1 Glutathione - S - Transferase ( GST ) P 1 , GSTM 1 , Exercise , Ozone and Asthma Incidence in School Children

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 interrelated 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 ile 105 homozygotes but not among those with at least one val 105 allele (interaction p-value=0.02). Risk was highest among ile 105 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 val 105 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. 3 INTRODUCTION Airway oxidative stress is a cardinal feature and an important pathway in asthma pathogenesis.[1] Although a growing body of evidence supports a joint role for air pollutants and variants in genes involved in oxidant defenses in asthma pathogenesis,[2] there have been few prospective studies of new onset asthma that have collected both genetic and environmental data needed to address these determinants with adequate power. We addressed this gap by using data from the Children's Health Study (CHS),[3, 4] a longitudinal study of children's respiratory health. We have previously reported that children who exercise more in communities with high ozone levels are at increased risk of developing asthma.[5] We have now investigated the impact of variants of oxidant defense genes in the context of these environmental and behavioral factors. The lung has multiple anti-oxidative defenses including the superfamily of glutathione S-transferases (GSTs)[6] that are essential for glutathione homeostasis[7] and …