Associations of tumor necrosis factor G-308A with childhood asthma and wheezing

Rationale: Tumor necrosis factor (TNF) mediates a spectrum of airway inflammatory responses, including those to air pollutants, and is an asthma candidate gene. One TNF promoter variant (G-308A) affects expression of TNF and has been associated with inflammatory diseases; however, studies of asthma have been inconsistent. Because ozone produces oxidative stress, increased airway TNF, and inflammation, the associations of the -308 TNF polymorphism with asthma may vary by ozone exposure and variants of oxidant defense genes glutathione-S-transferase (GST) M1 and GSTP1. Objectives: To investigate the association of TNF G-308A with asthma and wheezing and to determine whether these associations vary with ozone exposure and GSTM1 and GSTP1 genotype. Methods: We studied associations of TNF-308 genotype with lifetime and current wheezing and asthma among 3,699 children in the Children's Health Study. We examined differences in associations with community ozone and by GSTM1 null and GSTP1 105 Ile/Val (A105G) genotype. Results: Children with TNF-308 GG had decreased risk of asthma (odds ratio, 0.8; 95% confidence interval, 0.7-0.9) and lifetime wheezing (odds ratio, 0.8; 95% confidence interval, 0.7-0.9). The protective effects of GG genotype on wheezing outcomes were of greater magnitude in lower compared with higher ozone communities. These findings were replicated in the two cohorts of fourth-grade children recruited in 1993 and 1996. The reduction of the protective effect from the -308 GG genotype with higher ozone exposure was most marked in the GSTM1 null and GSTP1 Ile/Ile groups. Conclusions: The TNF-308 GG genotype may have a protective role in asthma pathogenesis, depending on airway oxidative stress levels.