GSTP1 and TNF Gene Variants and Associations between Air Pollution and Incident Childhood Asthma: The Traffic, Asthma and Genetics (TAG) Study

Abstract

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

Genome-Wide Interaction Analysis of Air Pollution Exposure and Childhood Asthma with Functional Follow-up

“…Because of these differences, we did not perform meta-analysis of the interaction bs, but we did present interaction bs and P values for each data set. Previous G 3 E interaction analyses using candidate gene approaches suggested that genes related to antioxidative stress systems, inflammation, and innate immunity (e.g., GSTP1, TNF and TLR2/4) are important effect modifiers (12,13). These genes were not among the top hits in our GWIS, but this did not exclude true interaction effects for key SNPs as previously reported.…”

“…Oxidative stress and inflammation represent pathogenic pathways involved in asthma development (3). Interactions between air pollution and allele variants in genes related to antioxidative stress systems, inflammation, and innate immunity have been reported in relation to the incidence of asthma (12,13). Such gene-environment (G 3 E) interactions may partially explain the inconsistencies between air pollution and the incidence of asthma.…”

“…In the discovery phase, meta-analysis was performed based on genome-wide interaction study (GWIS) results from three traffic pollution, asthma, genetics consortium (13) (17), the Netherlands (children with asthma: 155; children without asthma: 173). Detailed cohort descriptions are provided in the online data supplement and elsewhere (13).…”

Traffic-Related Air Pollution and Childhood Asthma: Recent Advances and Remaining Gaps in the Exposure Assessment Methods

“…Figure 1 shows the flow of papers. A total of 42 studies met our inclusion criteria [31,32,33,34,36,37,38,39,40,41,42,43,44,45,46,47,48,50,51,52,58,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87] (Table 1). …”

“…Where necessary, data items were missing from the main papers, data was extracted from the supplementary materials [31,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52], and the associated publications [53,54,55,56,57,58,59,60,61,62,63,64,65,66]. Data extraction was undertaken manually by one researcher (Haneen Khreis).…”