Abstract

Background: Microsomal epoxide hydrolase (EPHX1) metabolizes xenobiotics including polyaromatic hydrocarbons (PAH). Functional variants at this locus have been associated with respiratory diseases. The effects of EPHX1 variants may depend upon exposures from tobacco smoke and traffic emissions that contain PAHs as well as variants in other enzymes in PAH metabolic pathway, such as glutathione S-transferase (GST) genes. We investigated associations of variants in EPHX1, GSTM1, GSTP1 and GSTT1 with asthma and the relationships between asthma, EPHX1 metabolic phenotypes, and exposure to sources of PAHs.

Methods: Among 3,124 children from the Children’s Health Study, we computed odds ratios (ORs) and 95% confidence intervals (CIs) to estimate the associations of genetic variants and exposures with asthma phenotypes.

Results: High EPHX1 activity was associated with an increase risk for lifetime asthma (OR 1.51, 95% CI 1.14 to 1.98), which varied by GSTP1 Ile105Val genotype and by residential proximity to major roads (P for interaction = 0.006 and 0.03, respectively). Among children with GSTP1 105Val/Val genotype, those who had high EPHX1 phenotype had a 4-fold (95% CI 1.97 to 8.16) increased risk of lifetime asthma than children with low/intermediate EPHX1 phenotype. Among children living within 75m of a major road, those with high EPHX1 activity had a 3.2-fold (95% CI 1.75 to 6.00) higher asthma risk than those with low/intermediate activity. Results were similar for current, early persistent and late onset asthma. Children with high EPHX1 phenotype, GSTP1 Val/Val genotype, who lived <75m of a major road were at the highest asthma risk.

Conclusion: EPHX1 and GSTP1 variants contribute to childhood asthma occurrence and increase asthma susceptibility to exposures from major roads.