Interactions between glutathione S-transferase P1, tumor necrosis factor, and traffic-related air pollution for development of childhood allergic disease

Abstract

Background: Air pollutants may induce airway inflammation and sensitization due to generation of reactive oxygen species. The genetic background to these mechanisms could be important effect modifiers.

Objective: Our goal was to assess interactions between exposure to air pollution and single nucleotide polymorphisms (SNPs) in the beta2-adrenergic receptor (ADRB2), glutathione S-transferase P1 (GSTP1), and tumor necrosis factor (TNF) genes for development of childhood allergic disease.

Methods: In a birth cohort originally of 4,089 children, we assessed air pollution from local traffic using nitrogen oxides (traffic NO(x)) as an indicator based on emission databases and dispersion modeling and estimated individual exposure through geocoding of home addresses. We measured peak expiratory flow rates and specific IgE for inhalant and food allergens at 4 years of age, and selected children with asthma symptoms up to 4 years of age (n = 542) and controls (n = 542) for genotyping.

Results: Interaction effects on allergic sensitization were indicated between several GSTP1 SNPs and traffic NO(x) exposure during the first year of life (p(nominal) < 0.001-0.06). Children with Ile105Val/Val105Val genotypes were at increased risk of sensitization to any allergen when exposed to elevated levels of traffic NO(x) (for a difference between the 5th and 95th percentile of exposure: odds ratio = 2.4; 95% confidence interval, 1.0-5.3). In children with TNF-308 GA/AA genotypes, the GSTP1-NO(x) interaction effect was even more pronounced. We observed no conclusive interaction effects for ADRB2.

Conclusion: The effect of air pollution from traffic on childhood allergy appears to be modified by GSTP1 and TNF variants, supporting a role of genes controlling the antioxidative system and inflammatory response in allergy.

Keywords: ADRB2; GSTP1; TNF; air pollution; allergy; asthma; genetics; interaction; nitrogen oxides; polymorphism.

Figure 1

The BAMSE study design: selection of subjects for genotyping and exclusion of subjects following the genotyping procedure.

Figure 2

Block structure and correlation of the SNPs in the ADRB2 gene (A), TNF gene (B), and GSTP1 gene (C). We defined the block structure based on the LD coefficient D′ using Haploview (solid spine of LD) (Barrett et al. 2005). The numbers in each box correspond to the pairwise correlation coefficient r² between respective SNPs.