clear differences by TNF genotype.Conclusions: Children carrying GSTP1 rs1138272 or rs1695 minor alleles may constitute a susceptible population at increased risk of asthma associated with air pollution.Citation: MacIntyre EA, Brauer M, Melén E, Bauer CP, Bauer M, Berdel D, Bergström A, Brunekreef B, Chan-Yeung M, Klümper C, Fuertes E, Gehring U, Gref A, Heinrich J, Herbarth O, Kerkhof M, Koppelman GH, Kozyrskyj AL, Pershagen G, Postma DS, Thiering E, Tiesler CM, Carlsten C, TAG Study Group. 2014. GSTP1 and TNF gene variants and associations between air pollution and incident childhood asthma: the traffic, asthma and genetics (TAG) Study. Environ Health Perspect 122:418–424; http://dx.doi.org/10.1289/ehp.1307459

Background:Long-term exposure to ambient air pollution can lead to adverse health effects in children; however, underlying biological mechanisms are not fully understood.Objectives:We evaluated the effect of air pollution exposure during different time periods on mRNA expression as well as circulating levels of inflammatory cytokines in children.Methods:We measured a panel of 10 inflammatory markers in peripheral blood samples from 670 8-y-old children in the Barn/Child, Allergy, Milieu, Stockholm, Epidemiology (BAMSE) birth cohort. Outdoor concentrations of nitrogen dioxide (NO2) and particulate matter (PM) with aerodynamic diameter <10μm (PM10) from road traffic were estimated for residential, daycare, and school addresses using dispersion modeling. Time-weighted average exposures during infancy and at biosampling were linked to serum cytokine levels using linear regression analysis. Furthermore, gene expression data from 16-year-olds in BAMSE (n=238) were used to evaluate links between air pollution exposure and expression of genes coding for the studied inflammatory markers.Results:A 10 μg/m3 increase of NO2 exposure during infancy was associated with a 13.6% (95% confidence interval (CI): 0.8; 28.1%) increase in interleukin-6 (IL-6) levels, as well as with a 27.8% (95% CI: 4.6, 56.2%) increase in IL-10 levels, the latter limited to children with asthma. However, no clear associations were observed for current exposure. Results were similar using PM10, which showed a high correlation with NO2. The functional analysis identified several differentially expressed genes in response to air pollution exposure during infancy, including IL10, IL13, and TNF.Conclusion:Our results indicate alterations in systemic inflammatory markers in 8-y-old children in relation to early-life exposure to traffic-related air pollution. https://doi.org/10.1289/EHP460

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.

SummaryBackgroundDietary antioxidant intake has been hypothesized to influence the development of allergic diseases; however, few prospective studies have investigated this association.ObjectiveOur aim was to study the association between total antioxidant capacity (TAC) of the diet at age 8 years and the subsequent development of asthma, rhinitis and sensitization to inhalant allergens between 8 and 16 years, and to assess potential effect modification by known risk factors.MethodsA total of 2359 children from the Swedish birth cohort BAMSE were included. Dietary TAC at age 8 years was estimated by combining information on the child's diet the past 12 months from a food frequency questionnaire with a database of common foods analysed with the oxygen radical absorbance capacity method. Classification of asthma and rhinitis was based on questionnaires, and serum IgE antibodies were measured at 8 and 16 years.ResultsA statistically significant inverse association was observed between TAC of the diet and incident sensitization to inhalant allergens (adjusted odds ratio: 0.73, 95% confidence interval: 0.55–0.97 for the third compared to the first tertile, P‐value for trend = 0.031). Effect modification by traffic‐related air pollution exposure was observed, with a stronger association between dietary TAC and sensitization among children with low traffic‐related air pollution exposure (P‐value for interaction = 0.029). There was no evidence for effect modification by GSTP1 or TNF genotypes, although these results should be interpreted with caution. No clear associations were observed between TAC and development of rhinitis or asthma, although a significant inverse association was observed for allergic asthma (OR adj 0.57, 95% CI 0.34–0.94).Conclusions and Clinical RelevanceHigher TAC of the diet in early school age may decrease the risk of developing sensitization to inhalant allergens from childhood to adolescence. These findings indicate that implementing an antioxidant‐rich diet in childhood may contribute to the prevention of allergic disease.

Background The fractional concentration of nitric oxide in exhaled air (FeNO) is a biomarker of eosinophilic airway inflammation and associated with childhood asthma. Identification of common genetic variants associated with childhood FeNO may help to define biological mechanisms related to specific asthma phenotypes. Objective To identify genetic variants associated with childhood FeNO, and their relation with asthma. Methods FeNO was measured in children aged 5 to 15 years. In 14 genome-wide association (GWA) studies (N = 8,858), we examined the associations of ~2.5 million single nucleotide polymorphisms (SNPs) with FeNO. Subsequently, we assessed whether significant SNPs were expression quantitative trait loci (eQTLs) in genome-wide expression datasets of lymphoblastoid cell lines (N = 1,830), and were related with asthma in a previously published GWA dataset (cases: n=10,365; controls: n=16,110). Results We identified 3 SNPs associated with FeNO: rs3751972 in LYR motif containing 9 (LYRM9) (P = 1.97×10−10) and rs944722 in inducible nitric oxide synthase 2 (NOS2) (P = 1.28×10−9) both located at 17q11.2-q12, and rs8069176 near gasdermin B (GSDMB) (P = 1.88×10−8) at 17q12-q21. We found a cis eQTL for the transcript soluble galactoside-binding lectin 9 (LGALS9) that is in linkage disequilibrium with rs944722. Rs8069176 was associated with GSDMB and ORM1-like 3 (ORMDL3) expression. Rs8069176 at 17q12-q21, and not rs3751972 and rs944722 at 17q11.2-q12, were associated with physician-diagnosed asthma. Conclusion This study identified 3 variants associated with FeNO, explaining 0.95% of the variance. Identification of functional SNPs and haplotypes in these regions might provide novel insight in the regulation of FeNO. This study highlights that both shared and distinct genetic factors affect FeNO and childhood asthma.

Asthma and allergy are complex disorders influenced by both inheritance and environment, a relationship that might be further clarified by epigenetics. Neuropeptide S Receptor 1 (NPSR1) has been associated with asthma and allergy and a study suggested modulation of the genetic risk by environmental factors. We aimed to study DNA methylation in the promoter region of NPSR1 in relation to asthma and environmental exposures. Electrophoretic Mobility Shift Assay (EMSA) was used to investigate potential functional roles of both genotypes and methylation status in the NPSR1 promoter. DNA methylation was analysed using EpiTYPER in blood samples from two well-characterized cohorts; the BIOAIR study of severe asthma in adults and the Swedish birth cohort BAMSE. We observed that DNA methylation and genetic variants in the promoter influenced the binding of nuclear proteins to DNA, suggesting functional relevance. Significant, although small, differences in methylation were related to both adult severe asthma (p = 0.0001) and childhood allergic asthma (p = 0.01). Furthermore, DNA methylation was associated with exposures such as current smoking in adults for two CpG sites (p = 0.005 and 0.04), parental smoking during infancy in the children (p = 0.02) and in which month the sample was taken (p = 0.01). In summary, DNA methylation levels in the promoter of NPSR1 showed small but significant associations with asthma, both in adults and in children, and to related traits such as allergy and certain environmental exposures. Both genetic variation and the methylated state of CpG sites seem to have an effect on the binding of nuclear proteins in the regulatory region of NPSR1 suggesting complex regulation of this gene in asthma and allergy.