Background: Because asthma has been associated with exercise and ozone exposure, an association likely mediated by oxidative stress, we hypothesized that GSTP1, GSTM1, exercise and ozone exposure have inter-related effects on asthma pathogenesis.
Methods: We examined associations of the well characterized null variant of GSTM1 and four SNPs that characterized common variation in the GSTP1 locus with new-onset asthma in a cohort of 1,610 school children. Children's exercise and ozone-exposure were classified using participation in team sports and community annual average ozone levels, respectively.
Results: A two SNP model involving putatively functional variants (rs6591255, rs1695 [Ile105Val]) best captured the association between GSTP1 and asthma. The risk of asthma was lower for those with the Val allele of Ile105Val (HR 0.60, 95% CI 0.4, 0.8) and higher for the variant allele of rs6591255 (HR 1.40, 95%CI 1.1-1.9). Asthma risk increased with level of exercise among ile105 homozygotes but not among those with at least one val105 allele (interaction p-value=0.02). Risk was highest among ile105 homozygotes who participated in ≥3 sports in the high-ozone communities (HR: 6.15, 95%CI 2.2-7.4). GSTM1 null was independently associated with increased risk of asthma and showed little variation with air pollution or GSTP1 genotype. These results were consistent in two independent fourth-grade cohorts recruited in 1993 and 1996.
Conclusion: Children who inherit a val105 variant allele may be protected from the increased risk of asthma associated with exercise, especially in high-ozone communities. GSTM1 null genotype was associated with increased risk of asthma.